March/April 2011, Vol 4, No 2 by Dalia Buffery

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ MARCH/APRIL 2011

VOLUME 4, NUMBER 2

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

REGULATORY

Comparative Effectiveness Research in the United States: A Catalyst for Innovation Riaz Ali, MPP; Morgan Hanger, MPP; Tanisha Carino, PhD

™

BUSINESS

Comparing Treatment Persistence, Healthcare Resource Utilization, and Costs in Adult Patients with Major Depressive Disorder Treated with Escitalopram or Citalopram Eric Q. Wu, PhD; Paul E. Greenberg, MA; Rym Ben-Hamadi, MSc; Andrew P. Yu, PhD; Elaine H. Yang, PhD; M. Haim Erder, PhD

Stakeholder Perspective by Matthew Mitchell, PharmD, MBA

Recent Trends in the Dispensing of 90-Day-Supply Prescriptions at Retail Pharmacies: Implications for Improved Convenience and Access Joshua N. Liberman, PhD; Charmaine Girdish, MPH

Stakeholder Perspective by Walid F. Gellad, MD, MPH

CLINICAL

Strategies to Prevent Opioid Misuse, Abuse, and Diversion That May Also Reduce the Associated Costs Kathryn L. Hahn, PharmD, DAAPM, CPE

Stakeholder Perspective by Atheer A. Kaddis, PharmD

DEXILANT WORKS A

SECOND SHIFT TO HELP SHUT DOWN ACID PUMPS

DEXILANT is the first and only PPI with a Dual Delayed Releaseâ&#x201E;˘ (DDR) formulation, which provides a second release of drug Mean plasma concentration (in healthy subjects; day 5; ng/mL)1 1200 1000 800 600 400

DEXILANT 60 mg 200

DEXILANT 30 mg

0 0

Time (h)

t DEXILANT 30 mg provided full 24-hour heartburn relief in a majority of symptomatic non-erosive gastroesophageal reflux disease patients at week 41 Conclusions of comparative efficacy cannot be drawn from this information. Indications DEXILANT is indicated for healing all grades of erosive esophagitis (EE) for up to 8 weeks, maintaining healing of EE for up to 6 months, and treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.

Important Safety Information DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use. Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy. Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Most commonly reported treatment-emergent adverse reactions: diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%). Do not co-administer atazanavir with DEXILANT because atazanavir systemic concentrations may be substantially decreased. DEXILANT may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Concomitant tacrolimus use may increase tacrolimus whole blood concentrations. Please see adjacent brief summary of prescribing information for DEXILANT.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION DEXILANT (dexlansoprazole) delayed release capsules INDICATIONS AND USAGE DEXILANT is indicated for: M C74 740;8=6 >5 0;; 6A034B >5 4A>B8E4 4B>?7068C8B 5>A D? C> F44:B M <08=C08=8=6 740;8=6 >5 5>A D? C> <>=C7B 0=3 M C74 CA40C<4=C >5 740AC1DA= 0BB>280C43 F8C7 BH<?C><0C82 =>= 4A>B8E4 60BCA>4B>?70640; A4K DG 38B40B4 ' 5>A F44:B CONTRAINDICATIONS , ! #) 8B 2>=CA08=3820C43 8= ?0C84=CB F8C7 :=>F= 7H?4AB4=B8C8E8CH C> 0=H 2><?>=4=C >5 C74 5>A<D;0C8>= H?4AB4=B8C8E8CH 0=3 0=0?7H;0G8B 70E4 144= A4?>AC43 F8C7 , ! #) DB4 [see Adverse Reactions] WARNINGS AND PRECAUTIONS Gastric Malignancy (H<?C><0C82 A4B?>=B4 F8C7 , ! #) 3>4B =>C ?A42;D34 C74 ?A4B4=24 >5 60BCA82 <0;86=0=2H Bone Fracture (4E4A0; ?D1;8B743 >1B4AE0C8>=0; BCD384B BD664BC C70C ?A>C>= ?D<? 8=7818C>A %% C74A0?H <0H 14 0BB>280C43 F8C7 0= 8=2A40B43 A8B: 5>A >BC4>?>A>B8B A4;0C43 5A02CDA4B >5 C74 78? FA8BC >A B?8=4 )74 A8B: >5 5A02CDA4 F0B 8=2A40B43 8= ?0C84=CB F7> A4248E43 7867 3>B4 34J =43 0B <D;C8?;4 308;H 3>B4B 0=3 ;>=6 C4A< %% C74A0?H 0 H40A >A ;>=64A %0C84=CB B7>D;3 DB4 C74 ;>F4BC 3>B4 0=3 B7>AC4BC 3DA0C8>= >5 %% C74A0?H 0??A>?A80C4 C> C74 2>=38C8>= 148=6 CA40C43 %0C84=CB 0C A8B: 5>A >BC4>?>A>B8B A4;0C43 5A02CDA4B B7>D;3 14 <0=0643 022>A38=6 C> 4BC01;8B743 CA40C<4=C 6D834;8=4B ADVERSE REACTIONS Clinical Trials Experience )74 B054CH >5 , ! #) F0B 4E0;D0C43 8= ?0C84=CB 8= 2>=CA>;;43 0=3 D=2>=CA>;;43 2;8=820; BCD384B 8=2;D38=6 ?0C84=CB CA40C43 5>A 0C ;40BC <>=C7B 0=3

?0C84=CB CA40C43 5>A >=4 H40A %0C84=CB A0=643 8= 064 5A>< C> H40AB <4380= 064 H40AB F8C7 54<0;4 0D20B80= ;02: B80= 0=3 >C74A A024B (8G A0=3><8I43 2>=CA>;;43 2;8=820; CA80;B F4A4 2>=3D2C43 5>A C74 CA40C<4=C >5 <08=C4=0=24 >5 740;43 0=3 BH<?C><0C82 ' F7827 8=2;D343 ?0C84=CB >= ?;0241> ?0C84=CB >= , ! #) <6

?0C84=CB >= , ! #) <6 0=3 ?0C84=CB >= ;0=B>?A0I>;4 <6 >=24 308;H B 2;8=820; CA80;B 0A4 2>=3D2C43 D=34A F834;H E0AH8=6 2>=38C8>=B 03E4AB4 A402C8>= A0C4B >1B4AE43 8= C74 2;8=820; CA80;B >5 0 3AD6 20==>C 14 38A42C;H 2><?0A43 C> A0C4B 8= C74 2;8=820; CA80;B >5 0=>C74A 3AD6 0=3 <0H =>C A4K 42C C74 A0C4B >1B4AE43 8= ?A02C824 ">BC ><<>=;H '4?>AC43 3E4AB4 '402C8>=B )74 <>BC 2><<>= 03E4AB4 A402C8>=B â&#x2030;Ľ C70C >22DAA43 0C 0 78674A 8=2834=24 5>A , ! #) C70= ?;0241> 8= C74 2>=CA>;;43 BCD384B 0A4 ?A4B4=C43 8= )01;4 Table 2: Incidence of Treatment-Emergent Adverse Reactions in Controlled Studies %;0241>

DEXILANT !0=B>?A0I>;4 <6 )>C0; # #

DEXILANT <6 #

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3E4AB4 '402C8>=B '4BD;C8=6 8= 8B2>=C8=D0C8>= = 2>=CA>;;43 2;8=820; BCD384B C74 <>BC 2><<>= 03E4AB4 A402C8>= ;4038=6 C> 38B2>=C8=D0C8>= 5A>< , ! #) C74A0?H F0B 380AA740 $C74A 3E4AB4 '402C8>=B $C74A 03E4AB4 A402C8>=B C70C F4A4 A4?>AC43 8= 2>=CA>;;43 BCD384B 0C 0= 8=2834=24 >5 ;4BB C70= 0A4 ;8BC43 14;>F 1H 1>3H BHBC4< Blood and Lymphatic System Disorders: 0=4<80 ;H<?7034=>?0C7H Cardiac Disorders: 0=68=0 0AA7HC7<80 1A03H20A380 274BC ?08= 434<0 <H>20A380; 8=50A2C8>= ?0;?8C0C8>= C027H20A380 Ear and Labyrinth Disorders: 40A ?08= C8==8CDB E4AC86> Endocrine Disorders: 6>8C4A Eye Disorders: 4H4 8AA8C0C8>= 4H4 BF4;;8=6 Gastrointestinal Disorders: 013><8=0; 38B2><5>AC 013><8=0; C4=34A=4BB 01=>A<0; 5424B 0=0; 38B2><5>AC 0AA4CC B 4B>?706DB 14I>0A 1>F4; B>D=3B 01=>A<0; 1A40C7 >3>A 2>;8C8B <82A>B2>?82 2>;>=82 ?>;H? 2>=BC8?0C8>= 3AH <>DC7 3D>34=8C8B 3HB?4?B80 3HB?70680 4=C4A8C8B 4AD2C0C8>= 4B>?7068C8B 60BCA82 ?>;H? 60BCA8C8B 60BCA>4=C4A8C8B 60BCA>8=C4BC8=0; 38B>A34AB

60BCA>8=C4BC8=0; 7H?4A<>C8;8CH 38B>A34AB ' D;24AB 0=3 ?4A5>A0C8>= 74<0C4<4B8B 74<0C>274I80 74<>AA7>83B 8<?08A43 60BCA82 4<?CH8=6 8AA8C01;4 1>F4; BH=3A><4 <D2DB BC>>;B =0DB40 0=3 E><8C8=6 >A0; <D2>B0; 1;8BC4A8=6 ?08=5D; 345420C8>= ?A>2C8C8B ?0A4BC74B80 >A0; A42C0; 74<>AA7064 General Disorders and Administration Site Conditions: 03E4AB4 3AD6 A402C8>= 0BC74=80 274BC ?08= 278;;B 544;8=6 01=>A<0; 8=K 0<<0C8>= <D2>B0; 8=K 0<<0C8>= =>3D;4 ?08= ?HA4G80 Hepatobiliary Disorders: 18;80AH 2>;82 27>;4;8C780B8B 74?0C><460;H Immune System Disorders: 7H?4AB4=B8C8E8CH Infections and Infestations: 20=3830 8=542C8>=B 8=K D4=I0 =0B>?70AH=68C8B >A0; 74A?4B ?70AH=68C8B B8=DB8C8B E8A0; 8=542C8>= ED;E> E068=0; 8=542C8>= Injury, Poisoning and Procedural Complications: 50;;B 5A02CDA4B 9>8=C B?A08=B >E4A3>B4 ?A>243DA0; ?08= BD=1DA= Laboratory Investigations: !% 8=2A40B43 !) 8=2A40B43 () 8=2A40B43 18;8AD18= 342A40B43 8=2A40B43 1;>>3 2A40C8=8=4 8=2A40B43 1;>>3 60BCA8= 8=2A40B43 1;>>3 6;D2>B4 8=2A40B43 1;>>3 ?>C0BB8D< 8=2A40B43 ;8E4A 5D=2C8>= C4BC 01=>A<0; ?;0C4;4C 2>D=C 342A40B43 C>C0; ?A>C48= 8=2A40B43 F4867C 8=2A40B4 Metabolism and Nutrition Disorders: 0??4C8C4 270=64B 7H?4A20;24<80 7H?>:0;4<80 Musculoskeletal and Connective Tissue Disorders: 0AC7A0;680 0AC7A8C8B <DB2;4 2A0<?B <DB2D;>B:4;4C0; ?08= <H0;680 Nervous System Disorders: 0;C4A43 C0BC4 2>=ED;B8>= 38II8=4BB 74030274B <86A08=4 <4<>AH 8<?08A<4=C ?0A4BC74B80 ?BH27><>C>A 7H?4A02C8E8CH CA4<>A CA864<8=0; =4DA0;680 Psychiatric Disorders: 01=>A<0; 3A40<B 0=G84CH 34?A4BB8>= 8=B><=80 ;8183> 270=64B Renal and Urinary Disorders: 3HBDA80 <82CDA8C8>= DA64=2H Reproductive System and Breast Disorders: 3HB<4=>AA740 3HB?0A4D=80 <4=>AA70680 <4=BCAD0; 38B>A34A; Respiratory, Thoracic and Mediastinal Disorders: 0B?8A0C8>= 0BC7<0 1A>=278C8B 2>D67 3HB?=>40 7822D?B 7H?4AE4=C8;0C8>= A4B?8A0C>AH CA02C 2>=64BC8>= B>A4 C7A>0C Skin and Subcutaneous Tissue Disorders: 02=4 34A<0C8C8B 4AHC74<0 ?ADA8C8B A0B7 B:8= ;4B8>= DAC820A80 Vascular Disorders: 344? E48= C7A><1>B8B 7>C K DB7 7H?4AC4=B8>= 338C8>=0; 03E4AB4 A402C8>=B C70C F4A4 A4?>AC43 8= 0 ;>=6 C4A< D=2>=CA>;;43 BCD3H 0=3 F4A4 2>=B834A43 A4;0C43 C> , ! #) 1H C74 CA40C8=6 ?7HB8280= 8=2;D343 0=0?7H;0G8B 0D38C>AH 70;;D28=0C8>= 24;; ;H<?7><0 1DAB8C8B 24=CA0; >14B8CH 27>;42HBC8C8B 02DC4 342A40B43 74<>6;>18= 347H3A0C8>= 38014C4B <4;;8CDB 3HB?7>=80 4?8BC0G8B 5>;;82D;8C8B 60BCA>8=C4BC8=0; ?08= 6>DC 74A?4B I>BC4A 7H?4A6;H24<80 7H?4A;8?834<80 7H?>C7HA>838B< 8=2A40B43 =4DCA>?78;B " 342A40B4 =4DCA>?4=80 >A0; B>5C C8BBD4 38B>A34A A42C0; C4=4B<DB A4BC;4BB ;46B BH=3A><4 B><=>;4=24 C7A><1>2HC74<80 C>=B8;;8C8B $C74A 03E4AB4 A402C8>=B =>C >1B4AE43 F8C7 , ! #) 1DC >22DAA8=6 F8C7 C74 A024<0C4 ;0=B>?A0I>;4 20= 14 5>D=3 8= C74 ;0=B>?A0I>;4 ?02:064 8=B4AC + '( ' ) $#( B42C8>= Postmarketing Experience 3E4AB4 A402C8>=B 70E4 144= 834=C8J 43 3DA8=6 ?>BC 0??A>E0; >5 , ! #) B C74B4 A402C8>=B 0A4 A4?>AC43 E>;D=C0A8;H 5A>< 0 ?>?D;0C8>= >5 D=24AC08= B8I4 8C 8B =>C 0;F0HB ?>BB81;4 C> A4;801;H 4BC8<0C4 C748A 5A4@D4=2H >A 4BC01;8B7 0 20DB0; A4;0C8>=B78? C> 3AD6 4G?>BDA4 Eye Disorders 1;DAA43 E8B8>= Gastrointestinal Disorders >A0; 434<0 General Disorders and Administration Site Conditions 50280; 434<0 Immune System Disorders 0=0?7H;02C82 B7>2: A4@D8A8=6 4<4A64=2H 8=C4AE4=C8>= (C4E4=B >7=B>= BH=3A><4 C>G82 4?834A<0; =42A>;HB8B B><4 50C0; Musculoskeletal System DisorderB 1>=4 5A02CDA4 Respiratory, Thoracic and Mediastinal Disorders ?70AH=640; 434<0 C7A>0C C867C=4BB Skin and Subcutaneous Tissue Disorders 64=4A0;8I43 A0B7 ;4D2>2HC>2;0BC82 E0B2D;8C8B DRUG INTERACTIONS Drugs with pH-Dependent Absorption Pharmacokinetics , ! #) 20DB4B 8=7818C8>= >5 60BCA82 0283 B42A4C8>= , ! #) 8B ;8:4;H C> BD1BC0=C80;;H 342A40B4 C74 BHBC4<82 2>=24=CA0C8>=B >5 C74 + ?A>C40B4 8=7818C>A 0C0I0=0E8A F7827 8B 34?4=34=C D?>= C74 ?A4B4=24 >5 60BCA82 0283 5>A 01B>A?C8>= 0=3 <0H A4BD;C 8= 0 ;>BB >5 C74A0?4DC82 45542C >5 0C0I0=0E8A 0=3 C74 34E4;>?<4=C >5 + A4B8BC0=24 )74A45>A4 , ! #) B7>D;3 =>C 14 2> 03<8=8BC4A43 F8C7 0C0I0=0E8A C 8B C74>A4C820;;H ?>BB81;4 C70C , ! #) <0H 8=C4A54A4 F8C7 C74 01B>A?C8>= >5 >C74A 3AD6B F74A4 60BCA82 ? 8B 0= 8<?>AC0=C 34C4A<8=0=C >5 >A0; 18>0E08;018;8CH 4 6 0<?828;;8= 4BC4AB 386>G8= 8A>= B0;CB :4C>2>=0I>;4 Warfarin > 03<8=8BCA0C8>= >5 , ! #) <6 0=3 F0A50A8= <6 383 =>C 05542C C74 ?70A<02>:8=4C82B >5 F0A50A8= >A #' >F4E4A C74A4 70E4 144= A4?>ACB >5 8=2A40B43 #' 0=3 ?A>C7A><18= C8<4 8= ?0C84=CB A4248E8=6 %% B 0=3 F0A50A8= 2>=2><8C0=C;H =2A40B4B 8= #' 0=3 ?A>C7A><18= C8<4 <0H ;403 C> 01=>A<0; 1;4438=6 0=3 4E4= 340C7 %0C84=CB CA40C43 F8C7 , ! #) 0=3 F0A50A8= 2>=2><8C0=C;H <0H =443 C> 14 <>=8C>A43 5>A 8=2A40B4B 8= #' 0=3 ?A>C7A><18= C8<4 Tacrolimus >=2><8C0=C 03<8=8BCA0C8>= >5 34G;0=B>?A0I>;4 0=3 C02A>;8<DB <0H 8=2A40B4 F7>;4 1;>>3 ;4E4;B >5 C02A>;8<DB 4B?4280;;H 8= CA0=B?;0=C ?0C84=CB F7> 0A4 8=C4A<4380C4 >A ?>>A <4C01>;8I4AB >5 -%

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category B. There are no adequate and well-controlled studies with dexlansoprazole in pregnant women. There were no adverse fetal effects in animal reproduction studies of dexlansoprazole in rabbits. Because animal reproduction studies are not always predictive of human response, DEXILANT should be used during pregnancy only if clearly needed. A reproduction study conducted in rabbits at oral dexlansoprazole doses up to approximately 9-times the maximum recommended human dexlansoprazole dose (60 mg per day) revealed no evidence of impaired fertility or harm to the fetus due to dexlansoprazole. In addition, reproduction studies performed in pregnant rats with oral lansoprazole at doses up to 40 times the recommended human lansoprazole dose and in pregnant rabbits at oral lansoprazole doses up to 16 times the recommended human lansoprazole dose revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole. Nursing Mothers It is not known whether dexlansoprazole is excreted in human milk. However, lansoprazole and its metabolites are present in rat milk following the administration of lansoprazole. As many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies [see Carcinogenesis, Mutagenesis, Impairment of Fertility], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of DEXILANT in pediatric patients (less than 18 years of age) have not been established. Geriatric Use In clinical studies of DEXILANT, 11% of patients were aged 65 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment No dosage adjustment of DEXILANT is necessary in patients with renal impairment. The pharmacokinetics of dexlansoprazole in patients with renal impairment are not expected to be altered since dexlansoprazole is extensively metabolized in the liver to inactive metabolites, and no parent drug is recovered in the urine following an oral dose of dexlansoprazole. Hepatic Impairment No dosage adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A). DEXILANT 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C). OVERDOSAGE There have been no reports of significant overdose of DEXILANT. Multiple doses of DEXILANT 120 mg and a single dose of DEXILANT 300 mg did not result in death or other severe adverse events. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis. If an overdose occurs, treatment should be symptomatic and supportive. CLINICAL PHARMACOLOGY Pharmacodynamics Antisecretory Activity The effects of DEXILANT 60 mg (n=20) or lansoprazole 30 mg (n=23) once daily for five days on 24-hour intragastric pH were assessed in healthy subjects in a multiple-dose crossover study. Serum Gastrin Effects The effect of DEXILANT on serum gastrin concentrations was evaluated in approximately 3460 patients in clinical trials up to 8 weeks and in 1023 patients for up to 6 to 12 months. The mean fasting gastrin concentrations increased from baseline during treatment with DEXILANT 30 mg and 60 mg doses. In patients treated for more than 6 months, mean serum gastrin levels increased during approximately the first 3 months of treatment and were stable for the remainder of treatment. Mean serum gastrin levels returned to pre-treatment levels within one month of discontinuation of treatment. Enterochromaffi n-Like Cell (ECL) Effects There were no reports of ECL cell hyperplasia in gastric biopsy specimens obtained from 653 patients treated with DEXILANT 30 mg, 60 mg or 90 mg for up to 12 months.

During lifetime exposure of rats dosed daily with up to 150 mg per kg per day of lansoprazole, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats [see Nonclinical Toxicology]. Effect on Cardiac Repolarization A study was conducted to assess the potential of DEXILANT to prolong the QT/QTc interval in healthy adult subjects. DEXILANT doses of 90 mg or 300 mg did not delay cardiac repolarization compared to placebo. The positive control (moxifloxacin) produced statistically significantly greater mean maximum and time-averaged QT/QTc intervals compared to placebo. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with lansoprazole at doses of 5 to 150 mg per kg per day, about 1 to 40 times the exposure on a body surface (mg/m2) basis of a 50 kg person of average height [1.46 m2 body surface area (BSA)] given the recommended human dose of lansoprazole 30 mg per day. Lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell carcinoids in both male and female rats [see Clinical Pharmacology]. In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg per kg per day (4 to 40 times the recommended human lansoprazole dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat. In a 24-month carcinogenicity study, CD-1 mice were treated orally with lansoprazole doses of 15 mg to 600 mg per kg per day, 2 to 80 times the recommended human lansoprazole dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 mg and 600 mg lansoprazole per kg per day (40 to 80 times the recommended human lansoprazole dose based on BSA) and female mice treated with 150 mg to 600 mg lansoprazole per kg per day (20 to 80 times the recommended human lansoprazole dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg per kg per day (10 to 80 times the recommended human lansoprazole dose based on BSA). The potential effects of dexlansoprazole on fertility and reproductive performance were assessed using lansoprazole studies. Lansoprazole at oral doses up to 150 mg per kg per day (40 times the recommended human lansoprazole dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats. PATIENT COUNSELING INFORMATION Information for Patients To ensure the safe and effective use of DEXILANT, this information and instructions provided in the FDA-approved patient labeling should be discussed with the patient. Inform patients of the following: Tell your patients to watch for signs of an allergic reaction as these could be serious and may require that DEXILANT be discontinued. Advise your patients to tell you if they take atazanavir, tacrolimus, warfarin and drugs that are affected by gastric pH changes. DEXILANT is available as a delayed release capsule. DEXILANT may be taken without regard to food. DEXILANT should be swallowed whole. M ;C4A=0C8E4;H , ! #) 20?BD;4B 20= 14 >?4=43 0=3 03<8=8BC4A43 as follows: â&#x20AC;&#x201C; Open capsule; â&#x20AC;&#x201C; Sprinkle intact granules on one tablespoon of applesauce; â&#x20AC;&#x201C; Swallow immediately. Granules should not be chewed. â&#x20AC;&#x201C; Do not store for later use. Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 DEXILANT is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc. ÂŠ2009, 2010 Takeda Pharmaceuticals America, Inc. For more detailed information, see the full prescribing information for DEXILANT or contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327. DEX006 R8-Brf; August 2010 L-LPD-0810-2

Reference: 1. DEXILANT (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. DEXILANT and Dual Delayed Release are trademarks of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc.

ÂŠ2011Takeda Pharmaceuticals North America, Inc. LPD-01450R1 01/11 Printed in U.S.A.

EDITORIAL BOARD

CLINICAL EDITOR

HEALTH INFORMATION TECHNOLOGY

PHARMACY BENEFIT DESIGN

Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA

J. B. Jones, PhD, MBA Research Associate, Geisinger Health System, Danville, PA

Joel V. Brill, MD Chief Medical Officer, Predictive Health, Phoenix, AZ

GOVERNMENT EDITOR

Victor J. Strecher, PhD, MPH Professor and Director, Center for Health Communications Research University of Michigan Schools of Public Health and Medicine, Ann Arbor Founder and Chief Visionary Officer HealthMedia, Johnson & Johnson Co.

William J. Cardarelli, PharmD Director of Pharmacy, Atrius Health Harvard Vanguard Medical Associates

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group Sr. Counselor, Fleishman-Hillard Washington, DC ACTUARY

David Williams Milliman Health Consultant Windsor, CT AGING AND WELLNESS

Eric G. Tangalos, MD, FACP, AGSF Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Al B. Benson, III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center, Northwestern University Immediate Past President, ACCC Past Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FACP Professor, Internal Medicine Director, Cancer Center Network Division of Hematology/Oncology Assistant Dean for Research University of Michigan Health Systems CARDIOLOGY RESEARCH

Michael S. Jacobs, RPh National Clinical Practice Leader Buck Consultants, Atlanta

HEALTH OUTCOMES RESEARCH

Diana Brixner, RPh, PhD Professor and Chair Department of Pharmacotherapy Executive Director Outcomes Research Center, University of Utah College of Pharmacy, Salt Lake City

Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Paul Anthony Polansky, BSPharm, MBA Senior Field Scientist, Health Outcomes and PharmacoEconomics (HOPE) Endo Pharmaceuticals Inc., Chadds Ford, PA

Gordon M. Cummins, MS Director, IntegriChain Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver

Scott R. Taylor, RPh, MBA Associate Director, Industry Relations Geisinger Health System, Danville, PA

Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA

POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy American Enterprise Institute

Timothy S. Regan, BPharm, RPh Executive Director, Xcenda Palm Harbor, FL

Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City

HEALTH & VALUE PROMOTION

Albert Tzeel, MD, MHSA, FACPE National Medical Director HumanaOne

Michael A. Weber, MD Professor of Medicine Department of Medicine (Cardiology) State University of New York

Sharad Mansukani, MD Chief Strategic Officer, Nations Health Senior Advisor, Texas Pacific Group, FL

ENDOCRINOLOGY RESEARCH

MANAGED MARKETS

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ

Leslie S. Fish, PharmD Sr. Director of Pharmacy Services Fallon Community Health Plan, MA

Alex Hathaway, MD, MPH, FACPM President & Founder, J.D. BioEdge Health quality and biomedical research consultancy

MANGED CARE AND MANAGEMENT

J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago

EMPLOYERS

Jeffrey A. Bourret, RPh, MS, FASHP Senior Director, Branded Specialty Pharmacy Programs, US Specialty Customers Pfizer, Specialty Care Business Unit, PA

Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA

Charles E. Collins, Jr, MS, MBA Vice President, Managed Markets Strategy Fusion Medical Communications

Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE

PATIENT ADVOCACY

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute of Integrated Healthcare Sharon, MA

REIMBURSEMENT POLICY

William E. Fassett, BSPharm, MBA, PhD Professor of Pharmacy Law & Ethics Vice Chair, Dept. of Pharmacotherapy College of Pharmacy, Washington State University, Spokane, WA

Vol 4, No 2

March/April 2011

Wayne A. Rosenkrans, Jr, PhD Chairman and President, Personalized Medicine Coalition, Distinguished Fellow, MIT Center for Biomedical Innovation PHARMACOECONOMICS

Jeff Jianfei Guo, BPharm, MS, PhD Associate Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

www.AHDBonline.com

RESEARCH & DEVELOPMENT

Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials Faculty, Center for Experimental Pharmacology and Therapeutics, HarvardMIT Division of Health Sciences and Technology, Cambridge, MA SPECIALTY PHARMACY

PERSONALIZED MEDICINE

EPIDEMIOLOGY RESEARCH

Joshua N. Liberman, PhD Vice President, Research Operations Center for Health Research Geisinger Health System, Danville, PA

Grant D. Lawless, BSPharm, MD, FACP Executive Director for Payor Relations Corporate Account, Amgen, CA

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI James T. Kenney, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care, Wellesley, MA

American Health & Drug Benefits

MARCH/APRIL 2011

VOLUME 4, NUMBER 2

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS Publisher Nicholas Englezos nick@engagehc.com 732-992-1884

REGULATORY

Comparative Effectiveness Research in the United States: A Catalyst for Innovation Riaz Ali, MPP; Morgan Hanger, MPP; Tanisha Carino, PhD

BUSINESS

Stakeholder Perspective by Matthew Mitchell, PharmD, MBA

Recent Trends in the Dispensing of 90-Day-Supply Prescriptions at Retail Pharmacies: Implications for Improved Convenience and Access Joshua N. Liberman, PhD; Charmaine Girdish, MPH

Stakeholder Perspective by Walid F. Gellad, MD, MPH

American Health & Drug Benefits is included in the following indexing and database services: EMBASE/Elsevier Bibliographic Database SCOPUS/Elsevier Bibliographic Database Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO research databases Standard Periodical Directory MEMBER: Committee on Publication Ethics (COPE) BPA Worldwide membership applied for August 2010.

American Health & Drug Benefits

Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889 Associate Editor Lara J. Reiman lara@engagehc.com 732-992-1892 Editorial Assistant Jessica A. Smith Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino

Continued on page 66

Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895

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Business Manager Blanche Marchitto Founding Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the improvement of healthcare. This publication further provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs.

Contact Information: For subscription information and editorial queries, please contact: editorial@AHDB online.com T: 732-992-1892 F: 732-992-1881

March/April 2011

Vol 4, No 2

DRAFT moving millimeters

NEW EDARBI: See how many millimeters you can move with this ARB EDARBI 80 mg was statistically superior to DIOVAN® 320 mg and BENICAR® 40 mg in reducing 24-hr mean ambulatory and clinic SBP1 REDUCTIONS IN 24-HR MEAN AMBULATORY SBP AT WEEK 61,2 Mean ambulatory baseline: Study 1=144.9 mm Hg

STUDY 1

▼ Similar results were observed across two other comparator studies: Study 2 vs BENICAR 40 mg and Study 3 vs DIOVAN 320 mg ▼ Clinic SBP differences between EDARBI and active comparators were consistent with mean ambulatory results Study 1 Design: A 6-week, randomized, double-blind, placebo-controlled, forced-titration study in patients (N = 1,291) with clinic SBP ≥150 mm Hg and ≤180 mm Hg and 24-hr mean SBP ≥130 mm Hg and ≤170 mm Hg. The primary endpoint was change in 24-hr mean ambulatory SBP. Placebo lowered 24-hr mean ambulatory SBP by 0.3 mm Hg. Data shown are placebo corrected.

IMPORTANT SAFETY INFORMATION WARNING: AVOID USE IN PREGNANCY When pregnancy is detected, discontinue EDARBI as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. DIOVAN 320 mg

-10.0 mm Hg BENICAR 40 mg

-11.7 mm Hg EDARBI 80 mg

-14.3 mm Hg P<0.001 vs DIOVAN 320 mg P=0.009 vs BENICAR 40 mg References: 1. EDARBI Prescribing Information. 2. White WB, Weber MA, Sica D, et al. Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension. Hypertension. 2011;57:413-420.

▼ Avoid fetal or neonatal exposure. ▼ Correct volume or salt depletion prior to administration of EDARBI, or start treatment at 40 mg. ▼ Monitor for worsening renal function in patients with renal impairment. ▼ In patients with an activated renin-angiotensin system, as by volume or salt depletion, reninangiotensin-aldosterone system (RAAS) blockers such as azilsartan medoxomil can cause excessive hypotension. In patients whose renal function may depend on the activity of the renin-angiotensin system, e.g., with renal artery stenosis, treatment with RAAS blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. ▼ Monitor renal function periodically in patients receiving EDARBI and NSAIDs who are also elderly, volume-depleted, or who have compromised renal function. ▼ The most common adverse reaction in adults was diarrhea (2%). For further information, please see adjacent Brief Summary of Prescribing Information.

INDICATION EDARBI is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension, either alone or in combination with other antihypertensive agents.

EDARBI is a trademark of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION for Edarbi (azilsartan medoxomil) tablets WARNING: AVOID USE IN PREGNANCY When pregnancy is detected, discontinue Edarbi as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. INDICATIONS AND USAGE Edarbi is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Fetal/Neonatal Morbidity and Mortality Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women during the second and third trimester. When pregnancy is detected, Edarbi should be discontinued as soon as possible. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Edarbi as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system is available. In these rare cases, the mother should be apprised of the potential hazards to the fetus and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, Edarbi should be discontinued unless it is considered life-saving for the mother. Contraction stress testing, a nonstress test or biophysical profiling may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function. Hypotension in Volume- or Salt-Depleted Patients In patients with an activated renin-angiotensin system, such as volume- and/or saltdepleted patients (eg, those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Edarbi. Correct volume or salt depletion prior to administration of Edarbi, or start treatment at 40 mg. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Impaired Renal Function As a consequence of inhibiting the renin-angiotensin system, changes in renal function may be anticipated in susceptible individuals treated with Edarbi. In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g., patients with severe congestive heart failure, renal artery stenosis, or volume depletion), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. Similar results may be anticipated in patients treated with Edarbi. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. There has been no long-term use of Edarbi in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 4814 patients were evaluated for safety when treated with Edarbi at doses of 20, 40 or 80 mg in clinical trials. This includes 1704 patients treated for at least 6 months; of these, 588 were treated for at least 1 year. Treatment with Edarbi was well-tolerated with an overall incidence of adverse reactions similar to placebo. The rate of withdrawals due to adverse events in placebo-controlled monotherapy and combination therapy trials was 2.4% (19/801) for placebo, 2.2% (24/1072) for Edarbi 40 mg, and 2.7% (29/1074) for Edarbi 80 mg. The most common adverse event leading to discontinuation, hypotension/ orthostatic hypotension, was reported by 0.4% (8/2146) patients randomized to Edarbi 40 mg or 80 mg compared to 0% (0/801) patients randomized to placebo.

Generally, adverse reactions were mild, not dose related and similar regardless of age, gender and race. In placebo controlled monotherapy trials, diarrhea was reported up to 2% in patients treated with Edarbi 80 mg daily compared with 0.5% of patients on placebo. Other adverse reactions with a plausible relationship to treatment that have been reported with an incidence of â&#x2030;Ľ0.3% and greater than placebo in more than 3300 patients treated with Edarbi in controlled trials are listed below: Gastrointestinal Disorders: nausea General Disorders and Administration Site Conditions: asthenia, fatigue Musculoskeletal and Connective Tissue Disorders: muscle spasm Nervous System Disorders: dizziness, dizziness postural Respiratory, Thoracic and Mediastinal Disorders: cough Clinical Laboratory Findings In controlled clinical trials, clinically relevant changes in standard laboratory parameters were uncommon with administration of Edarbi. Serum creatinine: Small reversible increases in serum creatinine are seen in patients receiving 80 mg of Edarbi. The increase may be larger when coadministered with chlorthalidone or hydrochlorothiazide. In addition, patients taking Edarbi who had moderate to severe renal impairment at baseline or who were >75 years of age were more likely to report serum creatinine increases. Hemoglobin/Hematocrit: Low hemoglobin, hematocrit, and RBC counts were observed in 0.2%, 0.4%, and 0.3% of Edarbi-treated subjects, respectively. None of these abnormalities were reported in the placebo group. Low and high markedly abnormal platelet and WBC counts were observed in <0.1% of subjects. DRUG INTERACTIONS No clinically significant drug interactions have been observed in studies of azilsartan medoxomil or azilsartan given with amlodipine, antacids, chlorthalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin, pioglitazone, and warfarin. Therefore, Edarbi may be used concomitantly with these medications. Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or who have compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including azilsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving azilsartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including azilsartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C (first trimester) and D (second and third trimesters). There is no clinical experience with the use of Edarbi in pregnant women. Nursing Mothers It is not known if azilsartan is excreted in human milk, but azilsartan is excreted at low concentrations in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients under 18 years of age have not been established. Geriatric Use No dose adjustment with Edarbi is necessary in elderly patients. Of the total patients in clinical studies with Edarbi, 26% were elderly (65 years of age and older); 5% were 75 years of age and older. Abnormally high serum creatinine values were more likely to be reported for patients age 75 or older. No other differences in safety or effectiveness were observed between elderly patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment Dose adjustment is not required in patients with mild-to-severe renal impairment or end-stage renal disease. Patients with moderate to severe renal impairment are more likely to report abnormally high serum creatinine values. Hepatic Impairment No dose adjustment is necessary for subjects with mild or moderate hepatic impairment. Edarbi has not been studied in patients with severe hepatic impairment. OVERDOSAGE Limited data are available related to overdosage in humans. During controlled clinical trials in healthy subjects, once daily doses up to 320 mg of Edarbi were administered for 7 days and were well tolerated. In the event of an overdose, supportive therapy should be instituted as dictated by the patientâ&#x20AC;&#x2122;s clinical status. Azilsartan is not dialyzable. CLINICAL PHARMACOLOGY Mechanism of Action Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensinconverting enzymes (ACE, kinase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Azilsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathway for angiotensin II synthesis.

An AT2 receptor is also found in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Azilsartan has more than a 10,000-fold greater affinity for the AT1 receptor than for the AT2 receptor. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction catalyzed by ACE. Because azilsartan does not inhibit ACE (kinase II), it should not affect bradykinin levels. Whether this difference has clinical relevance is not yet known. Azilsartan does not bind to or block other receptors or ion channels known to be important in cardiovascular regulation. Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of azilsartan on blood pressure. Pharmacodynamics Azilsartan inhibits the pressor effects of an angiotensin II infusion in a dose-related manner. An azilsartan single dose equivalent to 32 mg azilsartan medoxomil inhibited the maximal pressor effect by approximately 90% at peak, and approximately 60% at 24 hours. Plasma angiotensin I and II concentrations and plasma renin activity increased while plasma aldosterone concentrations decreased after single and repeated administration of Edarbi to healthy subjects; no clinically significant effects on serum potassium or sodium were observed. Effect on Cardiac Repolarization: A thorough QT/QTc study was conducted to assess the potential of azilsartan to prolong the QT/QTc interval in healthy subjects. There was no evidence of QT/QTc prolongation at a dose of 320 mg of Edarbi. Pharmacokinetics Absorption: Azilsartan medoxomil is hydrolyzed to azilsartan, the active metabolite, in the gastrointestinal tract during absorption. Azilsartan medoxomil is not detected in plasma after oral administration. Dose proportionality in exposure was established for azilsartan in the azilsartan medoxomil dose range of 20 mg to 320 mg after single or multiple dosing. The estimated absolute bioavailability of azilsartan following administration of azilsartan medoxomil is approximately 60%. After oral administration of azilsartan medoxomil, peak plasma concentrations (Cmax) of azilsartan are reached within 1.5 to 3 hours. Food does not affect the bioavailability of azilsartan. Distribution: The volume of distribution of azilsartan is approximately 16L. Azilsartan is highly bound to human plasma proteins (>99%), mainly serum albumin. Protein binding is constant at azilsartan plasma concentrations well above the range achieved with recommended doses. In rats, minimal azilsartan-associated radioactivity crossed the blood-brain barrier. Azilsartan passed across the placental barrier in pregnant rats and was distributed to the fetus. Metabolism and Elimination: Azilsartan is metabolized to two primary metabolites. The major metabolite in plasma is formed by O-dealkylation, referred to as metabolite M-II, and the minor metabolite is formed by decarboxylation, referred to as metabolite M-I. Systemic exposures to the major and minor metabolites in humans were approximately 50% and less than 1% of azilsartan, respectively. M-I and M-II do not contribute to the pharmacologic activity of Edarbi. The major enzyme responsible for azilsartan metabolism is CYP2C9. Following an oral dose of 14 C-labeled azilsartan medoxomil, approximately 55% of radioactivity was recovered in feces and approximately 42% in urine, with 15% of the dose excreted in urine as azilsartan. The elimination half-life of azilsartan is approximately 11 hours and renal clearance is approximately 2.3 mL/min. Steadystate levels of azilsartan are achieved within 5 days and no accumulation in plasma occurs with repeated once-daily dosing. Special Populations The effect of demographic and functional factors on the pharmacokinetics of azilsartan was studied in single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of the effect on azilsartan are presented in Figure 1 as change relative to reference (test/reference). Effects are modest and do not call for dosage adjustment. Figure 1 Impact of intrinsic factors on the pharmacokinetics of azilsartan Population Description

Fold Change and 90% CI

Recommendation

AGE

Cmax AUC

No dose adjustment

Cmax AUC

No dose adjustment

Cmax AUC

No dose adjustment

Mild/Normal

Cmax AUC

No dose adjustment

Moderate/Normal

Cmax AUC

No dose adjustment

Severe/Normal

Cmax AUC

No dose adjustment

ESRD/Normal

Cmax AUC

No dose adjustment

Mild/Normal

Cmax AUC

No dose adjustment

Moderate/Normal

Cmax AUC

>65y/18-45y GENDER Females/Males RACE Whites/Blacks RENAL IMPAIRMENT

HEPATIC IMPAIRMENT

No dose adjustment

Severe/Normal

NO EXPERIENCE NO EXPERIENCE

PEDIATRIC

0.5

1.0

1.5

2.0

Change relative to reference

2.5

3.0

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Azilsartan medoxomil was not carcinogenic when assessed in 26-week transgenic (Tg.rasH2) mouse and 2-year rat studies. The highest doses tested (450 mg azilsartan medoxomil/kg/day in the mouse and 600 mg azilsartan medoxomil/kg/day in the rat) produced exposures to azilsartan that are 12 (mice) and 27 (rats) times the average exposure to azilsartan in humans given the maximum recommended human dose (MRHD, 80 mg azilsartan medoxomil/day). M-II was not carcinogenic when assessed in 26-week Tg.rasH2 mouse and 2-year rat studies. The highest doses tested (approximately 8000 mg M-II/kg/day (males) and 11,000 mg M-II/kg/day (females) in the mouse and 1000 mg M-II/kg/day (males) and up to 3000 mg M-II/kg/day (females) in the rat) produced exposures that are, on average, about 30 (mice) and 7 (rats) times the average exposure to M-II in humans at the MRHD. Mutagenesis: Azilsartan medoxomil, azilsartan, and M-II were positive for structural aberrations in the Chinese Hamster Lung Cytogenetic Assay. In this assay, structural chromosomal aberrations were observed with the prodrug, azilsartan medoxomil, without metabolic activation. The active moiety, azilsartan was also positive in this assay both with and without metabolic activation. The major human metabolite, M-II was also positive in this assay during a 24 hr assay without metabolic activation. Azilsartan medoxomil, azilsartan, and M-II were devoid of genotoxic potential in the Ames reverse mutation assay with Salmonella typhimurium and Escherichia coli, the in vitro Chinese Hamster Ovary Cell forward mutation assay, the in vitro mouse lymphoma (tk) gene mutation test, the ex vivo unscheduled DNA synthesis test, and the in vivo mouse and/or rat bone marrow micronucleus assay. Impairment of Fertility: There was no effect of azilsartan medoxomil on the fertility of male or female rats at oral doses of up to 1000 mg azilsartan medoxomil/kg/day [6000 mg/m2 (approximately 122 times the MRHD of 80 mg azilsartan medoxomil/60 kg on a mg/m2 basis)]. Fertility of rats also was unaffected at doses of up to 3000 mg M-II/kg/day. Animal Toxicology and/or Pharmacology Reproductive Toxicology: In peri- and postnatal rat development studies, adverse effects on pup viability, delayed incisor eruption and dilatation of the renal pelvis along with hydronephrosis were seen when azilsartan medoxomil was administered to pregnant and nursing rats at 1.2 times the MRHD on a mg/m2 basis. Reproductive toxicity studies indicated that azilsartan medoxomil was not teratogenic when administered at oral doses up to 1000 mg azilsartan medoxomil/kg/day to pregnant rats (122 times the MRHD on a mg/m2 basis) or up to 50 mg azilsartan medoxomil/ kg/day to pregnant rabbits (12 times the MRHD on a mg/m2 basis). M-II also was not teratogenic in rats or rabbits at doses up to 3000 mg M-II/kg/day. Azilsartan crossed the placenta and was found in the fetuses of pregnant rats and was excreted into the milk of lactating rats. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). General Information Pregnancy: Female patients of childbearing age should be told that use of drugs like Edarbi that act on the renin-angiotensin system during pregnancy can cause serious problems in the fetus and infant including low blood pressure, poor development of skull bones, kidney failure, and death. These consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Discuss other treatment options with female patients planning to become pregnant. Women using Edarbi who become pregnant should notify their physicians as soon as possible. Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 Edarbi is a trademark of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. ÂŠ2011 Takeda Pharmaceuticals America, Inc. For more detailed information, see the full prescribing information for Edarbi at www.edarbi.com or contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327. AZL074 R1; February 2011 L-LXA-0211-2

MARCH/APRIL 2011

VOLUME 4, NUMBER 2

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS

(Continued)

CLINICAL

107 Strategies to Prevent Opioid Misuse, Abuse, and Diversion That May Also Reduce the Associated Costs Kathryn L. Hahn, PharmD, DAAPM, CPE 113 Stakeholder Perspective by Atheer A. Kaddis, PharmD

DEPARTMENTS

118 GENERIC DRUG TRENDS New Economic Analysis Zeroes in on Low Generic Utilization and Waste in Medicaid Dalia Buffery, MA, ABD INDUSTRY TRENDS 120 CMS Invites Feedback on the Proposed Accountable Care Organizations Rules 122 The Patient-Centered Medical Home: An Essential Destination on the Road to Reform Matt Adamson

CAPTION CONTEST

100

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American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2011 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Address all editorial correspondence to: editorial@AHDBonline.com Telephone: 732-992-1892 Fax: 732-992-1881 American Health & Drug Benefits 241 Forsgate Drive, Suite 205A Monroe Township, NJ 08831 The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. For permission to reuse material from American Health & Drug Benefits (ISSN 1942-2962), please access www. copyright.com <http://www.copyright. com/> or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400.

March/April 2011

Vol 4, No 2

THERE COULD BE DANGER BELOW

Renal impairment is the leading microvascular complication associated with type 2 diabetes (over 40%), followed by retinopathy (28.5%) and neuropathy (19.4%)— it is important to recognize these complications as soon as possible1-4 According to the National Kidney Foundation, diabetes and renal impairment are considerably underdiagnosed, which may lead to disease progression because of missed opportunities to provide appropriate care for patients with these conditions5 Microalbuminuria (albumin in the urine *30 mg/day or * 20 µg/min) is the earliest clinical evidence of renal disease 6 Patients with renal impairment may have poor glycemic control (A1C *7%), may have hypertension (BP *130/80 mm Hg), and may have dyslipidemia as well as other comorbidities 5,7

It’s important to recognize microvascular complications in patients with type 2 diabetes as early as possible. Microalbuminuria is the earliest sign of renal disease, the leading microvascular complication, in type 2 diabetes. References: 1. Plantinga LC, Crews DC, Coresh J, et al; for the CDC CKD Surveillance Team. Prevalence of chronic kidney disease in US adults with undiagnosed diabetes or prediabetes. Clin J Am Soc Nephrol. 2010;5(4):673-682. 2. Parving H-H, Lewis JB, Ravid M, Remuzzi G, Hunsicker LG; for the DEMAND Investigators. Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective. Kidney Int. 2006;69:2057-2063. 3. Zhang X, Saaddine JB, Chou C-F, et al. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA. 2010;304(6):649-656. 4. Gregg EW, Gu Q, Williams D, et al. Prevalence of lower extremity diseases associated with normal glucose levels, impaired fasting glucose, and diabetes among U.S. adults aged 40 or older. Diabetes Res Clin Pract. 2007;77(3):485-488. 5. National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis. 2007;49(2 suppl 2):S1-S179. 6. American Diabetes Association. Nephropathy in diabetes. Diabetes Care. 2004;27(suppl 1):S79-S83. 7. Mogensen CE, Poulsen PL. Microalbuminuria, glycemic control, and blood pressure predicting outcome in diabetes type 1 and type 2. Kidney Int. 2004;66(suppl 92):S-40–S-41.

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Comparative Effectiveness Research in the United States: A Catalyst for Innovation Riaz Ali, MPP; Morgan Hanger, MPP; Tanisha Carino, PhD

Morgan Hanger

Tanisha Carino

Am Health Drug Benefits. 2011;4(2):68-72. www.AHDBonline.com Disclosures are at end of text

Recent calls for value in the US healthcare system have spurred an increase in comparative effectiveness research, which generates evidence on competing treatment options to inform healthcare stakeholders. As a large healthcare purchaser, the federal government has made several significant investments in comparative effectiveness research. Notably, in 2009 the American Recovery and Reinvestment Act allocated $1.1 billion for comparative effectiveness research, and in 2010 the Patient Protection and Affordable Care Act established a federal institute to organize the federal investment in comparative effectiveness research going forward. Over the past several years, comparative effectiveness research from the public and private sectors has begun to provide a foundation for innovation within the insurance and life sciences industries. Health plans and other payers are experimenting with nuanced coverage and reimbursement policies informed by comparative effectiveness evidence. Anticipating changes in payer, patient, and provider behaviors, drug manufacturers are refocusing their efforts on the development of novel and betterdifferentiated medications. As more comparative research becomes available in the future, continued innovation in payer and manufacturer strategies appears likely.

s stakeholders continue to strive for greater value in the US healthcare system, many are calling for more research to inform treatment decisions, particularly for providers and patients choosing between available multiple interventions. This charge has helped to ignite interest in comparative effectiveness research (CER), which aims to provide evidence on the effectiveness, benefits, and harms of competing treatment options for a clinical condition. As a growing purchaser of healthcare and a provider of public goods, the federal government has expanded its role in recent years, making increasingly significant investments in CER. With healthcare costs outpacing inflation year after year, the policy community has been more attuned to ways of controlling spending, and one popular target has been the elimination of â&#x20AC;&#x153;wastefulâ&#x20AC;? or unnecessary care. At best, CER is seen as a potential way to identify this excess, while simultaneously providing better information for decision makers at the point of care. At worst, CER is seen as a way for the government and payers to rationalize cost-cutting, undermining the autonomy of providers, and limiting patient choice.

Mr Ali is Director, Ms Hanger is Manager, and Dr Carino is Senior Vice President, Avalere Health, Washington, DC. Avalere Healthâ&#x20AC;&#x2122;s core purpose is to create innovative solutions to complex healthcare problems (www.avalerehealth.net).

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CER may even hinder innovation by increasing the cost of drug development and failing to recognize the true value of incremental product improvements. The research expansion will have important implications for the insurance and life sciences industries; in particular, CER has the potential to stimulate innovation in healthcare. In fact, we already see 2 significant changes in the commercial areas of the healthcare system. First, payers are using research findings on competing treatments to deploy innovative payment methods, such as tiering and bundling, across a wider range of therapeutic areas. Second, drug manufacturers are anticipating payment changes, shifting their commercialization strategies to create novel and better-differentiated medications. Although the gradual market adjustment to these new realities may bring some nearterm difficulties across the healthcare system, and their robust application is not a foregone conclusion, an increase in CER may help to create a more efficient, innovative system in the future.

The State of Comparative Effectiveness Research For much of the past 3 decades, US investment in CER has been driven by myriad organizations in the public and private arenas, all of which pursued independently derived research agendas. These organizations include the BlueCross BlueShield Technology Evalua-

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tion Center, the Cochrane Collaboration, and the Drug Effectiveness Review Project, among others. Government organizations, such as the Agency for Healthcare Research and Quality (AHRQ) and the National Institutes of Health historically had dedicated a portion of their funding to CER, but did not influence the direction of the US investment overall. As part of the effort in 2003 to expand Medicare coverage for prescription drugs, the federal government made its first explicit investment in CER, allocating up to $50 million to AHRQ’s Effective Health Care Program for “the outcomes, comparative clinical effectiveness, and appropriateness of health care items and services (including prescription drugs); and strategies for improving the efficiency and effectiveness of such programs.”1 While CER was gaining momentum, some policymakers and thought leaders were seeing missed opportunities. The fragmented CER investment was reflecting the priorities of the entities asking the questions, and focused on a narrow set of topics; this left important areas of inquiry unaddressed. Existing incentives, however, provided little motivation for researchers to fill these research gaps. Furthermore, the model for determining research priorities lacked the necessary participant and stakeholder engagement to ensure that research focused on the most clinically relevant questions. Given these obstacles, many saw a role for the federal government in providing leadership and funding to optimize CER in the United States. Over the past 2 years, the federal government has taken significant strides to fill this role. In 2009, the American Recovery and Reinvestment Act (ARRA) allocated $1.1 billion for 2 years of research.2 In 2010, the Patient Protection and Affordable Care Act established a permanent US CER entity called the PatientCentered Outcomes Research Institute (PCORI) to guide the federal CER enterprise. The law appropriates $1.26 billion to this public–private, stakeholder-governed institute from 2010 to 2019,3 with a mandatory fee on health plans and Medicare beneficiaries augmenting the budget beginning in 2013. Given that PCORI’s central function is to organize and coordinate the federal CER investment, the model for determining research priorities is at the cusp of a transformation. PCORI has already appointed a methodology committee to establish research standards, and it plans to release CER priorities later in 2011.

Federal Investment as a Marker of CER Demand To understand the potential impact of recent federal CER efforts, it is important to examine how the federal investment has been deployed. The largest part of the ARRA CER awards—46%—supports projects to devel-

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KEY POINTS The intensifying focus on value in healthcare has helped to fuel public and private sector interest in comparative effectiveness research (CER), which provides evidence on the effectiveness, benefits, and harms of competing treatment options for a clinical condition. ➤ In 2009, the American Recovery and Reinvestment Act allocated $1.1 billion for 2 years of CER, and in 2010, the Patient Protection and Affordable Care Act established a permanent entity, the PatientCentered Outcomes Research Institute, to organize federally funded CER going forward. ➤ Concurrent with the increase in federal funding for CER, health plans and other payers are becoming more sophisticated, data-driven organizations. ➤ Recognizing changes in their customer base, drug manufacturers are beginning to reexamine their product development strategies. Increasingly stringent payer standards for value are likely to encourage the development of more innovative medications. ➤

op more sophisticated research infrastructures and methodologies.4 Infrastructure building includes activities such as linking patient registries and adapting existing data sources so that they can be used for CER. Although in the past there has been an imperative to demonstrate the immediate value of CER to policymakers and taxpayers, ARRA’s investment in infrastructure shows the intention to construct a more sustained research program. The next largest ARRA commitment to CER—38% of awards—supports new evidence development, primarily through observational trials and evidence synthesis.4 Approximately 27% of these awards (or 10% of ARRA awards overall) focus on generating new evidence on pharmaceuticals. The remaining 16% of the overall ARRA CER investment supports the dissemination and translation of evidence.4 This type of award includes the creation of multilingual reports for subpopulations at elevated risk for specific diseases, among other projects. The Figure displays the 422 research grants and contracts funded through ARRA, by therapeutic area. A large proportion of awards—41%—did not have a disease focus; this includes a number of infrastructure development awards, as well as studies on healthcare delivery system interventions, such as accountable care organizations and the medical home.4 Not surprisingly, among awards with a therapeutic focus, many concern high-cost or high-incidence diseases. Cardiovascular and oncology

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Figure ARRA CER Investment by Therapeutic Area (Avalere EBM Navigator) Neurologic disorders 2% Immune system, connective tissue, and joint disorders 2% Kidney and urinary tract disorders 3%

Other 7%

Respiratory diseases 3% Women’s health 3% Infectious diseases and biliary tract disorders 3% Not specified 41%

Alcoholism, drug dependency, and overdose 3%

“Not specified” includes infrastructure development and evidence translation/dissemination awards without a therapeutic focus; it also includes awards focused on the healthcare delivery system

Psychiatric disorders 5% Oncology and hematology 10%

Endocrinology, metabolic disorders, and geriatrics 5%

Cardiovascular and peripheral disease 13% N = 422 research grants

ARRA indicates American Recovery and Reinvestment Act; CER, comparative effectiveness research; EBM, evidence-based medicine. Courtesy of Avalere.

research received the highest number of awards, which totaled $121 million and $124 million, respectively.4 Although it is not yet clear whether the ARRA investment will lead to the creation of meaningful tools and resources for CER, the considerable focus on infrastructure is cause for optimism. The material question now is how well PCORI can build on the progress made under ARRA as it identifies, funds, and pursues its own CER priorities.

Health Plans’ Business Models Build on CER Demand The federal government is one marker of the state of CER in the United States, but it is not the only one. Health plans and other payers are important stakeholders and contributors in the US CER marketplace. Today we see 2 main manifestations of this. First, recognizing the possible applications of CER, the commercial sector is growing its data and analytic expertise. Second, plans are making a concerted effort to creatively leverage find-

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ings (internally or externally generated) to inform their decisions. Taken together, these changes demonstrate the transformation of health plans and pharmacy benefit managers (PBMs) from risk intermediaries to more sophisticated, data-driven organizations.

Positioning Research Expertise as a Commercial Asset Early signals of this movement date back a decade or more, with UnitedHealth’s founding of Ingenix in 19965 and WellPoint’s acquisition of HealthCore in 2003.6 Both deals marked a first step toward a more researchoriented business model. More recently, in fall 2010, the PBM Medco acquired United BioSource Corporation (UBC), a global scientific and medical affairs organization, to enhance and expand its own research capabilities. Not surprisingly, when discussing this with the investor community, Medco CEO David B. Snow, Jr., positioned CER as a healthcare reform opportunity and

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the acquisition of UBC as a component of the corporate growth strategy.7 Another marker of an evolving business model is the increased partnership between health plans and the federal government. For instance, the US Food and Drug Administration’s (FDA’s) Sentinel Initiative, launched after the passage of the FDA Amendments Act in 2007, is an active drug surveillance system and includes participation from a wide range of organizations, such as America’s Health Insurance Plans, Humana, HealthCore, and Kaiser Permanente Center for Effectiveness and Safety Research.8 An additional example is the contract that the Department of Health and Human Services awarded to Ingenix Public Sector Solutions in 2010 to build a multipayer claims database for CER.9

promising but uncertain early results; however, in 2 subsequent randomized controlled trials comparing treatment regimens with and without bevacizumab (which the FDA required of the manufacturer), the FDA found that the drug did not perform well.13 This led the agency to modify its earlier position on bevacizumab’s net benefit in patients with metastatic breast cancer. Although Palmetto GBA has rescinded the policy change while the FDA’s recommendation is under appeal (by the manufacturer), their initial actions, as well as the assurance that they “will continue to review relevant clinical trials results and literature addressing the effectiveness of Avastin in the treatment of breast cancer,”14 illustrate payer interest in leveraging CER findings for coverage decisions.

Expanding the Use of CER in Decision-Making The second part of the equation is how health plans and payers are translating the demand for CER into meaningful healthcare purchasing decisions. A few recent examples illustrate potential uses: • Creation of clearer standards for evidence use. In May 2010, WellPoint became the first health benefits company to release CER guidelines, making more transparent its evaluation process for coverage and reimbursement decisions.10 This effort to explicitly standardize the data that informs decisions signals WellPoint’s plan to use more diverse evidence in future decisions. • Innovative payment methods to incentivize efficiency. Last fall, UnitedHealth Group announced a new cancer payment model aimed at improving the quality of care for patients with breast, colon, and lung cancers.11 Under the pilot, an oncologist will be paid a flat fee based on the wholesale price of a predetermined drug regimen for a patient, plus a case management fee. Although other services will continue to be reimbursed on a fee-for-service basis, this payment change will encourage physicians to select appropriate products and apply them as efficiently as possible. The pilot represents a much different way to pay for care. By considering all services, including medical and pharmacy, as part of a single bundle, payers and clinicians are compelled to more explicitly assess the value of each available component of care. • CER-infused Medicare coverage policy. In January 2011, Medicare carrier Palmetto GBA announced its intent to drop coverage of bevacizumab (Avastin) for metastatic breast cancer.12 Palmetto GBA’s statement followed an FDA recommendation in December 2010 to remove this indication from bevacizumab’s label. The FDA had granted accelerated approval for Avastin for metastatic breast cancer in 2008, after

Innovation in the Life Sciences Industry In response to the wider availability and broader payer use of effectiveness data, manufacturers are also beginning to shift gears, modifying their approach to commercialization. Although this is an evolving process, so far we have seen the following 3 clear ways that drug manufacturers are adapting.

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Reassessing Drug Development and Commercialization Strategy Externally generated CER may expose drugs to headto-head comparisons and class reviews; commercial success in a crowded or partially generic class has become harder to achieve than it was 10 or 20 years ago. In this way, CER encourages 2 modifications in the traditional processes for development and commercialization. The first involves the compounds and assets developed. With increasing challenges to commercial success in certain drug classes and therapeutic areas, manufacturers are recognizing the need to invest in more targeted medications focused on subpopulations (be they demographic, genetic, or otherwise defined). The second shift, which is structural and operational, is that drug manufacturers are seeking product differentiation earlier in the development pipeline. This is not surprising, because many industry leaders have acknowledged for some time the need to adjust course. Comments dating as far back as 2006 reflect clear understanding that the pharmaceutical business model is at a crossroad. Reimagining Their Customer Base Another change we are seeing is in the way manufacturers are engaging their customers. As payers become savvier, drug manufacturers are turning more of their energy toward satisfying evidentiary requirements, and focusing less on their traditional customer base—physi-

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cians and patients. A recent article on drug development summarized this change, suggesting that “physicians have been demoted from key decision-maker to stakeholder, while payers have gone from stakeholder to key decision-maker.”15 In line with this shift, AstraZeneca recently announced a collaboration with WellPoint to conduct real-world CER studies using a range of electronic health data.16 With a focus on chronic conditions, their goal is to maximize value by identifying and encouraging the most efficient use of medications. Although it presents a meaningful risk to AstraZeneca brands (because they may not always fare well in the research), this unique partnership acknowledges the need for drug manufacturers to work with payers to meet their increasingly stringent effectiveness standards.

Transform and Redeploy Clinical Research Expertise For some companies, there are more seismic changes afoot, which may lead to a very different pharmaceutical sector. For example, Pfizer recently announced its plans to close its research facility in Kent, England. This move was part of an effort to refocus its research and development program, shifting away from urology and internal medicine to maintain or expand focus in immunology, oncology, neuroscience, and inflammation.17 Pfizer CEO Ian Read explained, “We continue to closely evaluate our global research and development function and will accelerate our current strategies to improve innovation and overall productivity.”18 In other words, industry leaders are responding to the greater demand for different kinds of scientific evidence with significant structural and organizational changes. Conclusion The rise in CER is encouraging interesting and important changes across the healthcare sector. The federal CER investment is but one indicator of the demand for more comparative evidence. The private sector has also begun to focus more on CER-generation, suggesting that regardless of the direction of government funding, the marketplace is actively seeking inventive ways to create and apply this evidence. With more data available, payers are experimenting with coverage and reimbursement policies that promote the use of high-value products. In turn, manufacturers have begun to rethink ways of developing products that meet payers’ high standards for value. The cumulative effect of this increase in CER may not be fully understood for some time. However, the

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business environment is already changing as various participants find their role and support their value proposition. For interested parties, there is a great deal of opportunity to help shape the way scientific evidence is used in healthcare decision-making in the future. ■ Author Disclosure Statement Mr Ali, Ms Hanger, and Dr Carino have reported no conflicts of interest.

References 1. H.R.1.ENR. Medicare Prescription Drug, Improvement, and Modernization Act of 2003. http://thomas.loc.gov/cgi-bin/query/z?c108:H.R.1.ENR:. 108th Congress (2003-2004). Accessed February 22, 2011. 2. H.R.1.ENR. American Recovery and Reinvestment Act of 2009. http://thomas.loc.gov/cgi-bin/query/D?c111:364:./temp/~c111Qob9RQ::. Accessed March 21, 2011. 3. H.R.3590.ENR. Patient Protection and Affordable Care Act. 2010. http://thomas.loc.gov/cgi-bin/query/D?c111:127:./temp/~c111vmT49M::. Accessed March 21, 2011. 4. Avalere Health. EBM navigator. http://ebm.avalerehealth.net. Updated February 10, 2011. Accessed February 10, 2011. 5. Ingenix. The Ingenix era of collaboration. www.ingenix.com/about/history/. Accessed February 22, 2011. 6. WellPoint Health Networks. WellPoint acquires Health Core Inc. Press release. http://phx.corporate-ir.net/phoenix.zhtml?c=130104&p=irol-newsArticle_general &t=Regular&id=736587&. Accessed February 22, 2011. 7. Snow DB, Jr. Medco: the next decade. Presented at the 29th Annual J.P. Morgan Healthcare Conference; January 10, 2011. http://google.brand.edgar-online.com/ EFX_dll/EDGARpro.dll?FetchFilingHtmlSection1?SectionID=7649149-688343469&SessionID=VC_WHC33MvZ9u47. Accessed February 22, 2011. 8. Mini-Sentinel. Collaborators. http://mini-sentinel.org/about_us/collaborators. aspx. Accessed February 22, 2011. 9. Centers for Medicare & Medicaid Services. Recovery-Multi-Payor Claims Database. 2010. www.fbo.gov/index?s=opportunity&mode=form&tab=core&id= 853906cbdf5be4a8df46f7cb900a3270. Updated September 14, 2010. Accessed February 22, 2011. 10. WellPoint. WellPoint is first health benefits company to release CER guidelines for use in evaluating pharmaceuticals. WellPoint website. May 20, 2009. www.well point.com/pdf/CERGuidelines.pdf. Accessed March 21, 2011. 11. UnitedHealthcare. New UnitedHealthcare cancer care payment model to focus on best treatment practices and better health outcomes. News release. www.uhc.com/ news_room/2010_news_release_archive/new_unitedhealthcare_cancer_care_pay ment_model/relatedinformation/9c7afaf31c9cb210VgnVCM1000002f10b10a____. htm. Updated October 20, 2010. Accessed February 9, 2011. 12. Pollack A. Medicare contractor will pay for Avastin during appeal. New York Times. January 7, 2011. http://prescriptions.blogs.nytimes.com/2011/01/07/medicarecontractor-will-pay-for-avastin-during-appeal/. Accessed March 21, 2011. 13. Pazdur R, for the FDA Center for Drug Evaluation and Research. Memorandum to the file BLA 125085 Avastin (bevacizumab). December 15, 2010. www.fda.gov/ downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsand Providers/UCM237171.pdf. Accessed March 21, 2011. 14. Palmetto GBA. Ohio part B carrier Avastin notice. January 7, 2011. www.pal mettogba.com/palmetto/providers.nsf/docsCat/Providers~Ohio%20Part%20B%20 Carrier~Browse%20by%20Specialty~Oncology%20Hematology~Avastin%20 Notice?open. Accessed March 21, 2011. 15. Longman R. Sex, payers & product development. The RPM Rep. 2011;4. 16. Levine DS. AstraZeneca/WellPoint explore comparative effectiveness in effort to combat generics. Seeking Alpha. February 6, 2011. http://seekingalpha.com/article/ 251041-astrazeneca-wellpoint-explore-comparative-effectiveness-in-effort-tocombat-generics. Accessed February 15, 2011. 17. Carroll J. Pfizer carving $1.5B from R&D budget, dropping diseases. Fierce Biotech. www.fiercebiotech.com/story/pfizer-carving-15b-rd-budget-dropping-diseases/ 2011-02-01?utm_medium=nl&utm_source=internal. February 1, 2011. Accessed February 15, 2011. 18. Pfizer reports fourth-quarter and full-year 2010 results; provides 2011 financial guidance and updates 2012 financial targets. February 1, 2011. www.pfizer.com/files/ investors/presentations/q4performance_020111.pdf. Accessed February 15, 2011.

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ULORIC powerfully lowers serum uric acid levels for the long-term control of gout Long-term control of hyperuricemia to a serum uric acid level of <6 mg/dL is the key to managing gout1 SUPERIOR EFFICACY OF ULORIC 80 MG PROVEN IN HEAD-TO-HEAD STUDIES1,2 • ULORIC 40 mg effectively lowered serum uric acid similar to allopurinol1 • ULORIC 80 mg was superior to allopurinol at lowering serum uric acid1

6–12 months

100

70% 70 0%‡ 50

45%

40% % 25

Proportion of patients with a serum uric acid level of <6 mg/dL at the final visit*

ULORIC 80 mg

ULORIC 40 mg

Allopurinol 300 mg†

N=1258

N=757

N=1260

Based on results combined across three phase 3 studies; ULORIC 40 mg was only included in one of the studies, and ULORIC 80 mg and allopurinol were included in each of the studies. † In APEX, allopurinol patients (n=10) with serum creatinine >1.5 mg/dL and ≤2 mg/dL were dosed at 100 mg daily. In CONFIRMS, allopurinol patients (n=145) with estimated Clcr ≥30 mL/min and Clcr ≤59 mL/min were dosed at 200 mg daily. All other patients received 300 mg daily. ‡ p<0.001 vs allopurinol. *

References: 1. ULORIC® (febuxostat) full prescribing information, February 2009. 2. Data on file, Takeda Pharmaceuticals North America, Inc.

Indication ULORIC is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout. ULORIC is not recommended for the treatment of asymptomatic hyperuricemia.

Important Safety Information • ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline. • An increase in gout flares is frequently observed during initiation of anti-hyperuricemic agents, including ULORIC. If a gout flare occurs during treatment, ULORIC need not be discontinued. Prophylactic therapy (i.e. - NSAIDs or colchicine) upon initiation of treatment may be beneficial for up to six months. • Cardiovascular Events: In randomized controlled studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) in patients treated with ULORIC [0.74 per 100 P-Y (95% CI 0.36-1.37)] than allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)]. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of MI and stroke.

• Liver Enzyme Elevations: In randomized controlled studies, transaminase elevations greater than 3 times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2% in ULORIC and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted. Laboratory assessment of liver function is recommended at, for example, 2 and 4 months following initiation of ULORIC and periodically thereafter. • Adverse reactions occurring in at least 1% of ULORIC-treated patients, and, at least 0.5% greater than placebo, are liver function abnormalities, nausea, arthralgia, and rash. Individual results may vary based on factors such as baseline serum uric acid levels. Please see brief summary of complete Prescribing Information on adjacent pages.

For more information, please visit www.ULORIC.com

ULORIC is a trademark of Teijin Pharma Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. ©2010 Takeda Pharmaceuticals North America, Inc. TXF-00873 07/10

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION for ULORIC® (febuxostat) tablets INDICATIONS AND USAGE ULORIC® is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout. ULORIC is not recommended for the treatment of asymptomatic hyperuricemia. CONTRAINDICATIONS ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline [see Drug Interactions]. WARNINGS AND PRECAUTIONS Gout Flare After initiation of ULORIC, an increase in gout flares is frequently observed. This increase is due to reduction in serum uric acid levels resulting in mobilization of urate from tissue deposits. In order to prevent gout flares when ULORIC is initiated, concurrent prophylactic treatment with an NSAID or colchicine is recommended. Cardiovascular Events In the randomized controlled studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) in patients treated with ULORIC [0.74 per 100 P-Y (95% CI 0.36-1.37)] than allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)] [see Adverse Reactions]. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of myocardial infarction (MI) and stroke. Liver Enzyme Elevations During randomized controlled studies, transaminase elevations greater than 3 times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2% in ULORIC and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted. Laboratory assessment of liver function is recommended at, for example, 2 and 4 months following initiation of ULORIC and periodically thereafter. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 2757 subjects with hyperuricemia and gout were treated with ULORIC 40 mg or 80 mg daily in clinical studies. For ULORIC 40 mg, 559 patients were treated for r 6 months. For ULORIC 80 mg, 1377 subjects were treated for r 6 months, 674 patients were treated for r 1 year and 515 patients were treated for r 2 years. Most Common Adverse Reactions In three randomized, controlled clinical studies (Studies 1, 2 and 3), which were 6 to 12 months in duration, the following adverse reactions were reported by the treating physician as related to study drug. Table 1 summarizes adverse reactions reported at a rate of at least 1% in ULORIC treatment groups and at least 0.5% greater than placebo. Table 1: Adverse Reactions Occurring in r 1% of ULORIC-Treated Patients and at Least 0.5% Greater than Seen in Patients Receiving Placebo in Controlled Studies Placebo

Adverse Reactions Liver Function Abnormalities Nausea Arthralgia Rash

ULORIC

allopurinol*

(N=134)

40 mg daily (N=757)

80 mg daily (N=1279)

(N=1277)

0.7%

6.6%

4.6%

4.2%

0.7%

1.1%

1.3%

0.8%

1.1%

0.7%

0.5%

1.6%

*Of the subjects who received allopurinol, 10 received 100 mg, 145 received 200 mg, and 1122 received 300 mg, based on level of renal impairment. The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of ULORIC 40 mg, 1.2% of ULORIC 80 mg, and in 0.9% of allopurinol-treated subjects. In addition to the adverse reactions presented in Table 1, dizziness was reported in more than 1% of ULORIC-treated subjects although not at a rate more than 0.5% greater than placebo. Less Common Adverse Reactions In phase 2 and 3 clinical studies the following adverse reactions occurred in less than 1% of subjects and in more than one subject treated with doses ranging from 40 mg to 240 mg of ULORIC. This list also includes adverse reactions (less than 1% of subjects) associated with organ systems from Warnings and Precautions.

Blood and Lymphatic System Disorders: anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia; Cardiac Disorders: angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia; Ear and Labyrinth Disorders: deafness, tinnitus, vertigo; Eye Disorders: vision blurred; Gastrointestinal Disorders: abdominal distention, abdominal pain, constipation, dry mouth, dyspepsia, flatulence, frequent stools, gastritis, gastroesophageal reflux disease, gastrointestinal discomfort, gingival pain, haematemesis, hyperchlorhydria, hematochezia, mouth ulceration, pancreatitis, peptic ulcer, vomiting; General Disorders and Administration Site Conditions: asthenia, chest pain/discomfort, edema, fatigue, feeling abnormal, gait disturbance, influenza-like symptoms, mass, pain, thirst; Hepatobiliary Disorders: cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly; Immune System Disorder: hypersensitivity; Infections and Infestations: herpes zoster; Procedural Complications: contusion; Metabolism and Nutrition Disorders: anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased; Musculoskeletal and Connective Tissue Disorders: arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness, musculoskeletal pain/stiffness, myalgia; Nervous System Disorders: altered taste, balance disorder, cerebrovascular accident, Guillain-Barré syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental impairment, migraine, paresthesia, somnolence, transient ischemic attack, tremor; Psychiatric Disorders: agitation, anxiety, depression, insomnia, irritability, libido decreased, nervousness, panic attack, personality change; Renal and Urinary Disorders: hematuria, nephrolithiasis, pollakiuria, proteinuria, renal failure, renal insufficiency, urgency, incontinence; Reproductive System and Breast Changes: breast pain, erectile dysfunction, gynecomastia; Respiratory, Thoracic and Mediastinal Disorders: bronchitis, cough, dyspnea, epistaxis, nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory tract congestion, sneezing, throat irritation, upper respiratory tract infection; Skin and Subcutaneous Tissue Disorders: alopecia, angio edema, dermatitis, dermographism, ecchymosis, eczema, hair color changes, hair growth abnormal, hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin discoloration/altered pigmentation, skin lesion, skin odor abnormal, urticaria; Vascular Disorders: flushing, hot flush, hypertension, hypotension; Laboratory Parameters: activated partial thromboplastin time prolonged, creatine increased, bicarbonate decreased, sodium increased, EEG abnormal, glucose increased, cholesterol increased, triglycerides increased, amylase increased, potassium increased, TSH increased, platelet count decreased, hematocrit decreased, hemoglobin decreased, MCV increased, RBC decreased, creatinine increased, blood urea increased, BUN/creatinine ratio increased, creatine phosphokinase (CPK) increased, alkaline phosphatase increased, LDH increased, PSA increased, urine output increased/decreased, lymphocyte count decreased, neutrophil count decreased, WBC increased/decreased, coagulation test abnormal, low density lipoprotein (LDL) increased, prothrombin time prolonged, urinary casts, urine positive for white blood cells and protein. Cardiovascular Safety Cardiovascular events and deaths were adjudicated to one of the pre-defined endpoints from the Anti-Platelet Trialists’ Collaborations (APTC) (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in the randomized controlled and long-term extension studies. In the Phase 3 randomized controlled studies, the incidences of adjudicated APTC events per 100 patient-years of exposure were: Placebo 0 (95% CI 0.00-6.16), ULORIC 40 mg 0 (95% CI 0.00-1.08), ULORIC 80 mg 1.09 (95% CI 0.44-2.24), and allopurinol 0.60 (95% CI 0.16-1.53). In the long-term extension studies, the incidences of adjudicated APTC events were: ULORIC 80 mg 0.97 (95% CI 0.57-1.56), and allopurinol 0.58 (95% CI 0.02-3.24). Overall, a higher rate of APTC events was observed in ULORIC than in allopurinoltreated patients. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of MI and stroke. DRUG INTERACTIONS Xanthine Oxidase Substrate Drugs ULORIC is an XO inhibitor. Drug interaction studies of ULORIC with drugs that are metabolized by XO (e.g., theophylline, mercaptopurine, azathioprine) have not been conducted. Inhibition of XO by ULORIC may cause increased plasma concentrations of these drugs leading to toxicity [see Clinical Pharmacology]. ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline [see Contraindications]. Cytotoxic Chemotherapy Drugs Drug interaction studies of ULORIC with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of ULORIC during cytotoxic chemotherapy. In Vivo Drug Interaction Studies Based on drug interaction studies in healthy subjects, ULORIC does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine. Therefore, ULORIC may be used concomitantly with these medications.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. ULORIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Febuxostat was not teratogenic in rats and rabbits at oral doses up to 48 mg per kg (40 and 51 times the human plasma exposure at 80 mg per day for equal body surface area, respectively) during organogenesis. However, increased neonatal mortality and a reduction in the neonatal body weight gain were observed when pregnant rats were treated with oral doses up to 48 mg per kg (40 times the human plasma exposure at 80 mg per day) during organogenesis and through lactation period. Nursing Mothers Febuxostat is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ULORIC is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients under 18 years of age have not been established. Geriatric Use No dose adjustment is necessary in elderly patients. Of the total number of subjects in clinical studies of ULORIC, 16 percent were 65 and over, while 4 percent were 75 and over. Comparing subjects in different age groups, no clinically significant differences in safety or effectiveness were observed but greater sensitivity of some older individuals cannot be ruled out. The Cmax and AUC24 of febuxostat following multiple oral doses of ULORIC in geriatric subjects (r 65 years) were similar to those in younger subjects (18-40 years). Renal Impairment No dose adjustment is necessary in patients with mild or moderate renal impairment (Clcr 30-89 mL per min). The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg, ULORIC 80 mg is recommended. There are insufficient data in patients with severe renal impairment (Clcr less than 30 mL per min); therefore, caution should be exercised in these patients. Hepatic Impairment No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); therefore, caution should be exercised in these patients. Secondary Hyperuricemia No studies have been conducted in patients with secondary hyperuricemia (including organ transplant recipients); ULORIC is not recommended for use in patients whom the rate of urate formation is greatly increased (e.g., malignant disease and its treatment, Lesch-Nyhan syndrome). The concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract. OVERDOSAGE ULORIC was studied in healthy subjects in doses up to 300 mg daily for seven days without evidence of dose-limiting toxicities. No overdose of ULORIC was reported in clinical studies. Patients should be managed by symptomatic and supportive care should there be an overdose. CLINICAL PHARMACOLOGY Pharmacodynamics Effect on Uric Acid and Xanthine Concentrations: In healthy subjects, ULORIC resulted in a dose dependent decrease in 24-hour mean serum uric acid concentrations, and an increase in 24-hour mean serum xanthine concentrations. In addition, there was a decrease in the total daily urinary uric acid excretion. Also, there was an increase in total daily urinary xanthine excretion. Percent reduction in 24-hour mean serum uric acid concentrations was between 40% to 55% at the exposure levels of 40 mg and 80 mg daily doses. Effect on Cardiac Repolarization: The effect of ULORIC on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy subjects and in patients with gout. ULORIC in doses up to 300 mg daily, at steady state, did not demonstrate an effect on the QTc interval. Special Populations Renal Impairment: Following multiple 80 mg doses of ULORIC in healthy subjects with mild (Clcr 50-80 mL per min), moderate (Clcr 30-49 mL per min) or severe renal impairment (Clcr 10-29 mL per min), the Cmax of febuxostat did not change relative to subjects with normal renal function (Clcr greater than 80 mL per min). AUC and half-life of febuxostat increased in subjects with renal impairment in comparison to subjects with normal renal function, but values were similar among three renal impairment groups. Mean febuxostat AUC values were up to 1.8 times higher in subjects with renal impairment compared to those with normal renal function. Mean Cmax and AUC values for 3 active metabolites increased up to 2- and 4-fold, respectively. However, the percent decrease in serum uric acid concentration for subjects with renal impairment was comparable to those with normal renal function (58% in normal renal function group and 55% in the severe renal function group).

No dose adjustment is necessary in patients with mild to moderate renal impairment [see Dosage and Administration and Use in Specific Populations]. The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg, ULORIC 80 mg is recommended. There is insufficient data in patients with severe renal impairment; caution should be exercised in those patients [see Use in Specific Populations. ULORIC has not been studied in end stage renal impairment patients who are on dialysis. Hepatic Impairment: Following multiple 80 mg doses of ULORIC in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an average of 20-30% increase was observed for both Cmax and AUC24 (total and unbound) in hepatic impairment groups compared to subjects with normal hepatic function. In addition, the percent decrease in serum uric acid concentration was comparable between different hepatic groups (62% in healthy group, 49% in mild hepatic impairment group, and 48% in moderate hepatic impairment group). No dose adjustment is necessary in patients with mild or moderate hepatic impairment. No studies have been conducted in subjects with severe hepatic impairment (Child-Pugh Class C); caution should be exercised in those patients [see Use in Specific Populations. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Two-year carcinogenicity studies were conducted in F344 rats and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of urinary bladder was observed at 24 mg per kg (25 times the human plasma exposure at maximum recommended human dose of 80 mg per day) and 18.75 mg per kg (12.5 times the human plasma exposure at 80 mg per day) in male rats and female mice, respectively. The urinary bladder neoplasms were secondary to calculus formation in the kidney and urinary bladder. Mutagenesis: Febuxostat showed a positive mutagenic response in a chromosomal aberration assay in a Chinese hamster lung fibroblast cell line with and without metabolic activation in vitro. Febuxostat was negative in the in vitro Ames assay and chromosomal aberration test in human peripheral lymphocytes, and L5178Y mouse lymphoma cell line, and in vivo tests in mouse micronucleus, rat unscheduled DNA synthesis and rat bone marrow cells. Impairment of Fertility: Febuxostat at oral doses up to 48 mg per kg per day (approximately 35 times the human plasma exposure at 80 mg per day) had no effect on fertility and reproductive performance of male and female rats. Animal Toxicology A 12-month toxicity study in beagle dogs showed deposition of xanthine crystals and calculi in kidneys at 15 mg per kg (approximately 4 times the human plasma exposure at 80 mg per day). A similar effect of calculus formation was noted in rats in a six-month study due to deposition of xanthine crystals at 48 mg per kg (approximately 35 times the human plasma exposure at 80 mg per day). PATIENT COUNSELING INFORMATION [see FDA-Approved Patient Labeling in the full prescribing information] General Information Patients should be advised of the potential benefits and risks of ULORIC. Patients should be informed about the potential for gout flares, elevated liver enzymes and adverse cardiovascular events after initiation of ULORIC therapy. Concomitant prophylaxis with an NSAID or colchicine for gout flares should be considered. Patients should be instructed to inform their healthcare professional if they develop a rash, chest pain, shortness of breath or neurologic symptoms suggesting a stroke. Patients should be instructed to inform their healthcare professional of any other medications they are currently taking with ULORIC, including over-the-counter medications. Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 U.S. Patent Nos. - 6,225,474; 7,361,676; 5,614,520. ULORICÂŽ is a registered trademark of Teijin Pharma Limited and used under license by Takeda Pharmaceuticals America, Inc. All other trademark names are the property of their respective owners ÂŠ2009 Takeda Pharmaceuticals America, Inc. February 2009 For more detailed information, see the full prescribing information for ULORIC (febuxostat) tablets (PI1114 R1; February 2009) or contact Takeda Pharmaceuticals America, Inc. at 1.877.825.3327. PI1114 R1-Brf; February 2009 L-TXF-0209-3

CALL FOR PAPERS Cardiometabolic Health & Wellness Special Issue American Health & Drug Benefits will be publishing a Special Issue on Cardiometabolic Health & Wellness later this year. The editors of AHDB invite readers to submit articles for publication in this special issue on topics relevant to the clinical, business, and policy aspects of cardiometabolic health and wellness amidst an economic downturn and inconsistent healthcare outcomes. Original research studies, white papers, evidence-based comprehensive reviews, and case studies are of particular interest. The editors invite all healthcare stakeholders—actuaries, employers, economists, manufacturers, patients, payers, policymakers, providers, purchasers, regulators, and researchers—to present their data, best practices, innovations, and initiatives to facilitate patient-centered management strategies and benefit design models toward the prevention of cardiometabolic risk factors and outcomes improvement in patients with cardiovascular disease, diabetes, or obesity.

Readers are invited to submit original, outcomes-based research, white papers, evidence-based comprehensive reviews, and case studies on topics such as: • Benefit designs to improve cardiometabolic outcomes • Best practices in diabetes management and prevention • Best practices in insulin control, lipid management, or blood pressure control • Current recommendations for optimizing A1C targets • Comparative effectiveness analyses of best therapies for cardiovascular health • Cost-effectiveness comparisons of current therapies for diabetes • Employers’ strategies to enhance employees’ cardiometabolic wellness • Emerging therapies for diabetes, cardiovascular disease, obesity • Health plan initiatives for cardiometabolic health and prevention • Hot topics in diabetes management, obesity, or cardiovascular disease • Insulin resistance and type 2 diabetes • Lifestyle strategies and cardiometabolic health and wellness • Lipid management in patients with diabetes • Medication adherence and diabetes progression • New biomarkers for assessing cardiometabolic risk • New therapies for diabetes or cardiovascular disease • Optimal therapies for cardiovascular disease, diabetes, or obesity • Prevention strategies for diabetes risk reduction • Wellness programs for patients with heart disease, diabetes, or obesity Submission deadline for this issue is June 30, 2011. Articles submitted by May 31 will be given publication priority. All articles will undergo the Journal’s standard peer-review process. Articles should follow the Manuscript Instructions for Authors (www.AHDBonline.com) For more information contact editor@AHDBonline.com, or call 732-992-1889

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ARZERRA HCPCS Code J9302 Announcing a NEW J-Code for ARZERRA ARZERRA will have a permanent HCPCS code effective January 1, 2011 The new J9302 Code replaces miscellaneous HCPCS Codes J9999, J3590, J3490, and C9260 that most providers have used to bill for ARZERRA to date

HCPCS code

Description

Effective

J9302

Injection, ofatumumab, 10mg

January 1, 2011

Contact your GSK representative for additional information or visit www.ARZERRA.com.

BUSINESS

ORIGINAL RESEARCH

Eric Q. Wu

Stakeholder Perspective, page 87

Am Health Drug Benefits. 2011;4(2):78-87 www.AHDBonline.com Disclosures are at end of text

Background: Major depressive disorder is the most common type of depression, affecting 6.6% of adults in the United States annually. Citalopram and escitalopram are common second-generation antidepressants used for the treatment of patients with this disorder. Because citalopram is available in generic forms that have lower acquisition costs compared with the branded escitalopram, some health plans may provide incentives to encourage the use of the generic option. Decisions based solely on drug acquisition costs may encourage the use of a therapy that is less cost-effective when treatment persistence, healthcare utilization, and overall costs are factored in. Objective: To compare, in a real-world setting, the treatment persistence, healthcare utilization, and overall costs of managing adult patients with major depressive disorder who are treated with escitalopram or citalopram. Methods: Administrative claims data (from January 1, 2003, to June 30, 2005) were analyzed for patients with major depressive disorder aged ≥18 years. Patients filled ≥1 prescriptions for citalopram or for escitalopram (first-fill time was defined as the index date) and had no second-generation antidepressant use during the 6-month preindex period. Treatment persistence, healthcare utilization, and healthcare costs were measured over the 6-month preindex and 6-month postindex periods and compared between patients treated with citalopram or escitalopram, using unadjusted and multivariate analyses. Results: Patients receiving escitalopram (N = 10,465) were less likely to discontinue the treatment (hazard ratio 0.94; P = .005) and switch to another second-generation antidepressant (hazard ratio 0.83; P <.001) than patients receiving citalopram (N = 4212). Patients receiving escitalopram were also less likely to have a hospital admission (odds ratio 0.88; P = .036) or an emergency department visit and had lower total healthcare costs (–$1174) and major depressive disorder–related costs (–$109; P <.001) during the study period. Conclusion: Although the drug acquisition costs are lower for generic citalopram than for the brand-name escitalopram, patients treated with escitalopram had better treatment persistence, lower healthcare utilization, and lower overall costs compared with patients treated with citalopram over the study period. This may suggest that other considerations, in addition to acquisition cost, may need to be factored in to assess the cost-effectiveness of drug therapy.

ajor depressive disorder (MDD) often presents as a chronic and recurrent illness. It is the most common type of depression, affecting 6.6% of adults in the United States annually, with a lifetime

prevalence of 16.2%.1 Patients with MDD are more likely to suffer from multiple comorbidities, including other mental illnesses or chronic conditions, compared with patients without MDD.2 MDD is also associated with

Dr Wu is Managing Principal, Mr Greenberg is Managing Principal and Director, Health Economics, Ms Ben-Hamadi is Manager, Dr Yu is Manager, and Dr Yang is Associate, Analysis Group, Boston, MA; Dr Erder was Vice President, Global Health Economics and Outcomes Research, Forest Research Institute, at the time of the study. This study was presented at the American Psychiatric Association’s 59th Annual Institute on Psychiatric Services, October 11-14, 2007, New Orleans, LA.

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Healthcare Resource Utilization and Costs in MDD

increased risk for substance abuse, particularly alcohol abuse, leading to more severe depressive symptoms and impairment.3 Because of its clinical features, untreated or undertreated MDD can have significant negative impacts on an individual’s health, quality of life, and functional status, as well as work productivity and employment.2,4 Consequently, patients with MDD are among the highest users of healthcare and incur substantial indirect costs resulting from premature deaths, reduced productivity, and increased disability associated with the disease.2,5 The economic burden of MDD was estimated to have amounted to $83.1 billion in 2000 in the United States.5 Of this total cost, $26.1 billion (31%) was for direct medical costs, $5.4 billion (7%) was for suiciderelated mortality costs, and the remaining $51.5 billion (62%) was for work-related costs.5 Effective treatment can substantially reduce the economic burden assumed by the healthcare system, employers, and society. Pharmacotherapy is a major type of treatment for MDD. Currently, the most widely prescribed antidepressants in the United States are selective serotonin reuptake inhibitors (SSRIs). These secondgeneration antidepressants have been shown to be effective and better tolerated than older antidepressants.6 Both escitalopram (Lexapro) and citalopram (Celexa) are SSRIs, and escitalopram is the pure S-enantiomer of the racemic citalopram. An enantiomer is composed of 2 compounds that are nonsuperimposable mirror images of each other. Citalopram is a racemate that comprises a 1:1 mixture of S(+)-enantiomer (escitalopram) and an R(−)-enantiomer (R-citalopram). It is the S-enantiomer that possesses the pharmacologic effect of the drug. The R-enantiomer in citalopram counteracts the activity of the S-enantiomer, which may be the underlying reason for the differences in the pharmacologic and clinical effects between escitalopram and citalopram.7-9 Citalopram was approved by the US Food and Drug Administration (FDA) for acute and maintenance treatment of adults with MDD in July 1998, and escitalopram was approved for acute and maintenance treatment of MDD in adults in August 2002. Citalopram became generic in October 2004. Because citalopram and escitalopram are chemically related, payers may assume that they provide similar clinical benefits, and that the lower acquisition cost of generic citalopram will lead directly to reductions in overall treatment costs. However, citalopram and escitalopram are different medications and may not be interchangeable. Many clinical trials and analyses have compared citalopram and escitalopram, and have consistently shown that escitalopram is more efficacious.10-14 In one

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KEY POINTS ➤

➤

Major depressive disorder is the most common type of depression, affecting 6.6% of adults in the United States annually. The economic burden of this disorder was estimated to amount to $83.1 billion in 2000, of which 62% was for work-related costs, 31% for direct medical costs, and 7% for suicide-related costs. Citalopram and escitalopram are similar medications indicated for the treatment of major depression, but they may not be interchangeable. Many clinical trials comparing these agents have shown a superior efficacy to escitalopram compared with citalopram. Because citalopram is now available in generic forms, with lower acquisition costs than the branded escitalopram, health plans may offer incentives to encourage the use of a generic option. Decisions based solely on drug acquisition cost, however, may encourage a less cost-effective therapy; it is important to understand the cost implications of drugs in the real-world setting. This retrospective analysis shows that treatment with escitalopram was associated with greater treatment persistence and lower depressive disorder– related and overall healthcare utilization and costs than with citalopram in this patient population.

study, escitalopram 10 mg/day was found to be at least as effective as citalopram 40 mg/day in an 8-week study of 491 outpatients with MDD.10 A placebo-controlled trial of 469 patients with moderate-to-severe depression revealed that by the end of 8 weeks of treatment, significantly more patients responded to escitalopram 10 to 20 mg daily than to citalopram 20 to 40 mg daily.11 Continuation of treatment with escitalopram has also demonstrated efficacy in preventing relapse of MDD.12,13 A double-blind trial of 280 patients with MDD randomized to escitalopram 20 mg/day or to citalopram 40 mg/day over 8 weeks demonstrated significant improvements in depression rating scales and in treatment response rates with escitalopram.14 Both groups demonstrated similar tolerability.14 Furthermore, an economic evaluation that was conducted parallel with a double-blind, randomized clinical trial in France showed that escitalopram is more costeffective than citalopram.12 Although conducted outside the United States, this economic evaluation has some value in understanding the relative cost-effectiveness of these 2 treatments, especially when similar evaluation is lacking in this country. Among ambulatory care patients with MDD followed for 8 weeks, escitalopram 20 mg/day

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resulted in 41% lower mean per-patient costs compared with citalopram 40 mg/day.12 The cost differential was mainly a result of lower hospitalization costs.12 Driven by cost-containment considerations, healthcare systems have adopted a variety of policies designed to encourage physicians and patients toward lower-cost drugs, including use of generic drugs when they become available. However, without a comprehensive understanding of the total healthcare cost implications of these 2 antidepressants in the real world, promoting or mandating citalopram in drug formularies to replace escitalopram based solely on acquisition costs may not be cost-effective. A comparison of the economic outcomes of patients treated with escitalopram and citalopram is valuable for decision makers to consider the total costs of MDD treatment. Although some published claims studies have compared escitalopram with other SSRIs as a group,8,9 to our knowledge very few real-world studies have compared escitalopram with citalopramâ&#x20AC;&#x201D;2 antidepressants that are often assumed to be equivalent as a result of their molecular structure. One analysis based on claims data recently compared clinical and economic profiles of escitalopram and citalopram in a geriatric population with MDD.15 The objective of this current study is to generalize this real-world comparison with adult patients with MDD.

Methods Data Source In this current study, we analyzed claims data from the Ingenix Impact Database, which included complete medical and pharmacy claims for more than 25 million noncapitated managed care lives from more than 35 health plans, covering all census regions of the United States. Data elements used in the present analysis included enrollment records, patient demographics, inpatient and outpatient medical services, and pharmacy dispensing claims. The data collection period started January 1, 2003, because escitalopram was approved by the FDA for MDD treatment in August 2002. Study Design Patients were included in the study if they had at least 1 inpatient claim or 2 medical claims of other types incurred on different dates that were associated with an MDD diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification 296.2x, 296.3x) between January 1, 2003, and June 30, 2005, and if they filled at least 1 prescription either for escitalopram or for citalopram during that same period. The first prescription filling date was defined as the index date. The antidepressant filled on the index date (either escitalopram or citalopram) was defined as the index drug.

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Patients were classified into the citalopram group or the escitalopram group based on the index drug they received. Because this study was intended to compare citalopram and escitalopram, the brand-name and generic forms of citalopram were not distinguished. All patients who received either brand-name or generic citalopram and met the study criteria were included in the same citalopram group. Because the National Committee for Quality Assurance criteria for the appropriate treatment of MDD requires a minimum duration of 6 months, the study period was set to 6 months after therapy initiation.16 The baseline period was defined as the 6 months before the index date, and the study period was defined as the 6 months after the index date. Patients had to meet the following additional inclusion criteria: (1) they were aged â&#x2030;Ľ18 years as of the index date; (2) they were continuously enrolled in the plan for at least 12 months, including a minimum of 6 months before and 6 months after the index date; (3) they did not use any second-generation antidepressant drug (eg, SSRIs, serotonin-norepinephrine reuptake inhibitors, bupropion, nefazodone, trazodone, fluoxetine-olanzapine, or mirtazapine) during the baseline period; and (4) they were not initiated on combination therapy (ie, did not use any second-generation antidepressants other than citalopram or escitalopram within 2 weeks after the index date).9,15

Outcome Measures Treatment persistence. Treatment persistence was measured up to the time of discontinuation of therapy by the rate of discontinuation of the index drug during the study period. Patients were considered to discontinue the index drug if they did not have another refill within 45 days after the last day of the latest supply of the index drug recorded in the claims database.17 Patients who had discontinued and switched to another second-generation antidepressant were further identified, with switching defined as filling a prescription for another secondgeneration antidepressant within 45 days of the last day of the latest supply of the index drug. Healthcare resource utilization. Healthcare resource utilization was observed in all-cause hospitalizations and emergency department visits during the study period. In particular, MDD-related hospitalizations and emergency department visits were also measured. A hospitalization or an emergency department visit was considered MDDrelated if it was associated with a primary or secondary diagnosis for MDD. The proportions of patients who used these types of services were estimated, as well as the number of hospitalization days and number of emergency department visits for each patient.

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Healthcare costs. Healthcare costs were examined from the insurerâ&#x20AC;&#x2122;s perspective. Average costs per patient were estimated on the basis of payment data in the claims database for procedures, services, and prescription drugs, over the 6-month study period by the type of service (ie, professional services, including physicians and other medical professionalsâ&#x20AC;&#x2122; care; hospitalization cost; outpatient cost; emergency department cost; and prescription drug cost). Total healthcare costs were calculated as the sum of total medical services costs and total prescription drug costs. In addition, MDD-related costs (total and by service type) were also calculated. A medical service cost was considered MDD-related if it was associated with a diagnosis of MDD. MDD-related pharmacy costs included the costs of antidepressants. Because MDD is often associated with multiple comorbidities,2 including other mental illnesses or chronic conditions, it is important to analyze not only MDD-related costs but also the total cost of disease. Statistical Analysis Study outcomes were first compared between the citalopram and escitalopram groups using unadjusted analysis. Chi-square tests were used to compare the rates of discontinuation and discontinuation with switching to another second-generation antidepressant, hospitalization, and any emergency department visit during the study period. Wilcoxon tests were used to compare statistical differences in the number of hospitalization days, number of emergency department visits, and healthcare costs between the 2 groups. The study outcomes were further compared using a multivariate analysis to control for differences in baseline characteristics between the 2 treatment groups. Patient baseline characteristics were measured during the baseline period and included age, sex, the Deyo adaptation of the Charlson Comorbidity Index (CCI),18 individual comorbidities selected from the literature, and baseline healthcare utilization and costs. (The CCI has become a common measure for comorbidity burden in observational studies, especially those using administrative claims databases. This index has been used in the literature related to depression and is intended as a measure of overall health outcomes of the patient, not as a measure of disease severity associated with depression.19) To compare the rates of discontinuation and discontinuation with switching between the 2 groups, Cox proportional hazard models were used. Logistic regressions were applied to estimate the probability of hospitalization and emergency department visits during the study period. The number of hospitalization days and the num-

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ber of emergency department visits were compared between the 2 groups using negative binomial regressions. Generalized linear model (GLM) regressions with log link and gamma distribution were used to analyze healthcare costs. For MDD-related total medical services costs, a 2-part model was used, because a large portion of patients had no hospital and medical costs.

Sensitivity Analysis To assess the robustness of the study results to variations in the price of antidepressant drugs, it was assumed that all second-generation antidepressants used by patients in the citalopram group had zero cost, whereas the prescription drug cost in the escitalopram group was kept unchanged. Under this assumption, the new total healthcare cost for the citalopram group was calculated and compared with the total healthcare cost of the escitalopram group using both Wilcoxon test and GLM regression as described above. The analysis represented a conservative estimation of the cost impact of escitalopram over citalopram by deducting all antidepressant drug costs from the total healthcare costs for the citalopram group. Results A total of 14,677 patients met the inclusion criteria in this study, of which 10,465 were taking escitalopram, and 4212 were taking citalopram. Patient baseline characteristics are presented in Table 1. Compared with patients using citalopram, patients using escitalopram had similar age (41.7 vs 42.1; P = .0131); fewer females (67.5% vs 69.5%; P = .019); a lower average CCI (0.77 vs 0.90; P = .005); a higher prevalence of generalized anxiety disorder, panic disorder, sleep disorder, and hyperlipidemia; and a lower prevalence of schizophrenia and cancer. In addition, patients taking escitalopram used more prescription drugs at baseline (4.54 vs 4.35; P = .003) and had more physician office visits (94.1% vs 91.0%; P <.001), but had fewer inpatient visits (13.5% vs 15.7%; P = .001), outpatient hospital visits (54.5% vs 58.6%; P <.001), and emergency department visits (22.0% vs 23.5%; P = .040) than patients taking citalopram. In addition, patients taking escitalopram had numerically lower baseline drug, medical, and total costs compared with patients taking citalopram, although the difference was significant only for the drug costs. Treatment Persistence During the 6-month study period, 57.8% of patients taking escitalopram and 60.3% of those taking citalopram (P = .006) discontinued the index treatment (Table 2). The rate of discontinuation with switching

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Table 1 Baseline Characteristics of Adult Patients with MDD, by Index Therapy with Escitalopram or Citalopram Escitalopram (N = 10,465)

Baseline characteristicsa Demographics

Citalopram (N = 4212)

Age on index date (mean, SD)

41.7 (13.7)

42.1 (14.1)

.131

Female, %

67.5

69.5

.019c

Comorbidities 0.77 (2.16)

0.90 (2.35)

.005c

Dementia and Alzheimerâ&#x20AC;&#x2122;s disease

0.6

0.8

.299

Generalized anxiety disorder

6.2

4.2

<.001c

Deyo Charlson Comorbidity Index (mean, SD) Mental diseases, %

Obsessive-compulsive disorder

1.1

0.9

.283

Other psychotic disorders

1.0

1.4

.049c

Panic disorder

3.1

1.8

<.001c

Phobia

1.2

1.1

.709

Posttraumatic stress disorder

2.1

2.2

.796

Schizophrenia

0.5

0.8

.046c

Sleeping disorder

4.4

3.0

<.001c

Cancer

3.2

4.6

<.001c

Cardiovascular disease

9.3

10.0

.243

Other diseases, %

Chronic obstructive pulmonary disease and allied conditions

8.7

9.1

.505

Diabetes

5.4

6.2

.073

Epilepsy

0.8

0.9

.733

Hyperlipidemia

14.4

13.0

.024c

Hypertension

14.3

14.1

.734

Irritable bowel syndrome

1.9

2.1

.396

Renal disease

1.3

1.5

.361

Rheumatoid arthritis and osteoarthritis

4.8

4.4

.394

Stroke

0.9

1.1

.308

4.54 (4.65)

4.35 (4.58)

.003c

Healthcare utilization Number of prescription drugs used (mean, SD) Medical services, % Inpatient visit

13.5

15.7

.001c

Outpatient hospital visit

54.5

58.6

<.001c

Office visit

94.1

91.0

<.001c

Emergency department visit

22.0

23.5

.040c

665 (1455)

669 (1475)

.005c

Medical service

4319 (11,854)

5538 (19,916)

.779

Total healthcare costs

4984 (12,263)

6206 (20,216)

.756

Healthcare costs, $ (mean, SD) Prescription drug

Baseline characteristics were measured during the 6-month preindex period. Wilcoxon test was used for continuous variables; chi-square test was used for categorical variables. P <.05.

b c

MDD indicates major depressive disorder; SD, standard deviation.

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Healthcare Resource Utilization and Costs in MDD

Table 2 Treatment Discontinuation and Healthcare Utilization, by Index Therapy with Escitalopram or Citalopram Unadjusted analyses

Multivariate analysis

Escitalopram (N = 10,465)

Citalopram (N = 4212)

Adjusted HR, OR, or IRRb and 95% CI

All discontinuationc

57.8

60.3

.006d

0.94 (0.90, 0.98)

Discontinuation with switchingc

24.7

29.3

<.001d

0.83 (0.78, 0.88)

Hospitalization for any reason, %e

11.6

13.6

.001d

0.88 (0.78, 0.99)

Hospitalization, MDD-related, %e

4.0

4.4

.256

0.96 (0.80, 1.16)

Number of hospitalization days (mean, SD)f

1.0 (5.1)

1.5 (7.3)

.003d

0.72 (0.60, 0.85)

Outcomesa Discontinuation, %

Healthcare utilization

Emergency department visit for any reason, %e

19.8

23.0

<.001d

0.83 (0.76, 0.91)

Emergency department visit, MDD-related, %e

1.2

1.9

.003d

0.60 (0.45, 0.80)

0.3 (1.1)

0.4 (1.3) <.001d

0.81 (0.74, 0.88)

Number of emergency department visits, any reason (mean, SD)f a

All outcomes were observed during the 6-month study period. All ratios were adjusted for the baseline characteristics. HR was used for comparison; adjustment based on Cox proportional hazard model. d P <.05 based on Wilcoxon tests for continuous variables and chi-square tests for categorical variables. e OR was used for comparison; adjustment based on logistic regression. f IRR was used for comparison; adjustment based on negative binomial model. b c

CI indicates confidence interval; HR, hazard ratio; IRR, incidence rate ratio; MDD, major depressive disorder; OR, odds ratio; SD, standard deviation.

to another second-generation antidepressant was also lower in the escitalopram group (24.7% vs 29.3%; P <.001). After controlling for differences in baseline characteristics, results of the unadjusted analysis were confirmed for escitalopram by hazard ratio of 0.94 for overall discontinuation (P = .006) and 0.83 for discontinuation and switching to another second-generation antidepressant (P <.001).

Healthcare Resource Utilization Among patients in the escitalopram group, 11.6% experienced a hospitalization during the study period compared with 13.6% in the citalopram group (P = .001; Table 2). The rates of MDD-related hospitalizations were not significantly different between the 2 groups (4.0% vs 4.4%; P = .256). The escitalopram group also had shorter inpatient stays during the same period (1.0 vs 1.5 hospitalization days; P = .001). Results of the multivariate analysis were consistent with findings from the unadjusted analysis. Patients in the escitalopram group were less likely to be hospitalized (odds ratio [OR] 0.88; P = .036). In other words, the odds of patients in the escitalopram group being

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hospitalized was 12% lower than for patients in the citalopram group, and patients in the escitalopram group had 28% fewer hospitalization days than patients in the citalopram group (P = .001). The rates of MDDrelated hospitalizations were not significantly different between the 2 groups. Similarly, there was a smaller proportion of patients with emergency department visits for any reason in the escitalopram group during the study period (19.8% vs 23.0%; P <.001; Table 2). Patients receiving escitalopram were also less likely to have an MDD-related emergency department visit (1.2% vs 1.9%; P = .001). These results remained significant after adjustment for baseline characteristics, both for emergency department visits for any reason (OR 0.83; P <.001) and for MDD-related emergency department visits (OR 0.60; P = .001). On average, patients in the escitalopram group had 0.3 emergency department visits, whereas those in the citalopram group had 0.4 visits during the study period (P <.001). Results from the negative binomial model showed that patients in the escitalopram group had 19.0% fewer emergency department visits after controlling for differences in baseline characteristics (P <.001).

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Table 3 Six-Month Healthcare Costs, by Index Therapy with Escitalopram or Citalopram

6-month healthcare costs

Escitalopram (N = 10,465) [A]

Citalopram (N = 4212) [B]

Difference [A] – [B]

Pb [A] vs [B]

Prescription drug (mean, SD) Total prescription drug cost, $c

1142

(1715)

1259

(1955)

–117

<.001

Total antidepressant cost, $

326

(217)

366

(240)

–40

<.001

1885

(2529)

2050

(2735)

–165

.001

472

(908)

509

(1041)

–37

.224

1127

(7589)

1686

(10,474)

–558

<.001

174

(1903)

208

(1669)

–34

.023

786

(2910)

1059

(8751)

–273

<.001

(290)

(273)

–4

<.001

106

(495)

126

(493)

–19

<.001

(62)

(58)

–2

.001

4410

(12,247)

5752

(18,704)

–1342

<.001

680

(2264)

758

(2282)

–77

.014

5551

(12,772)

7010

(19,199)

–1459

<.001

1006

(2297)

1124

(2326)

–117

<.001

Medical service (mean, SD)d Professional service Professional service, MDD-related Inpatient visit Inpatient visit, MDD-related Outpatient visit Outpatient visit, MDD-related Emergency department visit Emergency department visit, MDD-related Total medical service cost, $ Total medical service cost, MDD-related, $ Total healthcare cost (mean, SD) Total healthcare cost, $ Total healthcare cost, MDD-related, $ a

Costs were measured during the 6-month study period. All numbers are the average cost per person. Adjusted for all baseline characteristics using generalized linear models with log link and gamma distribution. For MDD-related total medical service costs, a 2-part model was used. c Total prescription drug costs included total antidepressant costs and other prescription drug costs; other prescription drug costs were not presented in this table. d Total medical services included professional services, hospitalizations, outpatient visits, emergency department visits, and other medical services; other medical services were not presented in this table. e P <.05 based on Wilcoxon tests for the unadjusted differences and generalized linear model or 2-part model for the adjusted differences. b

MDD indicates major depressive disorder; SD, standard deviation.

Healthcare Costs The average total healthcare cost per patient during the study period was $5551 in the escitalopram group, $1459 less than that in the citalopram group (P <.001; Table 3). Patients in the escitalopram group also had lower costs in every category. Approximately 92% of the difference in total healthcare costs was attributable to reduction in total medical services costs in the escitalopram group (−$1342; P <.001), of which $558 resulted from lower hospitalization costs (P <.001). Significantly lower costs in the escitalopram group were also manifested in outpatient visits (−$273; P <.001) and professional services (−$165; P = .001). Results from multivariate

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analyses indicate that the total healthcare costs were an average of $1174 less in the escitalopram group (P <.001), and that the average total medical services costs and total prescription drug costs were both significantly lower in the escitalopram group (−$972 and −$170, respectively; both P <.001). MDD-related total healthcare costs during the study period were also lower in the escitalopram group. On average, patients in this group incurred $117 less per patient during the study period than those in the citalopram group (P <.001). The majority of the difference resulted from reduction in MDD-related total medical services costs (−$77; P = .014), and the rest of

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Healthcare Resource Utilization and Costs in MDD

Discussion In this present retrospective study, a large administrative claims database was used to compare treatment persistence, healthcare utilization, and costs for patients treated with escitalopram compared with patients treated with citalopram in a real-world setting. Although patients taking citalopram and escitalopram had different baseline comorbidity profiles, these differences were controlled for in this study with the multivariable regression analysis described above. Results indicate that although a majority of patients in both treatment groups discontinued treatment within 6 months after the index date, patients treated with escitalopram had better treatment persistence as measured by overall discontinuation rate, as well as rate of discontinuation with switching to another second-generation antidepressant. These results are consistent with those in a recent clinical trial, which also showed a lower withdrawal rate in the escitalopram group compared with the citalopram group.14 More than one third of the difference in total healthcare costs was attributable to lower hospitalization costs in the escitalopram group. The results were consistent using both unadjusted analysis and multivariate analysis and were supported by the sensitivity analysis, in which it was assumed that all second-generation antidepressants had zero costs in the citalopram group. These results are also consistent with findings from recent claims data analyses conducted in an elderly population with MDD.15 In that study of patients with MDD aged â&#x2030;Ľ65 years, those treated with escitalopram showed significantly better treatment persistence,

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Figure Sensitivity Analysis: Comparing Healthcare Costs per Patient, Escitalopram versus Citalopram Escitalopram Citalopram

7000

P <.001 6649 6229

6000 5000

Costs, $

the difference was attributable to the lower antidepressant costs (â&#x2C6;&#x2019;$40; P <.001). Among MDD-related total medical services costs, hospitalization, outpatient, and emergency department costs were all significantly lower in the escitalopram group. After controlling for differences in baseline characteristics, the adjusted MDD-related total healthcare costs were $109 lower in the escitalopram group (P = .003). The adjusted total antidepressant costs and MDD-related total medical services costs were $39 and $43 lower, respectively, in the escitalopram group (both P â&#x2030;¤.001). Results from the sensitivity analysis showed that, even assuming zero costs for all second-generation antidepressants used by patients in the citalopram group, the average total healthcare costs were still lower in the escitalopram group ($5551 vs $6644; P = .010). After adjustment for baseline characteristics using a GLM model, patients in the escitalopram group still showed an average savings of $420 in total healthcare costs compared with patients in the citalopram group (P <.001; Figure).

4000 3000 2000

P <.001 1307 1010

1000 0

Total drug costs during study period

Total healthcare costs during study period

Note: All costs were adjusted for baseline characteristics using the generalized linear model.

fewer hospitalizations, and lower medical and total healthcare costs than patients treated with citalopram.15 Similar to findings in the current study, most of the cost reduction was attributable to significantly lower hospitalizations and total medical costs.15 Treatment persistence not only contributes to the therapeutic success of MDD treatment but also to the cost-effectiveness of an antidepressant.20 Previous studies have provided some evidence that the lack of persistence is associated with higher total medical costs among patients with depression.21,22 Lack of persistence could prolong the disease episode and lead to a higher rate of recurrent events. Therefore, improved persistence will likely save the long-term cost of treating MDD. Furthermore, better persistence in patients with MDD and better outcomes may reduce the healthcare resource utilization and costs associated with comorbidities beyond depression itself. In this present analysis, a substantial portion of the difference in healthcare utilization and costs between the escitalopram and citalopram groups was not MDD-related. The cause of these differences cannot be determined from claims data. It may be related to the potential advantage of escitalopram in safety and effectiveness, but the extent of this factor is unknown. The economic benefits of escitalopram over citalopram have been suggested by numerous cost-effectiveness analyses.23-27 Findings in this present study are consistent with such previous analyses. It should be noted

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that persistence, healthcare utilization, and healthcare costs are directly related to the clinical efficacy and the tolerability of a treatment. Thus, clinicians and thirdparty payers should carefully consider the relative benefits of different therapeutic options when making patient care and policy decisions rather than rely solely on drug acquisition costs.

Limitations This present study has several limitations. First, it is subject to the usual limitations associated with claims data as a result of the absence of detailed clinical information. Therefore, there may be selection bias if patients in one treatment group had more severe depression than patients in the second group. Such difference may have affected treatment persistence and healthcare utilization during the study period. However, to minimize selection bias, this study only included patients who were not treated with any other second-generation antidepressant during the baseline period, and every effort was made to control for differences in observed baseline characteristics. Second, discontinuation was measured by prescription refills in the pharmacy claims database instead of the actual use of the medications. Although not the most accurate measurement of treatment persistence, pharmacy data have been extensively used in other studies of treatment persistence.28-30 To the extent that the measurement error was not systematically different between the 2 treatment groups, the results regarding treatment persistence in this study can be considered valid. Drug sampling bias could be another limitationâ&#x20AC;&#x201D; because additional drug samples provided free of charge by the physicians cannot be observed in the claims data but they may influence the persistence measure. However, the direction of the bias is unclear. In addition, the claims database used did not report any information related to patient copayment for medications; such information was therefore not available for this analysis. Finally, the study focuses on relatively short-term benefits of treatment with escitalopram versus treatment with citalopram, and thus does not provide empirical evidence on long-term benefits. Future research is warranted to consider long-term and indirect effects of these therapies on work productivity and disability. Conclusion Adding to previous literature, this study shows that the clinical and economic benefits of escitalopram are not only observed in clinical trials, but also manifested in the real-world setting. In this present study, compared with citalopram, escitalopram was associated with higher treatment persistence and lower MDD-related and over-

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all healthcare utilization and costs among adult patients with MDD. Funding Source This study was funded by Forest Laboratories, Inc. Author Disclosure Statement Mr Greenberg, Ms Ben-Hamadi, Dr Eric Wu, Dr Yang, and Dr Andrew Yu are consultants to Forest Laboratories. Dr Erder was employed by Forest Laboratories at the time of the study.

References 1. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289:3095-3105. 2. Bloom BS. Prevalence and economic effects of depression. Manag Care. 2004;13(6 suppl):9-16. 3. Ostacher MJ. Comorbid alcohol and substance abuse dependence in depression: impact on the outcome of antidepressant treatment. Psychiatr Clin North Am. 2007;30:69-76. 4. Croom KF, Plosker GL. Spotlight on the pharmacoeconomics of escitalopram in depression. CNS Drugs. 2004;18:469-473. 5. Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003;64:1465-1475. 6. Weilburg JB. An overview of SSRI and SNRI therapies for depression. Manag Care. 2004;13:25-33. 7. Fantino B, Moore N, Verdoux H, Auray JP. Cost-effectiveness of escitalopram vs. citalopram in major depressive disorder. Int Clin Psychopharmacol. 2007;22:107-115. 8. Esposito D, Wahl P, Daniel G, et al. Results of a retrospective claims database analysis of differences in antidepressant treatment persistence associated with escitalopram and other selective serotonin reuptake inhibitors in the United States. Clin Ther. 2009;31:644-656. 9. Wu EQ, Greenberg PE, Yang E, et al. Treatment persistence, healthcare utilisation and costs in adult patients with major depressive disorder: a comparison between escitalopram and other SSRI/SNRIs. J Med Econ. 2009;12:124-135. 10. Burke WJ, Gergel I, Bose A. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry. 2002;63:331-336. 11. Lepola UM, Loft H, Reines EH. Escitalopram (10-20 mg/day) is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol. 2003;18:211-217. 12. Rapaport MH, Bose A, Zheng H. Escitalopram continuation treatment prevents relapse of depressive episodes. J Clin Psychiatry. 2004;65:44-49. 13. Wade A, Despiegel N, Heldbo Reines E. Escitalopram in the long-term treatment of major depressive disorder. Ann Clin Psychiatry. 2006;18:83-89. 14. Moore N, Verdoux H, Fantino B. Prospective, multicentre, randomized, doubleblind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder. Int Clin Psychopharmacol. 2005;20:131-137. 15. Wu E, Greenberg PE, Yang E, et al. Comparison of escitalopram versus citalopram for the treatment of major depressive disorder in a geriatric population. Curr Med Res Opin. 2008;24:2587-2595. 16. Antidepressant medication management. The state of health care quality 2006. National Committee for Quality Assurance; Washington, DC; 2006. www.ncqa.org/ Portals/0/Publications/Resource%20Library/SOHC/SOHC_2006.pdf. Accessed February 28, 2011. 17. McCombs JS, Luo M, Johnstone BM, Shi L. The use of conventional antipsychotic medications for patients with schizophrenia in a Medicaid population: therapeutic and cost outcomes over 2 years. Value Health. 2000;3:222-231. 18. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45:613-619. 19. Birnbaum HG, Ben-Hamadi R, Greenberg PE, et al. Determinant of direct cost differences among US employees with major depressive disorders using antidepressants. Pharmacoeconomics. 2009;27:507-517. 20. Patient compliance in depression. Based on a presentation by James Jefferson, MD. Am J Manag Care. 2000;6(2 suppl):S31-S38. 21. Revicki DA, Simon GE, Chan K, et al. Depression, health-related quality of life, and medical cost outcomes of receiving recommended levels of antidepressant treatment. J Fam Pract. 1998;47:446-452. 22. Thompson D, Buesching D, Gregor KJ, Oster G. Patterns of antidepressant use and their relation to costs of care. Am J Manag Care. 1996;2:1239-1246. 23. Demyttenaere K, Hemels ME, Hudry J, Annemans L. A cost-effectiveness model of escitalopram, citalopram,and venlafaxine as first-line treatment for major depres-

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sive disorder in Belgium. Clin Ther. 2005;27:111-124. 24. Hemels ME, Kasper S, Walter E, Einarson TR. Cost-effectiveness of escitalopram versus citalopram in the treatment of severe depression. Ann Pharmacother. 2004;38: 954-960. 25. Sullivan PW, Valuck R, Saseen J, MacFall HM. A comparison of the direct costs and cost effectiveness of serotonin reuptake inhibitors and associated adverse drug reactions. CNS Drugs. 2004;18:911-932. 26. Wade AG, Toumi I, Hemels ME. A probabilistic cost-effectiveness analysis of escitalopram, generic citalopram and venlafaxine as a first-line treatment of major depressive disorder in the UK. Curr Med Res Opin. 2005;21:631-642. 27. Wade AG, Toumi I, Hemels ME. A pharmacoeconomic evaluation of escitalo-

pram versus citalopram in the treatment of severe depression in the United Kingdom. Clin Ther. 2005;27:486-496. 28. Hess LM, Raebel MA, Conner DA, Malone DC. Measurement of adherence in pharmacy administrative databases: a proposal for standard definitions and preferred measures. Ann Pharmacother. 2006;40:1280-1288. 29. Turner BJ, Newschaffer CJ, Zhang D, et al. Antiretroviral use and pharmacybased measurement of adherence in postpartum HIV-infected women. Med Care. 2000;38:911-925. 30. Wilensky J, Fiscella RG, Carlson AM, et al. Measurement of persistence and adherence to regimens of IOP-lowering glaucoma medications using pharmacy claims data. Am J Ophthalmol. 2006;141(1 suppl):S28-S33.

STAKEHOLDER PERSPECTIVE Efficacy and Cost-Effectiveness: Escitalopram versus Citalopram MEDICAL/PHARMACY DIRECTORS: Despite the availability of several generic options, antidepressants remain in the top 5 therapeutic drug classes in terms of spending. Currently, 2 brand-name agents maintain substantial market shareâ&#x20AC;&#x201D;escitalopram and duloxetine. Claims data collected from January 1, 2003, to June 30, 2005, were analyzed as part of this study. During that time, few payers required step therapy with a generic antidepressant, but many payers have since implemented step therapy for antidepressants. However, few payers require the use of citalopram specifically before escitalopram. With so many antidepressants available, a stepwise approach using escitalopram after failure of citalopram may not make sense, because of their molecular similarity. The scope of the present study is a little narrow with regard to how many plans manage the entire class of antidepressants. Although the study results are very interesting, questions remain, such as what doses of citalopram and escitalopram were used; what was the effect of promotion/sampling; what was the difference in patient responsibility (ie, copay/coinsurance); and why was the drug cost higher in the citalopram group? In a very recent study, researchers evaluated persistence of brand and generic antidepressants, concluding that the likelihood of discontinuing therapy was similar for patients who initiated therapy with brand or with generic antidepressants.1 They also noted that shortterm pharmacy and healthcare costs were lower in patients starting generic therapy.1 And a 2009 meta-analysis comparing the efficacy and acceptability of 12 new-generation antidepressants showed that escitalopram and sertraline have the best profile of acceptability, leading to fewer discontinuations compared with other antidepressants.2 Further

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analysis suggested that sertraline might be the best choice when starting treatment, because of the favorable balance between benefits, acceptability, and acquisition cost.2 Generic availability of escitalopram and duloxetine are expected within the next 18 months. Therefore, the discussion of restrictions specific to escitalopram may soon be a moot point. However, with new and future antidepressants becoming available, such as the recently approved vilazodone, and the expense of atypical antipsychotics for the treatment of depression, utilization management techniques will continue to be a topic of interest. Overall healthcare costs and drug acquisition costs will continue to be evaluated to determine coverage requirements. PATIENTS: As this present study shows, discontinuation of antidepressant therapy within 6 months is very high. Additional studies have demonstrated poor adherence with other antidepressants as well. The choice of an antidepressant should be individualized to the patient based on past therapy, published clinical data, adverse event profiles, and overall cost-effectiveness of the therapy. Regardless of the therapy chosen, patient education is key. Understanding the length of therapy required to see an effect and expected minimum duration of therapy, and knowing potential side effects, will likely increase adherence. 1. Vlahiotis A, Devine ST, Eichholz J, Kautzner A. Discontinuation rates and health care costs in adult patients starting generic versus brand SSRI or SNRI antidepressants in commercial health plans. J Manag Care Pharm. 2011;17:123-132. 2. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746-758.

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Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT

American Health & Drug Benefits

INDICATION EXALGO® tablets are an extended release oral formulation of the opioid agonist hydromorphone hydrochloride that is indicated for once daily administration for the management of moderate to severe pain in opioid p tolerant patients requiring continuous, around-the-clock opioid analgesia for an extended period of time. IMPORTANT RISK INFORMATION WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE Potential for Abuse EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Proper p Patient Selection EXALGO is an extended-release formulation of hydromorphone hydrochloride indicated for the management of moderate to severe pain in opioid tolerant patients when a continuous around-the-clock opioid analgesic is needed for an extended period of time. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/ hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day or an equianalgesic dose of another opioid, for a week or longer. EXALGO is for use in opioid tolerant patients only. Fatal respiratory depression could occur in patients who are not opioid tolerant. Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone. Limitations of Use EXALGO is not indicated for the management of acute or postoperative pain. EXALGO is not intended for use as an as-needed analgesic. EXALGO tablets are to be swallowed whole and are not to be broken, chewed, dissolved, crushed or injected. Taking broken, chewed, dissolved or crushed EXALGO or its contents leads to rapid release and absorption of a potentially fatal dose of hydromorphone. • EXALGO is also contraindicated in patients who: - need management of mild pain or pain not expected to persist - have significant impaired respiratory function including those with acute or severe bronchial asthma or hypercarbia. - have or are suspected to have paralytic ileus - have narrowed or obstructed gastrointestinal tract including those from previous surgery or “blind loops” in the GI tract - have known hypersensitivity to any components including hydromorphone hydrochloride and sulfites. • Avoid concurrent use of alcohol and EXALGO. Concurrent use of EXALGO with CNS depressants, including alcohol, increases risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death. EXALGO may impair the ability to drive a car or operate machinery. • Not intended in patients who have received MAO inhibitors within 14 days of starting EXALGO. • Use with caution and in reduced doses in older or debilitated patients, as well as patients with renal or hepatic insufficiency, Addison’s disease, delirium tremens, myxedema or hypothyroidism, prosthetic hypertrophy or urethral stricture, toxic psychosis. May aggravate convulsions in patients with convulsive disorders; may induce or aggravate seizures in some clinical settings. Consider use of an alternate analgesic in patients with severe renal impairment. • Respiratory depression, which occurs more frequently in elderly or debilitated patients, is the chief hazard with EXALGO. • Most common adverse events (>10%) seen in clinical studies (N=2474) were: constipation (31%), nausea (28%), vomiting, somnolence, headache, asthenia and dizziness. Serious adverse events could also include head injury, hypotensive effects, GI effects, cardiac arrest from overdose and precipitation of withdrawal. • Use EXALGO with extreme caution in patients susceptible to intracranial effects of CO 2 retention. • Do not abruptly discontinue EXALGO Please see brief summary of Full Prescribing Information, including boxed warning on following pages. COVIDIEN, COVIDIEN with logo and Covidien logo are U.S. and internationally registered trademarks of Covidien AG. EXALGO is a registered trademark of Mallinckrodt Inc. © 2011 Mallinckrodt Inc., a Covidien company. MK20024 January 2011 Printed in USA.

Up. Down. Up. Down. Up. Down. Will the lack of steady blood levels be your chronic pain patients’ downfall?

Once-daily EXALGO® reaches steady-state concentrations in 3 to 4 days, reducing peaks and troughs.1

Plasma Hydromorphone (ng/mL)

Hydromorphone IR 4 mg q6h

EXALGO 16 mg q24h

Hour 6

Hour 12

Hour 18

Hour 24

Day 5 Postdose

• Comparable in bioavailability with immediate-release (IR) hydromorphone given 4 times daily

EXALGO. The power of hydromorphone in a once-daily dose. With 24-hour, extended-release hydromorphone, EXALGO helps minimize peaks and troughs at steady state. So, your patients don’t have to worry as much about when their medication may wear off. To find out more, visit www.keeppainwaiting.com. Reference: 1. EXALGO® Prescribing Information.

BRIEF SUMMARY - Consult full prescribing information before use. EXALGO® (hydromorphone HCl) Extended-Release Tablets WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE Potential for Abuse EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression [see Drug Abuse and Dependence (9)]. Proper Patient Selection EXALGO is an extended-release formulation of hydromorphone hydrochloride indicated for the management of moderate to severe pain in opioid tolerant patients when a continuous around-the-clock opioid analgesic is needed for an extended period of time. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/hour, 30 mg of oral oxycodone/ day, 8 mg oral hydromorphone/day, 25 mg of oral oxymorphone/day or an equianalgesic dose of another opioid, for a week or longer [see Indications and Usage (1) and Dosage and Administration (2)]. EXALGO is for use in opioid tolerant patients only [see Indications and Usage (1) and Dosage and Administration (2)]. Fatal respiratory depression could occur in patients who are not opioid tolerant. Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone [see Warnings and Precautions (5.1)]. Limitations of Use EXALGO is not indicated for the management of acute or postoperative pain [see Indications and Usage (1)]. EXALGO is not intended for use as an as-needed analgesic [see Indications and Usage (1)]. EXALGO tablets are to be swallowed whole and are not to be broken, chewed, dissolved, crushed or injected. Taking broken, chewed, dissolved or crushed EXALGO or its contents leads to rapid release and absorption of a potentially fatal dose of hydromorphone [see Warnings and Precautions (5)]. CONTRAINDICATIONS Opioid Non-Tolerant Patients EXALGO is contraindicated in opioid non-tolerant patients. Fatal respiratory depression could occur in patients who are not opioid tolerant. Impaired Pulmonary Function EXALGO is contraindicated in patients with significant respiratory depression, especially in the absence of resuscitative equipment or in unmonitored settings and in patients with acute or severe bronchial asthma or hypercarbia. Paralytic Ileus EXALGO is contraindicated in patients who have or are suspected of having a paralytic ileus. Preexisting Gastrointestinal (GI) Surgery or Narrowing of GI Tract EXALGO is contraindicated in patients who have had surgical procedures and/or underlying disease that would result in narrowing of the gastrointestinal tract, or have “blind loops” of the gastrointestinal tract or gastrointestinal obstruction. Allergy or Hypersensitivity EXALGO is contraindicated in patients with known hypersensitivity to any of its components including the active agent, hydromorphone hydrochloride or known allergy to sulfite-containing medications [see Warnings and Precautions (5.8)]. WARNINGS AND PRECAUTIONS Information Essential for Safe Administration EXALGO tablets are to be swallowed whole, and are not to be broken, chewed, crushed, dissolved or injected. Taking broken, chewed, crushed, dissolved EXALGO or its contents leads to the rapid release and absorption of a potentially fatal dose of hydromorphone [see Boxed Warning]. EXALGO is for use only in opioid tolerant patients. Ingestion of EXALGO may cause fatal respiratory depression when administered to patients who are not opioid tolerant [see Boxed Warning]. EXALGO tablets must be kept in a secure place out of the reach of children. Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone. Misuse and Abuse EXALGO contains hydromorphone, an opioid agonist, and is a Schedule II controlled substance. Opioid agonists have the potential for being abused and are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing EXALGO in situations where the healthcare professional is concerned about an increased risk of misuse, abuse, or diversion. Breaking, crushing, chewing, or dissolving the contents of an EXALGO tablet results in the uncontrolled delivery of the opioid and poses a significant risk of overdose and death [see Drug Abuse and Dependence (9)]. If attempts are made to extract the drug from the hard outer shell for purposes of parenteral abuse, the injection of tablet excipients may be toxic and may result in lethal complications. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Respiratory Depression Respiratory depression is the chief hazard of EXALGO. Respiratory depression occurs more frequently in elderly or debilitated patients as well as those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation, and when opioids are given in conjunction with other agents that depress respiration. Use EXALGO with extreme caution in patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea, myxedema, kyphoscoliosis or CNS depression. In these patients, even moderate therapeutic doses of hydromorphone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. In these patients, consider alternative non-opioid analgesics, and use EXALGO only under careful medical supervision at the lowest effective dose. Interactions with Alcohol and Other CNS Depressants The concurrent use of EXALGO with other central nervous system (CNS) depressants, including but not limited to other opioids, illicit drugs, sedatives, hypnotics, general anesthetics, phenothiazines, muscle relaxants, other tranquilizers, and alcohol, increases the risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death. Use with caution and in reduced dosages in patients taking CNS depressants. Avoid concurrent use of alcohol and EXALGO [see Clinical Pharmacology (12.3)]. Head Injury and Increased Intracranial Pressure In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the respiratory depressant effects of EXALGO and its potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated. Furthermore, EXALGO can produce effects on pupillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries. Hypotensive Effect EXALGO may cause severe hypotension. There is added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines, general anesthetics, or other agents that compromise vasomotor tone. Administer EXALGO with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. Gastrointestinal Effects Because the EXALGO tablet is nondeformable and does not appreciably change in shape in the GI tract, do not administer EXALGO to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel’s diverticulum). There have been reports of obstructive symptoms in patients with known strictures or risk of strictures, such as previous GI surgery, in association with the ingestion of drugs in nondeformable extended-release formulations. The administration of EXALGO may obscure the diagnosis or clinical course in patients with acute abdominal condition. It is possible that EXALGO tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized. Sulfites EXALGO contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. MAO Inhibitors EXALGO is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Special Risk Groups EXALGO should be administered with caution in elderly (≥ 65 years) and debilitated patients and in patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease [see Use in Specific Populations (8)]. EXALGO should also be used with caution in the following conditions: adrenocortical insufficiency (e.g., Addison’s disease); delirium tremens; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and, toxic psychosis. EXALGO may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings. Use in Pancreatic/Biliary Tract Disease EXALGO can cause an increase in biliary tract pressure as a result of spasm in the sphincter of Oddi. Caution should be exercised in the administration of EXALGO to patients with inflammatory or obstructive bowel disorders, acute pancreatitis secondary to biliary tract disease and in patients about to undergo biliary surgery. Driving and Operating Machinery EXALGO may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Caution patients accordingly. Also warn patients about the potential combined effects of EXALGO with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics, and alcohol [see Drug Interactions (7)]. Precipitation of Withdrawal Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should not be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic, including EXALGO. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. Do not abruptly discontinue EXALGO. Clinical conditions or medicinal products that cause a sudden and significant shortening of gastrointestinal transit time may result in decreased hydromorphone absorption with EXALGO and may potentially lead to withdrawal symptoms in patients with a physical dependence on opioids. ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Respiratory Depression [see Warnings and Precautions (5.3)] • Head Injury and Increased Intracranial Pressure [see Warnings and Precautions (5.5)] • Hypotensive Effect [see Warnings and Precautions (5.6)] • Gastrointestinal Effects [see Warnings and Precautions (5.7)] • Cardiac Arrest [see Overdosage (10)] • Precipitation of Withdrawal [see Warnings and Precautions (5.13)]

Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. EXALGO was administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies. Of these, 423 patients were exposed to EXALGO for greater than 6 months and 141 exposed for greater than one year. The overall incidence of adverse reactions in patients greater than 65 years of age was higher, with a greater than 5% difference in rates for constipation and nausea when compared with younger patients. The overall incidence of adverse reactions in female patients was higher, with a greater than 5% difference in rates for nausea, vomiting, constipation and somnolence when compared with male patients. A 12-week double-blind, placebo-controlled, randomized withdrawal study was conducted in opioid tolerant patients with moderate to severe low back pain [see Clinical Studies (14)]. A total of 447 patients were enrolled into the open-label titration phase with 268 patients randomized into the double-blind treatment phase. The adverse reactions that were reported in at least 2% of the patients are contained in Table 1. Table 1. Number (%) of Patients with Adverse Reactions Reported in ≥2% of Patients with Moderate to Severe Low Back Pain During the Open-Label Titration Phase or Double-Blind Treatment Phase by Preferred Term Open-Label Double-Blind Treatment Phase Preferred Term Titration Phase EXALGO (N=447) EXALGO (N=134) Placebo (N=134) 69 (15) 10 (7) 5 (4) Constipation 53 (12) 12 (9) 10 (7) Nausea Somnolence 39 (9) 1 (1) 0 (0) Headache 35 (8) 7 (5) 10 (7) Vomiting 29 (6) 8 (6) 6 (4) 13 (10) 16 (12) Drug Withdrawal Syndrome 22 (5) Pruritus 21 (5) 1 (1) 0 (0) Dizziness 17 (4) 3 (2) 2 (1) Asthenia a 16 (4) 2 (1) 6 (4) 13 (3) 7 (5) 5 (4) Insomnia 13 (3) 5 (4) 9 (7) Diarrhea Back Pain 13 (3) 6 (4) 8 (6) Dry Mouth 13 (3) 2 (1) 0 (0) Edema Peripheral 13 (3) 3 (2) 1 (1) 13 (3) 2 (1) 2 (1) Hyperhidrosis Anorexia b 10 (2) 2 (1) 0 (0) 9 (2) 8 (6) 3 (2) Arthralgia Anxiety 9 (2) 0 (0) 4 (3) Abdominal Pain c 9 (2) 4 (3) 3 (2) Muscle Spasms 5 (1) 3 (2) 1 (1) Weight Decreased 3 (1) 4 (3) 3 (2) a b c

Fatigue was grouped and reported with asthenia Decreased appetite was grouped and reported with anorexia Abdominal pain upper was grouped and reported with abdominal pain

The adverse reactions that were reported in at least 2% of the total treated patients (N=2,474) in the 14 chronic clinical trials are contained in Table 2. Table 2. Number (%) of Patients with Adverse Reactions Reported in ≥2% of Patients with Chronic Pain Receiving EXALGO in 14 Clinical Studies by Preferred Term Preferred Term All Patients (N=2,474) Constipation 765 (31) Nausea 684 (28) Vomiting 337 (14) Somnolence 367 (15) Headache 308 (12) Asthenia a 272 (11) Dizziness 262 (11) Diarrhea 201 (8) Pruritus 193 (8) Insomnia 161 (7) Hyperhidrosis 143 (6) Edema Peripheral 135 (5) 139 (6) Anorexia b Dry Mouth 121 (5) 115 (5) Abdominal Pain c Anxiety 95 (4) Back Pain 95 (4) d Dyspepsia 88 (4) Depression 81 (3) 76 (3) Dyspnea e Muscle Spasms 74 (3) Arthralgia 72 (3) Rash 64 (3) Pain in Extremity 63 (3) Pain 58 (2) Drug Withdrawal Syndrome 55 (2) Pyrexia 52 (2) Fall 51 (2) 51 (2) Chest Discomfort f a b c d e f

Fatigue was grouped and reported with asthenia Decreased appetite was grouped and reported with anorexia Abdominal pain upper was grouped and reported with abdominal pain Reflux esophagitis, gastroesophageal reflux disease and Barrett’s esophagus were grouped and reported with dyspepsia Dyspnea exacerbated and dyspnea exertional were grouped and reported with dyspnea Chest pain and non-cardiac chest pain were grouped and reported with chest discomfort

The following Adverse Reactions occurred in patients with an overall frequency of <2% and are listed in descending order within each System Organ Class: Cardiac disorders: palpitations, tachycardia, bradycardia, extrasystoles Ear and labyrinth disorders: vertigo, tinnitus Endocrine disorders: hypogonadism Eye disorders: vision blurred, diplopia, dry eye, miosis Gastrointestinal disorders: flatulence, dysphagia, hematochezia, abdominal distension, hemorrhoids, abnormal feces, intestinal obstruction, eructation, diverticulum, gastrointestinal motility disorder, large intestine perforation, anal fissure, bezoar, duodenitis, ileus, impaired gastric emptying, painful defecation General disorders and administration site conditions: chills, malaise, feeling abnormal, feeling hot and cold, feeling jittery, hangover, difficulty in walking, feeling drunk, hypothermia Infections and infestations: gastroenteritis, diverticulitis Injury, poisoning and procedural complications: contusion, overdose Investigations: weight decreased, hepatic enzyme increased, blood potassium decreased, blood amylase increased, blood testosterone decreased, oxygen saturation decreased Metabolism and nutrition disorders: dehydration, fluid retention, increased appetite, hyperuricemia Musculoskeletal and connective tissue disorders: myalgia Nervous system disorders: tremor, sedation, hypoesthesia, paraesthesia, disturbance in attention, memory impairment, dysarthria, syncope, balance disorder, dysgeusia, depressed level of consciousness, coordination abnormal, hyperesthesia, myoclonus, dyskinesia, hyperreflexia, encephalopathy, cognitive disorder, convulsion, psychomotor hyperactivity Psychiatric disorders: confusional state, nervousness, restlessness, abnormal dreams, mood altered, hallucination, panic attack, euphoric mood, paranoia, dysphoria, listless, crying, suicide ideation, libido decreased, aggression Renal and urinary disorders: dysuria, urinary retention, urinary frequency, urinary hesitation, micturition disorder Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction Respiratory, thoracic and mediastinal disorders: rhinorrhoea, respiratory distress, hypoxia, bronchospasm, sneezing, hyperventilation, respiratory depression Skin and subcutaneous tissue disorders: erythema Vascular disorders: flushing, hypertension, hypotension DRUG INTERACTIONS CNS Depressants The concomitant use of EXALGO with central nervous system depressants such as hypnotics, sedatives, general anesthetics, antipsychotics and alcohol may cause additive depressant effects and respiratory depression. Additionally, hypotension and profound sedation or coma could occur. When this combination is indicated, the dose of one or both agents should be reduced. The concomitant use of alcohol should be avoided [see Clinical Pharmacology (12.3)]. Monoamine Oxidase (MAO) Inhibitors MAO inhibitors may cause CNS excitation or depression, hypotension or hypertension if co-administered with opioids including EXALGO. EXALGO is not intended for patients taking MAO inhibitors or within 14 days of stopping such treatment. Mixed Agonist/Antagonist Opioid Analgesics The concomitant use of EXALGO with morphine agonist/antagonists (buprenorphone, nalbuphine, pentazocine) could lead to a reduction of the analgesic effect by competitive blocking of receptors, thus leading to risk of withdrawal symptoms. Therefore, this combination is not recommended. Anticholinergics Anticholinergics or other medications with anticholinergic activity when used concurrently with EXALGO may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Cytochrome P450 Enzymes In vitro data suggest that hydromorphone in clinically relevant concentrations has minimal potential to inhibit the activity of human hepatic CYP450 enzymes including CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A11. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Hydromorphone crosses the placenta. EXALGO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.2)]. Hydromorphone was not teratogenic in pregnant rats given oral doses up to 6.25 mg/kg/day or in pregnant rabbits administered oral doses up to 25 mg/kg/day during the period of organogenesis (~1.2 times the human exposure following 32 mg/day). Hydromorphone administration to pregnant Syrian hamsters and CF-1 mice during major organ development revealed teratogenicity likely the result of maternal toxicity associated with sedation and hypoxia. In Syrian hamsters given single subcutaneous doses from 14 to 258 mg/kg during organogenesis (gestation days 8 to 10), doses ≥ 19 mg/kg hydromorphone produced skull malformations (exencephaly and cranioschisis). Continuous infusion of hydromorphone (5 mg/kg, s.c.) via implanted osmotic mini pumps during organogenesis (gestation days 7 to 10) produced soft tissue malformations (cryptorchidism, cleft palate, malformed ventricals and retina), and skeletal variations (supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites). The malformations and variations observed in the hamsters and mice were at doses approximately three-fold higher and <one-fold lower, respectively, than a 32 mg human daily oral dose on a body surface area basis. Nonteratogenic Effects In the pre- and post-natal effects study in rats, neonatal viability was reduced at 6.25 mg/kg/day (~1.2 times the human exposure following 32 mg/day). Neonates born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal. Approaches to the treatment of the syndrome have included supportive care and, if indicated, drugs such as paregoric or phenobarbital.

Labor and Delivery EXALGO is not recommended for use in women during and immediately prior to labor and delivery. Administration of EXALGO to the mother shortly before delivery may result in some degree of respiratory depression in the neonate. However, neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression. Nursing Mothers Low concentrations of hydromorphone have been detected in human milk in clinical trials. Withdrawal symptoms can occur in breastfeeding infants when maternal administration of an opioid analgesic is stopped. Nursing should not be undertaken while a patient is receiving EXALGO since hydromorphone is excreted in the milk. Pediatric Use The safety and effectiveness of EXALGO in pediatric patients 17 years of age and younger have not been established. Geriatric Use Elderly patients have been shown to be more sensitive to the adverse effects of EXALGO compared to the younger population. Therefore, use extra caution when prescribing EXALGO in elderly patients and reduce the initial dose. Neonatal Withdrawal Syndrome Chronic maternal use of opiates or opioids during pregnancy coexposes the fetus. The newborn may experience subsequent neonatal withdrawal syndrome (NWS). Manifestations of NWS include irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight loss, and failure to gain weight. The onset, duration, and severity of the disorder differ based on such factors as the addictive drug used, time and amount of mother’s last dose, and rate of elimination of the drug from the newborn. Approaches to the treatment of this syndrome have included supportive care and, when indicated, drugs such as paregoric or phenobarbital. Hepatic Impairment In a study that used a single 4 mg oral dose of immediate-release hydromorphone tablets, four-fold increases in plasma levels of hydromorphone (Cmax and AUC0-|) were observed in patients with moderate hepatic impairment (Child-Pugh Group B). Start patients with moderate hepatic impairment on a reduced dose and closely monitored during dose titration. The pharmacokinetics of hydromorphone in severe hepatic impairment patients have not been studied. Further increase in Cmax and AUC0-| of hydromorphone in this group is expected, therefore, use an even more conservative starting dose [see Dosage and Administration (2.4)]. Renal Impairment Renal impairment affected the pharmacokinetics of hydromorphone and its metabolites following administration of a single 4 mg dose of immediate-release tablets. The effects of renal impairment on hydromorphone pharmacokinetics were two-fold and four-fold increases in plasma levels of hydromorphone (Cmax and AUC0-48h) in moderate (CLcr = 40 to 60 mL/min) and severe (CLcr < 30 mL/min) impairment, respectively. In addition, in patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with longer terminal elimination half-life (40 hours) compared to subjects with normal renal function (15 hours). Start patients with moderate renal impairment on a reduced dose and closely monitored during dose titration. As EXALGO is only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment [see Dosage and Administration (2.4)]. DRUG ABUSE AND DEPENDENCE Controlled Substance EXALGO contains hydromorphone, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. EXALGO can be abused and is subject to misuse, abuse, addiction, and criminal diversion [see Warnings and Precautions (5.2)]. The high drug content in the extended release formulation adds to the risk of adverse outcomes from abuse. Abuse All patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. “Drug-seeking” behavior is very common to addicts and drug abusers. Drugseeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers, people suffering from untreated addiction and criminals seeking drugs to sell. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since EXALGO may be diverted for non-medical use, careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. EXALGO is intended for oral use only. Misuse or abuse by breaking, crushing, chewing, or dissolving EXALGO poses a hazard of overdose and death. This risk is increased with concurrent abuse of EXALGO with alcohol and other substances. With intravenous abuse, the tablet excipients, especially polyethylene oxide, can be expected to result in necrosis and inflammation of cardiac tissues. In addition, parenteral drug abuse is commonly associated with transmission of infectious disease such as hepatitis and HIV. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Dependence Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

Tolerance could occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1, 8.2)]. OVERDOSAGE Symptoms Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia, hypotension and death. The extended release characteristics of EXALGO should also be taken into account when treating the overdose. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects. Deaths due to overdose could occur with abuse and misuse of EXALGO. Due to the delayed mean apparent peak plasma level of EXALGO occurring at 16 hours following administration as well as the 11 hour mean elimination half-life of EXALGO, patients who receive an overdose will require an extended period of monitoring and treatment that may go beyond 24 to 48 hours. Treatment Give primary attention to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Employ supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. The pure opioid antagonists, such as naloxone and naltrexone are specific antidotes to respiratory depression from opioid overdose. Since the duration of reversal would be expected to be less than the duration of action of hydromorphone in EXALGO, the patient must be carefully monitored until spontaneous respiration is reliably re-established. EXALGO will continue to release and add to the hydromorphone load for up to 24 hours after administration and the management of an overdose should be monitored accordingly, at least 24 to 48 hours beyond the overdose. Only administer opioid antagonists in the presence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose. In patients who are physically dependent on any opioid agonist including EXALGO, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use. OROS is a registered trademark of ALZA Corporation. EXALGO is a registered trademark of Mallinckrodt Inc. COVIDIEN, COVIDIEN with logo and Covidien logo are U.S. and/or internationally registered trademarks of Covidien AG. © 2010 Mallinckrodt Inc., a Covidien company Distributed by: Mallinckrodt Brand Pharmaceuticals, Inc. Hazelwood, MO 63042 USA Issued 11/2010

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CALL FOR PAPERS American Health & Drug Benefits offers an open forum for all healthcare participants to exchange ideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Evaluators, Manufacturers, Patients, Payers, Providers, Purchasers, Regulators, and Researchers. Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being, the health of communities and patient populations, as well as other topics relevant to benefit design with specific implications to policymakers, payers, and employers.

Areas of High Interest Include: • Health Economics Research • Health Plan Initiatives • Health Information Technology • Industry Trends • Innovations in Healthcare • Literature Reviews • Medicare/Medicaid

• Adherence Concerns • Benefit Design • Case Studies • Comparative Effectiveness Research • Cost Analyses • Decision-Making Tools • Ethics in Medicine

• Patient Advocacy/Patient Care • Pharmacoeconomics • Policy Issues • Prevention Initiatives • Reimbursement Strategies • Survey Results • Wellness Programs

NOTE TO AUTHORS: AHDB is a member of the Committee on Publication Ethics (COPE). Membership in COPE indicates that this journal upholds COPE’s Code of Conduct standards and intends to take appropriate action in cases of possible misconduct, such as plagiarism, attempted or actual redundant publication, any attempts to pass off fraudulent data, unethical research, or breaches of confidentiality.

Clinical Topics of Interest Include: AGING/DEMENTIA—With the aging of the US population there is a growing need for early implementation of outcomebased preventive and therapeutic strategies for older people. ALLERGIES—Allergies, such as allergic or seasonal rhinitis, affect millions of Americans daily, resulting in a significant economic burden and human cost. Undertreatment and lack of adherence are common obstacles to patient management. ARTHRITIS—Musculoskeletal conditions are on the increase, yet many patients are undiagnosed and untreated. Comparing new and available therapies is a key target for improving patient outcomes and reducing costs. CANCER CARE—The growing focus on biologic agents dictates an enhanced study of these therapeutic options, including reimbursement policies and cost management. CARDIOVASCULAR DISEASE—Original, outcomesbased research on appropriate therapies, cost comparisons, emerging prevention strategies, and comparative effectiveness of best practices will enhance readers’ decision-making.

DIABETES, OBESITY—The increasing comorbid epidemics of these twin conditions mandates a thorough examination of best therapies, adherence issues, access, and prevention strategies. We invite articles that will address how to improve patient outcomes and best patient care. GASTROINTESTINAL CONDITIONS—Recognizing GI conditions, such as hepatitis C, Crohn’s disease, or inflammatory bowel disorder, remains a challenge. INFECTIOUS DISEASES—The spread of common and emerging pathogens within the hospital and in the community remains a major concern requiring increased vigilance. MENTAL DISORDERS—Depression and bipolar disorder and schizophrenia exert a huge financial and human burden on individuals, employers, and payers. Topics of interest include comparative effectiveness analyses, best practices, and reimbursement.

PAIN MANAGEMENT—Chronic pain is associated with a slew of complicated medical disorders and an enormous economic burden, yet pain medications are still underused.

Manuscripts should follow the Manuscript Instructions for Authors (available at www.AHDBonline.com). For more information, call 732-992-1892

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ORIGINAL RESEARCH

Recent Trends in the Dispensing of 90-Day-Supply Prescriptions at Retail Pharmacies: Implications for Improved Convenience and Access Joshua N. Liberman, PhD; Charmaine Girdish, MPH Background: Mail-service pharmacies offer consumers the convenience of prescriptions filled with a 90-day supply of medication. Unlike mail-service pharmacies, retail pharmacies traditionally dispensed maintenance medication prescriptions with a 30-day supply. However, the retail landscape changed in May 2008 with Walmartâ&#x20AC;&#x2122;s announcement of an extension of its $4 Prescription Program to include 90-day-supply prescriptions. Objective: To evaluate recent changes in access to and use of 90-day-supply maintenance medications dispensed via retail pharmacy. Summary: As of the first quarter of 2007, the proportion of retail-dispensed maintenance medications with a 90-day supply (compared with all maintenance prescriptions dispensed) among Medicare Part D plans, self-insured employers, and private health plans was 5.1%, 5.1%, and 5.0%, respectively. As of December 2009, this ratio had risen to 8.0% for Medicare plans and 8.1% for commercial health plans; the ratio among employers had risen more modestly to 6.1%. Of particular interest and importance, the proportion increased similarly for brand and for generic medications. Conclusion: There has been substantial growth in 90-day prescriptions dispensed via retail pharmacy, a trend that is likely to continue as more insurance providers adopt compatible benefit designs. It is important to continue monitoring these trends and to identify opportunities to rigorously evaluate their impact on medication adherence and healthcare costs.

early 96% of all employers allow employees and covered beneficiaries to fill medication prescriptions from either retail or mail-service pharmacy.1 In 2009, mail-service pharmacies dispensed approximately 238 million prescriptions, representing 6.6% of the 3.6 billion prescriptions dispensed that year.2 Mailservice pharmacies have enjoyed high levels of consumer satisfaction.3 Mail-service pharmacies offer consumers the convenience of home delivery, online ordering and renewal processes, and prescriptions filled with a 90-day supply of medication. Unlike mail-service pharmacies, retail pharmacies traditionally dispensed maintenance medication prescriptions with a 30-day supply. However, the retail landDr Liberman was Vice President, Strategic Research, CVS Caremark, Hunt Valley, MD, at the time of this research, and Ms Girdish is Senior Analyst, Strategic Research, CVS Caremark, Scottsdale, AZ.

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Joshua N. Liberman

Stakeholder Perspective, page 99

Am Health Drug Benefits. 2011;4(2):95-100. www.AHDBonline.com Disclosures are at end of text

scape changed in May 2008 with Walmartâ&#x20AC;&#x2122;s announcement of an extension of the $4 Prescription Program to include 90-day-supply prescriptions of select maintenance medications for $10.4 Although positioned primarily as a program to lower drug costs for the uninsured for a limited number of chronic medications, the program was available to virtually all consumers. Many retail pharmacy chains followed this lead, instituting similar low-cost, 90-day-supply drug programs. For individuals with a pharmacy insurance benefit, access to a 90-day supply of maintenance medications, either through mail or retail pharmacy, expanded as payers and pharmacy benefits managers (PBMs) began enhancing their retail pharmacy networks and pharmacy benefit designs. As a response to these initiatives, CVS Caremark, Rite Aid Health Solutions, and Walgreens Health Initiatives now offer programs that allow consumers to receive 90-day-supply prescriptions via mail or retail pharmacy. Today, even stand-alone

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grams by consumers. Understanding this trend has important implications for payers and patients.

KEY POINTS ➤

➤

Traditionally, retail pharmacies predominantly dispensed prescription medications for the treatment of chronic disease with a 30-day-supply limit. However, in 2008 Walmart fundamentally changed access to retail pharmacy–dispensed 90-day-supply prescriptions by launching a program to dispense select maintenance medications in 90-day supplies for $10 via its retail pharmacy. This current study measured changes in paid pharmacy claims between January 2007 and December 2009, using 467 million claims purchased at retail pharmacies and adjudicated by CVS Caremark. Results showed that in that 3-year period, the ratio of 90-day prescription dispensing increased from 5.1% to 8.0% and from 5.0% to 8.1% among beneficiaries of select Medicare Part D and commercial health plans, respectively. Recent studies have shown increased medication adherence with expanded drug supply with mailservice pharmacies compared with retail pharmacies. It is therefore reasonable to assume that extended access to medications in retail pharmacy is similarly likely to improve adherence, which may have important implications on overall healthcare costs and utilization. Studies are needed to investigate the impact of 90-day prescription supply at retail pharmacies on medication adherence.

PBMs, such as Express Scripts and Medco Health Solutions, have retail pharmacy networks that accommodate 90-day prescriptions. According to the 2010-2011 Prescription Drug Benefit Cost and Plan Design report, 96.3% of employers offer access to mail-service pharmacy for maintenance medications (routinely dispensed with 90-day supplies) but 58.3% also use retail pharmacies to dispense maintenance supplies of medications.1 The availability of prescriptions with an expandedday supply in retail pharmacies may have important implications for medication adherence. Recent evaluations of mail-service pharmacy have documented improved medication adherence compared with prescriptions dispensed with 30-day supplies via retail pharmacy, in large part because of the availability of extended-day supply dispensed with each prescription.5,6 Yet despite the recent expansion of 90-day prescription drug access at retail pharmacies, little has been documented in peer-reviewed literature about the use of these pro-

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Methods To document recent medication trends, we measured changes in paid pharmacy claims purchased at retail pharmacies and adjudicated by CVS Caremark during the 3-year period from 2007 through 2009. To be eligible, a payer had to fulfill the following criteria: • Provide covered beneficiaries with pharmacy insurance benefits administered by CVS Caremark continuously from January 1, 2007, through December 31, 2009 • Not mandate maintenance medications to be dispensed by a mail-service pharmacy • Have no more than ±15% change in average membership between calendar years 2008 and 2009. During the study period (2007-2009), the use of 90day-supply prescriptions among Medicaid beneficiaries was negligible and thus excluded. Eligible paid pharmacy claims were (1) submitted by a retail pharmacy, (2) designated as a maintenance medication by either MediSpan or First DataBank, and (3) adjudicated and paid during the 3-year study period. In January 2009, CVS Caremark launched Maintenance Choice—a pharmacy benefit design which, in general, provides members with the choice of receiving their 90-day prescriptions through CVS Caremark mailservice pharmacy or at a CVS/pharmacy retail location for the same out-of-pocket (ie, copayment) cost as a mail prescription. Because the CVS Caremark PBM data overrepresents this Maintenance Choice pharmacy benefit, we stratified the results by retail pharmacy— CVS/pharmacy versus all other retail pharmacies. The overall trend in dispensing 90-day prescriptions was tested for statistical significance using the CochranArmitage test for trend, testing the frequency of 90-day– supply prescriptions monthly over the study period. Results In total, we included 467 million claims adjudicated for 27 million members covered by 1115 insurers. Figure 1 (page 97) displays the percent of maintenance prescriptions dispensed with a 90-day supply (thereafter, 90-day ratio) from January 2007 through December 2009. As of the first quarter of 2007, the 90day ratio was 5.1%, 5.1%, and 5.0% for Medicare Part D plans, self-insured employers, and private health plans, respectively. As of December 2009, the 90-day ratio had risen to 8.0% for Medicare and 8.1% for health plans; the ratio among employers had risen more modestly to 6.1%. Among the network of CVS/pharmacy retail stores, the 90-day ratio increased by 13.4 percentage points

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Figure 1 Percent of Maintenance Prescriptions Filled as 90-Day Supply in Retail Pharmacies by Market Segment and Pharmacy Employer CVS/pharmacy Employer other retail Health plan all pharmacies Medicare all pharmacies

19.0

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among employers, with substantial increases subsequent to the launch of Maintenance Choice. Of particular interest, the 90-day ratio increased similarly for brand and generic medications, with the ratio increasing by 3.3 percentage points for brand-name and for generic drugs. Comparable increases were noted for generic drugs that were included on and omitted from the $10/90 generic drug program lists (Figure 2, page 98). The increase in dispensed 90-day prescriptions at retail pharmacies during this period was significant (P <.001).

Discussion The growth in the 90-day ratio reveals a preference by consumers and further supports the growing body of evidence in support of offering consumers access to extended-day supplies of prescriptions at mail and retail pharmacies. Consumers cite high levels of overall satisfaction with retail and mail pharmacy services3,7,8 and value choice in pharmacy and prescription drug access.9 According to recent market research conducted by Walgreens, nearly 4 of 5 patients stated a preference for

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receiving their 90-day prescription at a retail pharmacy rather than by mail.10 Furthermore, in a recent study of consumer pharmacy preference, Liberman and colleagues showed that among commercially insured patients who transitioned from mandatory mail benefit to the Maintenance Choice benefit, 66.3% of those initiating therapy without a recent mail pharmacy prescription and 23.7% of current mail-service pharmacy users selected a retail pharmacy for subsequent 90-day-supply prescriptions.11 This benefit design, however, in general charges the consumer with the same copayment, regardless of the pharmacy channel selected. Not all pharmacy programs apply identical copayments for mail or retail pharmacy dispensed as 90-day prescriptions, and this will likely alter consumer preference and program uptake. The growth in 90-day prescriptions at retail pharmacies has implications for medication adherence. In a recent study of 13,922 patients from the Kaiser Permanente Northern California diabetes registry, Duru and colleagues reported that mail-order pharmacy users

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Figure 2 Percent of Retail Prescriptions Filled as 90-Day Supply by Brand and Generic Status 9.0 $10/90-day-supply generics All maintenance brands Nonâ&#x20AC;&#x201C;$10/90-day-supply generics 8.0

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had better adherence to antiglycemic, antihypertensive, and dyslipidemic medications.6 In a study of oral antidiabetic medication use, Devine and colleagues used propensity scores to match 14,600 cases to 43,800 controls selected from the MarketScan database.5 After adjustment, mail-service pharmacy users realized significantly higher adherence rates. In addition, the improved adherence was associated with lower total and diabetesrelated medical costs over time. Although we are unaware of any research that demonstrates improved adherence with 90-day medication access at retail pharmacy, it is reasonable to assume that access to a 90-day supply of medication, regardless of point of access (retail or mail), would be associated with an improvement in adherence and improved control of many chronic conditions. If so, the recent studies of mail-service pharmacy by Devine and colleagues and Duru and colleagues provide compelling, supporting evidence for that likely improvement in adherence.5,6

Limitations This analysis was limited to prescriptions managed

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through insurance benefits of a major PBM. As such, it is potentially not representative of the consumer behavior related to prescriptions purchased without the use of such insurance (ie, cash purchases) nor those related to some government programs that provide beneficiaries copay assistance (ie, Medicaid). Furthermore, because of the increasing availability of cash-only programs, it is possible that the actual access to, and use of, 90-day prescription supplies are higher than our estimates.

Conclusion Optimizing access to essential medications while managing pharmacy expenditures is a key function of PBMs.12 Benefit managers must weigh the potential value of increased convenience against the potential costs of providing access through different distribution channels. Nonetheless, the growth in 90-day prescriptions at retail pharmacy is likely to continue as more insurance providers adopt compatible benefit designs. Preliminary research indicates the potential benefits to the consumer by providing greater convenience and

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satisfaction, and overall health benefits resulting from improved medication adherence. It is important to continue monitoring these trends and to identify opportunities to rigorously evaluate their impact on healthcare costs and utilization. ■ Author Disclosure Statement Dr Liberman has reported no conflicts of interest. Ms Girdish owns stock in CVS Caremark. CVS Caremark provided support for this study.

References 1. Pharmacy Benefits Management Institute. Prescription Drug Benefit Cost and Plan Design Online Report, 2010-2011 Edition. www.pbmi.com/BenefitDesign.asp. Accessed December 9, 2010. 2. National Association of Chain Drug Stores. Industry facts-at-a-glance. www.nacds. org/wmspage.cfm?parm1=6536#pharmpricing. Accessed September 9, 2010. 3. Birtcher KK, Shepherd MD. Users’ perceptions of mail-service pharmacy. Am

Pharm. 1992;NS31:35-41. 4. Walmart. Walmart launches phase three of $4 Prescription Program. May 5, 2008. http://walmartstores.com/pressroom/news/8248.aspx. Accessed September 9, 2010. 5. Devine S, Vlahiotis A, Sundar H. A comparison of diabetes medication adherence and healthcare costs in patients using mail order pharmacy and retail pharmacy. J Med Econ. 2010;13:203-211. 6. Duru OK, Schmittdiel JA, Dyer WT, et al. Mail-order pharmacy use and adherence to diabetes-related medications. Am J Manag Care. 2010;16:33-40. 7. J.D. Power and Associates. 2009 National Pharmacy Study. www.jdpower.com/ healthcare/articles/2009-National-Pharmacy-Study/. Accessed February 25, 2011. 8. 90-day Rx solution. More health plans implement mandatory mail-order pharmacy programs, yielding greater savings and adherence rates. Drug Benefit News. 2010;11:1-2. www.silverlink.com/assets/pdfs/silverlinknews/dbn030510.pdf. Accessed March 11, 2011. 9. Desselle SP. Determinants of satisfaction with prescription drug plans. Am J Health Syst Pharm. 2001;58:1110-1119. 10. Business Wire. Walgreens to promote 90-day prescriptions at community pharmacies in Minneapolis. August 3, 2010. www.businesswire.com/news/home/ 20100803006228/en/Walgreens-Promote-90-Day-Prescriptions-CommunityPharmacies-Minneapolis. Accessed August 26, 2010. 11. Liberman JN, Wang Y, Hutchins DS, et al. Revealed preference for retail and mail-service pharmacy. J Am Pharm Assoc. 2011;51:50-57. 12. Shrank WH, Porter ME, Jain SH, Choudhry NK. A blueprint for pharmacy benefit managers to increase value. Am J Manag Care. 2009;15:87-93.

STAKEHOLDER PERSPECTIVE When More Is Almost Always Better POLICYMAKERS/PAYERS: The current relationship between mail order versus retail dispensing and 30-day versus 90-day prescriptions seems artificial. That 90-day prescriptions come by mail and 30-day prescriptions come from retail pharmacies is likely to be a side effect of the marketplace and of competition among pharmacy benefit managers (PBMs), insurers, and pharmacies rather than a rational, patient-centered approach to offering prescriptions. An alternative is seen in the Veterans Affairs (VA) Healthcare System, where I practice. At the VA system, the 90-day prescriptions for chronic medications (ie, noncontrolled substances) is the standard, and these typically come by mail, but some patients elect to receive a partial fill at the window during the visit. The 30-day prescriptions that are set to be dispensed at the window but are never picked up are subsequently mailed directly to the patient. This synergy between retail and mail-order prescriptions creates rates of abandonment of prescriptions of almost zero, unlike outside the VA system.1 In the private sector, more options for where to fill a prescription (and thus more competition) would likely lower costs. Each of the players in the equation, however, faces financial risks if costs are lowered.

Pharmacies that fill 90-day prescriptions are likely to receive fewer dispensing fees and lowered foot traffic through their pharmacies. These pharmacies could also, however, increase their market share if patients buy prescriptions at retail pharmacies instead of by mail. The mail-order operations run by PBMs face risks of dropping market share if patients can obtain 90-day prescription fills at retail pharmacies, although centralized mail-order pharmacies can achieve economies of scale and drive generic dispensing, making it difficult for retail pharmacies to compete. Employers are likely to benefit on several levels, from a more satisfied and potentially more adherent (and thus healthier) workforce, to more choice in pharmacy benefits. PATIENTS: From the patient’s perspective, it is difficult to argue against the availability of 90-day supplies of prescriptions at retail pharmacies. The proposition of offering more choices to patients for where and how to fill their prescriptions seems, on the surface, easily justified. As the present article by Dr Liberman and Ms Girdish describes, there is some evidence of greater satisfaction and improved adherence with 90day versus 30-day supplies. Although the evidence is by no means definitive, Continued

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STAKEHOLDER PERSPECTIVE (Continued) the conclusions make intuitive sense—I have yet to meet a patient using ongoing, stable medications in my own practice who complains about having to come back in 3 months for a prescription rather than in 1 month. I do hear, however, patients who complain about having to coordinate receiving their prescriptions from multiple sources, whether they get their generics from low-cost retail pharmacies, their chronic disease medications in the mail, and their acute-need medication for their child (eg, antibiotic) from the pharmacy nearest to their workplace. The availability of 90-day supplies of medications

from retail pharmacies may offer patients the option of receiving their long-term medications at the same location (and from the same pharmacists) where they pick up their short-term medications or over-the-counter products—more choice, better adherence, lower costs. 1. Shrank WH, Choudhry NK, Fischer MA, et al. The epidemiology of prescriptions abandoned at the pharmacy. Ann Intern Med. 2010;153:633-640.

Walid F. Gellad, MD, MPH Staff Physician, VA Pittsburgh Healthcare System Assistant Professor of Medicine, University of Pittsburgh Adjunct Scientist, RAND Health

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JOIN AHDB PEER REVIEW American Health & Drug Benefits (AHDB) is looking for medical and pharmacy directors, P & T Committee members, and other healthcare experts who are interested in joining our peer reviewers and assist in maintaining the high quality of articles published in the journal. You will be asked to review at least 1 or 2 articles per year in your area of expertise. Reviewers’ names will be published online at the end of the year. Please indicate at least 1 area of expertise in a health-related field for which they feel qualified to assess the content and quality of manuscripts submitted to AHDB.

Articles fall into 3 main areas related to healthcare: Regulatory, Business, and Clinical. These main categories are represented from the different vantage points of all stakeholders in healthcare and are divided into many subcategories, including (but not limited to):

® Administration/management ® Benefit design ® Disease management/state (eg, asthma, diabetes, ® ® ® ® ® ® ® ® ® ® ® ®

heart disease, infectious diseases, pain management, etc) Drug therapy (including biologics, generics) Drug utilization Employers/health plans Finance/health economics Health information technology Health policy/reform Patient education/initiatives/quality-of-life issues Payer perspectives Pharmacoeconomics analyses Pharmacy management: pharmacology, specialty pharmacy, pharmacy benefits Reimbursement: Medicare/Medicaid, health insurance, prior authorization Research: methods, study design, data collection/analysis

NOTE TO REVIEWERS: AHDB is a member of the Committee on Publication Ethics (COPE). Membership in COPE indicates that this journal upholds COPE’s Code of Conduct standards and intends to take appropriate action in cases of possible misconduct, such as plagiarism, attempted or actual redundant publication, any attempts to pass off fraudulent data, unethical research, or breaches of confidentiality. To become a peer reviewer, please complete the form below and fax to: 732-992-1881 or e-mail to editorial@AHDBonline.com Your Information _______________________________________________________________________________________ First Name

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Pharmacy Benefits: Plan Design and Management New in the International Foundation Bookstore

aabout bout u tthe he aauthor uthor

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F. Randy Vogenberg, R.Ph., Ph.D., is a principal with the Institute ffo or Integraated Healthcare in Sharon, Massachusetts, and a fo former national heallth benefits thougght leader with Aon Hewitt. Since 1981, he has consulted on economic issues for pharmaceutical services, drug benefit straateggy and decision making ffo or drug theraapy selection with ggo overnment and em mployer clients.

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If You Define Value as an Overall Survival Advantage:

In Previously Untreated Multiple Myeloma IMPORTANT 3-YEAR UPDATE- SUSTAINED BENEFIT UPDATED VISTA* OVERALL SURVIVAL (OS) ANALYSIS: VcMP† vs MP (36.7-month median follow-up) 100

MEDIAN OS NOT REACHED FOR VcMP

% Patients Without Event

80 70 60 50 40 30 20 10

VELCADE+MP (n=344) MP (n=338)

HR 0.65 (95% CI, 0.51-0.84); P=0.00084

0 0

Months Kaplan-Meier estimate.

Patients treated with VELCADE + MP as initial therapy sustained an overall survival benefit over patients randomized to MP alone The overall survival benefit was sustained despite subsequent treatments Median duration of VcMP treatment was 46 weeks/54 planned1 At the initial analysis (median 16.3-month follow-up), median TTP was 20.7 months with VELADE in combination with MP vs 15 months for MP alone (P=0.000002) * VISTA was a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. Primary endpoint was TTP and secondary endpoints were CR, ORR, PFS, and OS. At a prespecified interim analysis (median follow-up 16.3 months) VcMP resulted in significantly superior results for TTP, PFS, OS, and response rates. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. † VcMP=VELCADE + melphalan/prednisone (MP).

If You Define Value as Medication Cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1398.00 per 3.5mg vial as of January 1, 2011. Health plans should consider medication cost, length of therapy, and dosing regimens when determining the value of a prescription drug regimen. This list of considerations is not meant to be all-inclusive; there are multiple other factors to consider when determining value for a given regimen.

VELCADE Warnings, Precautions, and Adverse Events VELCADE is contraindicated where hypersensitivity to bortezomib, boron, or mannitol exists. Warnings and Precautions for VELCADE include: advising women to avoid pregnancy and breastfeeding; peripheral neuropathy, sometimes severe may occur—manage with dose modifications or discontinuation and carefully consider risk/benefit in pre-existing severe neuropathy; hypotension may occur, use caution with patients on antihypertensives, history of syncope, dehydration; closely monitor patients with risk factors for or existing heart disease; acute diffuse infiltrative pulmonary disease has been reported; nausea, diarrhea, constipation, and vomiting may require symptomatic treatment; regular monitoring of blood counts throughout treatment for thrombocytopenia or neutropenia. Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and acute hepatic failure have been reported. In patients with moderate or severe hepatic impairment use a lower starting dose. In addition, patients with diabetes may require close monitoring of blood glucose and antidiabetic medication. Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported.

Please see Brief Summary for VELCADE on the next page of this advertisement. To contact a reimbursement specialist: Please call 1-866-VELCADE, option 2 (1-866-835-2233).

www.VELCADE.com 1. San Miguel, Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma. New England Journal of Medicine 2008.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer's prescribing information. Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Cambridge, MA 02139 Copyright ©2009, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA V1215 12/09

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REVIEW ARTICLE

Strategies to Prevent Opioid Misuse, Abuse, and Diversion That May Also Reduce the Associated Costs Kathryn L. Hahn, PharmD, DAAPM, CPE

Stakeholder Perspective, page 113

Am Health Drug Benefits. 2011;4(2):107-114. www.AHDBonline.com Disclosures are at end of text

Background: The use of prescription opioid drugs has the potential to lead to patient abuse of these medications, addiction, and diversion. Such an abuse is associated with increased costs because of excessive healthcare utilization. Finding ways to minimize the risk for abuse and addiction can enhance patient outcomes and reduce costs to patients and to payers. Objective: To review current strategies that may reduce the risk for misuse and abuse of opioid medications, which in turn can enhance patient outcomes and lower costs to health insurers and patients. Discussion: Implementing approaches that will encourage the use of safe practices (universal precautions) in pain management by providers can reduce the risk for abuse and misuse associated with chronic pain medications, especially opioids. These approaches include, but are not limited to, extensive physician and patient education regarding these medications and their associated risks for abuse; the development of prescription monitoring programs to detect physician or pharmacy shopping; the detection of inappropriate prescribing and medical errors; the use of physician–patient contracts concerning opioid treatment; the requirement of presenting a photo identification to pick up an opioid prescription at the pharmacy; urine drug toxicology screening; provisions for safe disposal of unused opioids; referrals to pain and addiction specialists; and potentially encouraging the use of opioid formulations aimed at reducing abuse. Conclusion: Supporting such approaches by health insurers and educating providers and patients on the risks associated with chronic pain medications can help minimize the risk of prescription opioid abuse, addiction, and diversion; reduce health services utilization associated with opioid abuse; improve patient outcomes; and reduce overall costs.

t is well known that the use of prescription opioid medications, more than other medications, is associated with risks for misuse, abuse, and diversion.1-3 The government and pharmaceutical companies have addressed this issue by implementing specific strategies to minimize the risks associated with prescription drugs in general and with opioids in particular. In 2005, the US Food and Drug Administration (FDA) published 3 guidances for the pharmaceutical industry on risk management activities for drug and biologic products.4-6 In these publications, the FDA outlines several components of risk management, including “(1) assessing a product’s benefit-risk balance, (2) developing

Dr Hahn is Affiliate Faculty, Oregon State University College of Pharmacy, and Pharmacy Manager, Bi-Mart Corp, Springfield, OR.

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and implementing tools to minimize its risks while preserving its benefits, (3) evaluating tool effectiveness and reassessing the benefit-risk balance, and (4) making adjustments, as appropriate, to the risk minimization tools to further improve the benefit-risk balance.”4 In 2007, the FDA Amendments Act was passed into law, establishing the requirements for Risk Evaluation and Mitigation Strategies (REMS) for drugs with safety concerns. These REMS requirements are accompanied by stipulations for physician and pharmacist training and certification, and patient registries for some medications, including opioids.7 Currently, risk management strategies, including REMS, are used by the government and by pharmaceutical companies to minimize the risks associated with prescription opioid use, namely, the potential for abuse, addiction, and diversion. Risk management tools can

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KEY POINTS ➤

➤

The use of prescription drug opioids is associated with a risk for abuse and addiction. Between 1997 and 2006, retail sales of opioids have increased dramatically; sales of hydrocodone increased by 244%, oxycodone by 732%, and methadone by 1177%. These trends have coincided with increased rates of abuse and mortality associated with prescription opioid abuse. The financial cost is also substantial, resulting from increased healthcare utilization. One study reported that healthcare costs for opioid abusers were 8 times higher than for nonabusers, with an average per-person cost of $15,884 to payer for abusers compared with $1830 for nonabusers. Educating providers and patients on these drugs can minimize opioid abuse; current approaches include prescription monitoring programs, preventing prescription/medical errors, checking patient identification at the pharmacy, referral to pain specialists, and the use of abuse-deterrent opioid formulations. These strategies can improve patient outcomes, prevent abuse, and reduce overall healthcare utilization and costs.

also benefit health plans, by minimizing the potential health and economic risks associated with prescription opioid use for members who are using these medications. In this article, after reviewing the available information on the prevalence of prescription opioid abuse (the most abused of all prescription medications) and the resulting economic costs, the author outlines strategies that have the potential to minimize the risks associated with prescription opioid use and could enhance the patient’s health and reduce costs to health plans and patients.

The Scope of the Problem Abuse of Prescription Opioid Drugs in the United States The increasing prevalence of prescription opioid abuse and its emergence as a major public health concern have been extensively documented.1-3 According to 2007 data from the National Survey on Drug Use and Health, an estimated 5.2 million persons aged ≥12 years (approximately 2.1% of the US population) abused prescription opioids within the past month, and 2.1 million individuals initiated nonmedical use of prescription opioids.1 A survey of 8th-, 10th-, and 12th-grade students

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showed that in 2008, the annual rate of narcotic drug use other than heroin for twelfth-graders was 9%.8 When students were asked the source of the drugs, approximately 56% reported obtaining them for free from friends or from relatives, 9% reported buying them from friends or relatives, and 18% reported obtaining them by prescription from a physician.1 The nonmedical use of prescription opioids is dangerous, because the repeated recreational use of these medications can lead to addiction or death. Most abuse occurs by oral administration—swallowing the tablet or capsule whole, or chewing it and then swallowing.9-11 Chewing disrupts some of the extended-release opioid formulations and releases large amounts of the drug rapidly, increasing euphoria.12 Oral abuse, if frequent and at high doses, can lead to medication addiction.13 However, a significant subset of abusers progress to other, more sophisticated routes of ingestion, such as snorting (62% of abusers) or intravenous injection (26% of abusers).9 Snorting and parenteral delivery increase the rate and amount of delivery of the opioid and result in a greater euphoria than swallowing whole or chewing.12 Abuse through smoking is common for some drugs (approximately 50% of fentanyl abusers smoke it), but it is relatively uncommon with prescription opioids (only 2.3% of abusers smoke prescription opioids).3 Furthermore, although it has not been conclusively proved, it has been suggested that nonmedical prescription opioid use can be a gateway to abuse of other, equally dangerous drugs, such as heroin and crack cocaine.14 The frequency of abuse and addiction in patients with chronic pain who are treated long-term with opioids is unclear. A meta-analysis of 24 studies comprising 2507 patients treated with long-term opioid therapy for chronic, nonmalignant pain showed an overall abuse/addiction rate of 3.27%.15 However, studies that include routine urine toxicology screening as an objective method of testing drug abuse tend to show higher rates—ranging from 16% to 47%—of abuse or misuse among patients with chronic pain.16-19 Therefore, although many patients with chronic pain can safely benefit from prescription opioid treatment, some of these patients are vulnerable to abuse and addiction.

Healthcare Utilization and Costs: Prescription Opioid Abuse During the past decade, the treatment of noncancer pain with opioids has expanded.20 Between 1997 and 2006, retail sales of opioids (grams per 100,000 population) have increased20: • Sales of hydrocodone increased by 244% • Oxycodone by 732% • Methadone by 1177%.

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These trends have coincided with increased rates of abuse and mortality associated with prescription opioid abuse.1,20,21 The financial impact on payers from prescription opioid abuse is also substantial. White and colleagues demonstrated that compared with nonabusers receiving prescription opioids, prescription opioid abusers had significantly more physician visits, mental health inpatient and outpatient services, hospital admissions, emergency department visits, motor vehicle accidents, cases of trauma, and substance abuse treatment.22 Healthcare costs for opioid abusers were 8 times higher than for nonabusers—average per-person healthcare cost to payer was $15,884 for abusers compared with $1830 for nonabusers (P <.01).22 Hospital inpatient visits were the largest contributor to increased cost—$7239 for opioid abusers compared with $310 for nonabusers (P <.01). Treatment of comorbidities—which have a higher prevalence rate in opioid abusers—is also an important contributor to the higher costs; comorbidities, such as nonopioid poisoning, other substance abuse, hepatitis, pancreatitis, psychiatric illnesses, and chronic cirrhosis or acute liver disease occur 78.0, 43.0, 36.0, 21.0, 8.5, and 7.6 times more often, respectively, in abusers than in opioid users who are not abusers. Prescription costs in this study were also 5 times greater for abusers compared with nonabusers (mean costs, $2034 vs $386, respectively; P <.01).22 Birnbaum and colleagues reported similar findings; prescription opioid abuse resulted in approximately $9500 in annual medical costs per patient in 2001, which was 3 times more than that for matched nonabusers, amounting to a total healthcare cost of $2.6 billion for prescription opioid abuse that year.23 However, prescription opioid abuse costs went beyond healthcare costs; they also included $1.4 billion in criminal justice costs and $4.6 billion in workplace costs—totaling $8.6 billion in 2001.23 Prescription opioid abuse/misuse is also associated with increases in: 1. Visits to the emergency department2 2. Number of fatal opioid-related poisonings24 3. Admissions to addiction treatment centers.3 According to one study, the number of visits to emergency departments because of prescription opioid overdose increased approximately 43% between 2004 and 2006—from an estimated 172,726 to 247,669 visits.2 In addition, a 143% increase in mortality rates from prescription opioids occurred between 1999 and 2004— from 1.22 to 2.96 deaths per 100,000.24 Starting in 2004, prescription opioids have been more often shown to be involved in fatal overdoses than overdoses resulting from cocaine or heroin.24 The number of admissions to sub-

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stance abuse treatment programs for primary prescription opioid abuse increased by 342% from 1996 to 2006 (from 16,605 to 73,439).3 Insurance fraud by prescription drug abusers imposes additional costs on the healthcare system. Drug diversion costs to health insurers are estimated at $72.5 billion per year (including $24.9 billion for private insurers).25 The costs include fraudulent claims for prescriptions for spurious pain conditions, costs that accrue if individuals taking the diverted drugs become addicted, and costs as a result of additional comorbidities that occur in drug abusers.

Risk Minimization Approaches to Abuse Many approaches, which are detailed below, that can be promoted and supported by employers and health plans to control the abuse and diversion of prescription opioids are not new; they are part of a series of measures that have been recommended by various stakeholders to reduce the incidence of prescription opioid abuse in the United States. Some of these policies (detailed below) have already been put in place; others are still in the planning stage. Very little data exist regarding the effectiveness of these measures, because (1) most of them have not been systematically implemented (they exist only in limited geographical areas, or are only recommended and not mandatory), which strongly limits their impact; (2) some are too recent to demonstrate a trend yet; and (3) some have not been fully evaluated for their effectiveness in reducing abuse. Data on effectiveness, if available, are provided for each approach in the appropriate subsections below. In addition, the multifactorial aspect of prescription drug abuse makes it difficult to find an adequate measure to evaluate the impact of a particular policy on abuse in the real world. Nevertheless, some measures, such as prescription monitoring programs, have been shown to decrease abuse, as discussed below; however, the data are limited.26 Educating Physicians and Patients A comprehensive approach to risk reduction includes educating physicians on safe opioid prescribing. A system of universal precautions in pain medicine has been proposed and recommended for physicians to minimize the risk for opioid abuse by their patients, while allowing physicians to appropriately treat patients with pain.27,28 This approach is based on a comprehensive initial assessment of the patient and regular monitoring of patients who are prescribed opioids. Because safe opioid prescribing not only serves an important public health need but also can have a significant impact on healthcare costs, payers could benefit from promoting universal precau-

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tions. Payers could help to enhance this approach by providing physicians enrolled in their insurance plans with educational/training materials or training programs. It has also been recommended by the Substance Abuse and Mental Health Services Administration that physicians be educated on Screening, Brief Intervention, Referral and Treatment (SBIRT) guidelines for patients with substance abuse disorders and for those at risk for abuse.29 SBIRT measures could be promoted by providing performance initiatives in pain management (eg, SBIRT training sessions) and encouraging referrals to pain and addiction specialists when appropriate. Establishing opioid treatment contracts has been suggested.30 These are written commitments between doctors and patients stipulating the terms of treatment, in particular, patient compliance with treatment and monitoring, including the potential use of urine drug testing.30 Health information on safe opioid use could also be provided to patients. Educational and training sessions could be offered to patients on how to use opioids safely, especially information about appropriate storage (eg, lock boxes) and disposal of pharmaceuticals that are no longer needed.

Use of Prescription Monitoring Programs Prescription monitoring programs are data collection systems that determine the number of physicians who prescribe opioids for each patient and the number of pharmacies where opioids are dispensed for that patient.26 Prescription monitoring programs are administered on a state-by-state basis and are currently operational in 33 states, and are at various stages of implementation in 7 more states.31 Prescription monitoring programs collect information on the prescriber, pharmacy, product name, concentration, dose, and amount of medicine dispensed.26 Although the data are limited, they so far suggest that such programs reduce abuse practices.26 Prescription monitoring program threshold reports can be used to limit the prescribing of opioids to “doctorshoppers” and “pharmacy-shoppers.”32 Once a patient reaches the determined threshold, action can be taken, including notifying all the physicians who have prescribed an opioid to the patient, limiting the number of pharmacies used by the patient to one, notifying the patient of the knowledge of the suspicious activity, and if appropriate, referring the patient to law enforcement for investigation.25,32 Preventing Inappropriate Prescribing and Medical Errors An important aspect of risk minimization relevant to opioids is detecting inappropriate prescribing of opioids and medical errors, including incorrect patient selection

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(opioid-naive patients), off-label use, incorrect indication (eg, “as needed” use of extended-release formulations), incorrect dosage, and conversion errors. This could be accomplished by establishing algorithms that identify mismatches between diagnoses and medication/dose. The purpose of such measures should not be to prosecute prescribers (unless, of course, unlawful behavior is clearly proved), but to educate prescribers who made honest errors in safe opioid prescribing practices and ultimately help them to avoid malpractice lawsuits. Setting up systems in prescribers’ offices, such as electronic prescribing, may promote safe opioid prescribing and reduce medical errors. The US Drug Enforcement Administration issued a regulation effective June 1, 2010, approving the use of electronic prescribing for controlled substances in the United States.33 The regulation is expected to add another barrier to the diversion of prescription drugs by reducing prescription forgery. Moreover, it is intended to reduce the number of prescription errors caused by illegible handwriting, thereby enhancing safety. Implementation of the regulation is expected to take up to 18 months, because some operational issues need to be resolved and prescribing software must be updated.

Checking Patients’ Photo Identification at the Pharmacy Pharmacists may require that photo identification be presented by patients when they are picking up their opioid prescriptions at the pharmacy, because an increasing number of cases of abuse have involved identity theft. This could be achieved by mandating that the patient’s identification be checked before accepting a claim for prescription opioid medication. Some states, such as Virginia, are currently considering passing a bill that will require individuals to present a photo identification to pick up prescriptions for controlled substances.34 To reduce insurance fraud, the Government Accountability Office also recommends that insurers remove deceased patients and physicians from their systems to avoid paying claims for fraudulent prescriptions for controlled substances purportedly written by deceased physicians or to deceased patients.35 Referral to Pain Specialists Encouraging referrals to multidisciplinary pain management programs and referral resources for addiction specialists is another option. In addition, although reimbursing for services such as routine urine drug tests and referral to specialists may be more costly in the shortterm, the ability of these services to help detect and correctly manage patients at risk for prescription opioid abuse may reduce costs in the long-term.

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Table Abuse-Deterrent Opioid Formulations Trade name

Opioid

Mechanism

FDA status

OxyContin

Oxycodone

Hard plastic polymer that renders the tablet difficult to crush or dissolve

Approved in 2010

Remoxy

Oxycodone

Very viscous liquid intended to resist crushing, dissolution, injection, or inhalation

Under FDA review

Suboxone

Buprenorphine

Contains sequestered naloxone (an opioid antagonist), which is released when product is chewed/crushed and cancels the euphoric effects of buprenorphine

Approved in 2002

Embeda

Morphine

Contains sequestered naltrexone (an opioid antagonist), which is released when the product is chewed/crushed and cancels the euphoric effects of morphine

Approved in 2009

Acurox

Oxycodone Contains an aversive agent (niacin) that causes (immediate release) unpleasant effects when injected, inhaled, or taken orally in high doses

Under FDA review

FDA indicates US Food and Drug Administration.

Use of Abuse-Deterrent Formulations of Opioids Opioid manufacturers are addressing the problem of prescription opioid abuse pharmacologically by developing new opioid formulations with abuse-deterrent properties. Abuse-deterrent opioid formulations (Table) use a combination of old and new strategies that fall into 3 general categories: • The “fortress approach,” in which the formulation maintains its extended-release characteristics despite attempts to crush or dissolve it • The “neutralizing approach,” in which the formulation is relatively easy to alter, but tampering with the formulation results in the release of a neutralizing antagonist • The “aversive approach,” in which the opioid is formulated with an aversive agent that results in unpleasant side effects when a large quantity of the opioid is ingested. Some of these formulations are already on the market, including Suboxone (buprenorphine), Embeda (morphine), and the new OxyContin (oxycodone). Others are still in development or are currently under FDA review, as shown in the Table. The recently approved (April 2010) OxyContin formulation exemplifies the “fortress approach.” This new tablet is coated with a plastic polymer designed to prevent chewing, cutting, or crushing of the tablet.36 Suboxone (approved in 2002) and Embeda (approved in 2009) are examples of the “neutralizing approach,” characterized by extended-release opioid agonist-antagonist combinations. Suboxone contains buprenorphine and naloxone; Embeda contains morphine and naltrexone (which is a longer acting antagonist than naloxone).

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The strategy behind these products is to blunt the euphoric effects of the opioid if the formulation is altered. The antagonist agent (naltrexone or naloxone) is sequestered if the medication is taken as directed, but if it is tampered with (eg, chewed, crushed, or dissolved), the antagonist is released. A recent study has shown that Suboxone has a lower abuse liability than Subutex (buprenorphine alone).37 Similarly, crushed Embeda produces less euphoria (as measured by “drug high” on a visual analog scale) in substance abusers than either intact Embeda or immediate-release morphine sulfate.38 An example of the “aversive approach” is the immediate-release formulation of oxycodone containing niacin (Acurox), which is currently under FDA review (Table).39 Niacin causes unpleasant side effects, such as warmth or flushing, itching, sweating, and/or chills. The formulation is designed to release no or insignificant amounts of niacin if Acurox is taken as directed, but if it is taken in higher than recommended doses, temporary unpleasant (but not harmful) effects of niacin are experienced, as demonstrated in a clinical study comparing Acurox with oxycodone.40,41 If and when approved, the aversive strategy will be the only strategy that could prevent abuse of a medication by swallowing excessive numbers of tablets or capsules whole; the fortress and neutralizing approaches are likely to be inefficient against this form of abuse.

Practical Considerations A key question for payers will be the degree to which these new formulations deter abuse. The real question is whether these formulations truly reduce misuse, abuse,

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addiction, and diversion on a population basis (ie, in the real world). The payer community should have a reasonable skepticism about the real-world abuse deterrence of these formulations. Indeed, in the mid-1990s, claims were made that the pharmacokinetic properties of the extended-release oxycodone were less reinforcing than immediate-release oxycodone, and therefore extendedrelease oxycodone would have a lower abuse potential.42 What was not recognized, however, was the simplicity by which the extended-release mechanism could be subverted: just breaking, chewing, or crushing extendedrelease oxycodone tablets could lead to the rapid release and absorption of a high dose of oxycodone.42 The rapid increase in OxyContin abuse after the drug was launched is a good lesson in how the abuse potential of any drug is a function of the ease with which that formulation can be subverted. Most abuse-deterrent formulations on the market have been approved recently, and therefore no data are yet available to determine the impact of these formulations on the abuse and diversion of these opioids in the real world. Suboxone (which was approved in 2002) has some real-world abuse data. One study showed that of 64 patients switched from Subutex to Suboxone, 5 abused Suboxone intravenously (once each by 4 patients and twice by 1 patient), and all reported that it provided no euphoria or was unpleasant and that they would not repeat the experience.43 However, real-world data show that buprenorphine is still widely abused and diverted. In the United States, law enforcement and pharmacists report that Suboxone is being abused successfully when snorted,44 and data from the National Forensic Laboratory Information System, which tracks drug seizures by law enforcement, suggest that diversion of buprenorphine has been steadily rising despite the introduction of Suboxone.45 Data from 2003 to 2005 from US Poison Control Centers show that Subutex and Suboxone rates of abuse are similar,46 and a study in Malaysia showed that the introduction of Suboxone did not reduce the rate of intravenous buprenorphine abuse in that country.47

Conclusion Many approaches are currently in various stages of implementation to help decrease the incidence of prescription opioid misuse, abuse, and diversion. For each measure, health plans, employers, and other payers may have to consider (1) the feasibility of implementing the measure; (2) the cost of implementation versus the ultimate cost-savings; (3) the additional burden on the healthcare system (ie, physician, pharmacist, and insurer) that the measure creates; (4) the potential negative consequences on the appropriate treatment of pain

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(chilling effect); and (5) the true impact of the measure on misuse, abuse, and diversion of opioid medications. Therefore, policies and recommendations should come from consensus decisions from various stakeholders. The effectiveness of these programs will have to be evaluated and adapted for optimal reduction of prescription opioid abuse and diversion. ■ Acknowledgments Writing and editorial support for the initial manuscript was provided by Analgesic Solutions. King Pharmaceuticals provided funding to Analgesic Solutions. Author Disclosure Statement Dr Hahn is on the Speaker’s Bureau of King Pharmaceuticals, Meda Pharmaceuticals, Pfizer, and PriCara. She received no financial or other compensation for writing this article.

References 1. US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. Results from the 2007 National Survey on Drug Use and Health: national findings. Rockville, MD; 2008. DHHS Publication No. (SMA) 08-4343. http://oas.samhsa.gov/nsduh/2k7nsduh/2k7Results.pdf. Accessed August 14, 2008. 2. US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. Drug Abuse Warning Network, 2006: national estimates of drug-related emergency department visits. Rockville, MD; 2008. DAWN Series D-30; DHHS Publication No. (SMA) 08-4339. http://dawninfo.samhsa. gov/files/ED2006/DAWN2k6ED.pdf. Accessed October 15, 2009. 3. US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. Treatment episode data set (TEDS) 1996-2006. National admissions to substance abuse treatment services. Rockville, MD; 2008. DASIS Series S-43, DHHS Publication No. (SMA) 08-4347. http://wwwdasis.samhsa. gov/teds06/teds2k6aweb508.pdf. Accessed July 29, 2009. 4. US Food and Drug Administration Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. Guidance for industry: development and use of risk minimization action plans. March 2005. www.fda.gov/downloads/ RegulatoryInformation/Guidances/UCM126830.pdf. Accessed February 25, 2011. 5. US Food and Drug Administration Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. Guidance for industry: premarketing risk assessment. March 2005. www.fda.gov/downloads/RegulatoryInformation/ Guidances/ucm126958.pdf. Accessed February 25, 2011. 6. US Food and Drug Administration Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. Guidance for industry: good pharmacovigilance practices and pharmacoepidemiologic assessment. March 2005. www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126834.pdf. Accessed February 25, 2011. 7. Food and Drug Administration Amendments Act of 2007, Public Law 110-85, Food and Drug Administration. September 27, 2007. 8. Johnston LD, O’ Malley PM, Bachman JG, Schulenberg JE. Monitoring the Future National Results on Adolescent Drug Use: Overview of Key Findings, 2007. Bethesda, MD: National Institute on Drug Abuse; 2008. NIH Publication No. 086418. www.monitoringthefuture.org/pubs/monographs/overview2007.pdf. Accessed July 14, 2010. 9. Hays LR. A profile of OxyContin addiction. J Addict Dis. 2004;23:1-9. 10. Carise D, Dugosh KL, McLellan AT, et al. Prescription OxyContin abuse among patients entering addiction treatment. Am J Psychiatry. 2007;164:1750-1756. 11. Butler SF, Budman SH, Licari A, et al. National addictions vigilance intervention and prevention program (NAVIPPRO): a real-time, product-specific, public health surveillance system for monitoring prescription drug abuse. Pharmacoepidemiol Drug Saf. 2008;17:1142-1154. 12. Raffa RB, Pergolizzi JV Jr. Opioid formulations designed to resist/deter abuse. Drugs. 2010;70:1657-1675. 13. Compton WM, Volkow ND. Abuse of prescription drugs and the risk of addiction. Drug Alcohol Depend. 2006;83(suppl 1):S4-S7. 14. Colliver JD, Kroutil LA, Dai L, Gfroerer JC. Misuse of prescription drugs: data from the 2002, 2003, and 2004 national surveys on drug use and health. Rockville,

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Strategies to Prevent Opioid Misuse, Abuse, and Diversion

MD: US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Office of Applied Studies; 2006. DHHS Publication No. (SMA) 06-4192, Analytic Series A-28. www.oas.samhsa.gov/prescription/toc.htm. Accessed October 9, 2008. 15. Fishbain DA, Cole B, Lewis J, et al. What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/or aberrant drug-related behaviors? A structured evidence-based review. Pain Med. 2008;9:444-459. 16. Manchikanti L, Cash KA, Damron KS, et al. Controlled substance abuse and illicit drug use in chronic pain patients: an evaluation of multiple variables. Pain Physician. 2006;9:215-225. 17. Ives TJ, Chelminski PR, Hammett-Stabler CA, et al. Predictors of opioid misuse in patients with chronic pain: a prospective cohort study. BMC Health Serv Res. 2006;6:46. 18. Fishbain DA, Cutler RB, Rosomoff HL, Rosomoff RS. Validity of self-reported drug use in chronic pain patients. Clin J Pain. 1999;15:184-191. 19. Michna E, Jamison RN, Pham LD, et al. Urine toxicology screening among chronic pain patients on opioid therapy: frequency and predictability of abnormal findings. Clin J Pain. 2007;23:173-179. 20. Manchikanti L, Singh A. Therapeutic opioids: a ten-year perspective on the complexities and complications of the escalating use, abuse, and nonmedical use of opioids. Pain Physician. 2008;11(2 suppl):S63-S88. 21. Paulozzi LJ, Budnitz DS, Xi Y. Increasing deaths from opioid analgesics in the United States. Pharmacoepidemiol Drug Saf. 2006;15:618-627. 22. White AG, Birnbaum HG, Mareva MN, et al. Direct costs of opioid abuse in an insured population in the United States. J Manag Care Pharm. 2005;11:469-479. 23. Birnbaum HG, White AG, Reynolds JL, et al. Estimated costs of prescription opioid analgesic abuse in the United States in 2001: a societal perspective. Clin J Pain. 2006;22:667-676. 24. Paulozzi LJ, Xi Y. Recent changes in drug poisoning mortality in the United States by urban-rural status and by drug type. Pharmacoepidemiol Drug Saf. 2008; 17:997-1005. 25. Coalition Against Insurance Fraud. Prescription for peril: how insurance fraud finances theft and abuse of addictive prescription drugs. Washington, DC; 2007. www.insurancefraud.org/drugDiversion.htm. Accessed August 25, 2008. 26. Wang J, Christo PJ. The influence of prescription monitoring programs on chronic pain management. Pain Physician. 2009;12:507-515. 27. Gourlay DL, Heit HA, Almahrezi A. Universal precautions in pain medicine: a rational approach to the treatment of chronic pain. Pain Med. 2005;6:107-112. 28. Gourlay D, Heit H. Universal precautions: a matter of mutual trust and responsibility. Pain Med. 2006;7:210-211. 29. Substance Abuse and Mental Health Services Administration. Screening, brief intervention, and referral to treatment: new populations, new effectiveness data. November/December 2009. www.samhsa.gov/samhsanewsletter/Volume_17_Number _6/SBIRT.aspx. Accessed March 14, 2011. 30. Fishman SM, Bandman TB, Edwards A, Borsook D. The opioid contract in the management of chronic pain. J Pain Symptom Manage. 1999;18:27-37. 31. National Alliance for Model State Drug Laws. Status of prescription drug monitoring programs. March 7, 2011. www.namsdl.org/documents/StatusofStates March72011.pdf. Accessed March 14, 2011. 32. Katz N, Panas L, Kim M, et al. Usefulness of prescription monitoring programs

for surveillance—analysis of Schedule II opioid prescription data in Massachusetts, 1996-2006. Pharmacoepidemiol Drug Saf. 2010;19:115-123. 33. US Drug Enforcement Administration. Electronic prescriptions for controlled substances. Docket No. DEA-218I; RIN 1117-AA61. Federal Register. 2010;75: 16236-16319. 34. Lohr M. House Bill No. 964. Commonwealth of Virginia General Assembly; February 18, 2010. http://leg1.state.va.us/cgi-bin/legp504.exe?101+ful+HB964H1. Accessed May 21, 2010. 35. United States Government Accountability Office. Medicaid fraud and abuse related to controlled substances identified in selected states. Report to Congressional Requestors. September 2009. GAO-09-957. www.smpresource.org/Content/Navigation Menu/HealthCareFraud/Medicaid/GAO_Medicaid_controlled_substances.pdf. Accessed May 11, 2010. 36. Pharmacy Voice. FDA: Reformulated OxyContin may be less prone to abuse. April 7, 2010. http://nacds.rxpost.net/News/article.cfm?Article_ID=561428. Accessed March 14, 2011. 37. Comer SD, Sullivan MA, Vosburg SK, et al. Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusers. Addiction. 2010;105:709-718. 38. Stauffer J, Setnik B, Sokolowska M, et al. Subjective effects and safety of whole and tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extendedrelease capsules versus morphine solution and placebo in experienced non-dependent opioid users: a randomized, double-blind, placebo-controlled, crossover study. Clin Drug Investig. 2009;29:777-790. 39. Acura Pharmaceuticals. Acurox with Niacin tablets. 2010. http://acurapharm. com/products/acurox-tablets/. Accessed May 11, 2010. 40. ClinicalTrials.gov. Study of the abuse liability of oxycodone HCl/niacin in subjects with a history of opioid abuse. October 22, 2008. Identifier NCT00699010. www.clinicaltrials.gov/ct2/show/NCT00699010?term=acurox&rank=2. Accessed May 11, 2010. 41. Acura Pharmaceuticals. Study AP-ADF-102. 2010. http://acurapharm.com/ products/acurox-tablets/study-ap-adf-102/. Accessed May 11, 2010. 42. Shibuya RB. History of Oxycontin: labeling and risk management program. US Food and Drug Administration Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees; November 13-14, 2008. 43. Simojoki K, Vorma H, Alho H. A retrospective evaluation of patients switched from buprenorphine (Subutex) to the buprenorphine/naloxone combination (Suboxone). Subst Abuse Treat Prev Policy. 2008;3:16. 44. National Drug Intelligence Center. Intelligence bulletin: buprenorphine: potential for abuse. September 2004. Document ID: 2004-L0424-013. www.justice.gov/ ndic/pubs10/10123/index.htm. Accessed May 11, 2010. 45. Wong LL, for the US Drug Enforcement Administration Office of Diversion Control. Buprenorphine in the treatment of opioid addiction: reassessment 2010. Presented at the SAMHSA National Advisory Council. Washington, DC; May 1112, 2010. http://buprenorphine.samhsa.gov/bwns/2010_presentations_pdf/10a_ 10b_508.pdf. Accessed June 14, 2010. 46. Smith MY, Bailey JE, Woody GE, Kleber HD. Abuse of buprenorphine in the United States: 2003-2005. J Addict Dis. 2007;26:107-111. 47. Bruce RD, Govindasamy S, Sylla L, et al. Lack of reduction in buprenorphine injection after introduction of co-formulated buprenorphine/naloxone to the Malaysian market. Am J Drug Alcohol Abuse. 2009;35:68-72.

STAKEHOLDER PERSPECTIVE

Just Say No PAYERS/PROVIDERS: “Just say no to drugs.” Do you remember this phrase during the popular anti–drug abuse campaign created in the 1980s as part of the US “War on Drugs”? What you may not know is that marijuana use by high school seniors dropped from 50.1% before that campaign to 12% in 1991.1 In addition, cocaine use by the same demographic group dropped from 12% to 10%, and heroin use dropped from 1% to 0.5%, during the same time period.1

Critics, nevertheless, believed that the solutions to the drug abuse problem were never addressed by this campaign, and that the problem was reduced to a very costly catch phrase. There are many psychological, physical, and social factors that lead to drug abuse problems. Psychological and emotional factors, such as depression and schizophrenia, are linked to the development of drug abuse problems. Physical challenges, such as Continued

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STAKEHOLDER PERSPECTIVE (Continued) chronic pain or improper or undertreated pain, can lead to drug abuse. And social factors, such as stress, unemployment, poverty, and lack of education, can also lead to drug abuse. In her article in this issue, Dr Hahn provides an overview of several strategies that can be employed to prevent opioid misuse, abuse, and diversion. Strategies such as education of physicians and patients, use of prescription-monitoring programs, checking photo identification at the point of sale, referral to pain specialists, and use of abuse-deterrent opioid formulations are all legitimate strategies, and these should be used by healthcare stakeholders, such as payers and providers, but is it enough? Well, the catch is, we do not know. Dr Hahn correctly points out in the article that very little data exist regarding the effectiveness of these measures for many reasons, such as a lack of systematic implementation of these measures, some of the strategies are too new, and some have not been fully evaluated regarding their effectiveness. However, in addition to answering the questions regarding effectiveness of the various strategies that Dr Hahn lists, we must also remember the other causes for the development of drug abuse, because these other causes must be addressed if we want to prevent

misuse, abuse, and diversion. We can no longer only focus on “policing” patients who are treated with and providers who prescribe opioids. We must also address the underlying causes that lead to drug abuse. Effectively treating depression, schizophrenia, and chronic pain is as, if not more, critical than changing the formulation of an opioid if the goal is to prevent opioid misuse and abuse. Improving the education and financial future of our nation is as, if not more, critical than checking photo identification at the point of sale if we want to prevent drug diversion. POLICYMAKERS: We have a drug abuse problem in this country. If we want to prevent opioid misuse, abuse, and diversion, we need a comprehensive strategy that can be measured appropriately to truly understand whether we are having a positive effect on this problem. We may even want to consider a catch phrase as part of our comprehensive strategy as long as we can measure the results. 1. Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE. Monitoring the Future National Results on Adolescent Drug Use: Overview of Key Findings, 2010. Ann Arbor: Institute for Social Research, University of Michigan. 2011. www.monitoringthefuture.org/pubs/monographs/mtf-overview2010.pdf. Accessed March 30, 2011.

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy

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When you treat Attention Deficit/Hyperactivity Disorder (ADHD) with stimulants, for some patients, a question may be...

*Kapvay™ was FDA approved on September 28, 2010.

• When added to a stimulant, extended-release Kapvay™ demonstrated statistically significant improvement of ADHD symptoms compared with a stimulant alone at the end of 5 weeks of treatment, as measured by the ADHD RS-IV total score

Indication Kapvay™ (clonidine hydrochloride) extended-release tablets are indicated for the treatment of attention deficit/hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy to stimulant medications in children and adolescents ages 6-17. The efficacy of Kapvay™ is based on the results of 2 clinical trials in children and adolescents. Kapvay™ is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social) for patients with this syndrome. The effectiveness of Kapvay™ for longer-term use (more than 5 weeks) has not been systematically evaluated in controlled trials; therefore, the physician electing to use Kapvay™ for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Important Safety Information • Kapvay™ should not be used in patients with known hypersensitivity to clonidine • Kapvay™ can cause dose-related decreases in blood pressure and heart rate. Use caution in treating patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope • Somnolence/Sedation were commonly reported adverse reactions in clinical studies with Kapvay™. Potential for additive sedative effects with CNS-depressant drugs. Advise patients to avoid use with alcohol. Caution patients against operating heavy equipment or driving until they know how they respond to Kapvay™ • Patients should be instructed not to discontinue Kapvay™ therapy without consulting their physician due to the potential risk of withdrawal effects. Kapvay™ should be discontinued slowly in decrements of no more than 0.1 mg every 3 to 7 days • In patients who have developed localized contact sensitization or other allergic reaction to clonidine in a transdermal system, substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash, urticaria, or angioedema. Use cautiously in patients with vascular disease, cardiac conduction disease, or chronic renal failure: Monitor carefully and uptitrate slowly • Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs • Use caution when Kapvay™ is administered concomitantly with antihypertensive drugs, due to the additive pharmacodynamic effects (e.g., hypotension, syncope) • Kapvay™ should not be used during pregnancy unless clearly needed. Since clonidine hydrochloride is excreted in human milk, caution should be exercised when Kapvay™ is administered to a nursing woman • Caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers and beta-blockers) due to a potential for additive effects, such as bradycardia and AV block • Clonidine, the active ingredient in Kapvay™, is also approved as an antihypertensive. Do not use Kapvay™ in patients concomitantly taking other clonidine-containing products, (e.g., Catapres® [clonidine hydrochloride], JENLOGA) • Common adverse reactions (incidence at least 5% and twice the rate of placebo) include: somnolence, fatigue, upper respiratory tract infection, irritability, throat pain, insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth, and ear pain Kapvay™ is a trademark of Shionogi Pharma, Inc. Catapres® is a registered trademark of Boehringer Ingelheim.

Please see Brief Summary of full Prescribing Information on the adjacent page.

Atlanta, Georgia.

KAP10-PAD-002-00

KAPVAY (clonidine hydrochloride) extended-release tablets, oral, Rx only INDICATIONS AND USAGE KAPVAY™ is a centrally acting alpha2-adrenergic agonist indicated for the treatment of attention deficit hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy to stimulant medications. (1) The efficacy of KAPVAY is based on the results of two clinical trials in children and adolescents. (14) Maintenance efficacy has not been systematically evaluated, and patients who are continued on longer-term treatment require periodic reassessment. (1) This extended-release formulation of clonidine hydrochloride is also approved for the treatment of hypertension under the trade name JENLOGA. (1) CONTRAINDICATIONS KAPVAY should not be used in patients with known hypersensitivity to clonidine. WARNINGS AND PRECAUTIONS Hypotension/Bradycardia Treatment with KAPVAY can cause dose related decreases in blood pressure and heart rate. In patients that completed 5 weeks of treatment in a controlled, fixed-dose monotherapy study in pediatric patients, during the treatment period the maximum placebo-subtracted mean change in systolic blood pressure was -4.0 mmHg on KAPVAY 0.2 mg/day and -8.8 mmHg on KAPVAY 0.4 mg/day. The maximum placebosubtracted mean change in diastolic blood pressure was -4.0 mmHg on KAPVAY 0.2 mg/day and -7.3 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -4.0 beats per minute on KAPVAY 0.2 mg/day and -7.7 beats per minute on KAPVAY 0.4 mg/day. During the taper period of the fixed-dose monotherapy study the maximum placebo-subtracted mean change in systolic blood pressure was +3.4 mmHg on KAPVAY 0.2 mg/day and -5.6 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on KAPVAY 0.2 mg/day and -5.4 mmHg on KAPVAY 0.4 mg/day. The maximum placebosubtracted mean change in heart rate was -0.6 beats per minute on KAPVAY 0.2 mg/day and -3.0 beats per minute on KAPVAY 0.4 mg/day. Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Use KAPVAY with caution in patients with a history of hypotension, heart block, bradycardia, or cardiovascular disease, because it can decrease blood pressure and heart rate. Use caution in treating patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use KAPVAY with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Advise patients to avoid becoming dehydrated or overheated. Sedation and Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies. In patients that completed 5 weeks of therapy in a controlled fixed dose pediatric monotherapy study, 31% of patients treated with 0.4 mg/day and 38% treated with 0.2 mg/day vs 7% of placebo treated patients reported somnolence as an adverse event. In patients that completed 5 weeks of therapy in a controlled flexible dose pediatric adjunctive to stimulants study, 19% of patients treated with KAPVAY+stimulant vs 8% treated with placebo+stimulant reported somnolence. Before using KAPVAY with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with KAPVAY. Advise patients to avoid use with alcohol. Abrupt Discontinuation No studies evaluating abrupt discontinuation of KAPVAY in children with ADHD have been conducted. In children and adolescents with ADHD, physicians should gradually reduce the dose of KAPVAY in decrements of no more than 0.1 mg every 3 to 7 days. Patients should be instructed not to discontinue KAPVAY therapy without consulting their physician due to the potential risk of withdrawal effects. In adults with hypertension, sudden cessation of clonidine hydrochloride extended-release formulation treatment in the 0.2 to 0.6 mg/day range resulted in reports of headache, tachycardia, nausea, flushing, warm feeling, brief lightheadedness, tightness in chest, and anxiety. In adults with hypertension, sudden cessation of treatment with immediate-release clonidine has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. Allergic Reactions In patients who have developed localized contact sensitization to clonidine transdermal system, continuation of clonidine transdermal system or substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash. In patients who develop an allergic reaction from clonidine transdermal system, substitution of oral clonidine hydrochloride may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema). Patients with Vascular Disease, Cardiac Conduction Disease, or Renal Failure Clonidine hydrochloride should be used with caution in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease or chronic renal failure. Other Clonidine-Containing Products Clonidine, the active ingredient in KAPVAY, is also approved as an antihypertensive. Do not use KAPVAY in patients concomitantly taking other clonidine-containing products, (e.g. Catapres®). ADVERSE REACTIONS Clinical Trial Experience Two KAPVAY ADHD clinical studies evaluated 256 patients who received active therapy, in one of the two placebo-controlled studies (Studies 1 and 2) with primary efficacy end-points at 5-weeks. Study 1: Fixed-dose KAPVAY Monotherapy Study 1 was a multi-center, randomized, double-blind, placebo-controlled study with primary efficacy endpoint at 5 weeks, of two fixed doses (0.2 mg/day or 0.4 mg/day) of KAPVAY in children and adolescents (6 to 17 years of age) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes. Commonly observed adverse reactions (incidence of ≥ 2% in either active treatment group and greater than the rate on placebo) during the treatment period are listed in Table 2.

Table 2 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial- Treatment period (Study 1) Percentage of Patients Reporting Event KAPVAY KAPVAY Preferred Term Placebo 0.2 mg/day 0.4 mg/day (N=76) N=76 N=78 Somnolence1 Headache Upper Abdominal Pain Fatigue2 Upper Respiratory Tract Infection Irritability Throat Pain Nausea Nightmare Dizziness Insomnia Emotional Disorder Constipation Dry Mouth Nasal Congestion Body Temperature Increased Gastrointestinal Viral Diarrhea Ear Pain Nasopharyngitis Abnormal Sleep-Related Event Aggression Asthma Bradycardia Enuresis Inﬂuenza like Illness Tearfulness Thirst Tremor Epistaxis Lower Respiratory Tract Infection Pollakiuria Sleep Terror

31% 19% 13% 13% 6% 6% 6% 8% 9% 3% 6% 5% 6% 5% 5% 1% 0% 1% 0 3% 1% 1% 1% 4% 4% 3% 3% 3% 3% 0 0

38% 29% 20% 16% 11% 9% 8% 5% 3% 7% 4% 4% 1% 0 3% 5% 7% 4% 5% 3% 3% 3% 3% 0 0 1% 1% 1% 1% 3% 3%

5% 18% 17% 1% 4% 3% 3% 4% 0 5% 1% 1% 0 1% 1% 3% 4% 3% 1% 1% 0 1% 1% 0 0 1% 0 0 0 0 1%

0 0

3% 3%

0 0

1. Somnolence includes the terms “somnolence” and “sedation”. 2. Fatigue includes the terms “fatigue” and “lethargy”. Commonly observed adverse reactions (incidence of ≥ 2% in either active treatment group and greater than the rate on placebo) during the taper period are listed in Table 3. Table 3 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial- Taper period* (Study 1) Percentage of Patients Reporting Event KAPVAY KAPVAY Preferred Term Placebo 0.4 mg/day 0.2 mg/day (N=76) N=78 N=76 Abdominal Pain Upper Headache Gastrointestinal Viral Somnolence Heart Rate Increased Otitis Media Acute

6% 2% 5% 3% 3% 0

0 5% 0 2% 0 3%

3% 3% 0 0 0 0

*Taper Period: 0.2 mg dose, week 8; 0.4 mg dose, weeks 6-8; Placebo dose, weeks 6-8 Study 2: Flexible-dose KAPVAY as Adjunctive Therapy to Psychostimulants Study 2 was a multi-center, randomized, double-blind, placebo-controlled study, with primary efﬁcacy endpoint at 5 weeks, of a ﬂexible dose of KAPVAY as adjunctive therapy to a psychostimulant in children and adolescents (6 to 17 years) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes. KAPVAY was initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period. Most KAPVAY treated patients (75.5%) were escalated to the maximum dose of 0.4 mg/day. Commonly observed adverse reactions (incidence of ≥ 2% in the treatment group and greater than the rate on placebo) during the treatment period are listed in Table 4.

Table 4 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial- Treatment Period (Study 2) Preferred Term Somnolence1 Fatigue2 Abdominal Pain Upper Nasal Congestion Throat Pain Decreased Appetite Body Temperature Increased Dizziness Insomnia Epistaxis Rhinorrhea Abdominal Pain Anxiety Pain in Extremity

Percentage of Patients Reporting Event KAPVAY+STM PBO+STM (N=102) (N=96) 19% 8% 16% 4% 12% 7% 6% 5% 6% 3% 5% 4% 4% 2% 4% 2% 4% 2% 3% 0 3% 0 2% 1% 2% 0 2% 0

1. Somnolence includes the terms: “somnolence” and “sedation”. 2. Fatigue includes the terms “fatigue” and “lethargy”. Commonly observed adverse reactions (incidence of ≥ 2% in the treatment group and greater than the rate on placebo) during the taper period are listed in Table 5. Table 5 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial- Taper Period* (Study 2)

Preferred Term

Percentage of Patients Reporting Event KAPVAY+STM PBO+STM (N=102) (N=96) 4% 2% 3% 1% 3% 2% 3% 1% 2% 0 2% 0

Nasal Congestion Headache Irritability Throat Pain Gastroenteritis Viral Rash *Taper Period: weeks 6-8. Most common adverse reactions, deﬁned as events that were reported in at least 5% of drugtreated patients and at least twice the rate as in placebo patients, during the treatment period were somnolence, fatigue, upper respiratory tract infection, irritability, throat pain, insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth, and ear pain. The most common adverse reactions that were reported during the taper phase were upper abdominal pain and gastrointestinal virus. Adverse Reactions Leading to Discontinuation Thirteen percent (13%) of patients receiving KAPVAY discontinued from the pediatric monotherapy study due to adverse events, compared to 1% in the placebo group. The most common adverse reactions leading to discontinuation of KAPVAY monotherapy treated patients were from somnolence/sedation (5%) and fatigue (4%). Less common adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included: formication, vomiting, prolonged QT, increased heart rate, and rash. In the pediatric adjunctive treatment to stimulants study, one patient discontinued from KAPVAY + stimulant group because of bradyphrenia. Effects on Laboratory Tests, Vital Signs, and Electrocardiograms KAPVAY treatment was not associated with any clinically important effects on any laboratory parameters in either of the placebo-controlled studies. Mean decreases in blood pressure and heart rate were seen [see Warnings and Precautions (5.1)]. There were no changes on ECGs to suggest a drug-related effect. DRUG INTERACTIONS No drug interaction studies have been conducted with KAPVAY in children. The following have been reported with other oral immediate release formulations of clonidine. Interactions with CNS-depressant Drugs Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. Interactions with Tricyclic Antidepressants If a patient is receiving clonidine hydrochloride and also taking tricyclic antidepressants the hypotensive effects of clonidine may be reduced. Interactions with Drugs Known to Affect Sinus Node Function or AV Nodal Conduction Due to a potential for additive effects such as bradycardia and AV block, caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers and beta-blockers). Use with other products containing clonidine Do not use KAPVAY concomitantly with other products containing clonidine (e.g. Catapres®). Antihypertensive Drugs Use caution when KAPVAY is administered concomitantly with antihypertensive drugs, due to the potential for additive pharmacodynamic effects (e.g., hypotension, syncope) [see Warnings and Precautions (5.2)].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Oral administration of clonidine hydrochloride to pregnant rabbits during the period of embryo/fetal organogenesis at doses of up to 80 mcg/kg/day (approximately 3 times the oral maximum recommended daily dose [MRHD] of 0.4 mg/day on a mg/m2 basis) produced no evidence of teratogenic or embryotoxic potential. In pregnant rats, however, doses as low as 15 mcg/kg/day (1/3 the MRHD on a mg/m2 basis) were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating and throughout gestation. Increased resorptions were not associated with treatment at the same or at higher dose levels (up to 3 times the MRHD) when treatment of the dams was restricted to gestation days 6-15. Increases in resorptions were observed in both rats and mice at 500 mcg/kg/day (10 and 5 times the MRHD in rats and mice, respectively) or higher when the animals were treated on gestation days 1-14; 500 mcg/kg/day was the lowest dose employed in this study. No adequate and wellcontrolled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless clearly needed. Nursing Mothers Since clonidine hydrochloride is excreted in human milk, caution should be exercised when KAPVAY is administered to a nursing woman. Pediatric Use A study was conducted in which young rats were treated orally with clonidine hydrochloride from day 21 of age to adulthood at doses of up to 300 mcg/kg/day, which is approximately 3 times the maximum recommended human dose (MRHD) of 0.4 mg/day on a mg/m2 basis. A slight delay in onset of preputial separation was seen in males treated with the highest dose (with a no-effect dose of 100 mcg/kg/day, which is approximately equal to the MRHD), but there were no drug effects on fertility or on other measures of sexual or neurobehavioral development. KAPVAY has not been studied in children with ADHD less than 6 years old. Patients with Renal Impairment The impact of renal impairment on the pharmacokinetics of clonidine in children has not been assessed. The initial dosage of KAPVAY should be based on degree of impairment. Monitor patients carefully for hypotension and bradycardia, and titrate to higher doses cautiously. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental KAPVAY following dialysis. Adult Use in ADHD KAPVAY has not been studied in adult patients with ADHD. DRUG ABUSE AND DEPENDENCE Controlled Substance KAPVAY is not a controlled substance and has no known potential for abuse or dependence. OVERDOSAGE Symptoms Clonidine overdose: hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure. Treatment Consult with a Certified Poison Control Center for up-to-date guidance and advice. © 2010 Shionogi Pharma, Inc. Florham Park, NJ 07932 Last modified 10/2010

GENERIC DRUG TRENDS

New Economic Analysis Zeroes in on Low Generic Utilization and Waste in Medicaid By Dalia Buffery, MA, ABD

recent report from the American Enterprise Institute suggests that better utilization of generic drugs in the Medicaid population could save that federal program and the states much-needed funds, by eliminating unnecessary utilization of the more expensive brand-name drugs for which appropriate generic substitutes are available.1 For this report, Alex Brill, MA, former senior adviser and chief economist to the House Ways and Means Committee, examined the database of the 2009 Medicaid Drug Rebate Program, focusing on drug utilization of 20 “popular prescription drugs for which both brand and generic versions are available.”1 The study was limited to oral medications and demonstrated that significantly more drug sales in Medicaid involve brand-name drugs than their generic equivalent products.1 Mr Brill calculates that if the trends outlined in his report continue, unnecessary drug spending in Medicaid could reach up to “$430 million in 2012 as a direct result of states not utilizing more generic drugs.”1 The key findings of this analysis, based on 2009 data, show that1: 1. For the 20 popular (oral) drugs prescribed for Medicaid patients, the program overspent $329 million by reimbursing for brand-name products when less expensive therapeutic alternatives existed 2. Of these 20 drugs, Medicaid wasted, on average, $95 per prescription 3. As much as 85% of the unrealized savings was related to only 8 compounds, totaling $279 million 4. The following states had the greatest waste in drug spending in the Medicaid program1: • California, $102 million • Texas, $32 million • Georgia, $25 million • Ohio, $21 million • New York/Pennsylvania, $19 million each • Iowa, $15 million • Illinois/Florida, $11.5 million each • North Carolina, $6.8 million 5. Projections based on the 10 brand-name drugs that are expected to lose patent in 2011 and 2012 for which Medicaid reimbursement was high in 2009— assuming similar overspending patterns—would range from $289 million to $433 million. In support of his findings, Mr Brill cites a 2005 study that identified potential savings from generic substitu-

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tion across all patient categories, with overspending in Medicaid and other public programs estimated at $388 million in 2000.2 Mr Brill suggests that an “important and relatively simple approach to reducing wasteful spending is to maximize the use of less costly generic drugs in the Medicaid drug program.”1 This, however, is anything but “relatively simple.” In the current economic state of affairs, cutting costs is on the mind of all healthcare stakeholders. However, before any firm conclusions can be reached about waste in utilization of brand versus generic drugs, a thorough investigation is needed to demonstrate the reasons for what appears to be overutilization of the more expensive options, when therapeutically equivalent and less expensive options are available. The potential for cost-savings from generic substitutions is self-evident and potentially quite significant, but clinical experience and the medical literature have shown that individual variations in patients’ responses to medications, as well as patient variation in susceptibility to adverse events, must be considered, both of which are also directly related to medication adherence and patient outcomes. These issues must be factored in when costeffectiveness analyses are conducted. They were not included in this analysis. It is no longer possible to consider pure economic analyses when discussing cost-effectiveness and utilization-based waste of medications; the issues raised by personalized medicine must be considered in this area. Indeed, Mr Brill makes a small concession in that direction: after saying that “to ensure the highest possible cost‐effectiveness, it is important that Medicaid programs not reimburse for a more expensive version of a drug when a less expensive, therapeutically equivalent product is available,” he adds in a footnote that “there may be situations, albeit rare, in which a patient requires a brand product.”1 Whether these situations are rare needs to be further elucidated in evidence-based studies. Perhaps some answers would soon come from those involved in personalized medicine. ■ References 1. Brill A. Overspending on multi-source drugs in Medicaid. American Enterprise Institute. March 28, 2011. www.aei.org/docLib/Brill%20MedicaidWorkingPaper2 Final.pdf. Accessed April 4, 2011. 2. Haas JS, Phillips KA, Gerstenberger EP, Seger AC. Potential savings from substituting generic drugs for brand-name drugs: medical expenditure panel survey, 19972000. Ann Intern Med. 2005;142:891-897.

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INDUSTRY TRENDS

CMS Invites Feedback on the Proposed Accountable Care Organizations Rules By Dalia Buffery, MA, ABD

he release of the proposed new rules for accountable care organizations (ACOs)1 has elicited diverse reactions. The Centers for Medicare & Medicaid Services (CMS) encourages healthcare providers, suppliers, and Medicare beneficiaries to submit comments on the rules, which CMS will seriously consider before releasing the final rules on June 6.2 The ACO program will be launched on January 1, 2012.1 On the day the rules were released, CMS Administrator Donald M. Berwick, MD, wrote, “Whatever form ACOs eventually take, one thing is certain: the era of fragmented care delivery should draw to a close. Too many Medicare beneficiaries—like many other patients —have suffered at the hands of wasteful, ineffective, and poorly coordinated systems of care, with consequent costs that are proving unsustainable.”2 According to CMS, these rules will enable “providers to better coordinate care for Medicare patients through” ACOs. In addition to financial incentives for care coordination, however, “ACOs could also have to pay back Medicare for failing to provide efficient, cost-effective care.”1 The main points of the proposed ACO rules are1: ➤ An ACO will require teams of doctors, hospitals, and other providers to work together to coordinate care ➤ ACOs must meet high-quality standards to ensure patients are happy with their care and their health outcomes improve ➤ ACOs that save money this way will share in these savings with Medicare ➤ ACOs could also have to pay back Medicare for failing to provide cost-effective care ➤ Minimum requirements for an existing ACO to be accepted into the program are serving ≥5000 Medicare patients and agreeing to participate for 3 years ➤ Medicare providers who join an ACO that participates in this program would continue to receive payment under the original Medicare fee-for-service rules ➤ The ACO is responsible for monitoring and reporting of the care it delivers ➤ Each ACO will be measured against a performance benchmark for that ACO ➤ An established minimum savings rate accounts for variations in healthcare spending, representing a percentage of the benchmark that ACO savings must exceed to qualify for shared savings ➤ ACOs that participate in the 2-sided risk model can obtain greater shared savings.

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Initial responses from the medical community have been mixed. William F. Jessee, MD, FACMPE, President and CEO of the Medical Group Management Association (MGMA) was rather encouraging, saying, “The formation of ACOs has the potential to greatly improve the coordination of care received by Medicare beneficiaries, and offers the promise of safer, more efficient and effective care.…MGMA and our members will develop specific feedback to CMS and the other agencies to ensure that any overly restrictive or administratively burdensome requirements are addressed so this well-intended concept can become a practical reality.”3 Jeremy A. Lazarus, MD, speaker of the American Medical Association House of Delegates, sounded a similar tone, “ACOs offer great promise for improving care coordination and quality while reducing cost, but only if all physicians who wish to are able to lead and participate in them.”4 By contrast, Karen Ignagni, President and CEO of America’s Health Insurance Plans, said, “We remain concerned that ACOs could accelerate the trend of provider consolidation that drives up medical prices and result in additional cost-shifting to families and employers with private coverage.”5 Dr Berwick further wrote that “the Center for Medicare and Medicaid Innovation is also now exploring ways to test alternative models of ACOs that differ from the models specified in the proposed rule.”2 In the spirit of collaboration that has been the impetus for American Health & Drug Benefits, we urge all stakeholders to leave their silo’s perspective and provide comments to CMS, to avert potential pitfalls and encourage innovation in healthcare, for which no one group holds the key. It will require stakeholder integration to turn our sick system into a wellness-promoting enterprise. ■ References 1. Centers for Medicare and Medicaid Services. What providers need to know: accountable care organizations. March 31, 2011. https://aaos.aristotle.com/Shared %20Documents/ACO%20Rule/ACOs%20-%20CMS%20provider%20fact% 20sheet.pdf. Accessed April 2, 2011. 2. Berwick DM. Launching accountable care organizations—the proposed rule for the Medicare shared savings program. March 31, 2011. N Engl J Med online. http://healthpolicyandreform.nejm.org/?p=14106. Accessed April 2, 2011. 3. Medical Group Management Association. MGMA comments on ACO proposed rule. March 31, 2011. www.mgma.com/press/default.aspx?id=1248413. Accessed April 2, 2011. 4. Fiegel C. CMS releases proposed ACO rules. www.ama-assn.org/amednews/2011/ 03/28/gvse0331.htm. Accessed April 2, 2011. 5. America’s Health Insurance Plans. AHIP statement on Medicare shared saving program. March 31, 2011. www.ahipcoverage.com/2011/03/31/ahip-statement-onmedicare-shared-savings-program/. Accessed April 2, 2011.

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There is no quick fix. The cracks in our current healthcare system did not happen overnight, and the solutions we seek will, likewise, take time to build. At AstraZeneca, we believe that a new level of connectedness and collaboration can lead to innovative breakthroughs in healthcare. If you too want to be part of the solution for better healthcare, we welcome the opportunity to work together with you to connect new data sources, generate real-world evidence and insights, and accelerate delivery of dramatically improved patient outcomes at significantly lower costs. Are you up for the challenge?

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INDUSTRY TRENDS

The Patient-Centered Medical Home: An Essential Destination on the Road to Reform By Matt Adamson Vice President, Health Solutions, MEDecision, Inc.

n recent years, the patient-centered medical home (PCMH)—often referred to in its abbreviated form, the “medical home” —care delivery model has become one of the hottest topics in healthcare. Based on a holistic, patient-centric approach, the PCMH represents a methodology aimed at fostering increased collaboration among healthcare stakeholders. As such, the PCMH is widely believed to offer perhaps the best hope to transform and improve the system as a whole. For example, Geisinger Health System reduced hospital readmissions by 18% through its medical home program and by 44% with its ProvenCare one-price elective cardiac surgery medical home program.1 Paul Grundy, MD, MPH, Global Director of Healthcare Transformation for IBM and Chairman of the PatientCentered Primary Care Collaborative, recently stated in his keynote presentation of the Medical Home Summit in Philadelphia that his review of evidence from ongoing PCMH pilots has resulted in a 9.6% overall reduction in costs.2 To a certain degree, the PCMH is a reversal of the longstanding episode-based methodology that has been prevalent in healthcare for many years. Unlike the episodic-based care, the PCMH encourages patients and their providers to work closely together to ensure that care is more comprehensive, coordinated, and consistent. In essence, the medical home necessitates an ongoing, full-spectrum approach to patient care that requires the primary healthcare provider and the patients themselves to maintain complete awareness of the patients and their specific healthcare needs and experiences. This approach should result in more streamlined and appropriate care, reduced waste, lower costs and, most important, better outcomes. Although the PCMH model had already been building momentum on its own, interest in this concept skyrocketed after it received a significant endorsement in the Patient Protection and Affordable Care Act (ACA) of 2010. That legislation strongly encourages the proliferation of medical homes and accountable care organizations (ACOs) as innovative means of delivering and reimbursing for better coordinated and cost-effective care.

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The Patient-Centered Primary Care Collaborative (PCPCC.net) is an organization with the goals of facilitating improvements in patient–physician relations, and creating a more effective and efficient model of healthcare delivery. They have created a stakeholder group charged with showing that the PCMH provides the foundation for successful implementation of the ACO delivery model. Moving patients through the ACO will require a strong element of care coordination, so we look forward to seeing the results of this group.

ACOs and the Patient-Centered Medical Home An ACO is a business and a medical entity that accepts responsibility for the cost and the quality of care provided to a given population of patients and generates the data on their performance. This includes physician practices and may include hospitals, nursing homes, home health agencies, and other provider organizations. The ACO model is called out specifically within the ACA as a preferred solution for bending the healthcare cost curve, while improving patient outcomes. There is funding within the bill to implement ACOs for Medicare and Medicaid,3 and the criteria have already been determined for ACOs to become involved with both programs. Because the PCMH will provide the care coordination that is required to make the ACO model work, most ACOs will likely take root in areas that have a sufficient number of medical homes. The Benefits to Patients and Providers In addition to the system-wide improvements it is expected to foster, the PCMH can also offer distinct sets of benefits for healthcare’s primary stakeholders— patients, providers, and health plans. In a medical home structure, the patient is aligned with a care coordinator (normally a registered nurse, physician assistant, or social worker) at the provider practice level whose primary function is to manage the patient’s health across the care spectrum. The care coordinator interfaces on the patient’s behalf with the health plan, specialists, pharmacists, labs, and other stakeholders to formulate a more efficient

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and holistic approach to treatment. This generally results in a more informed and engaged patient—one who, through the care coordinator, has a more simplified access to care, better understands his or her own needs, and is more likely to comply with treatment recommendations and suggested preventive measures. For providers, the PCMH fosters an environment of transparent reporting on progress toward measurable outcomes that could potentially result in certain medical home incentives and bonus payments. Such additional reimbursement to the family physician also provides a benefit to society as a whole, because it addresses the primary care shortage that is predicted to occur if current trends in healthcare continue. This is important, because primary care is the foundation of the healthcare system. In areas where primary care is strong, patients have better outcomes and are more satisfied, while health disparities and healthcare costs are lower.4 In addition, with the ability to outsource aspects of care coordination to the health plan or to other entities, the provider can simultaneously maximize outcomes. That is, by reducing or eliminating certain associated administrative functions, clinical practices can manage more patients, at a lower cost. Health plans generally maintain the most comprehensive clinical data available for their individual members. In the medical home, they provide this information to provider practices electronically and establish bonus and incentive structures for relevant outcomes. Providers, in turn, can plan and manage related activities to maximize the benefits.

The Benefits to Health Plans For health plans, the medical home model can offer distinct competitive advantages in a number of key areas, including: • Reduced costs and improved health outcomes. Although this value proposition has yet to be fully tested, the PCMH model is the most promising way of significantly enhancing the efficiency and cost-effectiveness of care management. • Clinical relevance. A health plan adds value to the care management process with its rich patient data and expertise. Its willingness to collaborate with customers is attractive to employers investigating the PCMH as a means of keeping their workforce productive, and to providers making this paradigm shift. • Member satisfaction and retention. Members whose health is managed within the medical home structure generally report greater overall satisfaction. This becomes a significant factor under healthcare reform, wherein members will have a greater opportunity to switch between health plans.

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• Provider satisfaction. Early physician satisfaction scores show that primary care physicians derive greater satisfaction within the PCMH model compared with the existing fee-for-service approach. For example, Group Health of Puget Sound reported after implementation of the PCMH model, “less staff burnout, with only 10% of pilot clinic staff reporting high emotional exhaustion at 12 months compared to 30% of staff at control clinics, and, major improvement in recruitment and retention of primary care physicians.”5 Therefore, the medical home creates an opportunity for payers to strengthen relationships with provider networks, by offering systems and reimbursement frameworks that support care coordination and a team-based approach. • Improved care collaboration. By fostering an environment of patient-centric activity closer to the patient and leveraging the relationship patients have with their primary care physician, care management administration and oversight are shifted to the point of care. With the right tools in place, the payer remains connected.

This is important, because primary care is the foundation of the healthcare system. In areas where primary care is strong, patients have better outcomes and are more satisfied, while health disparities and healthcare costs are lower. Technology Key to Success of the Medical Home The PCMH model is heavily predicated on the effective use of technology, which is clearly outlined in the healthcare reform law. Technology is the most promising means of enabling the very collaboration among healthcare stakeholders that is the foundation for the medical home concept itself. In particular, analytics technology— especially that which is focused on optimizing care management and quality reporting—will be key to the success of the medical home approach and to optimizing health outcomes. Technology will enable medical home participants to receive patient data that have been analyzed and to identify factors such as gaps in care and medication adherence. This more inclusive, 360-degree view of the patient’s information that spans the full continuum of care, regardless of where the patient is seen, will enable more focused plans of care. An example of this involves the integration of pharmacy services as part of the medical home, which is a

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critical aspect of care when managing patients with many conditions who have received prescriptions from multiple physicians. The American College of Clinical Pharmacy has stated in its 2009 report, Integration of Pharmacists’ Clinical Services in the Patient-Centered Primary Care Medical Home, that “Over the last decade, the clinical consequences and economic costs of medication misuse, and medication-related problems, including patient non-adherence and suboptimal therapeutic outcomes, have become more fully recognized by clinicians, policymakers, and health care economists.”6 Inclusion of the pharmacist within the medical home workflow is a necessary first step in alleviating these issues by improved care coordination.

Technology will enable medical home participants to receive patient data that have been analyzed and to identify factors such as gaps in care and medication adherence.

rather than being required to maintain high numbers of full-time staff to provide a full range of services.

A Rare Opportunity With the PCMH, the healthcare reform law may indeed be on to something—a rare instance in which each healthcare stakeholder stands to gain a lot, while sacrificing or compromising little. A number of test programs and pilots to date have generated favorable returns.5 Naturally, not all have been without their share of obstacles, and countless lessons have been learned, but evidence is mounting to indicate that the medical home, in practice, can deliver what many people have believed it can, in theory.5 If the tenets and mandates of reform are to take hold and achieve their true potential, the PCMH will undoubtedly play a significant role in making it happen. ■ Author Disclosure Statement Mr Adamson reported no conflicts of interest.

References The effective deployment of technical solutions can enable any physician practice, regardless of its size or its patient population, to successfully participate in a medical home model by establishing what, in essence, is a virtual medical home. Within this environment, the physician practice will be able to electronically connect with the health plan and other outside resources to deliver the same advantages of a “true” medical home, but with significantly less financial investment and administrative overhead. This is the result of allowing smaller physician practices to use resources as needed

1. Geisinger CEO urges Senate to change healthcare reimbursement. September 16, 2008. https://webapps.geisinger.org/ghsnews/articles/GeisingerCEOUrgesSenateto7996. html. Accessed March 28, 2011. 2. Who was the shooter’s doctor? IBM. Slide 17. www.ehcca.com/presentations/med homesummit3/grundy_1.pdf. Accessed March 28, 2011. 3. Centers for Medicare & Medicaid Services. Medicare “Accountable Care Organizations” shared savings program—new section 1899 of Title XVIII. www.cms. gov/OfficeofLegislation/Downloads/AccountableCareOrganization.pdf. Accessed March 22, 2011. 4. Michigan Primary Care Consortium. Primary care is in crisis. www.mipcc.org/sites/ mipcc.org/files/u4/crisis_part1_web.pdf. Accessed March 22, 2011. 5. Patient-Centered Primary Care Collaborative. Proof in practice: a compilation of patient-centered medical home pilot and demonstration projects. 2009. www.pcpcc.net/files/PilotGuidePip.pdf. Accessed March 22, 2011. 6. American College of Clinical Pharmacy. Integration of pharmacists’ clinical services in the patient-centered primary care medical home. March 2009. www.accp. com/docs/misc/pcmh_services.pdf. Accessed March 22, 2011.

WEB EXCLUSIVE

Accountable Care Organizations: The End of Innovation in Medicine? By Scott Gottlieb, MD

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Victoza® (liraglutide [rDNA origin] injection) Rx Only BRIEF SUMMARY. Please consult package insert for full prescribing information. WARNING: RISK OF THYROID C-CELL TUMORS: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors [see Contraindications and Warnings and Precautions]. INDICATIONS AND USAGE: Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Important Limitations of Use: Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza® only to patients for whom the potential benefits are considered to outweigh the potential risk. Victoza® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators. Victoza® has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®. Use with caution in patients with a history of pancreatitis. Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. The concurrent use of Victoza® and insulin has not been studied. CONTRAINDICATIONS: Victoza® is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). WARNINGS AND PRECAUTIONS: Risk of Thyroid C-cell Tumors: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice. Malignant thyroid C-cell carcinomas were detected in rats and mice. A statistically significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure compared to controls. It is unknown whether Victoza® will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors could not be determined by clinical or nonclinical studies [see Boxed Warning, Contraindications]. In the clinical trials, there have been 4 reported cases of thyroid C-cell hyperplasia among Victoza®-treated patients and 1 case in a comparator-treated patient (1.3 vs. 0.6 cases per 1000 patient-years). One additional case of thyroid C-cell hyperplasia in a Victoza®-treated patient and 1 case of MTC in a comparator-treated patient have subsequently been reported. This comparator-treated patient with MTC had pre-treatment serum calcitonin concentrations >1000 ng/L suggesting pre-existing disease. All of these cases were diagnosed after thyroidectomy, which was prompted by abnormal results on routine, protocol-specified measurements of serum calcitonin. Four of the five liraglutide-treated patients had elevated calcitonin concentrations at baseline and throughout the trial. One liraglutide and one non-liraglutide-treated patient developed elevated calcitonin concentrations while on treatment. Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. The serum calcitonin assay used in the Victoza® clinical trials had a lower limit of quantification (LLOQ) of 0.7 ng/L and the upper limit of the reference range was 5.0 ng/L for women and 8.4 ng/L for men. At Weeks 26 and 52 in the clinical trials, adjusted mean serum calcitonin concentrations were higher in Victoza®treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. At these timepoints, the adjusted mean serum calcitonin values (~ 1.0 ng/L) were just above the LLOQ with between-group differences in adjusted mean serum calcitonin values of approximately 0.1 ng/L or less. Among patients with pre-treatment serum calcitonin below the upper limit of the reference range, shifts to above the upper limit of the reference range which persisted in subsequent measurements occurred most frequently among patients treated with Victoza® 1.8 mg/day. In trials with on-treatment serum calcitonin measurements out to 5-6 months, 1.9% of patients treated with Victoza® 1.8 mg/day developed new and persistent calcitonin elevations above the upper limit of the reference range compared to 0.8-1.1% of patients treated with control medication or the 0.6 and 1.2 mg doses of Victoza®. In trials with on-treatment serum calcitonin measurements out to 12 months, 1.3% of patients treated with Victoza® 1.8 mg/day had new and persistent elevations of calcitonin from below or within the reference range to above the upper limit of the reference range, compared to 0.6%, 0% and 1.0% of patients treated with Victoza® 1.2 mg, placebo and active control, respectively. Otherwise, Victoza® did not produce consistent dose-dependent or time-dependent increases in serum calcitonin. Patients with MTC usually have calcitonin values >50 ng/L. In Victoza® clinical trials, among patients with pre-treatment serum calcitonin <50 ng/L, one Victoza®-treated patient and no comparator-treated patients developed serum calcitonin >50 ng/L. The Victoza®-treated patient who developed serum calcitonin >50 ng/L had an elevated pre-treatment serum calcitonin of 10.7 ng/L that increased to 30.7 ng/L at Week 12 and 53.5 ng/L at the end of the 6-month trial. Follow-up serum calcitonin was 22.3 ng/L more than 2.5 years after the last dose of Victoza®. The largest increase in serum calcitonin in a comparator-treated patient was seen with glimepiride in a patient whose serum calcitonin increased from 19.3 ng/L at baseline to 44.8 ng/L at Week 65 and 38.1 ng/L at Week 104. Among patients who began with serum calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of Victoza®-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients, with an incidence of 1.1% among patients treated with 1.8 mg/day of Victoza®. The clinical significance of these findings is unknown. Counsel patients regarding the risk for MTC and the symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate the potential risk of MTC, and such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Patients with thyroid nodules noted on physical examination or neck imaging obtained for other reasons should be referred to an endocrinologist for further evaluation. Although routine monitoring of serum calcitonin is of uncertain value in patients treated with Victoza®, if serum calcitonin is measured and found to be elevated, the

patient should be referred to an endocrinologist for further evaluation. Pancreatitis: In clinical trials of Victoza®, there were 7 cases of pancreatitis among Victoza®-treated patients and 1 case among comparator-treated patients (2.2 vs. 0.6 cases per 1000 patient-years). Five cases with Victoza® were reported as acute pancreatitis and two cases with Victoza® were reported as chronic pancreatitis. In one case in a Victoza®-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. One additional case of pancreatitis has subsequently been reported in a Victoza®-treated patient. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. There are no conclusive data establishing a risk of pancreatitis with Victoza® treatment. After initiation of Victoza®, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, Victoza® and other potentially suspect medications should be discontinued promptly, confirmatory tests should be performed and appropriate management should be initiated. If pancreatitis is confirmed, Victoza® should not be restarted. Use with caution in patients with a history of pancreatitis. Use with Medications Known to Cause Hypoglycemia: Patients receiving Victoza® in combination with an insulin secretagogue (e.g., sulfonylurea) may have an increased risk of hypoglycemia. In the clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza®-treated patients and in two comparator-treated patients. Six of these 7 patients treated with Victoza® were also taking a sulfonylurea. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea or other insulin secretagogues [see Adverse Reactions]. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Victoza® or any other antidiabetic drug. ADVERSE REACTIONS: Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Victoza® was evaluated in a 52-week monotherapy trial and in five 26-week, add-on combination therapy trials. In the monotherapy trial, patients were treated with Victoza® 1.2 mg daily, Victoza® 1.8 mg daily, or glimepiride 8 mg daily. In the add-on to metformin trial, patients were treated with Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, placebo, or glimepiride 4 mg. In the add-on to glimepiride trial, patients were treated with Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, placebo, or rosiglitazone 4 mg. In the add-on to metformin + glimepiride trial, patients were treated with Victoza® 1.8 mg, placebo, or insulin glargine. In the add-on to metformin + rosiglitazone trial, patients were treated with Victoza® 1.2 mg, Victoza® 1.8 mg or placebo. Withdrawals: The incidence of withdrawal due to adverse events was 7.8% for Victoza®-treated patients and 3.4% for comparator-treated patients in the five controlled trials of 26 weeks duration or longer. This difference was driven by withdrawals due to gastrointestinal adverse reactions, which occurred in 5.0% of Victoza®-treated patients and 0.5% of comparator-treated patients. The most common adverse reactions leading to withdrawal for Victoza®-treated patients were nausea (2.8% versus 0% for comparator) and vomiting (1.5% versus 0.1% for comparator). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2-3 months of the trials. Tables 1, 2 and 3 summarize the adverse events reported in *5% of Victoza®-treated patients in the six controlled trials of 26 weeks duration or longer. Table 1: Adverse events reported in *5% of Victoza®-treated patients or *5% of glimepiride-treated patients: 52-week monotherapy trial All Victoza® N = 497 Glimepiride N = 248 (%) (%) Adverse Event Term Nausea 28.4 8.5 Diarrhea 17.1 8.9 Vomiting 10.9 3.6 Constipation 9.9 4.8 Upper Respiratory Tract Infection 9.5 5.6 Headache 9.1 9.3 Influenza 7.4 3.6 Urinary Tract Infection 6.0 4.0 Dizziness 5.8 5.2 Sinusitis 5.6 6.0 Nasopharyngitis 5.2 5.2 Back Pain 5.0 4.4 Hypertension 3.0 6.0 Table 2: Adverse events reported in *5% of Victoza®-treated patients and occurring more frequently with Victoza® compared to placebo: 26-week combination therapy trials Add-on to Metformin Trial All Victoza® + Placebo + Glimepiride + Metformin N = 724 Metformin N = 121 Metformin N = 242 (%) (%) (%) Adverse Event Term Nausea 15.2 4.1 3.3 Diarrhea 10.9 4.1 3.7 Headache 9.0 6.6 9.5 Vomiting 6.5 0.8 0.4 Add-on to Glimepiride Trial All Victoza® + Placebo + Rosiglitazone + Glimepiride N = 695 Glimepiride N = 114 Glimepiride N = 231 (%) (%) (%) Adverse Event Term Nausea 7.5 1.8 2.6 Diarrhea 7.2 1.8 2.2 Constipation 5.3 0.9 1.7 Dyspepsia 5.2 0.9 2.6

Add-on to Metformin + Glimepiride Placebo + Metformin Glargine + Metformin Victoza® 1.8 + + Glimepiride + Glimepiride Metformin + N = 232 N = 114 Glimepiride N = 230 (%) (%) (%) Adverse Event Term Nausea 13.9 3.5 1.3 10.0 5.3 1.3 Diarrhea Headache 9.6 7.9 5.6 Dyspepsia 6.5 0.9 1.7 Vomiting 6.5 3.5 0.4 Add-on to Metformin + Rosiglitazone ® All Victoza + Metformin + Placebo + Metformin Rosiglitazone N = 355 + Rosiglitazone N = 175 (%) (%) Adverse Event Term Nausea 34.6 8.6 Diarrhea 14.1 6.3 12.4 2.9 Vomiting Decreased Appetite 9.3 1.1 Anorexia 9.0 0.0 Headache 8.2 4.6 Constipation 5.1 1.1 Fatigue 5.1 1.7 Table 3: Treatment-Emergent Adverse Events in 26 Week Open-Label Trial versus Exenatide (Adverse events with frequency *5% and occurring more frequently with Victoza® compared to exenatide are listed) Exenatide 10 mcg twice Victoza® 1.8 mg once daily + metformin and/or daily + metformin and/or sulfonylurea N = 232 sulfonylurea N = 235 (%) (%) Preferred Term Diarrhea 12.3 12.1 Dyspepsia 8.9 4.7 Constipation 5.1 2.6 Gastrointestinal adverse events: In the five clinical trials of 26 weeks duration or longer, gastrointestinal adverse events were reported in 41% of Victoza®-treated patients and were dose-related. Gastrointestinal adverse events occurred in 17% of comparator-treated patients. Events that occurred more commonly among Victoza®-treated patients included nausea, vomiting, diarrhea, dyspepsia and constipation. In a 26-week study of Victoza® versus exenatide, both in combination with metformin and/or sulfonylurea overall gastrointestinal adverse event incidence rates, including nausea, were similar in patients treated with Victoza® and exenatide. In five clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time. Approximately 13% of Victoza®-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment. In a 26 week study of Victoza® versus exenatide, both in combination with metformin and/or sulfonylurea, the proportion of patients with nausea also declined over time. Immunogenicity: Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with Victoza® may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza®-treated patients in the five clinical trials of 26 weeks duration or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Low titers (concentrations not requiring dilution of serum) of anti-liraglutide antibodies were detected in 8.6% of these Victoza®-treated patients. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. Cross-reacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the Victoza®-treated patients in the 52-week monotherapy trial and in 4.8% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of the Victoza®-treated patients in the 52-week monotherapy trial and in 1.0% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. Among Victoza®-treated patients who developed anti-liraglutide antibodies, the most common category of adverse events was that of infections, which occurred among 40% of these patients compared to 36%, 34% and 35% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among Victoza®-treated antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred among 11% of Victoza®-treated antibody-positive patients; and among 7%, 7% and 5% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Among Victoza®-treated antibody-negative patients, the most common category of adverse events was that of gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Antibody formation was not associated with reduced efficacy of Victoza® when comparing mean HbA1c of all antibody-positive and all antibody-negative patients. However, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1c with Victoza® treatment. In clinical trials of Victoza®, events from a composite of adverse events potentially related to immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of Victoza®-treated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for Victoza®-treated patients. Patients who developed anti-liraglutide antibodies were not more likely to develop events from the immunogenicity events composite than were patients who did not develop anti-liraglutide antibodies. Injection site reactions: Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of Victoza®-treated patients in the five clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza®-treated patients discontinued due to injection site reactions.

Papillary thyroid carcinoma: In clinical trials of Victoza®, there were 6 reported cases of papillary thyroid carcinoma in patients treated with Victoza® and 1 case in a comparator-treated patient (1.9 vs. 0.6 cases per 1000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Hypoglycemia: In the clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza®-treated patients (2.6 cases per 1000 patient-years) and in two comparator-treated patients. Six of these 7 patients treated with Victoza® were also taking a sulfonylurea. One other patient was taking Victoza® in combination with metformin but had another likely explanation for the hypoglycemia (this event occurred during hospitalization and after insulin infusion) (Table 4). Two additional cases of hypoglycemia requiring the assistance of another person for treatment have subsequently been reported in patients who were not taking a concomitant sulfonylurea. Both patients were receiving Victoza®, one as monotherapy and the other in combination with metformin. Both patients had another likely explanation for the hypoglycemia (one received insulin during a frequently-sampled intravenous glucose tolerance test, and the other had intracranial hemorrhage and uncertain food intake). Table 4: Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in the 52-Week Monotherapy Trial and in the 26-Week Combination Therapy Trials Victoza® Active Placebo Treatment Comparator Comparator ® Monotherapy Victoza Glimepiride None (N = 497) (N = 248) Patient not able to self−treat 0 0 — Patient able to self−treat 9.7 (0.24) 25.0 (1.66) — Not classified 1.2 (0.03) 2.4 (0.04) — ® Placebo + Glimepiride + Add-on to Victoza + Metformin Metformin Metformin Metformin (N = 121) (N = 242) (N = 724) Patient not able to self−treat 0.1 (0.001) 0 0 Patient able to self−treat 3.6 (0.05) 22.3 (0.87) 2.5 (0.06) ® Add-on to Glimepiride Victoza + Placebo + Rosiglitazone + Glimepiride Glimepiride Glimepiride (N = 114) (N = 231) (N = 695) Patient not able to self−treat 0.1 (0.003) 0 0 Patient able to self−treat 7.5 (0.38) 4.3 (0.12) 2.6 (0.17) Not classified 0.9 (0.05) 0.9 (0.02) 0 Victoza® + Placebo + Add-on to None Metformin + Metformin + Metformin + Rosiglitazone Rosiglitazone Rosiglitazone (N = 175) (N = 355) Patient not able to self−treat 0 — 0 Patient able to self−treat 7.9 (0.49) — 4.6 (0.15) Not classified 0.6 (0.01) — 1.1 (0.03) Placebo + Victoza® + Add-on to Insulin glargine Metformin + Metformin + + Metformin + Metformin + Glimepiride Glimepiride Glimepiride Glimepiride (N = 114) (N = 232) (N = 230) Patient not able to self−treat 2.2 (0.06) 0 0 Patient able to self−treat 27.4 (1.16) 28.9 (1.29) 16.7 (0.95) Not classified 0 1.7 (0.04) 0 In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neoplasms (based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label study periods) was 10.9 for Victoza®, 6.3 for placebo, and 7.2 for active comparator. After excluding papillary thyroid carcinoma events [see Adverse Reactions], no particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication, six events among Victoza®treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not been established. Laboratory Tests: In the five clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of Victoza®-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparatortreated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. OVERDOSAGE: In a clinical trial, one patient with type 2 diabetes experienced a single overdose of Victoza® 17.4 mg subcutaneous (10 times the maximum recommended dose). Effects of the overdose included severe nausea and vomiting requiring hospitalization. No hypoglycemia was reported. The patient recovered without complications. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. More detailed information is available upon request. For information about Victoza® contact: Novo Nordisk Inc., 100 College Road West, Princeton, New Jersey 08540, 1−877-484-2869 Date of Issue: December 22, 2010 Version: 2 Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark Victoza® is a registered trademark of Novo Nordisk A/S. Victoza® is covered by US Patent Nos. 6,268,343; 6,458,924; and 7,235,627 and other patents pending. Victoza® Pen is covered by US Patent Nos. 6,004,297; 6,235,004; 6,582,404 and other patents pending. © 2011 Novo Nordisk 140586-R2 2/2011

For patients who need more than metformin

Help grab type 2 diabetes by the roots. Once-daily Victoza® provides powerful and sustained* reductions in A1C and:

Impacts beta-cell function to help regulate insulin secretion May reduce weight – Victoza® is not indicated for the management of obesity – Weight change was a secondary end point in clinical trials *Victoza® was evaluated in a 52-week monotherapy trial and in five 26-week, add-on combination trials.

Indications and usage Important safety information Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza® only to patients for whom the potential benefits are considered to outweigh the potential risk. Victoza® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators. Victoza® has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®. Use with caution in patients with a history of pancreatitis. Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. The concurrent use of Victoza® and insulin has not been studied.

Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors. If pancreatitis is suspected, Victoza® should be discontinued. Victoza® should not be re-initiated if pancreatitis is confirmed. When Victoza® is used with an insulin secretagogue (e.g. a sulfonylurea) serious hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia. There have been no studies establishing conclusive evidence of macrovascular risk reduction with Victoza® or any other antidiabetic drug. The most common adverse reactions, reported in ≥5% of patients treated with Victoza® and more commonly than in patients treated with placebo, are headache, nausea, diarrhea, and anti-liraglutide antibody formation. Immunogenicity-related events, including urticaria, were more common among Victoza®-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. Victoza® has not been studied in type 2 diabetes patients below 18 years of age and is not recommended for use in pediatric patients. Victoza® should be used with caution in patients with renal impairment and in patients with hepatic impairment. Please see brief summary of Prescribing Information on adjacent page.

To learn how Victoza® can help your patients manage their type 2 diabetes, visit VictozaPro.com/Benefit.

April 2011