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THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ MAY/JUNE 2011

VOLUME 4, NUMBER 3

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

PERSPECTIVES

Systematic Health Management: The Time Has Come to Do the Right Thing for Each Person By Jeff Rideout, MD, MA, FACP

New Efficiencies in Healthcare? Not Likely By Theodore Dalrymple

BUSINESS ™

Utilization, Spending, and Price Trends for Short- and Long-Acting BetaAgonists and Inhaled Corticosteroids in the Medicaid Program, 1991-2010 Shih-Feng Chiu, MPH; Christina M.L. Kelton, PhD; Jeff Jianfei Guo, MS, BPharm, PhD; Patricia R. Wigle, PharmD; Alex C. Lin, PhD; Sheryl L. Szeinbach, PhD, RPh

Stakeholder Perspective by Bryan Amick, PharmD, MBA

The Economic Impact of Delaying 5-Alpha Reductase Inhibitor Therapy in Men Receiving Treatment for Symptomatic Benign Prostatic Hyperplasia Michael Naslund, MD, MBA; Michael T. Eaddy, PharmD, PhD; Susan L. Hogue, PharmD, MPH; Eric J. Kruep, PharmD, MS; Manan B. Shah, PharmD, PhD

Stakeholder Perspective by Matthew Mitchell, PharmD, MBA CLINICAL

From A to Z: Medication Cost-Management Strategies for Disproportionate Share Hospitals Andrea Henry, PharmD, MBA; Goldina Ikezuagu Erowele, PharmD; Uche Anadu Ndefo, PharmD, BCPS; Jackie Milton-Brown, PharmD; Enock Anassi, PharmD, MD; Wendy Green, PharmD, MPA; Adriana Alvidrez, PharmD, BCPS; Alphonsus U. Okpara, PharmD

Stakeholder Perspective by Diana Rangaves, PharmD, CEO

AMCP HIGHLIGHTS

HIGHLIGHT

©2011 Engage Healthcare Communications, LLC www.AHDBonline.com


DEXILANT WORKS A

SECOND SHIFT TO HELP SHUT DOWN ACID PUMPS

DEXILANT is the first and only PPI with a Dual Delayed Release™ (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

6

12

18

24

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 C74740;8=6>50;;6A034B>54A>B8E44B>?7068C8B5>AD?C>F44:B M <08=C08=8=6740;8=6>55>AD?C><>=C7B0=3 M C74 CA40C<4=C >5 740AC1DA= 0BB>280C43 F8C7 BH<?C><0C82 =>=4A>B8E4 60BCA>4B>?70640;A4KDG38B40B4'5>AF44: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?>AC43F8C7,!#)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<0H140BB>280C43F8C70=8=2A40B43A8B:5>A>BC4>?>A>B8BA4;0C43 5A02CDA4B>5C7478?FA8BC>AB?8=4)74A8B:>55A02CDA4F0B8=2A40B438=?0C84=CB F7> A4248E43 78673>B4 34J=43 0B <D;C8?;4 308;H 3>B4B 0=3 ;>=6C4A< %% 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>B8BA4;0C43 5A02CDA4B B7>D;3 14 <0=0643 022>A38=6 C> 4BC01;8B743CA40C<4=C6D834;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 <>=C7B0=3

?0C84=CBCA40C435>A>=4H40A%0C84=CBA0=6438=0645A>< C>  H40AB<4380=064H40ABF8C754<0;40D20B80=;02: B80=0=3 >C74AA024B(8GA0=3><8I432>=CA>;;432;8=820;CA80;BF4A42>=3D2C43 5>AC74CA40C<4=C>5<08=C4=0=24>5740;430=3BH<?C><0C82'F7827 8=2;D343?0C84=CB>=?;0241>?0C84=CB>=,!#) <6

?0C84=CB >=,!#) <60=3  ?0C84=CB>=;0=B>?A0I>;4 <6>=24308;H B2;8=820;CA80;B0A42>=3D2C43D=34AF834;HE0AH8=62>=38C8>=B03E4AB4A402C8>= A0C4B>1B4AE438=C742;8=820;CA80;B>503AD620==>C1438A42C;H2><?0A43C>A0C4B8= C742;8=820;CA80;B>50=>C74A3AD60=3<0H=>CA4K42CC74A0C4B>1B4AE438=?A02C824 ">BC><<>=;H'4?>AC433E4AB4'402C8>=B )74<>BC2><<>=03E4AB4A402C8>=Bâ&#x2030;Ľ C70C>22DAA430C078674A8=2834=24 5>A,!#)C70=?;0241>8=C742>=CA>;;43BCD384B0A4?A4B4=C438=)01;4  Table 2: Incidence of Treatment-Emergent Adverse Reactions in Controlled Studies %;0241>

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3E4AB4'402C8>=B'4BD;C8=68=8B2>=C8=D0C8>= = 2>=CA>;;43 2;8=820; BCD384B C74 <>BC 2><<>= 03E4AB4 A402C8>= ;4038=6 C> 38B2>=C8=D0C8>=5A><,!#)C74A0?HF0B380AA740  $C74A3E4AB4'402C8>=B $C74A03E4AB4A402C8>=BC70CF4A4A4?>AC438=2>=CA>;;43BCD384B0C0=8=2834=24 >5;4BBC70= 0A4;8BC4314;>F1H1>3HBHBC4< 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 0AA4CCB 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<>DC73D>34=8C8B3HB?4?B803HB?706804=C4A8C8B4AD2C0C8>= 4B>?7068C8B60BCA82?>;H?60BCA8C8B60BCA>4=C4A8C8B60BCA>8=C4BC8=0;38B>A34AB

60BCA>8=C4BC8=0; 7H?4A<>C8;8CH 38B>A34AB '  D;24AB 0=3 ?4A5>A0C8>= 74<0C4<4B8B74<0C>274I8074<>AA7>83B8<?08A4360BCA824<?CH8=68AA8C01;4 1>F4;BH=3A><4<D2DBBC>>;B=0DB400=3E><8C8=6>A0;<D2>B0;1;8BC4A8=6 ?08=5D; 345420C8>= ?A>2C8C8B ?0A4BC74B80 >A0; A42C0; 74<>AA7064 General Disorders and Administration Site Conditions:03E4AB43AD6A402C8>=0BC74=80 274BC ?08= 278;;B 544;8=6 01=>A<0; 8=K0<<0C8>= <D2>B0; 8=K0<<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=KD4=I0 =0B>?70AH=68C8B >A0; 74A?4B ?70AH=68C8BB8=DB8C8BE8A0;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=2A40B431;>>360BCA8=8=2A40B431;>>36;D2>B48=2A40B431;>>3?>C0BB8D< 8=2A40B43;8E4A5D=2C8>=C4BC01=>A<0;?;0C4;4C2>D=C342A40B43C>C0;?A>C48= 8=2A40B43 F4867C 8=2A40B4 Metabolism and Nutrition Disorders: 0??4C8C4 270=64B7H?4A20;24<807H?>:0;4<80 Musculoskeletal and Connective Tissue Disorders:0AC7A0;6800AC7A8C8B<DB2;42A0<?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?=>407822D?B7H?4AE4=C8;0C8>=A4B?8A0C>AHCA02C2>=64BC8>=B>A4C7A>0C Skin and Subcutaneous Tissue Disorders: 02=434A<0C8C8B4AHC74<0?ADA8C8B A0B7 B:8= ;4B8>= DAC820A80 Vascular Disorders: 344? E48= C7A><1>B8B 7>C KDB77H?4AC4=B8>= 338C8>=0; 03E4AB4 A402C8>=B C70C F4A4 A4?>AC43 8= 0 ;>=6C4A< D=2>=CA>;;43 BCD3H 0=3 F4A4 2>=B834A43 A4;0C43 C> ,!#) 1H C74 CA40C8=6 ?7HB8280= 8=2;D3430=0?7H;0G8B0D38C>AH70;;D28=0C8>=24;;;H<?7><01DAB8C8B24=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>BC4A7H?4A6;H24<807H?4A;8?834<807H?>C7HA>838B<8=2A40B43=4DCA>?78;B "342A40B4=4DCA>?4=80>A0;B>5CC8BBD438B>A34AA42C0;C4=4B<DBA4BC;4BB ;46BBH=3A><4B><=>;4=24C7A><1>2HC74<80C>=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 3E4AB4A402C8>=B70E4144=834=C8J433DA8=6?>BC0??A>E0;>5,!#)B C74B4A402C8>=B0A4A4?>AC43E>;D=C0A8;H5A><0?>?D;0C8>=>5D=24AC08=B8I48C 8B=>C0;F0HB?>BB81;4C>A4;801;H4BC8<0C4C748A5A4@D4=2H>A4BC01;8B7020DB0; A4;0C8>=B78?C>3AD64G?>BDA4 Eye Disorders1;DAA43E8B8>= Gastrointestinal Disorders>A0;434<0 General Disorders and Administration Site Conditions50280;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><4C>G824?834A<0;=42A>;HB8BB><450C0; Musculoskeletal System DisorderB1>=45A02CDA4 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=8BC4A43F8C70C0I0=0E8A C8BC74>A4C820;;H?>BB81;4C70C,!#)<0H8=C4A54A4F8C7C7401B>A?C8>=>5 >C74A3AD6BF74A460BCA82?8B0=8<?>AC0=C34C4A<8=0=C>5>A0;18>0E08;018;8CH 460<?828;;8=4BC4AB386>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>5F0A50A8=>A#'>F4E4AC74A470E4144=A4?>ACB>58=2A40B43 #'0=3?A>C7A><18=C8<48=?0C84=CBA4248E8=6%%B0=3F0A50A8=2>=2><8C0=C;H =2A40B4B8=#'0=3?A>C7A><18=C8<4<0H;403C>01=>A<0;1;4438=60=34E4= 340C7%0C84=CBCA40C43F8C7,!#)0=3F0A50A8=2>=2><8C0=C;H<0H=443C> 14<>=8C>A435>A8=2A40B4B8=#'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. Š2009, 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.

Š2011Takeda Pharmaceuticals North America, Inc. LPD-01450R1 01/11 Printed in U.S.A.


EDITORIAL BOARD

CLINICAL EDITOR

HEALTH INFORMATION TECHNOLOGY

PHARMACOECONOMICS

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

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

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.

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

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

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

Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute of Integrated Healthcare Sharon, MA EPIDEMIOLOGY RESEARCH

PHARMACY BENEFIT DESIGN

Joel V. Brill, MD Chief Medical Officer, Predictive Health, Phoenix, AZ William J. Cardarelli, PharmD Director of Pharmacy, Atrius Health Harvard Vanguard Medical Associates

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

Leslie S. Fish, PharmD Sr. Director of Pharmacy Services Fallon Community Health Plan, MA Michael S. Jacobs, RPh National Clinical Practice Leader Buck Consultants, Atlanta

Gordon M. Cummins, MS Director, IntegriChain

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

Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver

Paul Anthony Polansky, BSPharm, MBA Senior Field Scientist, Health Outcomes and PharmacoEconomics (HOPE) Endo Pharmaceuticals Inc., Chadds Ford, PA

Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Timothy S. Regan, BPharm, RPh Executive Director, Xcenda Palm Harbor, FL

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

HEALTH & VALUE PROMOTION

POLICY & PUBLIC HEALTH

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

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

MANGED CARE AND MANAGEMENT

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

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

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

MANAGED MARKETS

Jeffrey A. Bourret, RPh, MS, FASHP Senior Director, Branded Specialty Pharmacy Programs, US Specialty Customers Pfizer, Specialty Care Business Unit, PA Charles E. Collins, Jr, MS, MBA Vice President, Managed Markets Strategy Fusion Medical Communications PATIENT ADVOCACY

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

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

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

Vol 4, No 3

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May/June 2011

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

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

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MAY/JUNE 2011

VOLUME 4, NUMBER 3 THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS BUSINESS

140 Utilization, Spending, and Price Trends for Short- and Long-Acting Beta-Agonists and Inhaled Corticosteroids in the Medicaid Program, 1991-2010 Shih-Feng Chiu, MPH; Christina M.L. Kelton, PhD; Jeff Jianfei Guo, MS, BPharm, PhD; Patricia R. Wigle, PharmD; Alex C. Lin, PhD; Sheryl L. Szeinbach, PhD, RPh 149 Stakeholder Perspective by Bryan Amick, PharmD, MBA 155 The Economic Impact of Delaying 5-Alpha Reductase Inhibitor Therapy in Men Receiving Treatment for Symptomatic Benign Prostatic Hyperplasia Michael Naslund, MD, MBA; Michael T. Eaddy, PharmD, PhD; Susan L. Hogue, PharmD, MPH; Eric J. Kruep, PharmD, MS; Manan B. Shah, PharmD, PhD 161 Stakeholder Perspective by Matthew Mitchell, PharmD, MBA

CLINICAL

172 From A to Z: Medication Cost-Management Strategies for Disproportionate Share Hospitals Andrea Henry, PharmD, MBA; Goldina Ikezuagu Erowele, PharmD; Uche Anadu Ndefo, PharmD, BCPS; Jackie Milton-Brown, PharmD; Enock Anassi, PharmD, MD; Wendy Green, PharmD, MPA; Adriana Alvidrez, PharmD, BCPS; Alphonsus U. Okpara, PharmD 179 Stakeholder Perspective by Diana Rangaves, PharmD, CEO

Mission Statement Continued on page 138

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.

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Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889 Director of Client Services Mark Timko 732-992-1897 Associate Editors Brett Kaplan brett@engagehc.com Lara J. Reiman lara@engagehc.com 732-992-1892 Editorial Assistant Jessica A. Smith Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino Business Manager Blanche Marchitto Founding Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com

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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.

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May/June 2011

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moving millimeters

NEW EDARBI: Head-to-head efficacy trials versus the highest marketed doses of DIOVAN® (320 mg) and BENICAR® (40 mg) 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 ▼ Similar results were observed across two other comparator studies: Mean ambulatory baseline: Study 2 vs BENICAR 40 mg and Study 3 vs DIOVAN 320 mg Study 1=144.9 mm Hg ▼ Clinic SBP differences between EDARBI and active comparators STUDY 1 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, renin-angiotensin-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.

Trademarks are the property of their respective owners. ©2011 Takeda Pharmaceuticals North America, Inc. All rights reserved. LXA-00331 04/11


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

PK

Fold Change and 90% CI

Recommendation

AGE >65y/18-45y

Cmax AUC

No dose adjustment

Cmax AUC

No dose adjustment

Cmax AUC

No dose adjustment

GENDER Females/Males RACE Whites/Blacks RENAL IMPAIRMENT 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

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. Š2011 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


MAY/JUNE 2011

VOLUME 4, NUMBER 3 THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS

(Continued)

PERSPECTIVES

152 Systematic Health Management: The Time Has Come to Do the Right Thing for Each Person By Jeff Rideout, MD, MA, FACP 185 New Efficiencies in Healthcare? Not Likely By Theodore Dalrymple

DEPARTMENTS

AMCP highlights 163 Economic and Clinical Value of integrating a Clinical Pharmacist into the Care Management team impact of Value-Based insurance Design on Medication Utilization and Costs in a large Retail Employer 164 Current trends in the Pharmaceutical Pipeline: Key Players to Watch, Few surprises 166 Degree of Adherence in Chronic Diseases inversely Correlates with healthcare Costs Do Medication therapy Management Programs Achieve their goals?

CAPTION CONTEST

180

POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

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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.

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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 Microalbuminuria (albumin in the urine *30 mg/day or *20 µg/min) is the earliest clinical evidence of renal disease6 Regular dilated eye examinations can be effective in detecting vision-threatening diabetic retinopathy6,7 Because diabetic neuropathy may be asymptomatic in about 50% of patients, it is important to conduct a physical examination of lower extremities and feet annually 6,8 It’s important to recognize and screen for microvascular complications in patients with type 2 diabetes as early as possible.7 Effective management of diabetes can help prevent or slow the progression of microvascular complications. 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. American Diabetes Association. Nephropathy in diabetes. Diabetes Care. 2004;27(suppl 1):S79-S83. 6. American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care. 2011;34(suppl 1):S11-S61. 7. Fong DS,Ferris FL, Aiello LP, Klein R. Diabetic retinopathy. Diabetes Care. 2004;27(10):2540-2553. 8. Boulton AJM, Arezzo JC, Malik RZ, et al. Diabetic somatic neuropathies. Diabetes Care. 2004;27(6):1458-1486.

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Utilization, Spending, and Price Trends for Short- and Long-Acting Beta-Agonists and Inhaled Corticosteroids in the Medicaid Program, 1991-2010 Shih-Feng Chiu, MPH; Christina M.L. Kelton, PhD; Jeff Jianfei Guo, MS, BPharm, PhD; Patricia R. Wigle, PharmD; Alex C. Lin, PhD; Sheryl L. Szeinbach, PhD, RPh

Shih-Feng Chiu

Christina M.L. Kelton

Stakeholder Perspective, page 149

Am Health Drug Benefits. 2011;4(3):140-149. www.AHDBonline.com Disclosures are at end of text

Background: Asthma is a chronic respiratory disease that afflicts millions of people and accounts for substantial utilization of healthcare resources in most industrialized countries, including in the United States. However, the exact cost and utilization of anti-asthma medications in Medicaid in the past 2 decades have not been well studied. Considering the safety issues surrounding the long-acting beta-agonists, guideline updates, and the increase in asthma prevalence, understanding anti-asthma medication prescribing trends is important to payers and patients. Goal: The purpose of this study was to analyze the utilization and spending trends for antiasthmatic agents in the US Medicaid program over the past 2 decades. Methods: This study was based on a retrospective, descriptive analysis of trends in utilization of and spending on anti-asthma medications, including short-acting beta-agonists, inhaled corticosteroids, long-acting beta-agonists, and inhaled corticosteroid/long-acting betaagonist combinations. Quarterly utilization and expenditure data were obtained from the national Medicaid pharmacy files provided by the Centers for Medicare & Medicaid Services from quarter 1 of 1991 through quarter 2 of 2010. Average reimbursement per prescription was calculated each quarter as a proxy for drug price. Results: The total number of prescriptions for the studied anti-asthma medications rose from 8.9 million in 1991 to 15.6 million in 2009, peaking at 20.8 million in 2005, the year before Medicare and Medicaid dual-eligible beneficiaries were moved to Medicare Part D. From 1991 to 2009, Medicaid spending on anti-asthma medications overall rose from $180.7 million to $1.3 billion, and spending on inhaled corticosteroid/long-acting beta-agonist combinations rose from $52.8 million in 2001—their first year on the market—to $411.7 million in 2009. The average price per prescription has risen in all the anti-asthma drug classes: overall, spending per prescription has increased 4-fold between 1991 and 2009, significantly faster than the consumer price index (57.5%) over the same period. In quarter 2 of 2010, Medicaid spent more on the combination medication fluticasone-salmeterol—$60 million—than on any other antiasthma medication. Conclusion: Anti-asthma medications are a major and growing expense for state Medicaid programs and can be expected to be the same for Medicare Part D in the future. Increased disease prevalence has in part contributed to the rise in pharmacotherapy cost. Nevertheless, drug therapy is crucial for managing asthma and asthma exacerbations.

Mr Chiu is PhD candidate, James L. Winkle College of Pharmacy, University of Cincinnati Medical Center; Dr Kelton is Professor of Economics, College of Business, University of Cincinnati; Dr Guo is Associate Professor of Pharmacoeconomics & Pharmacoepidemiology, James L. Winkle College of Pharmacy, University of Cincinnati Medical Center; Dr Wigle is Associate Professor of Pharmacy Practice, James L. Winkle College of Pharmacy, University of Cincinnati Medical Center; Dr Lin is Assistant Professor of Pharmacy Systems and Administration, James L. Winkle College of Pharmacy, University of Cincinnati; Dr Szeinbach is Professor, Division of Pharmacy Practice and Administration, College of Pharmacy, Ohio State University, Columbus; all in Ohio. This study was presented as a poster at the annual meeting of the International Society for Pharmacoeconomics and Outcomes Research, Orlando, FL, May 17-20, 2009.

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Utilization and Price Trends of Anti-Asthma Medications in Medicaid

A

sthma is a chronic respiratory disease that affects anywhere from 1% to 18% of the world population.1-4 In the United States, the prevalence rate is estimated at 11%, which represents approximately 36 million individuals.5 Because asthma is known to occur concomitantly with allergic rhinitis and is often associated with other comorbidities and risk factors,6-9 symptoms reported by patients are multifaceted and have consequences that are inimical to work productivity and health.10-12 In the United States, asthma accounts for more than 10 million missed work days for adults annually and for approximately 13 million missed school days.13 The economic burden of asthma includes the direct costs of health services utilized for prevention and treatment, as well as indirect costs of lost productivity, reduced work performance, and premature mortality.14,15 In 2009, annual total costs for asthma in the United States were estimated at more than $20 billion.16 Environmental changes, continued exposure to allergens, and infections are purported culprits underlying allergic events and account for the increasing prevalence of asthma, as well as the inability to control asthma symptoms in certain populations.17-19 Pharmacotherapy is essential for asthma management; according to the 2007 National Heart, Lung, and Blood Institute (NHLBI) guidelines, drug therapy should be based on stepwise treatment for different levels of asthma severity—intermittent, mild persistent, moderate persistent, and severe persistent.20 Before initiating drug therapy, the most important aspect of treatment is to ensure that patients undergo appropriate evaluation and diagnostic testing to determine the etiology underlying asthma or allergic-induced asthma symptoms; 70% of patients with allergies also have asthma.21 Asthma medications are broadly divided into 2 categories. Rescue medications or relievers, consisting of short-acting beta-agonists (SABAs), are utilized for immediate relief of asthma symptoms and are recommended for all patients with asthma, including those with intermittent disease. Controllers or maintenance medications, such as long-acting beta-agonists (LABAs) or inhaled corticosteroids (ICSs), are recommended for those with persistent asthma.22-25 Although SABAs provide immediate relief for acute bronchospasm, the guidelines for asthma therapy state that SABAs that are used more than twice weekly, with the exception of use for exercise-induced bronchospasm, generally indicate inadequate control of symptoms.20 Given the safety concerns surrounding LABA side effects, a patient whose persistent asthma symptoms are not controlled adequately with an ICS alone can be managed by increasing the ICS dose or adding a LABA to the ICS.26-29 Furthermore, findings from some studies

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KEY POINTS ➤

Approximately 36 million Americans are affected by asthma. Asthma accounts for approximately 10 million missed work days and 13 million missed school days annually. The prevalence and severity of asthma in the United States have been increasing in the past 2 decades, especially among children in low-income households. From 1991 to 2009, Medicaid spending on antiasthma medications rose by 595%, from $180.7 million to $1.3 billion; the total annual cost of asthma was estimated at $20 billion in 2009. The average price of an anti-asthma medication in the past 2 decades increased by 295%, as a result of a tremendous rise in demand for these medications by patients and payers; this rise in price greatly exceeded the 57.5% increase in the consumer price index over the same period. Despite these significant cost trends, pharmacotherapy is key to controlling the serious nature of asthma and its associated exacerbations, which often lead to hospitalizations and even greater costs and healthcare utilization.

indicated that using a LABA as monotherapy is not efficient for a significant reduction of asthma symptoms. Consequently, for patients with severe or persistent asthma, a LABA should be combined with an ICS to increase the control of asthma symptoms.30-32 Previous studies and several comprehensive metaanalyses have addressed issues related to safety and efficacy of SABAs, LABAs, and ICSs. However, only a few studies have examined market share and prescribing trends in the asthma medication market.33-35 Considering the safety issues surrounding LABA use, guideline updates, and worldwide increase in asthma prevalence, understanding medication prescribing trends would seem to be important. The objectives of this study were to describe trends in reimbursement, utilization, and prices of individual medications and classes of medications (SABAs, LABAs, ICSs, and ICS/LABA combination drugs) for the US Medicaid population over the past 2 decades. We realize that these medications are indicated for other diseases besides asthma, such as LABAs for chronic obstructive pulmonary disease (COPD). The trends that we identify will be for overall drug spending and utilization regardless of indication treated.

Methods This study was a retrospective, descriptive analysis of trends in utilization of and spending for SABAs, LABAs,

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Table 1 Study Drugs Brand name

Generic name

FDA approval date

Manufacturer

Patent expiration

Short-acting beta-agonists Alupent

Metaproterenol sulfate

01/01/1982

Boehringer Ingelheim

NA

Brethine

Terbutaline sulfate

01/01/1982

Novartis

NA

Maxair

Pirbuterol acetate

12/30/1986

3M

05/12/2004

ProAir HFA

Albuterol

10/29/2004

Teva Global

02/25/2014

Proventil

Albuterol

01/01/1982

Schering

Proventil HFA

Albuterol

08/15/1996

3M

07/06/2010

Ventolin

Albuterol

04/19/2001

GlaxoSmithKline

10/14/2015

Ventolin HFA

Albuterol

04/19/2001

GlaxoSmithKline

10/14/2015

Xopenex

Levalbuterol hydrochloride

03/25/1999

Sepracor

01/05/2010

Xopenex HFA

Levalbuterol tartrate

03/11/2005

Sepracor

07/06/2010

Aerobid

Flunisolide

08/17/1984

Roche Palo

06/12/2007

Asmanex

Mometasone furoate

03/30/2005

Schering

07/27/2014

Azmacort

Triamcinolone acetonide

04/23/1982

Abbott

12/31/2007

Flovent

Fluticasone propionate

05/14/2004

GlaxoSmithKline

08/19/2014

Flovent HFA

Fluticasone propionate

05/14/2004

GlaxoSmithKline

08/19/2014

Pulmicort

Budesonide

06/24/1997

AstraZeneca

08/27/2006

Pulmicort Flexhaler

Budesonide

07/12/2006

AstraZeneca

01/09/2018

Qvar

Beclomethasone dipropionate

09/15/2000

Ivax Res

11/28/2009

Vancenase

Beclomethasone dipropionate

01/01/1982

Schering

12/21/1999

Vanceril

Beclomethasone dipropionate

01/01/1982

Schering

NA

NA

Inhaled corticosteroids

Long-acting beta-agonists Foradil

Formoterol fumarate

02/16/2001

Novartis

03/08/2019

Serevent

Salmeterol xinafoate

02/04/1994

GlaxoSmithKline

02/12/2008

Inhaled corticosteroid + long-acting beta-agonist combinations Advair Diskus

Fluticasone propionate + salmeterol xinafoate

08/24/2000

GlaxoSmithKline

08/12/2008

Advair HFA

Fluticasone propionate + salmeterol xinafoate

06/08/2006

GlaxoSmithKline

08/12/2008

Symbicort

Budesonide + formoterol fumarate dihydrate

07/21/2006

AstraZeneca

09/23/2012

FDA indicates US Food and Drug Administration; NA, not applicable.

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Utilization and Price Trends of Anti-Asthma Medications in Medicaid

ICSs, and ICS/LABA combination drugs. Pharmacy utilization and expenditure data were obtained from the national Medicaid pharmacy files provided by the Centers for Medicare & Medicaid Services (CMS) from quarter 1 of 1991 through quarter 2 of 2010. These files contained the number of outpatient prescriptions and amount of payments made for all National Drug Code (NDC) drug forms by each of 49 states (all except Arizona) plus the District of Columbia.36 This large database was compiled across all states and contains some reporting errors. If data for a particular drug for a specific quarter were considered unreliable, data were imputed from values from previous and/or later quarters. Table 1 lists the anti-asthma drugs studied, as well as the manufacturers, approval dates, and patent expiration dates for those drugs. For each quarter, drug utilization was determined by summing the number of prescriptions across NDC codes associated with that drug. Similarly, reimbursement was calculated by summing across the reimbursements for individual NDCs. If a particular drug was produced by both branded and generic drug manufacturers, generic and branded data were both collected. In 2005, the US Food and Drug Administration (FDA) mandated that the propellant chlorofluorocarbon used in inhalers be replaced with the more environmentally friendly hydrofluoroalkane (HFA). Several HFA brands, including Xopenex (levalbuterol), Ventolin (albuterol sulfate), and Proventil (albuterol sulfate), entered the market during the study period, and (for purposes of this study) were combined with their non-HFA counterparts. By dividing the total reimbursement by the number of prescriptions, a prescription price was determined for each drug. This price is prerebate, because we do not have access to mandated or supplemental rebate data. The price does include reimbursement for pharmacy dispensing. The per-prescription cost was not adjusted by medication strength (eg, 40 mg or 80 mg). Because most medications in these drug classes are prescribed using standard protocols and exhibit similar trends in utilization, concerns for bias were minimal.37,38 Both SAS Version 9.1 (SAS Institute Inc, Cary, NC) and Microsoft Excel 2007 were used for the analysis.

Results Increased Overall Utilization, Cost Table 2 (page 144) shows annual utilization in Medicaid by anti-asthma drug class. The total number of prescriptions rose from 8.9 million in 1991 to 15.6 million in 2009, peaking at 20.8 million in 2005. Whereas the trend in SABA prescriptions has remained relatively

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flat, the number of prescriptions for combination ICS/LABA inhalers increased sharply from 0.4 million in 2001â&#x20AC;&#x201D;their first year of market entryâ&#x20AC;&#x201D;to 3.9 million in 2005, and then dropped to 2.0 million in 2009, after the movement of Medicare and Medicaid dual-eligible beneficiaries to Medicare Part D in 2006. Prescriptions for ICSs and LABAs were 4.6 million and 0.1 million, respectively, in 2009. From 1991 to 2009, Medicaid spending on antiasthma medications rose from $180.7 million to $1.3 billion annually, an increase of 595%. Spending on ICS/LABA combination drugs rose from $52.8 million in 2001 to $411.7 million in 2009, an increase of 680% in just 9 years. Average price per prescription has risen in all the anti-asthma drug classes. Overall spending per prescription has increased 4-fold between 1991 and 2009, significantly faster than the 57.5% increase of the consumer price index over the same period.39 The average price for an ICS/LABA combination prescription was $208.77 in 2009 compared with an average price of $119.60 in 2001.

Individual Drug Utilization, Cost: SABAs Figure 1 (page 145) presents the utilization of individual SABAs. It is clear that albuterol dominated the market during most of the study period, with a maximum of approximately 2.5 million prescriptions reimbursed by Medicaid each quarter in 2004 and 2005. In quarter 2 of 2010, the last quarter in the study, approximately 0.5 million prescriptions for albuterol were reimbursed. In the early 1990s, Proventil was the market leader, with utilization of approximately 800,000 to 1 million prescriptions per quarter. After 1995, the utilization of Proventil decreased dramatically, to less than 200,000 prescriptions per quarter, and its utilization kept decreasing through quarter 4 of 2005, although it rebounded after 2005. Ventolin was also widely prescribed in the early 1990s, with 500,000 to 850,000 prescriptions per quarter. Xopenex entered the anti-asthma medication market in 1999, and since 2001 has sold 100,000 to 500,000 or so prescriptions per quarter to Medicaid. As seen in Figure 2 (page 145), in the early 1990s Medicaid spent the most on the SABAs Proventil and Ventolin, but later, it spent the most on albuterol and Xopenex. In quarter 4 of 2001, Medicaid spent $55.5 million on albuterol and $51.5 million the next quarter. SABA prices have generally increased over time. The price of Xopenex rose from $78.52 in quarter 2 of 1999, its quarter of market entry, to $118.62 in quarter 2 of 2010 (Figure 3, page 145). The price of Maxair (pirbuterol acetate) increased impressively from $18.51 in quarter 1 of 1991 to $50.53 in quarter 4 of 1999, and

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8.9

8.5

8.4

8.4

11.6

10.8

11.0

10.0

9.5

8.7

8.1

6.8

7.1

7.9

9.4

9.5

10.0

4.6

4.0

3.8

3.8

4.9

4.7

4.6

4.6

4.8

4.1

3.8

3.5

4.4

4.1

0.1

0.1

0.1

0.1

0.4

0.6

0.4

0.1

0.2

0.1

0.1

0.0

0.1

0.1

2.0

2.0

1.8

1.8

3.9

3.4

2.5

1.4

0.4

136.3 158.6 173.5 269.3 285.3

286.5 338.2 392.3 610.6 783.3

1256.5

1176.7

1054.2

1051.6

1307.2

1189.6

403.4

375.1

335.6

335.6

271.0

289.1

298.0

164.4

334.8

1003.5

187.5

328.9

226.2

338.5

3.5

0.1

222.2

320.7

3.6

0.0

223.6

307.0

3.3

192.9

253.4

144.3

SABA

2.7

Total 180.7

LABA ICS/LABA

1.9

ICS

10.2 9.1 8.0

401.0 433.4

39.7

389.6

370.1

49.8

354.9

10.2

31.4

332.7

370.1

10.5

10.9

8.6

5.4

2.5

6.5

5.5

3.9

0.3

411.7

391.4

338.3

335.7

606.8

495.8

341.5

182.7

52.8

LABA ICS/LABA

304.8

277.6

210.2

174.2

147.7

164.0

135.8

108.3

98.2

83.4

60.5

36.4

ICS

Spending, $ million

80.63

80.53

75.34

75.24

62.79

61.46

54.38

48.52

40.88

30.35

28.33

27.76

28.75

27.19

26.07

24.48

23.01

21.93

20.39

Total

ICSs indicates inhaled corticosteroids; LABAs, long-acting beta-agonists; SABAs, short-acting beta-agonists.

15.6

20.8

2005

2009

19.4

2004

14.6

18.5

2003

2008

16.1

2002

14.0

14.9

2001

2007

12.9

2000

14.0

11.9

1999

2006

10.3

1998

13.0

1995

11.6

13.1

1994

1997

13.3

1993

12.1

11.6

1992

1996

7.0

8.9

1991

8.9

SABA

Utilization, millions of prescriptions

Total

Year

Table 2 Medicaid Annual Spending on SABAs, ICSs, LABAs, and ICS/LABA Combinations, 1991-2010

45.25

43.92

40.16

40.16

23.37

26.85

27.16

28.55

28.29

19.94

19.65

20.17

23.03

23.76

24.09

23.44

22.31

21.75

20.72

SABA

96.52

89.69

80.87

71.69

71.17

67.44

62.58

55.24

54.88

51.13

50.03

45.82

93.34 150.92

99.04 137.53

98.61 118.02

208.77

200.13

188.18

188.39

155.87

146.65

138.71

127.97

119.60

LABA ICS/LABA

98.61 118.02

79.27

76.25

71.83

66.60

57.58

51.30

46.11

42.00

37.33

33.16

30.84

27.15

25.15

22.53

19.19

ICS

Spending/prescription, $

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Utilization and Price Trends of Anti-Asthma Medications in Medicaid

Figure 1 Quarterly Utilization of Individual SABAs by Medicaid: 1991-2010 3,000,000

2,500,000

Number of prescriptions

then to $120.97 in quarter 2 of 2010. Although the price of Brethine (terbutaline) mimicked that for Xopenex for several years, reaching a maximum of $143.26 in quarter 2 of 2002, its price decreased quickly after that, and, indeed, was down to $60.63 in quarter 2 of 2010, about half the price of Xopenex. Prices for Proventil and Ventolin showed more modest increases from $22.18 and $17.43, respectively, in quarter 1 of 1991, to $51.88 and $36.34 in quarter 3 of 2010, although still considerably outpacing the rate of inflation. A prescription for albuterol cost Medicaid $19.81 in quarter 2 of 2010, an increase from $13.10 in quarter 1 of 1991.

Albuterol Maxair Proventil Xopenex

Alupent Metaproterenol Terbutaline

Brethine ProAir Ventolin

2,000,000

1,500,000

1,000,000

500,000

0 1991Q1

1993Q1

1995Q1

1997Q1

1999Q1

2001Q1

2003Q1

2005Q1

2007Q1

2009Q1

SABAs indicates short-acting beta-agonists.

Figure 2 Quarterly Spending on Individual SABAs by Medicaid, 1991-2010

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60,000,000

Albuterol Maxair Proventil Xopenex

Spending by Medicaid, $

50,000,000

Alupent Metaproterenol Terbutaline

Brethine ProAir Ventolin

40,000,000

30,000,000

20,000,000

10,000,000

0 1991Q1

1993Q1

1995Q1

1997Q1

1999Q1

2001Q1

2003Q1

2005Q1

2007Q1

2009Q1

SABAs indicates short-acting beta-agonists.

Figure 3 Quarterly Per-Prescription Spending on Individual SABAs by Medicaid, 1991-2010 160 140

Average prescription price, $

Individual Drug Utilization, Cost: LABAs As seen in Figure 1 for rescue medications, Figure 4 (page 146) depicts the prescription trends for individual maintenance medications, including ICSs, LABAs, and ICS/LABA combinations. As is evident from Figure 4, Advair (fluticasone and salmeterol), an ICS/LABA combination drug in a single inhaler, was the most prescribed maintenance medication between quarter 4 of 2002 and quarter 1 of 2009. The quarterly Advair prescription count reached almost 1.0 million in quarter 4 of 2005. Since quarter 1 of 2009, the prescriptions for Flovent (fluticasone propionate) have exceeded those for Advair. Utilization of Pulmicort (budesonide) was steady at 200,000 to 300,000 prescriptions per quarter at the end of the study period. In terms of Medicaid expenditures on maintenance medications, Advair has dominated the market (Figure 5, page 146). Medicaid spent more than $100 million each quarter from quarter 4 of 2003 through quarter 4 of 2005 on this drug alone. The second vertical axis in Figure 5 emphasizes the dominance of Advair in Medicaid spending. Some of the maintenance medications have seen steeply rising prices (Figure 6, page 146). The price of Advair rose steadily, from $118.27 in 2001 quarter 2 to $218.07 in 2010 quarter 2. The price of Symbicort, the other FDA-approved ICS/LABA combination drug, was $196.79 in quarter 2 of 2010. The per-prescription price of Pulmicort more than doubled from $105.52 in quarter 4 of 1997 to $274.44 in quarter 2 of 2010.

Albuterol Maxair Proventil Xopenex

Alupent Metaproterenol Terbutaline

Brethine ProAir Ventolin

120

100

80

60

40 20 0 1991Q1

1993Q1

1995Q1

1997Q1

1999Q1

2001Q1

2003Q1

2005Q1

2007Q1

2009Q1

 SABAs indicates short-acting beta-agonists.

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Quarterly Utilization of Individual ICSs, LABAs, and ICS/LABA Figure 4 Combinations by Medicaid, 1991-2010 1,000,000

800,000

Number of prescriptions

Pulmicort + budesonide Qvar + beclomethasone Serevent  Symbicort Vancenase Vanceril

Advair Aerobid + flunisolide Asmanex + mometasone Azmacort + triamcinolone Flovent + fluticasone Foradil + formoterol

900,000

700,000

 



600,000 500,000 400,000 300,000 200,000 100,000 0 1991Q1

1993Q1

1995Q1

1997Q1

1999Q1

2001Q1

2003Q1

2005Q1

2007Q1

2009Q1

ICSs indicates inhaled corticosteroids; LABAs, long-acting beta-agonists. 

  Spending on Individual ICSs, LABAs, and ICS/LABA Figure 5 Quarterly Combinations by Medicaid, 1991-2010

60,000,000

50,000,000

Aerobid + flunisolide Asmanex + mometasone Azmacort + triamcinolone Flovent + fluticasone Foradil + formoterol Pulmicort + budesonide

160,000,000

Qvar + beclomethasone Serevent Symbicort Vancenase Vanceril Advair

140,000,000 120,000,000 100,000,000

40,000,000 80,000,000 30,000,000 60,000,000 20,000,000 40,000,000 10,000,000

Spending by Medicaid for Advair, $

Spending by Medicaid for drugs other than Advair, $

70,000,000

20,000,000

0 1991Q1 1993Q1 1995Q1 1997Q1 1999Q1 2001Q1 2003Q1 2005Q1 2007Q1 2009Q1

0

ICSs indicates inhaled corticosteroids; LABAs, long-acting beta-agonists.

Quarterly Per-Prescription Spending on Individual ICSs, LABAs, and Figure 6 ICS/LABA Combinations by Medicaid, 1991-2010 300

Advair Aerobid + Flunisolide Asmanex + mometasone Azmacort + triamcinolone Flovent + fluticasone Foradil + formoterol

Average prescription price, $

250

200

Pulmicort + budesonide Qvar + beclomethasone Serevent  Symbicort Vancenase Vanceril

 



150

100

50

0 1991Q1

1993Q1

1995Q1

1997Q1

1999Q1

2001Q1

2003Q1

2005Q1

2007Q1

2009Q1

ICSs indicates inhaled corticosteroids; LABAs, long-acting beta-agonists.

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Discussion Increasing Disease Prevalence, and Severity The rise in utilization of asthma medications by Medicaid beneficiaries from 1991 to 2010 is not surprising. First, the prevalence rate of asthma has increased over time in the United States, from 3.5% in 1982 to 5.5% in 1996, and then from 7.3% in 2001 to 7.7% in 2007.40 The increase has been even sharper for children, who make up a fairly large percentage of the Medicaid population.13 Moreover, asthma disproportionately impacts households of a lower socioeconomic status. Complicating the treatment of asthma in Medicaid beneficiaries is the substantial exposure they have to asthma triggers, such as dust and dust reservoirs, dust mites, roaches, rodents, molds, and tobacco smoke that could exacerbate their condition.41 Meanwhile, the number of Medicaid beneficiaries has more than doubled over the past 2 decades. The average monthly enrollment in Medicaid in the year 1990 was 22.9 million.42 In 2009, that figure reached 50.7 million.42 In 2010, average monthly Medicaid enrollment was 53.6 million (more than one sixth of the US population),42 after the worst economic recession (December 2007-June 2009) in a quarter century. In fact, in October 2009, the national unemployment rate reached 10.1%.43 This cyclical component (more Medicaid beneficiaries in times of recession and declining numbers in expansions) may also explain some of the downward movement in medication use in the late 1990s, when the US economy was quite strong. With the implementation of Medicare Part D in 2006, dual-eligibles (those eligible for Medicaid and Medicare) were moved to Medicare Part D, explaining the decrease in utilization that year. As the prevalence rate for asthma has been increasing over time, its severity level has been rising as well.40 Because all patients with persistent asthma are encouraged to supplement their rescue medication with a maintenance medication, it is not surprising to see a rise in the utilization of LABAs, ICSs, and ICS/LABA combinations accompanying rising severity.

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The Introduction of Long-Acting Beta-Agonists The introduction of LABAs was considered a major advance in bronchodilator therapy, with evidence that their use led to improved lung function and quality of life.44-46 Because inhaled SABAs were effective for only 4 to 6 hours, they required frequent daily administration and were often ineffective in preventing common nighttime asthma episodes. Moreover, the SABAs Proventil and Ventolin, both of which contained a 50:50 racemic mixture of albuterol sulfate, appeared to produce unwanted side effects, such as bronchoconstriction and inflammatory responses in some patients with asthma.47 This undesired activity was attributed to (S)albuterol. When Xopenex, containing levalbuterol, entered the market in 1999, it was hoped that the newer drug could control symptoms at lower doses, reduce hospital admissions, decrease length of hospital stays, reduce side effects, and reduce the need for multiple medications.48,49 Although there is ongoing discussion regarding medication preference,50 these potential benefits to levalbuterol could account for the increasing market share for Xopenex since 2000. LABAs have also been plagued by safety issues; physicians have been reluctant to prescribe a LABA without concomitant use of an ICS, a combination that seems to mitigate some of the safety concerns.51 For this reason, and the convenience to the patient of having both medications in a single inhaler, it makes sense to see the extreme positive market reaction to the ICS/LABA combination drugs. In addition, the 2007 NHLBI guidelines recommend the use of LABA therapy as a supplemental treatment to SABAs and ICSs to achieve favorable long-term asthma control in children and adults with moderate-to-severe persistent asthma.20 Increased Medication Price Besides increasing utilization of anti-asthma medications, the increase in the average per-prescription price has certainly played a role in the increased Medicaid spending for SABAs, LABAs, ICSs, and ICS/LABA combination drugs. There has been a 295% increase in average price across all the medications studied between 1991 and 2009. The tremendous increase in demand for anti-asthma medications by patients and payers has exerted upward pressure on price. New entry of branded medications has had no effect on the price dynamics of other drugs in the market. This lack of effect of new entry on price trends of drugs already in the market has been found for other drug classes as well, for example, antipsychotics and anti-ulcer medications.37,52,53 Without generic medication entry, there is not much that Medicaid can do to cut its spending on prescription asthma medications. A number of previous studies have

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shown that the only significant remedy for skyrocketing drug costs is the entry of generic-manufactured drugs.37,52,53 Because some of the anti-asthma medications have been only fairly recently approved by the FDA, their patent protection will last a number of years. It is more than likely that when branded-drug patents do expire, state Medicaid programs will take advantage of available generic options.54

Pharmacotherapy Is Cost-Effective Despite the high and increasing cost of both rescue and maintenance therapy, to the extent that medication reduces the number of serious asthma exacerbations resulting in emergency department visits, hospitalizations, and intubations, spending on pharmaceuticals may be cost-effective. Increasing numbers of children are being hospitalized for asthma because of an increase in asthma severity, poor disease management, and rising poverty. In the United States, asthma is the most common reason for hospitalizations among 3- to 12-year-old children and the second most common reason for hospitalizations among all children, accounting for 7.4% of all pediatric hospitalizations.55 It is suspected that medication adherence is less than optimal especially among low-income, publicly insured children; therefore, some of the hospitalizations could potentially be avoidable.56 However, because of the dynamic nature of asthma, children may be hospitalized in any case, an unavoidable consequence of rising disease severity. Limitations This study has a number of limitations. First, patientspecific information was not available in the Medicaid pharmacy claims database; thus, it was not possible to determine the exact indication or overlapping indications for medication use. Although it is likely that most of the patients taking the study drugs had asthma, others might have had COPD or allergy problems. Because indications were not available, it was not possible to compare the use of these medications with prevalence rates provided by other studies. Nor have we studied an exhaustive list of drugs, which would include, for instance, leukotriene modifiers, mast-cell stabilizers, theophylline, and oral and intravenous steroids used in the treatment of asthma. Second, reimbursement per prescription is but a proxy for drug price. It does not account for manufacturer rebates. In addition, because we summarize reimbursement and prescriptions over all NDC codes for each drug, this does not allow for changes over time in the product mix (ie, varying strengths). Summing also means that some of the NDCs corresponding to generic

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drug formulations (especially mometasone and fluticasone) that are included in the study are not necessarily used in the treatment of asthma. Third, the CMS data contain possible reporting errors. To ensure reliability, some of the values in this study were imputed. Fourth, the results are specific to the Medicaid population and, hence, do not necessarily represent utilization and expenditure trends in other US markets. Finally, the CMS database includes pharmacy claims administered by the state Medicaid programs. Because there has been a significant trend toward Medicaid managed care, some of the pharmacy claims may be administered by managed care rather than through pharmacy carve-out plans. Our database does not allow us to determine the degree of managed care participation in pharmacy claim administration.

Conclusion Anti-asthma medications, including SABAs, LABAs, ICSs, and ICS/LABA combination drugs, are a major expense for US Medicaid programs. Moreover, rising asthma prevalence and worsening severity suggest a high expenditure future as far as these drugs are concerned. Although the rising prevalence is worse for children than for adults and is particularly severe among low-income households, Medicare is also predicted to experience a rising expenditure trend in the future, because this program covers prescription drugs for the elderly. Despite its cost, drug therapy is of paramount importance to control the serious events associated with asthma and its exacerbations. â&#x2013;  Author Disclosure Statement The authors did not receive any funding for this study. Dr Guo receives honoraria from AstraZeneca; is a consultant to Baxter Healthcare; and receives grant support from BristolMyers Squibb, Eli Lilly, Genentech, Janssen Ortho-McNeil, and Novartis. Dr Kelton receives grant support from Eli Lilly, Janssen Ortho-McNeil, and Novartis. Dr Lin receives research support from Hospira and Rite Aid. Dr Wigle receives grant support from Novartis. Mr Chiu and Dr Szeinbach have reported no conflicts of interest.

References 1. Klomp H, Lawson JA, Cockcroft DW, et al. Examining asthma quality of care using a population-based approach. CMAJ. 2008;178:1013-1021. 2. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. 2009. www.ginasthma.com/download.asp?intId=411. Accessed March 9, 2011. 3. Mannino DM, Homa DM, Pertowski CA, et al. Surveillance for asthmaâ&#x20AC;&#x201D;United States, 1960-1995. MMWR CDC Surveill Summ. 1998;47:1-27. 4. Senthilselvan A. Prevalence of physician-diagnosed asthma in Saskatchewan, 1981 to 1990. Chest. 1998;114:388-392. 5. Masoli M, Fabian D, Holt S, Beasley R; for the Global Initiative for Asthma (GINA) program. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004;59:469-478.

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6. Gaugris S, Sazonov-Kocevar V, Thomas M. Burden of concomitant allergic rhinitis in adults with asthma. J Asthma. 2006;43:1-7. 7. Celikel S, Isik SR, Demir AU, et al. Risk factors for asthma and other allergic diseases in seasonal rhinitis. J Asthma. 2008;45:710-714. 8. Boulet LP. Influence of comorbid conditions on asthma. Eur Respir J. 2009;33:897-906. 9. Szeinbach SL, Rodriguez-Monguio R, Baran RW, Williams PB. Sleep disorders and chronic constipation: relation to other co-morbidities? Open Allergy J. 2010;3:29-34. 10. Dean BB, Calimlim BM, Kindermann SL, et al. The impact of uncontrolled asthma on absenteeism and health-related quality of life. J Asthma. 2009;46:861-866. 11. Juniper EF. Quality-of-life considerations in the treatment of asthma. Pharmacoeconomics. 1995;8:123-138. 12. Bousquet J, Knani J, Dhivert H, et al. Quality of life in asthma. I. Internal consistency and validity of the SF-36 questionnaire. Am J Respir Crit Care Med. 1994;149:371-375. 13. Akinbami L. Asthma prevalence, health care use and mortality: United States, 2003-2005. CDC National Center for Health Statistics, 2006. www.cdc.gov/nchs/ data/hestat/asthma03-05/asthma03-05.htm. Accessed March 9, 2011. 14. Weiss KB, Sullivan SD. The economic costs of asthma: a review and conceptual model. Pharmacoeconomics. 1993;4:14-30. 15. Bahadori K, Doyle-Waters MM, Marra C, et al. Economic burden of asthma: a systematic review. BMC Pulm Med. 2009;9:24. 16. National Heart, Lung, and Blood Institute. Morbidity & Mortality: 2009 Chart Book on Cardiovascular, Lung, and Blood Diseases. www.nhlbi.nih.gov/resources/ docs/cht-book.htm. Accessed March 9, 2011. 17. Ho SM. Environmental epigenetics of asthma: an update. J Allergy Clin Immunol. 2010;126:453-465. 18. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med. 2006;355: 2226-2235. 19. Sawicki GS, Vilk Y, Schatz M, et al. Uncontrolled asthma in a commercially insured population from 2002 to 2007: trends, predictors, and costs. J Asthma. 2010; 47:574-580. 20. National Heart, Lung, and Blood Institute. Expert panel report 3: guidelines for the diagnosis and management of asthma. 2007. www.nhlbi.nih.gov/guidelines/ asthma/asthgdln.pdf. Accessed February 28, 2011. 21. World Health Organization. Global surveillance, prevention and control of chronic respiratory diseases: a comprehensive approach. 2007. www.who.int/gard/ publications/GARD_Manual/en/index.html. Accessed March 9, 2011. 22. Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet. 1990;336:1391-1396. 23. Mcivor RA, Pizzichini E, Turner MO, et al. Potential masking effects of salmeterol on airway inflammation in asthma. Am J Respir Crit Care Med. 1998;158:924-930. 24. Salpeter SR, Ormiston TM, Salpeter EE. Meta-analysis: respiratory tolerance to regular beta2-agonist use in patients with asthma. Ann Intern Med. 2004;140:802-813. 25. Hasford J, Virchow JC. Excess mortality in patients with asthma on long-acting beta2-agonists. Eur Respir J. 2006;28:900-902. 26. Price AH, Clissold SP. Salbutamol in the 1980s: a reappraisal of its clinical efficacy. Drugs. 1989;38:77-122. 27. Spitzer WO, Suissa S, Ernst P, et al. The use of beta-agonists and the risk of death and near death from asthma. N Engl J Med. 1992;326:501-506. 28. Pearce N, Beasley R, Crane J, et al. End of the New Zealand asthma mortality epidemic. Lancet. 1995;345:41-44. 29. Rider NL, Craig TJ. A safety review of long-acting beta2-agonists in patients with asthma. J Am Osteopath Assoc. 2006;106:562-567. 30. Lazarus SC, Boushey HA, Fahy JV, et al. Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial. JAMA. 2001;285:2583-2593. 31. Mann M, Chowdhury B, Sullivan E, et al. Serious asthma exacerbations in asthmatics treated with high-dose formoterol. Chest. 2003;124:70-74. 32. Lemanske RF Jr, Sorkness CA, Mauger EA, et al. Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial. JAMA. 2001;285:2594-2603. 33. Simpson CR, Sheikh A. Trends in the epidemiology of asthma in England: a national study of 333,294 patients. J Soc Med. 2010;103:98-106. 34. Shaya FT, Dongyi D, Akazawa MO, et al. Burden of concomitant asthma and COPD in a Medicaid population. Chest. 2008;134:14-19. 35. Broder MS, Gutierrez B, Chang E, et al. Ratio of controller to total asthma medications: determinants of the measure. Am J Manag Care. 2010;16:170-178. 36. Centers for Medicare & Medicaid Services. State drug utilization data. www.cms.hhs.gov/MedicaidDrugRebateProgram/SDUD/list.asp#TopOfPage. Accessed March 9, 2011. 37. Chen Y, Kelton CML, Jing Y, et al. Utilization, price, and spending trends for antidepressants in the US Medicaid program. Res Soc Adm Pharm. 2008;4:244-257. 38. Jing Y, Klein P, Kelton CML, et al. Utilization and spending trends for antiretroviral medications in the US Medicaid program from 1991 to 2005. AIDS Res Ther. 2007;4:22. 39. Bureau of Labor Statistics. Consumer price index-all urban consumers. US city average. All items. www.bls.gov/cpi. Accessed March 6, 2011. 40. American Lung Association. Trends in asthma morbidity and mortality. February 2010. www.lungusa.org/finding-cures/our-research/trend-reports/asthma-trend-

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report.pdf. Accessed on March 9, 2011. 41. Krieger JW, Song L, Takaro TK, Stout J. Asthma and the home environment of low-income urban children: preliminary findings from the Seattle-King County healthy homes project. J Urban Health. 2000;77:50-67. 42. Centers for Medicare & Medicaid Services. Data compendium, 2010 edition. www.cms.gov/DataCompendium/14_2010_Data_Compendium.asp#TopOfPage. Accessed March 9, 2011. 43. National unemployment rate. http://data.bls.gov/timeseries/LNS14000000. Accessed March 6, 2011. 44. Kemp JP, Bierman CW, Cocchetto DM. Dose-response study of inhaled salmeterol in asthmatic patients with 24-hour spirometry and Holter monitoring. Ann Allergy. 1993;70:316-322. 45. Derom EY, Pauwels RA, Van der Straeten ME. The effect of inhaled salmeterol on methacholine responsiveness in patients with asthma up to 12 hours. J Allergy Clin Immunol. 1992;89:811-815. 46. Boyd G, Morice AH, Pounsford JC, et al. An evaluation of salmeterol in the treatment of chronic obstructive pulmonary disease (COPD). Eur Respir J. 1997; 10:815-821. 47. Ameredes BT, Calhoun WJ. Levalbuterol versus albuterol. Curr Allergy Asthma Rep. 2009;9:401-409. 48. Truitt T, Witko J, Halpern M. Levalbuterol compared to racemic albuterol: efficacy and outcomes in patients hospitalized with COPD or asthma. Chest. 2003;123: 128-135.

49. Gawchik SM, Saccar CL, Noonan M, et al. The safety and efficacy of nebulized levalbuterol compared with racemic albuterol and placebo in the treatment of asthma in pediatric patients. J Allergy Clin Immunol. 1999;103:615-621. 50. Crader M, Borkowski J. Nebulized albuterol versus levalbuterol in pediatric and adult patients: a review. Formulary. 2009;44:108-118. 51. Jaeschke R, O’Byrne PM, Mejza F, et al. The safety of long-acting beta-agonists among patients with asthma using inhaled corticosteroids: systematic review and metaanalysis. Am J Respir Crit Care Med. 2008;178:1009-1016. 52. Jing Y, Kelton CML, Guo JJ, et al. Price, utilization, and spending for antipsychotic medications in the Medicaid program. Drug Benefit Trends. 2007;19:27-41. 53. Guo JJ, Kelton CML, Pasquale MK, et al. Price and market-share competition of anti-ulcer gastric medications in the Ohio Medicaid market. Int J Pharm Med. 2004; 18:271-282. 54. Kaiser Commission on Medicaid and the Uninsured. State Medicaid outpatient prescription drug policies: findings from a national survey, 2005 update. www.kff. org/medicaid/upload/State-Medicaid-Outpatient-Prescription-Drug-PoliciesFindings-from-a-National-Survey-2005-Update-report.pdf. Accessed March 9, 2011. 55. Owens PL, Thompson J, Elixhauser A, Ryan K. Care of children and adolescents in U.S. hospitals, 2003. HCUP Fact Book No. 4, publication No. 04-0004. Rockville, MD: Agency for Healthcare Research and Quality. 2003. www.ahrq.gov/data/hcup/ factbk4/factbk4.pdf. Accessed April 25, 2011. 56. Berger WE. Levalbuterol: pharmacologic properties and use in the treatment of pediatric and adult asthma. Ann Allergy Asthma Immunol. 2003;90:583-592.

STAKEHOLDER PERSPECTIVE Medicaid Spending on Asthma Medications PAYERS: Given the severe budget shortfalls currently experienced by Medicaid programs across the country, it is now more important than ever to scrutinize trends within pharmacy spending to ensure that increasingly precious dollars find their way to efficient use of effective medications. In evaluating those trends for asthma agents, the authors of the present article point out that the introduction of new technology, most notably the long-acting beta-agonists, is a significant contributor to the upward trend in the utilization of asthma medication class. Payers are now left to do what they can to drive the effective use of these newer medications, ensuring that factors such as the timing of onset do not lead to inappropriate utilization and nonadherence. These issues are often compounded in the Medicaid population, where health literacy levels are likely to be lower than in the general population, which often affects medication adherence. As the authors note, the lack of transparency in arriving at Medicaid’s “real” cost of medications makes this sort of analysis difficult. The Medicaid Drug Rebate program results in the offset of a substantial portion of Medicaid drug spending, with the system of rebate rate determination structured in such a way that the price benefit of generics is often minimized, and sometimes eliminated completely. In addition, because the rebate rate of brand agents is adjusted by Medicaid

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in an attempt to negate price increases over the consumer price index, the results of drug price inflation are seen in the initial drug spending but are partially counterbalanced by a corresponding increase in the rebate amount. These circumstances may result in a drastically different relative cost picture when evaluating initial pharmacy reimbursement costs than when considering costs after these rebates. PATIENTS: Patients are currently faced with a potentially more complicated regimen of therapy for the treatment of asthma than was the case in previous decades, requiring patients to have a better understanding of their pharmacotherapy. The pharmacology of controller medications, often not having an effect that is immediately noticeable, increases the potential that patients may forgo controller medications and rely on rescue inhalers that produce an immediate beneficial result. For the value of these newer controller medications to be realized, it is critical that patient adherence to the entire medication regimen be encouraged at every possible interaction, whether with the prescriber, the pharmacy, or the payer.

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Bryan Amick, PharmD, MBA Director, Clinical Services Magellan Medicaid Administration Columbia, SC

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Systematic Health Management: The Time Has Come to Do the Right Thing for Each Person By Jeff Rideout, MD, MA, FACP Senior Vice President, Cost and Care Management, and Chief Medical Officer, TriZetto Group, Greenwood Village, CO

T

he statistics and statements about how the current US healthcare system is failing patients and consumers continue like a beating drum. Examples of overutilization, underutilization, and misutilization of care are so common that many have become numb to their significance. Ten years ago, a report from the Institute of Medicine cited the alarming statistic that 98,000 preventable deaths occurred in hospitals every year, or the equivalent of several jumbo jets crashing regularly.1 Now we learn from an article published in April in Health Affairs that this number may be 10 times greater.2 The best evidence suggests that necessary care is provided just over 50% of the time,3 whereas the wrong care is administered up to 30% of the time,3 contributing to an estimated $600 billion to $800 billion in waste, or “unwarranted variations” in care.4 Still, these healthcare patterns persist and claim an ever-increasing percentage of national gross domestic product and personal income. All stakeholders in healthcare—including patients, clinicians, payers, and employers—claim to be ready for change. Benefits and care that match the specific needs of a patient are highly regarded by consumers, payers, clinicians, and employers alike.5 Furthermore, when such approaches are taken, they routinely show dramatic improvements in quality, cost, and patient satisfaction.6 Finally, many new solutions and care-delivery models are available, such as patient-centered medical homes (PCMHs), accountable care organizations (ACOs), payment bundling, value-based benefits, member-centric care management, and highly predictive analytics, each of which can now be delivered in a scalable and automated fashion. A recent report for the National Quality Forum conducted by RAND catalogued 11 different categories of insurance and caredelivery models that have shown the ability to improve quality and lower cost.7 This is but one of several studies that highlight the opportunity that is available for improving US healthcare.

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What Approach Do We Need to Take? Why is there such a disconnect between what people need and what actually happens? After 10 to 20 years of good-faith concern and effort, there is precious little to show in terms of quality and value improvement, except for our collective awareness of the challenges. Even with the recent passage of healthcare reform legislation, including a committed $10 billion for innovation that improves quality and lowers cost, most experts are not yet ready to declare victory over inappropriate care. In fact, most experts are cautious about how soon we will see any significant improvements. Why is that the case? The simple answer is that we really do not have a healthcare “system,” meaning that we do not have a systematic approach to improving value. Instead, a fragmented collection of approaches, most of which are based on individual encounters and reimbursement schemes, reward activity rather than impact. By contrast, a systematic approach would identify and deliver precisely the care that is needed in each case, for each person. As TriZetto’s founder and chairman Jeff Margolis stated, “Systematic health management is about proactively looking across populations of people—from the healthy to the chronically ill—to help healthy people stay healthy, sick people not get sicker, and patients along the entire spectrum improve their health status. Systematic health management includes identifying and segmenting people into groups according to their health needs, developing a health improvement plan or patient ‘itinerary,’ and monitoring progress over time to ensure that health goals are met.”8 Put another way, systematic health management requires information, actions, and payments that are aligned to provide the right care to the right individuals in the right setting at the right time. This is easy to say, but incredibly difficult to do. However, in one form or another, that is exactly the challenge we must meet if we want to move beyond analyzing our problems to actually solving them.

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Step 1: Defining the population to be served. Typically, most clinicians do not manage populations, they manage individuals; therefore, the first disconnect is between groups of individuals defined by disease category, insurance coverage, or employer affiliation versus individual patients. Solving this disconnect in the short run is extremely challenging, but newer care models, such as PCMH, episode-of-care payment, and ACOs, bring the notion of a population or group of individuals to the delivery system. Even without these new structures, clinicians should appreciate that individuals are a population of one, meaning that an individual’s needs are not defined solely or even largely by events surrounding a single visit; instead, a patient’s health changes over a period of time. Most critical events and decisions occur between interactions with the delivery system, and some of the most critical factors are independent of the clinical visit itself. At the same time, those who consider individuals part of a defined population, such as payers and employers, should appreciate that populations are composed of individuals, and these individuals have unique needs based on their individual health and socioeconomic status, their educational level, their behavior motivation, and their insurance benefits. Step 2: Determining the health needs of a population and the individuals within it. The critical difference between a population and an individual highlights the second critical step in systematic health management: specifically determining the health needs of a population and, more important, of the individuals who comprise it. Although this can be a complicated process, it comes down to determining the appropriate care for each individual, referencing evidence-based medicine guidelines when they exist. This can be relatively simple, such as a preventive health-screening test for everyone of a certain age, or a monitoring test for everyone with a specific condition, such as diabetes. However, to truly ensure that warranted (vs unwarranted) care is delivered, it is essential to go beyond the one-size-fits-all approach and apply sophisticated analytics, behavior awareness, and preference-sensitive information to smaller groups of individuals. A form of “mass customization,” this allows scarce resources to be applied to those individuals who need certain interventions the most. A simple but real example of this approach using commercially available analytics demonstrates the ability to target 10 times fewer individuals to achieve a better cost and quality outcome when the right analytic and behavior modification approaches are taken.9 A critical complement to the information that informs the right management approach is the application of financial reimbursement or incentives that

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encourage individuals and clinicians to “do the right thing” (or to not do the wrong thing). This can take many forms, but for patients it means reward systems that promote taking specific actions that are known to improve their particular health status. For clinicians it means providing the reimbursement and workflow support that reinforces the clinically appropriate recommendations and actions for an individual patient, even when they are part of a larger population. Step 3: Management approaches that facilitate doing the right thing. The last step is the use of solutions and management approaches that make doing the right thing something that can be applied broadly without the need for new workflow or manual processes. This may take the form of information technology, new work processes, or organizational realignments, but in the end, these are all enablers of the ultimate goal: providing the right care to individual patients in a way that supports the clinical process.

Applying the Systematic Health Management Approach: Value-Based Insurance Design and PCMH Theory is good, but identifying specific health needs of individuals and designing interventions to promote the right actions are not trivial tasks. It is essential to take first steps; we can afford neither inaction nor passivity in addressing poor clinical outcomes and rising healthcare costs. However, when blunt cost-control measures are applied indiscriminately across groups of individuals, even small changes have shown dramatic and negative effects on quality for patients, especially those with chronic diseases.10,11

Growing evidence consistently shows improved health, patient satisfaction, and decreased overall costs from using VBID, especially when focused on individuals with chronic illness. The good news is that many examples of pursuing the right strategy exist already, and recent healthcare reform legislation promotes widespread adoption. For consumers, programs to promote the right health activities for individuals are called value-based insurance design (VBID). These programs have generally been promoted by innovative employers and payers through customized and increasingly individualized benefit design. Typically, these programs take the form of reduced or eliminated copayments, incentives or rewards for preventive health screenings, completion of health risk appraisals and well-

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ness programs, or elimination of cost barriers for critical medications. Growing evidence consistently shows improved health, patient satisfaction, and decreased overall costs from using VBID, especially when focused on individuals with chronic illness.12,13 Notable examples include programs by Pitney Bowes; the city of Springfield, OR; the providersponsored Health Alliance Medical Plans in Illinois; and healthcare payer WellPoint, among many others.14 Encouraging patients to do the right thing is critical, but so is encouraging clinicians. Although there are many ways to support and incentivize clinicians, one of the most promising approaches to promoting individualized care is the PCMH model. In this model, physicians and their staff are given individual patient information and financial incentives to optimize care in conjunction with the patient. Enabling processes and information can include the use of electronic medical records, electronic prescribing, extended office hours, automated reminder systems, identification of gaps in care, and appropriate referral support. Appropriate referral support consists of meeting outstanding care needs, appropriate referrals, evidencebased treatment options, and information necessary to make good decisions about treatment options. Several formal studies have shown improvements in quality, reduction in hospitalizations and emergency department visits, and improved patient satisfaction with PCMH,6 not to mention high clinician satisfaction. How well do VBID and PCMH programs work together? Alternately, is there any systematic approach to encouraging patients and clinicians to do the right thing? The answer, to date, is no. VBID programs have largely been implemented independently of PCMH programs and often are driven by reasons other than those that drive PCMH. This is not surprising, given the fragmentation of our healthcare (non)system, but the failure to coordinate patient and clinician incentives based on a common set of objectives can compromise the intended outcome and even create confusion regarding health goals. There is, however, increasing awareness that VBID and PCMH are 2 sides of the same coin, driven by a common set of objectives that the patient and the clinician should embrace and promote.

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The Road Ahead: Long but Straight Despite years of discussion, we are truly just at the beginning of systematic health management. There are now proven processes, case examples, technology, and policy directives that make systematic health management a true possibility and imperative, perhaps for the first time. The tough news is that the road is long. The good news is that the road is very straight and logical: determine what each individual needs to optimize his or her own health and then create processes and incentives for the patient and the clinician to promote that behavior. For most of us, moving forward is always better than being stuck in place—it is time to get on with it. ■ Author Disclosure Statement Dr Rideout reported no conflicts of interest.

References 1. Kohn LT, Corrigan JM, Donaldson MS, eds, for the Institute of Medicine Committee on Quality of Health Care in America. To Err is Human: Building a Safer Health System. Consensus Report. Washington, DC: National Academy Press; 1999. http://books.nap.edu/openbook.php?record_id=9728. Accessed May 4, 2011. 2. Chassin M. ‘Global trigger tool’ shows that adverse events in hospitals may be ten times greater than previously measured. Health Aff (Millwood). 2011;30:581-589. 3. McGlynn EA. Multiple quality-of-care monograph reports. Santa Monica, CA: RAND Corporation; 1997-2000. www.rand.org/pubs/authors/m/mcglynn_elizabeth_ a.html. Accessed May 4, 2011. 4. Thomson Reuters. Waste in the U.S. healthcare system pegged at $700 billion in report from Thomson Reuters. Press release. October 26, 2009. www.reuters.com/ article/2009/10/26/idUS78128+26-Oct-2009+PRN20091026. Accessed May 15, 2011. 5. TriZetto Group. US healthcare survey: constituents are ready and willing to adopt value-based care models. Press release. June 28, 2010. www.trizetto.com/newsEvents/ pressReleases/2010-06-28_ConstituentSurvey.asp. Accessed May 4, 2011. 6. Paulus RA, Davis K, Steele GD. Continuous innovation in health care: implications of the Geisinger experience. Health Aff (Millwood). 2008;27:1235-1245. 7. Schneider EC, Hussey PS, Schnyer C, for RAND Health. Payment Reform: Analysis of Models and Performance Measurement Implications. Santa Monica, CA: RAND Corporation; 2011. www.rand.org/content/dam/rand/pubs/technical_reports/ 2011/RAND_TR841.pdf. Accessed May 4, 2011. 8. Margolis J. The Information Cure—Solving the Healthcare Crisis Systematically Through Integrated Healthcare Management. Greenwood Village, CO: TriZetto Group; 2009. 9. From author’s personal communication with leading analytics vendor, based on actual customer analysis in 2010. 10. Dunbar-Jacob J, Mortimer-Stevens MK. Treatment adherence in chronic disease. J Clin Epidemiol. 2001;54(suppl 1):S57-S60. 11. Trivedi AN, Moloo H, Mor V. Increased ambulatory care copayments and hospitalizations among the elderly. N Engl J Med. 2010;362:320-328. 12. Atlantic Information Services. Improving Adherence and Containing Rx Costs: New Health Plan/PBM. Washington, DC: Atlantic Information Services; 2011. http://aishealth.com/marketplace/improving-adherence-and-containing-rx-costsnew-health-planpbm-strategies. Accessed May 4, 2011. 13. Fendrick AM, Chernew ME. Value-based insurance design: maintaining a focus on health in an era of cost containment. Am J Manag Care. 2009;15:338-343. 14. Fendrick AM, for the Center for Value-Based Insurance Design, University of Michigan. Value-Based Insurance Design Landscape Digest. Washington, DC: National Pharmaceutical Council; 2009. www.vbhealth.org/wp-content/uploads/2009/ 08/NPC_VBIDreport_7-22-09.pdf. Accessed May 4, 2011.

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ORIGINAL RESEARCH

The Economic Impact of Delaying 5-Alpha Reductase Inhibitor Therapy in Men Receiving Treatment for Symptomatic Benign Prostatic Hyperplasia Michael Naslund, MD, MBA; Michael T. Eaddy, PharmD, PhD; Susan L. Hogue, PharmD, MPH; Eric J. Kruep, PharmD, MS; Manan B. Shah, PharmD, PhD Background: Pharmacologic treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia often includes alpha-blockers and 5-alpha reductase inhibitors. Many clinicians use alpha-blockers for rapid symptom control, later adding 5-alpha reductase inhibitors to modify long-term disease progression. Delaying the addition of these medications has been shown to result in reduced clinical outcomes. The economic impact of this practice has not been widely studied or reported to date. Objective: The objective of this study was to assess the economic impact of delaying initiation of concomitant 5-alpha reductase inhibitor therapy (≥30 days) in patients receiving alphablockers for lower urinary tract symptoms. Methods: Using 2 nationally representative databases (Integrated Health Care Information Solutions and PharMetrics), 2 retrospective analyses were conducted involving 2636 and 4260 men, respectively, aged ≥50 years treated for benign prostatic hyperplasia between 2000 and 2007. Economic outcomes (ie, the cost of therapy and the use of healthcare resources) were compared for adding 5-alpha reductase inhibitor therapy early (within <30 days of initiating an alpha-blocker) versus delaying these medications (≥30 days after initiating an alpha-blocker). Results: In the Integrated Health Care Information Solutions analysis, patients in the early add-on therapy group (n = 1572) had lower benign prostatic hyperplasia–related medical costs in the posttreatment period than those in the delayed-therapy group (n = 1064), $349 versus $618 (P <.0001). Similar trends were seen in the PharMetrics analysis—the medical costs in the early add-on therapy group (n = 2604) and delayed group (n = 1656) were $344 versus $449, respectively (P <.001). Pharmacy costs were $1068 for the early-treatment cohort and $989 for the delayed-treatment cohort for the Integrated Health Care Information Solutions database, yielding total costs of $1417 and $1606, respectively, for a $189 savings per patient over the initial year of treatment (P <.0001). In the PharMetrics analysis, pharmacy costs were $1391 for the early-treatment cohort and $1237 for the delayed-treatment cohort, resulting in total cost of $1735 and $1686, respectively, yielding $59 in additional costs per patient annually for those treated early (P = .8645). Conclusion: These results suggest that patients receiving 5-alpha reductase inhibitor therapy within 30 days after initiating alpha-blocker treatment have lower benign prostatic hyperplasia–related medical costs than those who start combination treatment later. The increase in pharmacy costs associated with early initiation of 5-alpha reductase inhibitor therapy resulted in total costs that were similar or significantly lower than those of delayed combination users.

Michael Naslund

Stakeholder Perspective, page 161

Am Health Drug Benefits. 2011;4(3):155-162. www.AHDBonline.com Disclosures are at end of text

Dr Naslund is Professor of Urology, University of Maryland School of Medicine, Baltimore; Dr Eaddy is Vice President, Data Analytics and Insights, Xcenda, Palm Harbor, FL; Dr Hogue was an employee of GlaxoSmithKline, Research Triangle Park, NC, when this study was conducted; Dr Kruep is Director, Managed Markets, Xcenda; and Dr Shah is Director, Data Analytics, Xcenda.

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B

enign prostatic hyperplasia (BPH), also known as enlarged prostate, is a significant health problem among aging men.1 It affects approximately 50% of American men aged 51 to 60 years, 70% of men aged 61 to 70 years, and 90% of men aged 81 to 90 years.2 The burden of BPH on the US healthcare system is expected to grow even further as the population of men aged ≥65 years increases from 17 million in 2010 to approximately 30 million by 2030.3 The clinical burden of BPH includes lower urinary tract symptoms, including frequency, urgency, nocturia, decreased or intermittent force of stream, and incomplete bladder emptying. Complications from BPH may include acute urinary retention (AUR), impaired bladder emptying, or the need for prostate surgery.4 Beyond the clinical burden imposed by BPH, the condition also carries a substantial economic burden. Direct and indirect costs to the private sector related to BPH treatment are estimated to be $3.9 billion annually.5 In 2000, approximately 4.5 million individual visits were made to physician offices for a primary diagnosis of BPH, and an additional 3.5 million visits for a secondary diagnosis of BPH. The direct costs of medical services provided at hospital inpatient and outpatient settings, emergency departments, and physician offices to treat BPH in the United States in 2000 were estimated to be approximately $1.1 billion.6 Furthermore, the treatment of men with BPH places a significant burden on patients and their employers through direct medical costs and lost work time.5 Current treatment options for BPH include watchful waiting, pharmacologic therapy, minimally invasive procedures, and prostate surgery.4 In most cases, first-line therapy is pharmacologic treatment with alpha-blockers and/or 5-alpha reductase inhibitors in men with bothersome lower urinary tract symptoms. Alpha-blockers rapidly improve urinary symptoms but do not affect prostate size.7 In contrast, 5-alpha reductase inhibitors shrink the prostate and decrease the risk of progression to AUR and prostate surgery. There is typically a 4- to 6-month delay from the start of 5-alpha reductase inhibitor therapy to the onset of clinical improvement.8,9 Of note, although the American Urological Association (AUA) guidelines on management of BPH recognize the distinction of 5-alpha reductase inhibitors to reduce the incidence of AUR and surgeries compared with alpha-blockers, these guidelines do not offer a decision tree of when to advance which treatment in their diagnosis and treatment algorithm.4 Previous studies have demonstrated that combining 5-alpha reductase inhibitor and alpha-blocker therapies is more effective at reducing the risk of overall

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KEY POINTS ➤

Benign prostatic hyperplasia is associated with a significant economic burden, with direct and indirect private-sector costs estimated at $3.9 billion annually. The expected growth in the numbers of older men in the next 2 decades is bound to add to the clinical and economic burden of this condition, which affects a majority of men aged ≥70 years. The most common pharmacologic strategy is initiating alpha-blocker therapy and then adding 5alpha reductase inhibitors. Previous studies show that delaying the addition of 5-alpha reductase inhibitors is negatively affecting clinical outcomes. This retrospective analysis is the first US-based study to distinctly quantify the real-world economic implications of 5-alpha reductase inhibitor timing by comparing the cost of adding 5-alpha reductase inhibitor therapy to alpha-blocker therapy early (≤30 days from initiating alpha-blocker therapy) and late (≥30 days) for men in a managed care population. Every 30-day delay in initiating 5-alpha reductase inhibitor therapy resulted in an increase in medical costs by an average of 25.1% and 13%, respectively, in each of the 2 databases of patients analyzed in this study. Patients who had delayed 5-alpha reductase inhibitor therapy for >30 days incurred from $105 to $269 greater costs in months 6 through 12 than men who started combination therapy ≤30 days after initiating therapy with alpha-blockers.

clinical progression—defined as worsening in the AUA symptom score of 4 points or more, AUR, urinary incontinence, renal insufficiency, or recurrent urinary tract infection4—than monotherapy with either agent alone.10-12 These results demonstrated significant differences in favor of combination therapy in men with bothersome symptoms of BPH at baseline and a confirmed enlarged prostate. A recent study demonstrated that delaying 5-alpha reductase inhibitor therapy in men receiving an alphablocker was associated with an increased rate of clinical progression (defined as occurrence of AUR- or BPH-related surgery).13 Although that study documented the clinical consequences of delaying 5-alpha reductase inhibitor therapy,13 the economic impact was not investigated. With the aging population and subsequent increase in the proportion of men with BPH, a substantial increase in future BPH treatment costs may occur. The present study compares the 12-month cost of therapy in

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men receiving alpha-blockers and early 5-alpha reductase inhibitor therapy versus delayed 5-alpha reductase inhibitor therapy in a managed care population.

Figure 1 Study Design 1-year postindex period

Study Population Men aged ≥50 years between January 1, 2000, and December 31, 2006, within the IHCIS and PharMetrics databases were eligible for study inclusion. The men had been diagnosed and treated for BPH with an alphablocker and a concomitant 5-alpha reductase inhibitor within 6 months of starting alpha-blocker therapy. Men were not included if they had been diagnosed with prostate or bladder cancer, used finasteride 1-mg tablets (for treatment of male-pattern baldness), had a history of prostate surgery, or used 5-alpha reductase inhibitor therapy before initiating alpha-blocker therapy. Inclusion and exclusion International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM) codes are shown in Table 1 (page 158).

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Index Rx

5-month periperiod

7-month outcomes assessment

{ {

6-month preperiod

Study Design This analysis was an observational retrospective cohort study and included patients who were eligible for medical and pharmacy services within those 2 databases, using data from January 1, 2000, through December 31, 2007. This period allowed for a sufficient number of patients to be enrolled in the study based on the selection criteria. The index date was defined as the date of the first fill for an alpha-blocker prescription. Patients had to be eligible for services at least 6 months before and 12 months after the index date. The 6-month preindex period (the preperiod) was used to assess the baseline characteristics of patients that might be associated with treatment initiation. The 5-month period after the index date was designated as the periperiod, for which outcomes were not assessed. The 7-month period after the periperiod was the time frame within which outcomes were assessed. The postindex period included the 12-month period after the index date, including the periperiod and the outcomes assessment period (Figure 1).

{

Methods Data Sources Patients were identified from 2 databases—(1) the Integrated Health Care Information Solutions (IHCIS) National Managed Care Benchmark Database (Waltham, MA), containing medical, pharmacy, and enrollment data for more than 30 million lives, and (2) the PharMetrics Integrated Medical and Pharmaceutical Database, containing data from more than 90 different managed healthcare plans, encompassing more than 52 million lives.

Assessment of Rx cost

Medical plus Rx cost assessment

Table 1 Study Inclusion and Exclusion ICD-9-CM Codes Inclusion codes Benign prostatic hyperplasia

222.2, 600.xx

Exclusion codes Prostate cancer

185, 198.82, 233.4, 236.5, 239.5, V10.46

Bladder cancer

188, 198.1, 223.3, 233.7, 239.4, V10.51

ICD-9-CM indicates International Classification of Diseases, Ninth Revision, Clinical Modification.

Outcomes The primary outcome was total healthcare costs and utilization associated with BPH after initiation of treatment. All costs related to BPH, defined by the dollars charged on medical claims with a primary ICD-9-CM code of 222.2 or 600.xx during the postindex period, were calculated. However, because 5-alpha reductase inhibitors take 4 to 5 months to affect the prostate, it was assumed that BPH-related costs before this interval would not be avoided by 5-alpha reductase inhibitor therapy. Therefore, only BPH-related medical costs occurring after 150 days of therapy were evaluated (a 150-day “clean” period). BPH-related pharmacy costs were assessed over the entire 1-year follow-up, because patients must initiate therapy at day 1 to avoid all future costs. Therefore, this analysis included the incremental reduction in medical costs and utilization that are offset by the incremental increase in pharmacy costs. Outcomes were compared between patients who started concomitant 5-alpha reductase inhibitor therapy within 30 days after initiation of alpha-blocker therapy (ie, early group) and those who started it after 30 days but within 180 days of alpha-blocker therapy (ie, delayed group). In the delayed group, outcomes were compared for every 30-day delay. Resource utilization costs (ie, cost

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Table 2 Benign Prostatic Hyperplasia Disease Stage Disease stage

ICD-9-CM code

0

Benign prostatic hyperplasia

222.2, 600.xx

1

With urinary tract infection

Stage 1.1 + 599.0

2

With bladder outlet obstruction

Stage 1.1 + 593.5, 596.0, 599.6

3

With hydronephrosis

Stage 1.1 + 591.xx

4

With renal failure

Stage 1.1 + 584.xx, 586.xx

5

With sepsis

Stage 1.1 + 038.xx

6

With shock

Stage 1.1 + 785.50, 785.59

ICD-9-CM indicates, International Classification of Diseases, Ninth Edition, Clinical Modification.

of BPH-related surgery and AUR events) were similarly compared between the early and delayed groups. Component BPH-related healthcare costs were categorized as inpatient and outpatient and included outpatient hospitalizations, emergency department, physician, laboratory, and other ancillary costs.

Statistical Analysis Ordinary least-squares regression models were used to estimate and compare mean healthcare costs and utilization between treatment cohorts, utilizing the following preindex baseline covariates: the presence of AUR, BPH stage, Charlson comorbidity index, age, number of unique diagnosis codes, number of unique nonâ&#x20AC;&#x201C;BPHrelated classes of prescriptions filled, and the presence of at least 1 urologist visit (specialty care). For BPH stage (Table 2), each patient was categorized into 1 of the 7 disease-severity stages based on the presence of ICD-9-CM codes in the 6-month period before the index date. The Charlson comorbidity index was used to assess comorbidities. This index encompasses 19 medical conditions, each assigned a weight ranging from 1 to 6. The possible total scores range from 0 to 37; the higher the score, the more severe the burden of comorbidity.14 Differences in background covariates across treatment cohorts were assessed by t-test when data were continuous in nature, and with chi-square test when data were categorical. Analyses were conducted using SAS Version 9.1.3 (SAS Institute, Cary, NC) with an a priori significance level of â?Ł = .05. Results A total of 2636 patients were identified from the IHCIS database and 4260 from the PharMetrics data-

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base. The early group (started on a 5-alpha reductase inhibitor within 30 days of an alpha-blocker initiation) comprised 59.6% of patients in the IHCIS database and 61.1% of those in the PharMetrics database. In the IHCIS delayed cohort, 30% of patients started 5-alpha reductase inhibitor therapy between 31 and 60 days, 21.3% between 61 and 90 days, 17.3% between 91 and 120 days, 15.3% between 121 and 150 days, and 16.1% between 151 and 180 days. Similarly, in the PharMetrics analysis, 27.0% of patients in the delayed cohort started 5-alpha reductase inhibitor therapy between days 31 and 60, 22.6% between days 61 and 90, 20.1% between days 91 and 120, 16.2% between days 121 and 150, and 14.1% between days 151 and 180. In both databases, patients in the early cohort had more comorbidity during the preperiod (measured by the Charlson comorbidity index) and more severe disease (measured by BPH stage and the presence of AUR at baseline) than those in the delayed group (started on a 5-alpha reductase inhibitor on days 31-180 of an alpha-blocker) as shown in Table 3.

Resource Utilization Naslund and colleagues previously reported that in the IHCIS database, patients in the late cohort were significantly more likely to have clinical progression (19.0% vs 11.2%, odds ratio [OR] = 1.857; P <.0001), significantly more likely to have AUR (13.2% vs 8.1%, OR = 1.709; P <.0001), and significantly more likely to have BPH-related surgery (9.5% vs 4.8%, OR = 2.083; P <.0001) compared with patients initiating 5-alpha reductase inhibitor therapy early.13 In the PharMetrics database, patients in the late cohort were significantly more likely to experience clinical progression (14.0% vs 10.2%, OR = 1.435; P = .0002), significantly more likely to have AUR (10.0% vs 7.0%, OR = 1.472; P = .0006), and more likely to have BPH-related surgery (6.3% vs 5.0%, OR = 1.282; P = .0699). BPH-Related Medical and Pharmacy Costs BPH-related medical costs were lower in each of the early groups compared with the delayed groups in both databases (Table 4). Furthermore, these costs were primarily composed of outpatient charges (Figure 2, page 160). In the IHCIS database, every 30-day delay in starting 5-alpha reductase inhibitor therapy resulted in an average 25.1% increase in medical costs (P <.0001); in the PharMetrics database, every 30-day delay in starting 5alpha reductase inhibitor therapy resulted in an average 13% increase in medical costs (P <.0001). In the IHCIS analysis, pharmacy costs per person for the initial year of pharmacologic treatment of BPH were $1068 for the early cohort and $989 for the delayed

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Table 3 Demographic Characteristics IHCIS

PharMetrics

Early group (n = 1572)

Delayed group (n = 1064)

P

Early group (n = 2604)

Delayed group (n = 1656)

P

Mean age, y

65.5

64.3

.0003

66.0

65.2

.1580

Charlson comorbidity index

1.04

0.77

<.0001

0.99

0.84

<.0001

Count of comorbid diagnosis codes

9.4

8.2

<.0001

9.0

8.5

.0003

Count of comorbid prescriptions filled

4.6

4.7

.7356

4.6

4.5

.4477

BPH stage

0.63

0.47

<.0001

0.52

0.37

<.0001

AUR, %

21.1

11.4

<.0001

18.5

11.2

<.0001

Specialty care, %

20.8

20.1

.6676

55.1

39.6

<.0001

Preperiod BPH-related medical costs, $

192

103

.0002

408

136

.0009

Variable

AUR indicates acute urinary retention; BPH, benign prostatic hyperplasia; IHCIS, Integrated Health Care Information Solutions.

Table 4 Medical, Pharmacy, and Total Costs IHCIS

PharMetrics

Early group Delayed group (n = 1572), $ (n = 1064), $

Cost

P

Early group Delayed group (n = 2604), $ (n = 1656), $

P

Medical

349

618

<.0001

344

449

<.001

Pharmacy

1068

989

.0006

1391

1237

<.0001

Total

1417

1606

<.0001

1735

1686

.8645

IHCIS indicates Integrated Health Care Information Solutions.

cohort, yielding total costs of $1417 for the early cohort and $1606 for the delayed cohort, or $189 per-patient savings (P <.0001) for those in the early cohort over their initial year of treatment. In the PharMetrics analysis, pharmacy costs were $1391 for the early cohort and $1237 for the delayed cohort, meaning that total cost for the early cohort was $1735 and that for the delayed cohort was $1686, yielding $59 in additional costs per patient annually for those treated early (P = .8645).

Discussion The clinical benefits of combination therapy with 5alpha reductase inhibitors and alpha-blockers for BPH have been established in clinical trials. The Medical

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Therapy of Prostatic Symptoms study demonstrated greater symptom improvement with the combination of an alpha-blocker plus a 5-alpha reductase inhibitor compared with an alpha-blocker or a 5-alpha reductase inhibitor as monotherapy, as well as reductions in AUR- and BPH-related surgery, which were similar to the 5-alpha reductase inhibitor monotherapy.10 The Combination of Avodart and Tamsulosin study also showed greater reductions and improvement of symptoms with combination therapy versus either monotherapy.11,12 Although randomized controlled trials are important for assessing the efficacy and safety of medical treatment options, an important limitation is that clinical trial results may not be representative of clinical practice,

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Figure 2 Mean Inpatient and Outpatient Medical Costs with Early and Delayed 5ARI Therapy in 2 Databases

Mean charge for months 6-12, $

1200

Outpatient Inpatient

IHCIS

800

PharMetrics $618

400

$449

$392 $349

$344

$234

$268

$115

$226 $76

$95

Early 5ARI

Late 5ARI

0

Early 5ARI

$354

Late 5ARI

IHCIS indicates Integrated Health Care Information Solutions; 5ARI, 5-alpha reductase inhibitor.

because many patients are excluded from clinical trials if they fail to meet entry criteria, and patients who participate in clinical trials may not be representative of patients who present to a physician for treatment. The recent managed care database study by Naslund and colleagues showed that in a real-world setting, a delay in treating a patient with a 5-alpha reductase inhibitor may increase the risk for BPH progression.13 The present study expands on this assessment by comparing the economic consequences associated with a delay in 5-alpha reductase inhibitor therapy. The results of the current analysis indicate that a patient who received delayed 5-alpha reductase inhibitor therapy incurred from $105 to $269 more annually in BPH-related medical costs than a patient who received early combination therapy. This finding is important, because it distinctly quantifies the real-world economic implications of 5-alpha reductase inhibitor timing. McDonald and colleagues also highlighted the cost-effectiveness of combined therapy by showing that the timingâ&#x20AC;&#x201D;early combination therapyâ&#x20AC;&#x201D;is a key factor for achieving optimal clinical benefit.15 This assessment is from a Canadian study based on clinical trial results; however, the results are similar to the findings of this present study. In recent years, there has been a gradual shift in the management of chronic and progressive conditions from only symptomatic management to also managing the underlying disease to decrease the risk for longterm negative outcomes. This has been especially pertinent to the management of BPH, a chronic and progressive condition.16

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With these considerations in mind, the present study quantifies the incremental clinical and economic benefits of early combination medical therapy for BPH from a medical and pharmacy perspective. In the IHCIS analysis, even when adding in the additional pharmacy costs of early 5-alpha reductase inhibitor therapy, the study results favored early 5-alpha reductase inhibitor initiation, with a net difference ranging from a savings of $189 per patient to no significant differences between groups (P = .8645). Alternatively, in the PharMetrics analysis, the reduction in medical costs with early therapy was not entirely outweighed by the additional pharmacy spending for the early group ($49 higher total costs in the early group; P = .8645).

Limitations Any retrospective database analysis has inherent limitations, such as the influence of selection bias and limited generalizability. The methods in this study attempted to minimize selection bias by controlling for differences in background covariates. However, based on background covariates, patients initiating 5-alpha reductase inhibitor therapy earlier were in worse condition in terms of comorbidity and previous complications arising from BPH. Even with the increased severity, the analysis showed that the early treatment group had lower costs. Also, the study population is comprised of patients enrolled in commercial plans; therefore, the results should not be generalized to other populations, such as Medicaid or Medicare enrollees. With the availability of generic finasteride, generic tamsulosin, and a branded fixed-dose combination of dutasteride and tamsulosin (Jalyn) in the US marketplace, decision makers should evaluate the anticipated pharmacy costs in relation to medical cost differences demonstrated in this study. This study showed consistent reductions in medical costs with earlier dual pharmacologic therapy in 2 different databases. However, the medical spending represents only one half of the total spending, and the pharmacy spending represents the other half. This study demonstrates that differences that range from cost-savings to cost-neutrality can result in the total spending (ie, medical and pharmacy costs) when both components are considered. The pharmacy costs evaluated in this study, however, are limited to the costs of the batch of branded and generic agents available for treatment in the 5-alpha reductase inhibitor and alpha-blocker classes at the time of the analysis. The study conclusions are drawn on class-effect level; the effect of unique combinations of specific 5-alpha reductase inhibitors and alpha-blockers was not assessed in this study. Treatment for BPH may be a lifelong proposition. The length of follow-up in the current study did not

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examine the long-term economic outcomes of various treatment regimens. This is an area for future study.

Conclusion Early combined therapy with an alpha-blocker and a 5-alpha reductase inhibitor results in direct medical costsavings compared with alpha-blocker therapy followed with delayed (â&#x2030;Ľ30 days) therapy with 5-alpha reductase inhibitors. The increase in pharmacy costs associated with early initiation of 5-alpha reductase inhibitor therapy resulted in total costs that were similar to or significantly lower than those of delayed combination users. The balance between lower medical spending related to fewer AUR- and prostate-related surgeries in men with BPH treated early with an alpha-blocker and a 5-alpha reductase inhibitor versus delayed addition of a 5-alpha reductase inhibitor to baseline alpha-blocker therapy, as well as the pharmacy spending for these medical treatments may attract increasing attention, especially with emerging generic medications and a new fixed-dose combination medication. â&#x2013;  Acknowledgment Funding for this study was provided by GlaxoSmithKline, which had no influence over the content. Author Disclosure Statement Dr Naslund is a Consultant and Speaker for GlaxoSmithKline; Drs Eaddy, Kruep, and Shah are Consultants for GlaxoSmithKline; Dr Hogue is a former employee of GlaxoSmithKline.

References 1. National Institute of Diabetes and Digestive and Kidney Diseases. Prostate enlargement: benign prostatic hyperplasia. National Kidney and Urologic Diseases Information Clearinghouse. 2006. www.kidney.niddk.nih.gov/kudiseases/pubs/ prostateenlargement/index.htm. Accessed February 16, 2010. 2. McVary KT. BPH: epidemiology and comorbidities. Am J Manag Care. 2006;12: S122-S128. 3. US Census Bureau. US interim projections by age, sex, race, and Hispanic origin: 2000-2050. www.census.gov/population/www/projections/usinterimproj/. Accessed February 11, 2010. 4. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: diagnosis and treatment recommendations. J Urol. 2003;170:530-547. 5. Saigal CS, Joyce G. Economic costs of benign prostatic hyperplasia in the private sector. J Urol. 2005;173:1309-1313. 6. Wei JT, Calhoun E, Jacobsen SJ. Benign prostatic hyperplasia. In: National Institute of Diabetes and Digestive and Kidney Diseases. Urologic Diseases in America. http://kidney.niddk.nih.gov/statistics/uda/. Accessed February 11, 2010. 7. Flomax (tamsulosin hydrochloride) prescribing information. Ridgefield, CT: Boehringer Ingelheim; 2001. 8. Proscar (finasteride) prescribing information. Whitehouse Station, NJ: Merck; 2007. 9. Avodart (dutasteride) prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2008. 10. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003;349:2387-2398. 11. Roehrborn CG, Siami P, Barkin J, et al. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol. 2008;179:616-621. Erratum in J Urol. 2008;180:1191. 12. Roehrborn CG, Siami P, Barkin J, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol. 2010;57:123-131. 13. Naslund M, Eaddy MT, Hogue SL, et al. Impact of delaying 5-alpha reductase inhibitor therapy in men on alpha-blocker therapy to treat BPH: assessment of acute urinary retention and prostate-related surgery. Curr Med Res Opin. 2009;25:2663-2669. 14. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373-383. 15. McDonald H, Hux M, Brisson M, et al. An economic evaluation of doxazosin, finasteride and combination therapy in the treatment of benign prostatic hyperplasia. Can J Urol. 2004;11:2327-2340. 16. Emberton M, Andriole GL, de la Rosette J, et al. Benign prostatic hyperplasia: a progressive disease of aging men. Urology. 2003;61:267-273.

STAKEHOLDER PERSPECTIVE Benefit Management Considerations for BPH Medications: Single Agent or Combination Therapy? PAYERS: Over the past few years, the prescription cost for the treatment of benign prostatic hyperplasia (BPH) has decreased substantially as a result of generic medications entering the market. The timing of when to begin the use of combination therapy is not always agreed on. What we do know is that alphaadrenergic antagonists, such as terazosin (Hytrin), doxazosin (Cardura), or tamsulosin (Flomax), provide quick therapeutic benefit. The available 5-alpha reductase inhibitors, such as finasteride (Proscar) and

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dutasteride (Avodart), require long-term treatment to provide appropriate efficacy. Several trials, including a large study conducted by the US Department of Veterans Affairs, demonstrate that combination-drug therapy offers little benefit in short-term therapy over an alpha-antagonist alone in patients with mild-to-moderate BPH.1 However, for patients with moderate BPH, added benefit has been demonstrated with long-term combination therapy compared with therapy with a single drug.2 For men Continued

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STAKEHOLDER PERSPECTIVE (Continued) with enlarged prostates, initiating therapy with a combination medication is recommended. In the present study, Naslund and colleagues suggest lower medical costs associated with the initiation of combination rather than single-agent therapy. Based on the available medical literature, combination therapy has a greater effect in men with severe symptoms and moderate-to-large prostates. From a drug benefit management perspective, it is difficult for a health plan or other payers to determine the optimal timing for using therapy with a single drug versus combination agents; optimal timing also does not warrant the payer’s resources to place step-therapy edits, particularly for generic-based combination therapy. PATIENTS: The question of initiating single- or combination-drug therapy for men with BPH should be mutually agreed on by the patient and the provider. It is a good thing for patients that a generic 5-alpha

reductase inhibitor is available when an initial combination therapy is chosen, or when adequate response is not obtained with a generic alpha-antagonist that is used as an initial single-drug therapy. Even without prescription coverage, the combined monthly cost for tamsulosin or finasteride is less than $35. These are great options for patients that can be tried first, before embarking on brand-name therapies. 1. Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. N Engl J Med. 1996;335:533-539. 2. McConnell JD, Roehrborn CG, Bautista OM, et al; for the Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003;349:2387-2398.

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

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AMCP HIGHLIGHTS

Continuing the trends from the past several years, economic concerns and cost-containment featured high among the oral discussions and posters presentations during the 2011 Annual Meeting of the Academy of Man-

aged Care Pharmacy (AMCP), April 27-29, 2011, in Minneapolis, MN. The following summaries represent areas of direct relevance to payers, employers, and other healthcare stakeholders highlighted at the meeting.

Economic and Clinical Value of Integrating a Clinical Pharmacist into the Care Management Team Health plans seeking to improve their care management programs and reduce costs may wish to add a clinical pharmacist to their care management team, according to results of a study presented at the meeting by a group of pharmacy residents at OptumHealth Care Solutions Pharmaceutical Solutions Pharmacy Residency program at OptumHealth, in Golden Valley, MN. Many studies have demonstrated over the years the value that clinical pharmacists bring to any healthcare setting. However, according to YK Mach, PharmD, and his pharmacy resident colleagues, no study has yet demonstrated the incremental value, or return on investment (ROI), of adding a pharmacist to a case management team, which is usually overseen by nurses and medical directors. The group set out to (1) develop work flow and processes for integrating a pharmacist into the case management team, (2) identify opportunities for the pharmacist to improve medication management in this context, and (3) measure the incremental value of including a clinical pharmacist on the management team. The team of pharmacists performed 42 comprehensive medication reviews between October 2010 and March 2011 of cases referred by the care management

team of OptumHealth or from claims that revealed inappropriate prescribing, medication nonadherence, or a patient’s prescription costs exceeding $35,000 annually. Even for this small number of cases, applying the pharmacists’ medication reviews allowed the team to identify 377 opportunities for improving medication therapy management, involving 130 (34%) occasions for improving medication safety, 130 instances (34%) for reducing medication costs, 99 (27%) opportunities for improving adherence, and 18 times (5%) of facilitating better coordination of provider care. In addition, although medication safety issues are normally detected by automated safety mechanisms, among the 130 medication safety concerns identified in this study, 67% required a review by and an interpretation of a pharmacist. The economic impact of this pharmacist-directed medication review resulted in total potential savings of $392,806—amounting to an average of $9353 potential cost-saving per case, which translated to a potential ROI of 10:1 and an actual claims-confirmed ROI of 3:1. These results, the investigators suggest, clearly indicate that adding a pharmacist to care management programs (disease or case management programs) adds a significant clinical and economic value. ■

Impact of Value-Based Insurance Design on Medication Utilization and Costs in a Large Retail Employer Value-based insurance design (VBID) has been a driving force in lowering patients’ cost-sharing for evidence-based interventions that improve clinical outcomes. Yoona A. Kim, PharmD, and colleagues from the University of California San Francisco, the University of Texas at Austin, and Mercer Health & Benefits in San Francisco measured the impact of implementing a VBID program in a large retail employer on medication utilization and cost among employees taking medications for diabetes, asthma, coronary artery disease, or heart failure.

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Patients were eligible for reduced cost-sharing if they had any of these diagnoses and agreed to enroll in a disease management program. Patients in the disease management program received either nurse counseling or health education materials, depending on their risk stratification, with those at higher disease risk receiving active nurse counseling and those at lower risk receiving educational materials. Regression analysis showed that among those receiving passive education materials, medication adherence improved significantly only among patients with diaContinued

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betes; in those receiving active counseling by a nurse, improvement was seen in patients taking antidiabetes medications, antihypertensives, or statins. After 1.5 years, those in the nurse counseling group had significantly lower total overall cost ($44 ± $467) compared with those in the matched control group ($1861 ± $401) per member per year (PMPY). Those in the health education materials group had an overall total cost of $1261 PMPY compared with $182 PMPY in the control group. The results, the team suggest, show that VBID can

improve adherence, at least with some interventions and some types of patients. Active counseling appears to be a better strategy than providing passive educational materials for increasing appropriate healthcare utilization, improving clinical outcomes, and reducing total healthcare costs. The team noted that the risk stratification and different intervention modalities may be a limitation of this study; they suggest that future studies should not separate the assessment of active counseling and passive education to assess the true impact of each intervention. ■

Current Trends in the Pharmaceutical Pipeline: Key Players to Watch, Few Surprises The slowing pace of research & development (R&D) among major pharmaceutical manufacturers is expected to continue for the foreseeable future, according to Brian Kolling, PharmD, Senior Director, Pipeline and Trend Forecasting, Part D, Prescription Solutions, San Diego, CA. Presenting what has become one of the best-attended sessions at the AMCP meeting and titled “Scanning the Pharmaceutical Pipeline,” Dr Kolling observed that although the overall pace of drug development has remained stable for the past 2 years, it has declined considerably from its peak 4 or 5 years ago. Despite a significant increase in the number of drugs in early-phase clinical trials compared with the past decade, the number of new drugs approved by the US Food and Drug Administration (FDA) has not kept pace with the investment in R&D. In 2011, the number of drugs in phase 1 clinical trials was approximately 150% greater than that in 2001, but the number of new drug applications (NDAs) declined by about 17%. Fewer drugs today are reaching phase 3 trials, and consequently, fewer new drugs are reaching the market, and major drug manufacturers are reducing their investment in R&D. The reasons for this, according to Dr Kolling, include the “patent cliff,” along with the maturation and saturation of many therapeutic classes. These challenges have forced drug makers to rethink their market entry, development timelines, and therapeutic focus. These R&D limitations are further compounded by the need for greater investment to overcome increasing barriers to market entry, in part by the FDA’s growing requirements for safety and eliminating redundancy, and the astronomical cost of initiating clinical trials for products that will never see the light of day. In this current landscape, Dr Kolling noted, manu-

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facturers are especially reluctant to commit their resources to therapeutic classes in saturated markets. In fact, most money is spent on phase 1 or 2 clinical trials, in which the failure rate is greatest. The major pharmaceutical companies have been addressing these concerns with the following strategies: • In-licensing of products in later stages of development and assigning the early R&D to partners • Partnering with same-size drug manufacturers to share in the R&D risk • Concentrating on “friendlier” markets, such as specialty pharmacy and emerging markets • Slashing investment in R&D, or exiting the market altogether. The 8 top disease states in the pipeline, according to Dr Kolling, are being led, not surprisingly, by cancer, followed by central nervous system diseases, diabetes, infectious diseases, respiratory diseases, cardiovascular disease (CVD), vaccines, and arthritis. Some of the most promising agents to watch for in the current pipeline are listed in the Table (page 165). Despite the prominence of CVD as the leading cause of death in the United States, the CVD pipeline has slowed down considerably, likely because of market maturation. In 2006 it was the third targeted disease in the pipeline; today it has moved to 6th place, trailing behind infectious and respiratory diseases. Still, suggested Dr Kolling there are some exciting medications that will either be entering the market soon or are in late-stage development that payers will want to watch and plan for, such as the impending patent loss for Zyprexa and Lipitor; the recent FDA approval of the 2 hepatitis C drugs telaprevir and boceprevir; and the phase 3 trial results for the rheumatoid arthritis drug tofacitinib. ■

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Table Important Drugs to Watch for in the Pipeline Drug, by clinical category Cardiovascular AMR101 Dalcetrapib Edoxaban Eliquis (apixiban) Lomitapide MK-0524A Vorapaxar Central nervous system Cariprazine (RGH-188) Levadex (dihydroergotamine) Levomilnacipran TC-5214 Telcagepant (MK-0974) Diabetes Afrezza (inhaled insulin) Albiglutide Aleglitazar Bydureon (exenatide) Degludec Lixisenatide Gastrointestinal Budesonide MMX Linaclotide Respiratory Eklira (aclidinium) Glycopyrronium (NVA237) GSK573719/vilanterol QVA149 Relovair (fluticasone furoate/vilanterol) Spiriva (olodaterol) Specialty drugs Fostamatinib Tofacitinib BG-12 Laquinimod Teriflunomide

Drug type, potential indication Oral ethyl icosapentate for familial hypertriglyceridemia and mixed dyslipidemia CETP inhibitor for dyslipidemia Factor Xa inhibitor for AF and VTE Factor Xa inhibitor for preventing stroke in AF and VTE Oral MTP inhibitor for homozygous familial hypercholesterolemia Niacin + laropiprant (antiflushing agent) for hypercholesterolemia; MK-0524B adds simvastatin TRAP inhibitor that blocks PAR-1 for ACS; secondary prevention of ACS Atypical antipsychotic for schizophrenia and bipolar mania Inhaled formulation of DHE for migraine SNRI for depression Nicotinic ion channel blocker for major depressive disorder CGRP receptor antagonist for migraine; central action may lower risk of CV events Inhaled insulin GLP-1 analog fused to human albumin PPAR coagonist for type 2 diabetes after a CV event GLP-1 analog Ultra-long-acting basal insulin GLP-1 analog Oral controlled-release budesonide for ulcerative colitis Oral guanylate cyclase receptor agonist for chronic constipation and IBS Inhaled LAMA for COPD Inhaled LAMA for COPD Inhaled LAMA/LABA combination for COPD Inhaled LAMA/LABA combination for COPD Inhaled once daily for COPD and asthma Inhaled LAMA/LABA combination for COPD Oral SYK inhibitor for rheumatoid arthritis Oral JAK1 and JAK3 inhibitor for rheumatoid arthritis Oral dimethyl fumarate for multiple sclerosis Oral immunomodulator for multiple sclerosis Active metabolite of leflunomide for multiple sclerosis

ACS indicates acute coronary syndrome; AF, atrial fibrillation; CETP, cholesterylester transfer protein; CGRP, calcitonin gene–related peptide; COPD, chronic obstructive pulmonary disorder; CV, cardiovascular; DHE, dihydroergotamine; GLP, glucagon-like peptide; IBS, irritable bowel syndrome; JAK, Janus kinase inhibitor; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist; MTP, microsomal triglyceride transfer protein; PAR, protease activated receptor; PPAR, peroxisome proliferator-activated receptor; SYK, spleen tyrosine kinase; SNRI, serotonin–norepinephrine reuptake inhibitor; TRAP, thrombin receptor-activating peptide; VTE, venous thromboembolism. Source: Brian Kolling, “Scanning the Pharmaceutical Pipeline: What’s on the Horizon?” oral presentation at the Academy of Managed Care Pharmacy, April 27-29, 2011, Minneapolis, MN.

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Degree of Adherence in Chronic Diseases Inversely Correlates with Healthcare Costs One successful strategy for employers and health plans wishing to cut spending on their employees or members with chronic diseases is to implement ways of encouraging strong medication adherence. In a poster presentation led by Patty M. Fong, PharmD, researchers from American Health Care plan, Rocklin, CA, have demonstrated that the degree of a patient’s medication adherence inversely correlates with the amount of total healthcare dollars spent on that patient. Using pharmacy claim data, the team evaluated the correlation between several levels of medication adherence and the amount of medical costs in patients with 1 of 3 chronic diseases over a 12-month period. They divided 4999 patients with hypertension (N = 2610), dyslipidemia (N = 1669), or diabetes (N = 720) into 1 of 5 groups according to the level of their medication adherence, based on medication possession ratio (MPR). Cost measures included prescription costs, medical costs, and total healthcare costs. In each disease state, >75% of patients had an MPR between 80% and 100%. Greater medication adherence across all 3 dis-

ease states was associated with significantly lower medical and total healthcare costs, even as total prescription costs were highest among the most medicationadherent patients. The strongest correlation was found in patients with dyslipidemia, in which annual prescription costs ranged from $1259 for the least adherent patients to $2252 for the most adherent. In contrast, annual medical cost was $2869 for the most adherent patients compared with $12,393 for the least adherent patients, amounting to total annual healthcare costs of $5121 for the most adherent compared with $13,653 for the least adherent patients. The same inverse trend was seen in the patients with hypertension or diabetes; however, in the case of diabetes, the most adherent patients also had the highest total healthcare costs—$11,950—of all patients with an MPR between 80% and 100%, which “makes patients with diabetes part of the 5% of the total population who contribute to 75% of healthcare costs,” Dr Fong and colleagues observed. ■

Do Medication Therapy Management Programs Achieve Their Goals? Do medication therapy management (MTM) programs required by the Centers for Medicare & Medicaid Services for eligible Medicare Part D beneficiaries actually achieve their goals of demonstrating optimal outcomes? Two poster presentations addressed this question, resulting in different findings. One presentation came from a team of pharmacists led by Sejal V. Patel, PharmD, at the Kelsey-Seybold Clinic, Houston, TX, who analyzed claims data to compare adherence rates and cost trends in patients with diabetes and an MTM program and a control group of diabetic patients without MTM. Overall, both cohorts demonstrated an adequate adherence level, but the adherence ratio did not differ significantly among the MTM enrollees (0.87) and those not enrolled in an MTM (0.88). However, among adherent members, the average drug cost per member per month (PMPM) was $44.16 for MTM enrollees and $26.90 for the non-MTM members. Similarly, the PMPM drug costs for nonadherent patients were $34.98 for MTM members and $17.86 for non-MTM members. Dr Patel and colleagues suggested that these gaps can reflect that MTM enrollees “generally take a higher

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number of medications and have more chronic conditions than non-MTM members.” In fact, they pointed out, these data suggest “that MTM members may have started with a lower adherence rate and were faced with complex barriers to attain a PDC [proportion of days covered] greater than 80%.” A second team of pharmacists, led by Wendy L. Sui, PharmD, of Blue Cross of California, evaluated the impact of a health-plan–sponsored MTM program on medication persistence, cost, and utilization. Their findings showed a trend of cost-savings with the MTM program for patients with chronic diseases (eg, diabetes, hypertension, asthma), as well as for the health plan, and a decrease in medical utilization, especially inpatient admissions and length of hospitalization. Dr Sui and colleagues noted that this review of the MTM program also brought to light issues of medication nonpersistence, gaps in care, and gaps in patients’ knowledge about their medications that should be addressed by the plan sponsor. They suggested that plan sponsors should continue to evaluate their MTM programs to address such challenges and prepare for impending legislative changes to these plans. ■

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INDICATION %8!,'/ÂŽTABLETSAREANEXTENDEDRELEASEORALFORMULATIONOFTHEOPIOIDAGONISTHYDROMORPHONEHYDROCHLORIDETHATISINDICATEDFORONCEDAILY ADMINISTRATIONFORTHEMANAGEMENTOFMODERATETOSEVEREPAININOPIOIDTOLERANTPATIENTSREQUIRINGCONTINUOUS AROUND THE CLOCKOPIOID ANALGESIAFORANEXTENDEDPERIODOFTIME 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 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.


s%8!,'/ISALSOCONTRAINDICATEDINPATIENTSWHO NEEDMANAGEMENTOFMILDPAINORPAINNOTEXPECTEDTOPERSIST HAVESIGNIlCANTIMPAIREDRESPIRATORYFUNCTIONINCLUDINGTHOSEWITH ACUTEORSEVEREBRONCHIALASTHMAORHYPERCARBIA HAVEORARESUSPECTEDTOHAVEPARALYTICILEUS HAVENARROWEDOROBSTRUCTEDGASTROINTESTINALTRACTINCLUDINGTHOSE FROMPREVIOUSSURGERYORhBLINDLOOPSvINTHE')TRACT HAVEKNOWNHYPERSENSITIVITYTOANYCOMPONENTSINCLUDING HYDROMORPHONEHYDROCHLORIDEANDSULlTES s!VOIDCONCURRENTUSEOFALCOHOLAND%8!,'/#ONCURRENTUSEOF %8!,'/WITH#.3DEPRESSANTS INCLUDINGALCOHOL INCREASESRISK OFRESPIRATORYDEPRESSION HYPOTENSION ANDPROFOUNDSEDATION POTENTIALLYRESULTINGINCOMAORDEATH%8!,'/MAYIMPAIRTHE ABILITYTODRIVEACAROROPERATEMACHINERY s.OTINTENDEDINPATIENTSWHOHAVERECEIVED-!/INHIBITORS WITHINDAYSOFSTARTING%8!,'/ s5SEWITHCAUTIONANDINREDUCEDDOSESINOLDERORDEBILITATED PATIENTS ASWELLASPATIENTSWITHRENALORHEPATICINSUFlCIENCY !DDISONSDISEASE DELIRIUMTREMENS MYXEDEMAORHYPOTHYROIDISM

PROSTATICHYPERTROPHYORURETHRALSTRICTURE TOXICPSYCHOSIS-AY AGGRAVATECONVULSIONSINPATIENTSWITHCONVULSIVEDISORDERSMAY INDUCEORAGGRAVATESEIZURESINSOMECLINICALSETTINGS#ONSIDERUSE OFANALTERNATEANALGESICINPATIENTSWITHSEVERERENALIMPAIRMENT s2ESPIRATORYDEPRESSION WHICHOCCURSMOREFREQUENTLYINELDERLYOR DEBILITATEDPATIENTS ISTHECHIEFHAZARDWITH%8!,'/ s3ERIOUSADVERSEEVENTSCOULDALSOINCLUDEHYPOTENSIVEEFFECTS ')EFFECTS CARDIACARRESTFROMOVERDOSEANDPRECIPITATION OFWITHDRAWAL-OSTCOMMONADVERSEEVENTS SEENIN CLINICALSTUDIES. WERECONSTIPATION NAUSEA VOMITING SOMNOLENCE ASTHENIAANDDIZZINESS s5SE%8!,'/WITHEXTREMECAUTIONINPATIENTSSUSCEPTIBLE TOINTRACRANIALEFFECTSOF#/RETENTION s$ONOTABRUPTLYDISCONTINUE%8!,'/ Please see brief summary of Full Prescribing Information, including boxed warning, on following pages. #/6)$)%. #/6)$)%.WITHLOGOAND#OVIDIENLOGOARE53ANDINTERNATIONALLYREGISTERED TRADEMARKSOF#OVIDIEN!'%8!,'/ISAREGISTEREDTRADEMARKOF-ALLINCKRODT)NC ¥-ALLINCKRODT)NC A#OVIDIENCOMPANY-+-AY0RINTEDIN53!

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BRIEF SUMMARY - Consult full prescribing information before use. EXALGOÂŽ (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 â&#x20AC;&#x153;blind loopsâ&#x20AC;? 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, â&#x20AC;&#x153;short gutâ&#x20AC;? syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckelâ&#x20AC;&#x2122;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 (â&#x2030;Ľ 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., Addisonâ&#x20AC;&#x2122;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:  K &3A>7@/B=@G3>@3AA7=<[see Warnings and Precautions (5.3)]  K Head Injury and Increased Intracranial Pressure [see Warnings and Precautions (5.5)]  K G>=B3<A7D34431B[see Warnings and Precautions (5.6)]  K /AB@=7<B3AB7</:4431BA [see Warnings and Precautions (5.7)]  K /@27/1@@3AB[see Overdosage (10)]  K %@317>7B/B7=<=4+7B62@/E/:[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 â&#x2030;Ľ2% of Patients with Moderate to Severe Low Back Pain During the Open-Label Titration Phase or Double-Blind Treatment Phase by Preferred Term Preferred Term Open-Label Double-Blind Treatment Phase Titration Phase EXALGO (N=447) EXALGO (N=134) Placebo (N=134) Constipation 69 (15) 10 (7) 5 (4) Nausea 53 (12) 12 (9) 10 (7) Somnolence 39 (9) 1 (1) 0 (0) Headache 35 (8) 7 (5) 10 (7) Vomiting 29 (6) 8 (6) 6 (4) Drug Withdrawal Syndrome 22 (5) 13 (10) 16 (12) Pruritus 21 (5) 1 (1) 0 (0) Dizziness 17 (4) 3 (2) 2 (1) 16 (4) 2 (1) 6 (4) Asthenia a Insomnia 13 (3) 7 (5) 5 (4) Diarrhea 13 (3) 5 (4) 9 (7) Back Pain 13 (3) 6 (4) 8 (6) Dry Mouth 13 (3) 2 (1) 0 (0) Edema Peripheral 13 (3) 3 (2) 1 (1) Hyperhidrosis 13 (3) 2 (1) 2 (1) 10 (2) 2 (1) 0 (0) Anorexia b Arthralgia 9 (2) 8 (6) 3 (2) Anxiety 9 (2) 0 (0) 4 (3) 9 (2) 4 (3) 3 (2) Abdominal Pain c 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 â&#x2030;Ľ2% 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) Anorexia b 139 (6) Dry Mouth 121 (5) Abdominal Pain c 115 (5) Anxiety 95 (4) Back Pain 95 (4) Dyspepsia d 88 (4) Depression 81 (3) Dyspnea e 76 (3) 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) Chest Discomfort f 51 (2) 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��&#x20AC;&#x2122;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

Mallinckrodt


CLINICAL

ORIGINAL ARTICLE

From A to Z: Medication Cost-Management Strategies for Disproportionate Share Hospitals Andrea Henry, PharmD, MBA; Goldina Ikezuagu Erowele, PharmD; Uche Anadu Ndefo, PharmD, BCPS; Jackie Milton-Brown, PharmD; Enock Anassi, PharmD, MD; Wendy Green, PharmD, MPA; Adriana Alvidrez, PharmD, BCPS; Alphonsus U. Okpara, PharmD

Andrea Henry

Stakeholder Perspective, page 179

Am Health Drug Benefits. 2011;4(3):172-180. Disclosures are at end of text

Background: Harris County Hospital District, Houston, TX, is a publicly funded hospital system that provides care to residents of Harris County with a need-based payment system. The Harris County Hospital District pharmacy department, with a drug budget of more than $75 million in fiscal year 2010, utilizes a closed formulary system that is managed by the Formulary Management and Pharmacoeconomics Service, along with the medical staff. This service is comprised of clinical pharmacists whose goal is to provide a comprehensive, safe, and cost-effective formulary. Objective: To describe the unique formulary management process at a county hospital system and what makes this process cost-effective, which may benefit pharmacy departments in institutions serving an indigent patient population. Summary: The Harris County Hospital District drug formulary is overseen by the Pharmacy & Therapeutics committee, which is supported by 5 therapeutic subcommittees, including antimicrobials, cardiovascular, general formulary, central nervous system, and oncology. The Pharmacy & Therapeutics Committee consists of a medical staff committee that is supported by clinical pharmacists, who serve as the facilitators of these 5 subcommittees. Their responsibilities include the provision of drug information for formulary decisions, providing parameters to govern the use of certain medications, communicating changes to the formulary, conducting class reviews and medication utilization evaluations, coordinating annual pharmaceutical bids, reviewing and writing medication use policies and procedures, facilitating the use of cost-effective medications, and monitoring the use of medications in the hospital system. Conclusion: The processes incorporated by Harris County Hospital District in its formulary management are cost-effective and may be beneficial to other pharmacy departments, especially those institutions that serve an indigent patient population and are interested in cost-effective management strategies.

T

he Harris County Hospital District (HCHD) is an integrated public healthcare system for Harris County, TX, the nationâ&#x20AC;&#x2122;s third most populous county.1 More than 27% of Harris County residents are uninsured, and Texas state law requires counties to serve the indigent; therefore, most of these uninsured patients receive care at HCHD.2 HCHD is comprised of 3 hospitals, 13 community health centers, 13 satellite homeless

shelter clinics, 8 school-based clinics, 4 mobile health clinics, and a free-standing dental center. The hospital district operates 975 licensed hospital beds and provides more than 1 million outpatient visits each year. Each hospital and community health center has a dedicated pharmacy that provides comprehensive and cost-effective pharmaceutical care to residents of Harris County.3 With a pharmacy budget of more than $75 mil-

Dr Henry is Manager; Dr Okpara is Director; Dr Erowele, Dr Anassi, Dr Green, and Dr Alvidrez are Clinical Pharmacist III, Formulary Management & Pharmacoeconomics Service; Dr Milton-Brown is Formulary Command Center Clinical Pharmacist; all at the Department of Pharmacy, Harris County Hospital District, Houston, TX; Dr Anadu Ndefo is Assistant Professor, Department of Pharmacy Practice, College of Pharmacy and Health Sciences, Texas Southern University, and Drug Information Specialist, Harris County Hospital District. The views expressed in this article reflect those of the authors and do not necessarily reflect the views of Harris County Hospital District.

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lion in fiscal year 2010 (March 1, 2009, through February 28, 2010), the department served more than 40,000 inpatients and filled more than 2.6 million prescriptions throughout the year. Ben Taub General Hospital (BTGH) is the district’s largest hospital. It houses a Level I trauma center and serves as a teaching hospital for Baylor College of Medicine. Lyndon B. Johnson General Hospital is the area’s second busiest emergency center (second to BTGH) and serves as the teaching hospital for the University of Texas Medical School at Houston. Quentin Mease is a 49-bed geriatric and physical rehabilitation facility that is staffed by faculty and residents of Baylor College of Medicine.

Formulary Decision Process The medications on the formulary at HCHD are selected based on need, safety, and cost-effectiveness.4 The formulary is managed by a Pharmacy & Therapeutics (P&T) Committee that consists of physicians, pharmacists, dieticians, nurses, and administrators. The P&T Committee encompasses 5 therapeutic subcommittees, including general medicine, oncology, infectious disease, cardiovascular, and central nervous system, facilitated by the clinical pharmacy specialists on the Formulary Management and Pharmacoeconomics Service (FMPS). The latter consists of 1 formulary manager, 4 clinical pharmacy specialists, 1 formulary command center pharmacist, and 0.8 full-time equivalent of a drug information specialist. The P&T Committee meets monthly for 10 months of the year, breaking in August and December. The subcommittees alternate monthly to manage the enormous workload on the committees. A clinical pharmacy specialist from FMPS serves as the facilitator for each subcommittee. The subcommittees consist of stakeholders in each specialty, including physicians and clinical pharmacists. The P&T Committee may decide to admit a drug to the formulary without restriction, not admit, delete, change restriction status, or deny a restriction change. Addition of Medications to Drug Formulary Physicians may request for a medication to be added to the formulary by completing a request for formulary addition form, which is readily available on the HCHD intranet. The requester is required to attach clinical trials, practice guidelines, estimated use, alternate comparable agents, or other pertinent information to support the request for the addition of the medication. The requester is also required to disclose any potential conflict of interest. The request is then sent to the appropriate chief of service (eg, the urology chief of service would have to review requests submitted by a urologist). If the

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KEY POINTS ➤

Harris County Hospital District is located in the nation’s third most populous county and is a publicly funded hospital system that provides care to low-income local residents using a need-based payment system. In 2010, the drug budget for the pharmacy department in this hospital system was more than $75 million. The unique formulary management process at this hospital system is dependent on a complex yet effective formulary design that is overseen by various groups of clinical pharmacists whose goal is to provide comprehensive, safe, and cost-effective prescribed medications for its indigent patient population. This article outlines the elaborate and carefully designed pharmacy structure that enables this complex system to function in an efficient and effective way to ensure the safe and cost-effective drug utilization in this large disproportionate share hospital. The pharmacy system described in the article can serve as a model for pharmacy departments within similar care settings with disproportionate share hospitals or with a significant indigent patient population.

chief of service approves the request, it is then forwarded to the FMPS. The facilitator for the appropriate subcommittee then completes a comprehensive drug monograph and forwards it to the subcommittee members for review. This drug monograph consists of efficacy data, safety data, estimated use, alternate agents, and cost analysis. The monograph also takes into account systemwide expenses, such as administration costs, nursing time, and other expenses that may be incurred as a result of adding or not adding the medication to the formulary. Cost considerations are always secondary to safety and efficacy. In addition to the drug monograph, a drug class review may be performed by an FMPS clinical pharmacy specialist. This review is utilized to inform the P&T Committee members about the choices available within a given therapeutic class. The review of the addition request is then presented at a subcommittee meeting, where the requesting physician may appear to present reasons for the request. The subcommittee will review all materials presented and make a recommendation to the P&T Committee. The recommendations can range from “addition to the formulary,” “addition with restrictions,” “remain nonformulary,” or “addition to the ‘do not dispense’ list.” The P&T Committee reviews the information pre-

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sented by the subcommittee and makes a recommendation to the medical board, which consists of chiefs of staff, chiefs of individual services, and hospital administrators. The medical board reviews the information presented by the P&T Committee members and approves, denies, or modifies their recommendations. Cost-savings associated with this process are calculated based on cost-avoidance of medications that are not added to the formulary and medications that are deleted from the formulary. Upon the addition of a new medication to the formulary, a retrospective review that includes assessment of prescribing patterns, utilization, adverse effects, dosing errors, and cost-effectiveness must be conducted by the clinical pharmacy specialist facilitator at 3, 6, or 12 months after the addition of the drug. The FMPS continues to track, trend, and report information regarding cost, utilization, and adverse effects to the P&T Committee and to the medical board. The results of this review are used for additional educational campaigns, updates to the clinical decision-support system, and/or reevaluation of formulary status. In 2009, 66 medications were reviewed by the P&T Committee, of which 21 were admitted to the formulary without restrictions, 9 were admitted with restrictions, 11 were not admitted, and 10 were removed from the formulary. Changes were made to restriction status on 14 drugs, and 1 restriction change was denied. The effectiveness of the HCHD formulary system can be gauged when compared with drug utilization patterns nationwide. According to DrugTopics.com, atorvastatin (Lipitor), esomeprazole (Nexium), and clopidogrel (Plavix) were the top 3 branded medications dispensed in 2009.5 In that same timeframe at HCHD outpatient clinics, atorvastatin, which has restrictions, ranked 98; esomeprazole, which also has restrictions, ranked 104; and clopidogrel, which was restricted until 2007, ranked 27.

Nonformulary Process The Joint Commission requires that hospitals have a process by which medications can be retrieved off formulary. Medications that are not added to the formulary after the process described above, or those that have not been reviewed, require the completion of a nonformulary form to be dispensed to a specific patient. Medications that are newly approved by the US Food and Drug Administration (FDA) can also be dispensed, pending completion of a nonformulary form. The process begins when the pharmacist receives a request for a nonformulary medication for a patient, which usually comes from a physician and has been cosigned by the chief of service or the chief of the department. The nonformulary form includes the

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patientâ&#x20AC;&#x2122;s information; the drug requested with dose, frequency, and route; the anticipated duration of therapy; and detailed justification for the request. Nonformulary drugs are not stocked in the pharmacy; therefore, it may take up to 72 hours before therapy can be initiated. The nonformulary request is then submitted to the pharmacy supervisor. Upon receipt of the request, the pharmacy supervisor reviews it and then recommends available formulary alternatives. In the event that formulary alternatives are not accepted, the supervisor is also permitted to approve nonformulary medications that have a low-cost impact and are within the scope of services in our institution. HCHD does not offer therapy for infertility, transplants, sexual dysfunction, or cosmetic purposes, involving medications such as clomiphene (Clomid, Serophene) for ovulation, sildenafil (Viagra) for erectile dysfunction, or onabotulinumtoxinA (Botox) for wrinkles. Because HCHD does not provide transplant services, it does not offer transplant rejection medications on an outpatient basis as a part of its formulary; however, HCHD does continue transplant rejection medications when a transplant patient is admitted to the hospital. If the supervisor cannot approve the nonformulary agent, it is referred to the clinical pharmacy specialist on call. The clinical pharmacy specialist on-call pager is held by the pharmacy resident, and a clinical pharmacy specialist is the pharmacy residentâ&#x20AC;&#x2122;s backup. In the event that the clinical pharmacy specialist cannot approve the request, and the prescribing physician does not accept an alternative, the request is forwarded to the formulary command center (FCC) clinical physician on call, who is either the liaison to the chairperson of the P&T Committee or his/her designee. The approval or denial of the request is then relayed to the pharmacy and is documented in a shared pharmacy database. The approvals are indefinite, unless otherwise specified. Requests for medications that are outside of our scope of service are referred to case workers.

Formulary Restriction Programs Formulary Command Center, Prior Authorization Program In an effort to control costs and encourage cost-effective prescribing, HCHD implemented a prior authorization (PA) restriction program modeled after those used in the managed care environment. The program is designed to promote a tier structure to guide medication prescribing practices. Drugs are selected for this program because of high acquisition cost, safety concerns, or the potential for misuse or abuse. At the time of the programâ&#x20AC;&#x2122;s inception in 1998, fewer than 10 agents were included, with a volume of 2700 calls annually.

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Figure 1 Oral Nutritional Supplement Purchases 500,000 400,000

Purchases, $

The criteria established for each medication are developed by subcommittees using evidence-based medicine, and are approved by the P&T Committee and the medical board. Currently, 76 agents are under the program, which is managed by 1 clinical pharmacist. Approximately 13% of the drugs in the program are for cardiovascular conditions, 12% are central nervous system agents, and 7% are for diabetes. The remainder of the list is comprised of a wide range of therapeutic areas. The volume has increased to more than 10,000 calls annually, with the top requests for losartan (Cozaar), pioglitazone (Actos), and insulin glargine (Lantus). During normal business hours, the FCC clinical pharmacist answers a central phone line to approve or deny restricted medication requests according to preset criteria approved by the P&T Committee. If the criteria are not met, the pharmacist recommends an alternative formulary agent. If the alternative is not accepted by the prescribing physician, the caller is referred to the physician on call. A physician is on call 24 hours a day, 7 days a week, including holidays, to respond to denials and after-hours requests. If an approval is granted, the FCC clinical pharmacist enters the approval in the notes or comments section of the patientâ&#x20AC;&#x2122;s inpatient and/or outpatient profiles. Denials are documented in the FCC database. The pharmacist receiving approvals after hours, or on holidays or weekends, enters the approval in the same manner as the FCC pharmacist. Unless otherwise specified in the restriction criteria, approvals are valid indefinitely. The physician on call providing after-hours approvals sends the approval list to the FCC for record keeping. Physician compliance with this program is measured by periodic medication use evaluations for agents that are identified as our top expenditures despite being a part of the restriction program. The medication use evaluations are also developed to strengthen the present criteria for certain agents and to evaluate the need for medications from the program. New agents added to the restriction program are also monitored through medication use evaluations. For example, physician compliance rate with the PA criteria for the leukotriene inhibitor and the tyrosine kinase inhibitor was 87% and 81%, respectively. Issues with compliance with prescribing guidelines can be identified and reported to our P&T Committee for further actions and/or recommendations. Pharmacist compliance is reviewed quarterly by requesting a report from the information technology (IT) department on all new FCC prescriptions dispensed during that period, and verifying whether an approval is noted in the patientâ&#x20AC;&#x2122;s profile. Pharmacy areas with low compliance can be identified, and corrective measures

300,000 200,000 100,000 0

Before restriction

After restriction

are implemented. Medications that were previously on the formulary and later added to the FCC are reviewed after 6 months for changes in utilization, and a noticeable change in prescribing patterns is usually evident. For example, HCHDâ&#x20AC;&#x2122;s purchases for oral nutritional supplements decreased significantly after their addition to our PA program, from $440,000 to $250,000 after only 6 months in the program (Figure 1). This information is used to calculate the cost-savings associated with the FCC. The cost-avoidance for agents added directly to the FCC, however, has been more difficult to ascertain, because the FCC serves as a deterrent to the prescribing of the restricted drugs.

Service Line Restrictions Program Medications on the service line restrictions program are restricted according to a medical specialty or a particular quantity. Drugs are placed on this list to ensure proper use by the appropriate clinical specialist. These restrictions are upheld by the dispensing pharmacist. When the pharmacist receives a medication order, the order is assessed for restrictions and is dispensed accordingly. If the prescription is not written by the appropriate service or physician, the pharmacist contacts the prescriber, who has the option of requesting an override from the FCC physician on call. Currently, 50 drugs are on this list; 12% of them are restricted to oncology, 8% are restricted to either rheumatology or hematology, and 6% each, to pediatrics, neonates, and renal services. These medications are reviewed before and after restriction to assess whether utilization, and therefore cost, has increased or decreased. For example, hydrocodone tablets were on the service line restrictions program, requiring a signature from an attending physician for use. When the restriction was removed, the use of this medication doubled over time, indicating that the restriction had been working before the change (Figure 2).

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Table 1 Selected Examples of Antimicrobial Approval Program Restriction programs

Drug list

Infectious disease faculty approval required before dispensing

Ampicillin/sulbactam, piperacillin/ tazobactam, ertapenem, doripenem, meropenem, daptomycin, linezolid, tigecycline, voriconazole, micafungin, abelcet, ambisome

Length of therapy for empiric use

Vancomycin, azithromycin, ciprofloxacin, moxifloxacin, levofloxacin

Infectious disease faculty approval required for high doses

Ceftriaxone and cefepime

Restricted to a service or an indication

Cefotaxime (pediatrics), azithromycin 600 mg (MAC prophylaxis)

MAC indicates Mycobacterium avium complex.

place, and the conversion is noted in the patientâ&#x20AC;&#x2122;s profile and in the medical chart. To accommodate this law, an automatic substitution waiver is signed by all physicians before substituting prescriptions written by them. Currently, 23 drugs are on the automatic substitution list. The list includes many classes, such as angiotensin II receptor blockers, calcium channel blocker and statin combinations, sulfonylureas, insulin analogs, and serotonin reuptake inhibitors. In 2009, 8 therapeutic interchanges and generic switches were authorized by the P&T Committee, with an approximate cost-avoidance of $3.2 million. The automatic substitution waiver includes all medications that have been approved by the P&T Committee for direct therapeutic conversions, which are listed according to their therapeutic class. The waiver includes TSBP mandates, as well as a note to inform the pharmacist that if the dose falls outside of any of the guidelines, the prescribing physician must be contacted for proper dosing conversion. The physician must sign and date the form, and the pharmacy maintains a file of these forms.

Figure 2 Hydrocodone/Acetaminophen Utilization in 2009 5000

Cost, $

4000 3000 2000 1000 0 Dec Jan 2008 2009

Feb

Mar

Apr

May

June

Aug

July

Sept

Oct

Nov

2009 Utilization

Therapeutic Substitutions/Interchanges Program The Texas State Board of Pharmacy (TSBP) allows a pharmacy to interchange prescribed drugs as long as there is P&T Committee oversight and a formulary is established with a method for prescribers to override the interchange. The TSBP also requires that the pharmacist-in-charge or designee be a voting member of the committee.6 In the outpatient setting, physician approval is required for all therapeutic interchanges. The physician signs a waiver through the physician services orientation, authorizing pharmacy to interchange a list of medications according to the P&T Committee protocols. Signature cards are maintained in a database for pharmacy to access and verify authorizations. In the inpatient setting, the physician is notified by the pharmacist when a conversion has taken

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Antimicrobial Approval Program Systematic approaches have been implemented in many institutions as a means of reducing inappropriate use of antibiotics and achieving optimal outcomes.7 The purpose of this program is to reduce cost, decrease resistance, and minimize adverse events.8,9 Selected antimicrobials require infectious disease faculty approval before dispensing, to decrease antimicrobial expenditures and improve susceptibilities without compromising patient outcomes or length of stay.10,11 The P&T Committee approves which antimicrobials should require infectious disease approval, by considering evidence-based data presented by the antimicrobial subcommittee. The subcommittee bases its decisions on medication cost, resistance, and/or adverse effects and reviews the list periodically to add or remove agents. The program has evolved over time to include different layers of restriction, including restricting length of therapy for empiric use and restricting to a service or an indication (Table 1). The FMPS clinical pharmacist for the antimicrobial subcommittee is responsible for monitoring drugs on the antimicrobial restrictions list and evaluating use through medication use evaluations, monthly purchase variances, and prescribing pattern changes on monthly utilization reports. Restriction Compliance Assessment Medication Utilization Evaluations Medication utilization evaluations are continuously performed by the FMPS. The need for these evaluations

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are generally identified by the addition of a new drug to the formulary, an increase in spending on a particular drug, inappropriate use, adverse effects, or a change in the formulary status of a drug. These needs are typically identified by the subcommittee assigned to the drug or by the facilitator or the clinical pharmacy specialist of the subcommittee. To perform a medication utilization evaluation, an abstract containing the background, methods, and end points, along with a data collection form, are prepared by the clinical pharmacy specialist. These are then reviewed by the subcommittee, which can give input for revision. This information is then presented to the Medication Use Safety subcommittee, which can also provide input for revisions. Once the information has been presented to and approved by both subcommittees, the data collection begins from an IT report that lists patients who received the drug for a specific time period. The data are generally collected from inpatient paper charts and from electronic medical records for outpatient visits. The data are then analyzed and summarized by the clinical pharmacy specialist, and the results are presented to the subcommittee. The subcommittee reviews the results of the medication utilization evaluation and makes recommendations, which can consist of changing the formulary status of a drug, adding an alert in computerized systems, education information for providers and/or pharmacists, or not making any changes at all. These recommendations are presented to the P&T Committee along with the results of the medication utilization evaluations. For example, a recent medication utilization evaluation was completed for intravenous (IV) proton pump inhibitors (PPIs). Service line restriction criteria stated that patients must be admitted to the intensive care unit or to the emergency department with a gastrointestinal bleed to be prescribed IV PPIs. Such patients needed to receive a bolus dose followed by a maintenance infusion for less than 72 hours. The FMPS evaluated the adherence level to the medication utilization criteria and discovered that these criteria were met comprehensively only 8.7% of the time.12

Other Cost-Saving Processes Brand and Generic Substitutions Monitoring medication patent expirations can help to mitigate increasing drug costs by allowing the interchange of branded drugs to generic or nonproprietary formulations. Various online resources are dedicated to monitoring generic drug approvals, and the FDA publishes monthly reports on generic drug approvals. Although generic drugs typically provide cost-effective alternatives, there is a caveat. As generics enter the

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Table 2 Selected Cost-Saving Initiatives, Fiscal Year 2010 Therapeutic alternative conversions

Savings, $

Alavert to loratadine

86,918

Alendronate-D to alendronate

103,694

All proton pump inhibitors to omeprazole

384,186

Factor VIII drugs (brand to brand)

11,912

Factor IX drugs (brand to brand)

32,698

Flutamide to bicalutamide

17,000

Fluticasone HFA to mometasone

93,787

Fluticasone/salmeterol to budesonide/formoterol

288,000

Zolmitriptan to rizatriptan

57,937

Zolmitriptan to sumatriptan

165,164

Protocols Erythropoiesis-stimulating agents

953,755

Factor VII

12,000

Immune globulin

165,000

Pharmaceutical bids Contrast media

226,000

Esomeprazole

1,810,157

Ezetimibe/simvastatin

332,682

Brand-to-generic conversions Arimidex to anastrozole

413,613

Casodex to bicalutamide

15,000

Temovate E to clobetasol

27,252

Depakote ER to divalproex ER

45,456

Proscar to finasteride

137,455

Camptosar to irinotecan

12,000

Lamictal to lamotrigine

194,180

CellCept to mycophenolate

196,852

Zofran to ondansetron

20,304

Rebetol to ribavirin

124,914

Generic-to-generic conversions Clindamycin

29,000

Enalapril

38,980

Lisinopril/hydrochlorothiazide

22,264

Education programs Neupogen/Neulasta Total

353,849 6,372,009

NOTE: This list does not include any initiatives with a costsavings of <$10,000. ER indicates extended release; HFA, hydrofluoroalkane.

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Table 3 Key Factors to Consider in Pharmaceutical Bids

Brand-to-generic conversions Cost of the drug Dispensing data Inpatient utilization Market share analysis Outpatient utilization Patient assistance programs Product availability Purchase history market, branded drugs may decrease in cost to compete for market share, making the branded product more costeffective than the newly approved generic agent. The clinical pharmacist assigned to the relevant subcommittee tracks the pricing of medications in that subcommittee and works with the inventory team to provide the most cost-effective option. Premier is the group purchasing organization that works to negotiate lowercost contracts for pharmaceuticals for HCHD. Premier provides a program that monitors brand-to-generic switches and automatically switches products when the generic becomes available. Premier’s program, however, only applies to our inpatient formulary and may not always identify the most cost-effective product; therefore, continuous monitoring is always appropriate. On occasion, generic-to-generic conversions occur as a result of less-expensive generics becoming available from different manufacturers and price fluctuations between generics. These pricing opportunities are usually determined by using an inflation/deflation report provided by the wholesaler or by monitoring top-utilized generics on a monthly basis. This report shows the increased or decreased dollar amount and/or the increased or decreased percent for each drug from the previous month. Table 2 shows examples of switches that occurred in fiscal year 2010.

Annual Outpatient Pharmaceutical Bid Review The bid review is a comprehensive process that involves extensive data collection. The purpose is to solicit and receive the best possible price for branded medications based on previous utilization and purchase history. This process involves the FMPS’ clinical pharmacy specialist preparing therapeutic classes review (ie, a bid list) and conducting a cost analysis for potential cost-savings opportunities with therapeutic alternatives or with therapeutic tiers. The bid list must be evaluated for discontinued products and brand-to-generic conversions.

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The previous year’s utilization must be gathered and presented to an HCHD purchasing agent for bid posting. Once bids have been offered by pharmaceutical companies, the bid pricing list must be compiled with current 340B pricing (a federal outpatient drug discount program for disproportionate share hospitals), and Premier drug pricing (inpatient) and utilization for all our drugs (inpatient and outpatient). This information is evaluated by the subcommittees to determine if any changes need to be made based on pricing. Recommendations are then forwarded to the P&T Committee for approval, and final approval is made by the medical board. The recommendations are compiled and communicated to the staff. The FMPS educates the staff via newsletters, in-service training, department meetings, and through other methods. The FMPS also works with the inventory team to ensure that adequate drug stock is available. When this process is completed, online formulary databases get updated. Key factors to consider when preparing a pharmaceutical bid list and process are listed in Table 3.

Budget Forecasting Budget projections for the upcoming fiscal year can help to identify differences between current formulary alternatives and new drugs. It also helps in predicting the potential financial impact of new drugs on the pharmaceutical budget. We can expect to see a decrease in expenditures when branded medications become generic. In budget projecting, it is prudent to know which drugs have recently been FDA-approved or are pending approval for the upcoming fiscal year, new drug indications, utilization of the formulary alternative(s), anticipated cost of the new drug, and the potential for the new agent to fully or partially replace the formulary alternative(s). The American Society of Health-System Pharmacists (ASHP) provides an annual update titled “Projecting Future Drug Expenditures” that is a useful reference for detailed information on budget projections (with the 2011 update recently published)13; Cardinal Health and Medco offer similar publications. Cost-Effectiveness According to an ASHP health policy alert issued on January 26, 2009, clinical pharmacists working in hospitals, ambulatory care clinics, physician offices, or community pharmacies provide a benefit-to-cost ratio of $4.81:$1.14 However, this information is not readily available for formulary management services. The FMPS at HCHD employs 6 full-time pharmacist equivalents whose primary responsibilities are outlined in this article. Other responsibilities of these pharmacists include drug shortage management, education on new initia-

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tives, variance reporting, lectures, precepting pharmacy students, and other scholarly activities. Based on the selected cost-savings presented in Table 2, comparing the wages and benefits (28.5% of wages) for the 6 fulltime pharmacist equivalents results in a $6.38:$1 benefit-to-cost ratio.

Conclusion Various avenues, including formulary decision processes, nonformulary processes, restriction programs, stewardship and streamlining programs, medication use evaluations, and pharmaceutical-pricing programs are used by HCHD to manage its drug formulary. These processes are cost-effective and may be beneficial for other pharmacy departments that serve indigent patient populations and are interested in cost-effectiveness strategies to control their drug costs. ■ Author Disclosure Statement Drs Henry, Erowele, Anadu Ndefo, Milton-Brown, Anassi, Green, Alvidrez, and Okpara reported no conflicts of interest related to the contents of this article.

References 1. Harris County Hospital District home page. March 29, 2011. www.hchdonline. com/about/news/2011/us-news-ranking.htm. Accessed June 17, 2010.

2. Thompson JA, Lee V. The effect of health insurance disparities on the health care system. AORN J. 2007;86:745-756. 3. Harris County Hospital District. Department of Pharmacy. www.hchdonline.com/ health/pharmacy/main.htm. Accessed June 17, 2010. 4. Harris County Hospital District. Policy and Regulations Manual. Revised March 2010. On file at HCHD. 5. SDI/Verispan, VONA. 2009 top 200 branded drugs by total prescriptions. Drug Topics. 2010. http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard// drugtopics/252010/674969/article.pdf. Accessed July 28, 2010. 6. Texas State Board of Pharmacy. Pharmacy rules and laws. 2002-2004. Title 22; Part 15; Chapter 291; Subchapter D; Section 291.73 b2E. www.tsbp.state.tx.us/rules/. Accessed July 15, 2010. 7. Bryan CS. Strategies to improve antibiotic use. Infect Dis Clin North Am. 1989;3: 723-734. 8. Raymond DP, Pelletier SJ, Sawyer RG. Antibiotic utilization strategies to limit antimicrobial resistance. Semin Respir Crit Care Med. 2002;23:497-501. 9. White AC Jr, Atmar RL, Wilson J, et al. Effects of requiring prior authorization for selected antimicrobials: expenditures, susceptibilities, and clinical outcomes. Clin Infect Dis. 1997;25:230-239. 10. Anassi EO, Ericsson C, Lal L, et al. Experience briefs: using a pharmaceutical restriction program to control antibiotic use. Formulary. 1995;30:711. 11. Carling P, Fung T, Killion A, et al. Favorable impact of a multidisciplinary antibiotic management program conducted during 7 years. Infect Control Hosp Epidemiol. 2003;24:699-706. 12. Ndefo UA, Erowele GI, Batubo DB. Retrospective analysis of esomeprazole use and adherence to established or approved prescribing guidelines in hospitalized patients. Poster presented at the American Society of Health-System Pharmacists (ASHP) Midyear Clinical Meeting, December 6-10, 2009, Las Vegas, NV. 13. Doloresco F, Fominaya C, Schumock GT, et al. Projecting future drug expenditures—2011. Am J Health Syst Pharm. 2011;68:e1-e12. www.ajhp.org/site/Drug expenditures_2011.pdf. Accessed January 11, 2011. 14. American Society of Health-System Pharmacists. Clinical pharmacists yield a median five-fold return on investment among 31 studies, review shows. Health Policy Alerts. January 26, 2009. www.ashp.org/policy-alert. Accessed January 11, 2011. www.ashp.org/DocLibrary/Advocacy/PolicyAlert/Pharmacist_ROI_Review.pdf.

STAKEHOLDER PERSPECTIVE A Collaborative Approach to Drug Selection, Driven by Clinical Outcomes Excellence PAYERS: The formulary selection process is treacherous, convoluted, and involved. Keeping the rational approach in the forefront takes exertion and integrity. All too often other standards—emotional, personal, financial, special interests, pharmaceutical marketing, and unconscious desire of power—take the place of excellence. In the formulary decision-making process, these must all be rejected. The final shared paradigm must be one of quality. The model for drug decision-making for formulary purposes discussed in the present article by Dr Henry and colleagues is described by the System of Objectified Judgment Analysis (SOJA).1 The goal is to provide a comprehensive, safe, and cost-effective approach to drug therapy. In the SOJA method, medication selection principles are specified for each therapeutic drug category, based on clinical efficacy, incidence and severity of adverse effects, dosage frequency,

drug interactions, acquisition cost, documentation, pharmacokinetics, and pharmaceutical aspects. Additional significance is given to the development of resistance for antimicrobial agents. The use of the SOJA method means that drug selection decisions are based solely on rational criteria. The utilization of interactive software creates a transparent, realistic, and specific dashboard. The example of the Harris County Hospital District discussed in this article illustrates this type of formulary management process, which makes use of process elements to cost-effectively benefit pharmacy departments in institutions and serve an indigent patient population. When healthcare resources are limited, decisions will have far-reaching consequences with individual magnitudes greater than initially thought.2 Decision makers may be unaware of the power exerted by these Continued

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STAKEHOLDER PERSPECTIVE (Continued) multiple factors. Evidence-based medicine applies the use of balanced health outcomes information. The SOJA method ensures that health outcomes information is given appropriate weight, based on decision-making processes in economics; such an approach is a valuable tool in discussions about drug selection for formularies.2 The sequence of the decision matrix is efficacy, safety, tolerance, ease of use, applicability, and cost. Each medication is compared with the theoretical “perfect” agent within a therapeutic classification—to be administered once daily and have optimal clinical benefits and no side effects in 100% of patients. This is the benchmark of excellence.3 PATIENTS: Prescription drug spending in the United States increased at a rate of >10% annually and currently represents 11% of all healthcare expenditures. This imbalance will continue to trend worldwide.4 The Harris County Hospital District approach allows drug selection within a therapeutic category across a range of indications, confers clinical effective-

ness primacy over cost, and is suitable for the development of formularies that would stimulate cost-effective prescribing across primary or secondary care.4 In this collaborative approach, the team of physicians, nurses, pharmacists, and healthcare professionals are dedicated to the dissemination of evidence-based, noncommercial information to physicians and healthcare providers, with the goal of achieving better prescribing and patient outcomes—a unique form of excellence. 1. Janknegt R, Steenhoek A. The System of Objectified Judgment Analysis (SOJA). A tool in rational drug selection for formulary inclusion. Drugs. 1997;53: 550-562. 2. Janknegt R. Using health outcomes data to inform decision-making. Pharmacoeconomics. 2001;19(suppl 2):49-52. 3. van den Bemt BJ, van den Hoogen FH, Breedveld FC, et al. InforMatrix: treatment of rheumatoid arthritis using biologicals. Expert Opin Pharmacother. 2006;7: 1769-1789. 4. Alabbadi I, Crealey G, Scott M, et al. Impact of Modified System of Objectified Judgement Analysis (SOJA) methodology on prescribing costs of ACE inhibitors. Clin Drug Investig. 2006;26:485-494.

Diana Rangaves, PharmD, CEO Clinical Consultant Services Santa Rosa, CA

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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

90

% 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

3

6

9

12

15

18

21

24

27

30

33

36

39

42

45

48

51

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


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

• Health Economics Research • Health Plan Initiatives • Health Information Technology • Industry Trends • Innovations in Healthcare • Literature Reviews • Medicare/Medicaid

• 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 Vol 4, No 3

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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.

Victoza® is a registered trademark and VictozaCare™ is a trademark of Novo Nordisk A/S. © 2011 Novo Nordisk 0311-00001944-1

April 2011


May/June 2011, Vol 4, No 3