Winter 2015

Bridging the gap between the hospital and alternate-site care Volume 4 • Number 1 • February/March 2015 • specialtypharmacycontinuum.com

In This Issue Ask the Expert

3

Q&A: Kate Keeping on the global outlook for biosimilars.

Affordability = survival for some patients

PAPs Offer Safety Net For Soaring Drug Prices

Clinical

6 8 12 13

Reducing pill burden in end-stage renal disease.

Innovative strategies for managing PAH. As orphan drug market spikes, SPs respond.

Meeting the clinical challenges of oral cancer chemotherapy.

How To Become A Data ‘Star’ In SP Contracts Philadelphia—Gaining access to—and keeping—hard-fought specialty drug contracts often hinges on the quality of the product-specific data you can provide to Pharma. Given this critical performance measure, is your specialty pharmacy (SP) a star, a rising star, a problem child or a dog in the eyes of these crucial partners?

You’d better be on the rising star side of this equation, said Marc Duey, MBA, the founder and president of ProMetrics, Inc., at the recent Specialty Data Optimization Summit. Although the

•

see DATA CONTRACTING, page 21

Operations & Mgmt

20

Data optimization tips for SPs and drug manufacturers.

Policy

22

Getting ACOs up to speed on med management.

Educational Review

Immune Globulins: Therapeutic, Pharmaceutical, Cost, and Administration Considerations See insert after page 12.

The Push Is On For Boosting Drug Adherence

For $178,000, you could buy: • A 2,050-square-foot, four-bedroom home in Broken Arrow, Okla.

• An oceanfront lot in Australia • A 2014 Aston Martin DB9 Volante • Tuition, room and board, and fees for three years of full-fare undergraduate education at Harvard University Or you could go through two courses of treatment with Amgen’s new leukemia drug, blinatumomab (Blincyto), which, at $89,000 per cycle, is the most expensive cancer medication approved to date.

Although most patients won’t have to pay full freight for blinatumomab and other high-priced medications, the financial body blows from copays and coverage gaps can be painful. As a result, manufacturers’ patient assistance programs (PAPs)—and specialty pharmacies’ ability to offer guidance for navigating these complex programs— have become critically important in keeping patients’ therapy on track.

Recent data underscore how difficult a task that may be. A study published last year ((J Clin Oncoll 2014;32:306-311) found that patients with copayments of $53 or more were 70% more likely to discontinue therapy in the first six months of treatment than those with lower copays.

Even when patients stay on therapy, waiting for payment approval by third-party payors can delay treatment, according to Geoffrey Uy, MD, an associate professor of medicine in the oncology division and a leukemia specialist at Washington University in St. Louis. “We’re absolutely seeing gaps in treatment due to delays in

Philadelphia—The Pharmacy Quality Alliance (PQA) is developing new pharmacy quality measures focused on specialty medication adherence, according to Lynn Pezzullo, RPh, CPEHR, PQA’s director of performance measurement.

The two measures currently in draft form are Adherence to Non-Infused Biologic Medications Treating Rheumatoid Arthritis and Other Inflammatory Conditions and Adherence to Medications Used to Treat Multiple Sclerosis. Hepatitis C and oral oncology adherence measures are also a high priority for PQA, Ms. Pezzullo said recently at the World Congress Summit on Specialty Market Access and Channel Optimization.

see SOARING PRICES, page 18

see ADHERENCE, page 4

•

•

Now Available SPC iPad App. See pages 19 and 23

New Approval FDA approves Cosentyx for plaque psoriasis.

See page 4.

Technology To Help You Enhance Your Patient Care

Clinical Therapy Management (CTM) is an innovative software application that provides a clinical support pathway that can help the specialty pharmacy provider enhance their patient care and facilitate specialty reporting through the collection of essential clinical and dispensing metrics.

CTM modules are designed to meet your needs in the following key therapeutic areas: • Hepatitis C • HIV • Immune Globulin Therapy ‡ ,QӿDPPDWRU\ &RQGLWLRQV • Multiple Sclerosis • Select Oncology Regimens • Bleeding Disorders* • Universal Specialty Module*

7R OHDUQ PRUH DERXW 0+$¡V &OLQLFDO 7KHUDS\ 0DQDJHPHQW FRQWDFW XV DW 973-805-2870 0+$6SHFLDOW\#PKDLQF FRP RU YLVLW www.mhainc.com. *Coming soon

Š MHA Specialty Pharmacy Solutions

3

Specialty Pharmacy Continuum • February/March 2015

ASK THE EXPERT

Kate Keeping of Decision Resources Group

Global Biosimilar Hotspots T

he FDA has established a pathway for approval of biosimilar products, culminating in the recent advisory committee recommendation that Sandoz’s biosimilar of filgrastim (Neupogen, Amgen) be approved. We spoke with Kate Keeping, the senior director of biosimilars research at Decision Resources Group, a global provider of health care research and advisory services, with headquarters in Burlington, Mass., about what it will mean to finally have biosimilars in the United States after years of availability abroad, as well as ways to reduce common concerns about them moving forward.

Q: Why did you start tracking biosimilar hotspots and clinical development?

A: We have been following the biosimilar pipeline for several years now. It is important for us to track this information so that we can estimate biosimilar launch dates, because the patent expiry date rarely equates to the first biosimilar entry at the moment as it typically does with small-molecule generics. We also compile the information for our clients’ competitive intelligence purposes, so that they can understand their competition.

Q: Why does Europe have such a dominant global position in terms of biosimilar clinical trials?

A: Legislation to support the approval of biosimilars came into effect in Europe in 2001—earlier than any other region.

The first biosimilar guidelines were also

developed there in 2005. Because of its well-defined path to approval and its large target market, most biosimilar developers have an interest in penetrating this market. The United States, in contrast, only created a pathway in 2010 [351(k)], and the first guidelines were not produced until 2012. This relatively late introduction of legislation and regulations forced developers to stay away from the U.S. market, up until the past few years.

Q: Which countries have the most potential to develop biosimilars in the next few years?

A: We expect the number of biosimilars intended for the United States to increase due to improvements in FDA guidelines, coupled with the U.S. being the largest biologics market in the world. The number of biosimilars in

clinical trials in Brazil will also almost certainly increase in the near future.

There have been a huge number of productive development partnerships struck between the Brazilian government and private firms with the aim of bringing biosimilar manufacturing into the country. The biosimilars will also need to be tested in clinical trials in Brazil to gain approval, so we expect the number of clinical-stage biosimilar programs to increase rapidly in the next couple of years.

Q: What is the current state of biosimilars in the United States?

A: The publication of the FDA’s clinical pharmacology guidance document in May 2014 was certainly a noteworthy development. This document provided further detail on clinical pharmacokinetic/phar-

macodynamic testing of biosimilars, and introduced the concept of four different categories of similarity: not similar; similar; highly similar; and highly similar with fingerprint-like similarity. These grades are not pathways, and unless the biosimilar is deemed to be not similar, the manufacturer would still be aiming to file via 351(k). The four categories are simply a way for the FDA to define the varying levels of supporting evidence that a biosimilar will likely need to gain approval.

The recent advisory committee recommendation to approve Sandoz’ application to market a biosimilar version of Neulasta is obviously a huge step forward as well.

Q: What are the most cited concerns about biosimilars?

A: Although concerns vary from spe-

•

see HOTSPOTS, page 19

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ART/PRODUCTION STAFF

HOME INFUSION

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Randy Fasnacht, RPh Director of Pharmacy Advanced Infusion Services Akron, OH

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Volume 4 • Number 1 • February/March 2015

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4

Specialty Pharmacy Continuum • February/March 2015

CLINICAL

ADHERENCE continued from page 1

The Centers for Medicare & Medicaid Services (CMS) has announced that three of PQA’s existing adherence measures—on renin–angiotensin system (RAS) antagonists, non-insulin diabetes medications and statins—will be included in the beta-test measure set for qualified health plans participating in the health insurance marketplaces for 2015. All issuers that offer coverage during the 2014 coverage year will be required to participate in the beta test of the Quality Rating System in 2015, according to CMS. PQA uses the standard proportion of days covered (PDC) formula to determine adherence. The PDC provides a comprehensive, but conservative, estimate of the adherence rate in situations when the patient switches medications within a class or concurrently uses more than one drug in a class.

Even when using the PDC methodology, developing adherence measures for specialty medications is challenging. Success will not come from a one-size-fits-all approach, said Richard Faris, PhD, the director of health outcomes and pharmacoeconomics with the pharmaceutical company UCB. “There are issues of loading doses, longer intervals between doses, weekly and monthly and now even dosing that is once or twice a year.

How do you measure adherence with these different intervals? And when you have a drug that’s taken once or twice a year, do you even measure adherence?” he asked.

Additionally, some therapeutic classes include medications that are selfadministered and billed under the prescription benefit and others that are infused and billed under the medical benefit. This adds an additional level of complexity, as the two data sets then need to be merged to provide a complete and accurate assessment of adherence across the medication class.

A Vote for Medication Possession Ratio There are also continuing questions about what level of adherence constitutes “optimal.” In January, a CVS Caremark/Brigham and Women’s study published in the American Heart Journal (2014;167[1]:51-58) validated another widely used measure of adherence, the 80% medication possession ratio (MPR) standard, finding that patients with adherence of 80% MPR or greater were 24% more likely than a control group to avoid hospital readmission for another heart-related issue; those with MPR of 79% or less had no significant improvement in outcomes over the control group.

‘Traditional adherence metrics like MPR and PDC may no longer provide value in this [HCV] space.’

—Kelly Pokuta, PharmD But the figure is still rather arbitrary, Dr. Faris said, and can vary significantly by condition and class. “In multiple sclerosis, perhaps 85% is a better number; with HIV, it’s probably 90% to 95%. And then how do you measure adherence in an episodic drug, such as one for bleeding events, versus a prophylactic drug?”

One area of specialty pharmacy where adherence measures are perhaps more important than ever, but also are changing rapidly, is hepatitis C. “Traditional adherence metrics like MPR and PDC may no longer provide value in this space,” said Kelly Pokuta, PharmD, the director of specialty pharmacy at Catamaran, a pharmacy benefits management company based in Schaumberg, Ill. With current therapies having a 12-week treatment duration for certain genotypes and with future therapies potentially offering even shorter durations, the time for assessing adherence and persistency is condensed. “That’s wonderful for patients, but what does it do in terms of measurement and monitoring?” asked Dr. Pokuta. “With the minimal side-effect profile and an eight-week regimen in the future, you might expect 100% adherence.

But there is still the issue of patient inertia, as well as payor plan designs that can complicate things. We are

seeing split fills of a 15-day or 30-day supply, because no one wants to pay $84,000 right out of the gate for a full course of Sovaldi [sofosbuvir, Gilead], for example.”

Catamaran has begun to couple adherence metrics with other measurable

outcomes, Dr. Pokuta said, including: • Genotype and subgenotype classification at start of therapy; • Sustained virologic response (SVR) at 12 weeks; • Persistency with therapy; • Patient satisfaction rates; and • Frequency of patient outreach.

Catamaran’s hepatitis C patient outreach program is designed to “touch” patients more frequently than just at the time of refill and is front-loaded for an increased number of contacts during the early period of therapy. “Our pharmacist and nursing support may reach out every week for the first month, and every two weeks thereafter until done, although the protocol varies according to the patient’s needs,” Dr. Pokuta said.

“It’s an opt-out program; patients are in it with the first script being filled, unless they decide not to participate.”

Because of the changing factors surrounding adherence to hepatitis C and other specialty medications, PQA’s measure concepts, now in development by the PQA’s Specialty Pharmacy Measures Task Force, would also differ from the draft for rheumatoid arthritis and multiple sclerosis adherence measures, Ms. Pezzullo said. “The task force is considering a set of metrics that in addition to adherence, may assess outcomes (i.e., sustained virologic response), outreach program elements, and patient experience and satisfaction.”

—Gina Shaw Dr. Pokuta reported that she has provided consultative service for Biogen Idec, Gilead and Sanofi. Dr. Faris and Ms. Pezzullo reported no relevant financial conflicts of interest.

NEW APPROVAL

FDA Approves Cosentyx To Treat Plaque Psoriasis

T

he FDA approved secukinumab (Cosentyx, Novartis) as first-line therapy for the treatment of adults with moderate to severe plaque psoriasis. This is the first approved human monoclonal antibody (mAb) that selectively binds to interleukin (IL)-17A, which is involved in the inflammatory process.

Administered as an injection under the skin, secukinumab is intended for patients who are candidates for systemic therapy, phototherapy with ultraviolet light or a combination of both.

The safety and efficacy of secukinumab (300 and 150 mg) were established in four randomized, placebo-controlled, Phase III clinical trials with 2,403 participants with plaque psoriasis. Secukinumab met all primary and key secondary end points, showing significant skin clearance at week 12.

Because secukinumab is an immune modulator, patients may have a greater risk for infection and serious allergic reactions. Caution should be exercised when considering the use of secukinumab in patients with a chronic infection or history of recurrent infection, and in patients with active Crohn’s disease. The most common side effects include diarrhea and upper respiratory infections.

—From FDA and Novartis press materials

Take a bite out of G-CSF acquisition costs Based on whole esale acquissition cost (WAC C) of o all sho ort rt-a -act -a c in ct i g GG-CS CSF F pr prod oduc od ucts uc t ts as of November 11, 201 13. WAC AC rep pre rese sent se ntss pu nt publ blis bl ishe is he ed ca cata talo log gue gu g e or lisst pr pric ices e and es n may not represent acctual transa a tion ac o al pri r ce es. s. Ple leas ase e co con ntac actt yo your urr sup uppl plie er fo forr ac actu tual al pri r ce c s. s

GRANIX® is an option in short-acting G-CSF therapy » A 71 7 % red duct c io on in dur urat a io at ion n off sev ever ere e ne neutrro openia a vs placebo (1.1 days vs 3.8 8 da d ys, p<0 0.0 000 001) 11 – Effica c cyy was eva valu uat ae ed d in a m multtin mu nat ational, m multice enter, randomized, controlled, Phase III study of chem motherapy-naïve p tien pa ntss witth hi hig g -ris gh-r gh iskk br brea east stt cance er receivving do oxorubicin (60 mg/m2 IV bo olus)/docetaxel (75 mg/m2)1 » Th he sa safe fe etyy of GR GRA A IX was esta AN ablishe ed in 3 Phase III trials,, with 680 p patients receiving g chemotherapy py for either breast 1 ca ancer nccer er,, lu lung ng can ance ce er, or non-Ho odgkin lympho oma (N NHL) » No Now w of offe f ri fe ring n a new e presentation for self-ad dministration

Indication » GR G AN ANIX IX is a leukocyte ocyte growth factor indicat indicated ted forr reduction in the duration of severe ne neutropenia eutropenia in p patients atients with wi th non onm myeloid malig gnancies receiving myelosuppresssive anticancer drugs associated with a clinically significant inci in cide denc n e of febrile neu utropenia.

Important Safety Information » Sple Spleni n c ru upture: Splen nic rupture, including fatal cases, can occur following the administrattion of human granulocyte colo co lony-stimulating facttors (hG-CSFs). Discontinue GRAN NIX and evaluate for an enlarged spleen or sp s le enic rupture in patients who report up pa pper abdominal or shoulder pain after receiving GRANIX. » Ac Acut ute resspiratory disttress syndrome (ARDS): ARDS ca an occur in patients receiving hG-CSFs. Evaluate pa p tients t who wh o deve elop fever and d lung infiltrates or respiratory disstress after receiving GRANIX, forr ARDS. Discontinue GRANIX in patients with ARDS. » Al A lergic reactions: Serrious allergic reactions, including anaphylaxis, can occur in patientts receiving hG G-CSF S s. Reactions n ca an occurr on initial exp exposure. posure Permanentlyy discontinue GRANIX in patients with serious allergic reac actions. tions D Do o no not administe er GRANIX to patients with a histo ory of serious allergic reactions to o filgrastim or pe egfilgr g astim. » Use e in pa atients with sickle cell disease: Severe and sometimes fatal sickle e cell crises can occur in pa patients with sickkle cell diseasse receiving hG-CSFs. Consider the potential risks and benefits prrior to the administration of GRAN NIX X in patients with sickle cell disease. Discontinu ue GRANIX in patients undergoin ng a sickle cell crisis. » Capillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and iss charac a teriize z d by hyp pote ensiion o , hypoalbuminemia, edema and hemoconce entration. Episodes vary in freque ency, severity and may be life f -thre eatening if treatme ent is delayed. Patients who develop symptoms of CLS should be closelyy monitored and d re ece c ivve sttanda dard r symptoma atic treatment, which may include e a need for intensive care. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimullating fa actor o (G-CSF) re eceptor, through which GRANIX acts, has been fo f und on tumor ce ell lines. The pos o sibility tha hat GRAN NIX X acts as a grow wth factor for any tumor type, inclu uding myelo oid d malignancies and myelodysplasia, diseasses e for which GRA ANIX is not app proved, cannot be excluded. » Most com mmon treatment-emergent adve erse e reaction: The most common n treatment-eme ergent ad dvers r e re ea action that occurred in patients treated with GRANIX at the recommended do d se with an incidence of at leastt 1% or gre eat e a er and two ti t mess more frequent than in the placebo group wass bone pain.

Please see brief summary of Full Prescribin ng Information on adjacent page.

For more information, visit GRANIXhcp.com.

Refe Re fere renc nce: e 1. GRA ANIX® (tbo-filgrastim) Injection Prescribing g Info orm r ation. North h Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva a Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved.. GRX-40582 January 2015.

6

Specialty Pharmacy Continuum • February/March 2015

CLINICAL

Pill burden in end-stage renal disease:

When Is Enough Too Much?

Philadelphia—Polypharmacy is a significant issue for patient safety that cuts across multiple disease states managed by specialty pharmacy. But the problem is particularly acute in patients with end-stage renal disease (ESRD), who live with a pill burden greater than almost any other patient group.

Studies have found that patients on dialysis take an average of 19 or more

pills on a daily basis, with many taking more than 25 pills per day (Clin J Am Soc Nephroll 2009;4:1089-1096). By contrast, patients with diabetes take an average of four pills per day and congestive heart failure patients about 10 or 11 pills per day.

This is one case in which more is not necessarily better, said experts at a session on the pill burden in ESRD,

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: UÊ -« i VÊ,Õ«ÌÕÀiÊQsee Warnings and Precautions (5.1)] UÊ VÕÌiÊ,ië À>Ì ÀÞÊ ÃÌÀiÃÃÊ-Þ `À iÊQsee Warnings and Precautions (5.2)] UÊ -iÀ ÕÃÊ iÀ} VÊ,i>VÌ ÃÊQsee Warnings and Precautions (5.3)] UÊ 1ÃiÊ Ê*>Ì i ÌÃÊÜ Ì Ê- V iÊ i Ê Ãi>ÃiÊQsee Warnings and Precautions (5.4)] UÊ >« >ÀÞÊ i> Ê-Þ `À i [see Warnings and Precautions (5.5)] UÊ * Ìi Ì > Êv ÀÊ/Õ ÀÊ À ÜÌ Ê-Ì Õ >Ì ÀÞÊ vviVÌÃÊ Ê > } > ÌÊ i ÃÊQsee Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

6.1 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 clinical practice.

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian.

In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of *10,000 x 106/L after nadir was reached.

offered during the Clinical Nephrology Conference at the American Society of Nephrology’s 2014 Kidney Week.

“The pill burden is so high that some patients reach the point where they essentially give up,” said Kamyar Kalantar-Zadeh, MD, PhD, a professor of medicine and pediatrics and public health at the University of California, Irvine School of Medicine and one of the moderators of the session. “Just today, I had a patient tell me that a few months ago she stopped taking all her medications. Many other patients are

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-USapproved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day.

Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day.

This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

probably doing the same thing but are not brave enough to tell their doctors.

Honestly, we don’t know what they’re taking and not taking.”

“It’s not unusual to see somebody who takes 40 to 60 pills a day,” said Mohamed A. Sekkarie, MD, FASN, a nephrologist with Nephrology and Hypertension Associates in Bluefield, W.Va., and another session moderator. “The costs and just the difficulty swallowing them are excessive. When people start choosing which ones to take and which ones not to take, they may end up taking the ones of questionable benefit and omitting others that are really necessary.”

Phosphate Binders a Problem Probably the greatest single contributor to pill burden for dialysis patients is the use of phosphate binders—drugs that are designed to control the backup of phosphorus in the blood that occurs with compromised kidney function.

“The amount of phosphorus removed by dialysis is not even half of what patients usually get in their diet,” Dr. Sekkarie said. “High phosphorus is linked to calcification of blood vessels and bone disease, and phosphate binders are used to control that. Some people may be taking as many as 20 pills a day.”

If phosphorus remains high, still more phosphate binders may be prescribed.

“There are half a dozen of them in different classes, different categories and types,” Dr. Kalantar-Zadeh said.

Some novel lower-dose phosphate binders are being studied ((Kidney Int 2014;86:638-647). Dr. Sekkarie also suggests that dietary approaches should receive more attention. “It’s difficult, because you want these people to take in more protein to preserve their nutrition, but in general higher-protein foods are also higher in phosphorus.

But you can consider recommending that a patient eat more foods with a low phosphorus-to-protein ratio, like egg whites and certain seafoods. There are also studies showing that if you give patients a magnifying glass and teach them to read labels and avoid foods with added phosphorus, that can be beneficial in reducing phosphorus load” ((JAMA 2009;301:629-635).

Beyond phosphate binders, other common categories of medications used in patients with ESRD include lipid-lowering agents, antihypertensive agents, vitamins, vitamin D products and medications to control other comorbid conditions—anticoagulants, steroids and diabetes medications, for example.

For many of these medications, there is a paucity of literature to specifically support their efficacy when used in patients with ESRD. Statins, for example, have been shown to be beneficial in many cases, but for people on dialysis, several trials have shown little to

7

Specialty Pharmacy Continuum • February/March 2015

CLINICAL

‘Some [studies] indicate that lowering blood pressure can cause more harm than help for [patients with ESRD], leading to more compromised circulation and ischemia.’

—Kamyar Kalantar-Zadeh, MD, PhD

no benefit for cardiovascular events or mortality (Cochrane Database Syst Rev 2013;9:CD004289).

“Perhaps vascular disease in this population may be different,” Dr. Sekkarie posited. “There are a lot of people who advocate not even checking cholesterol in this population, much less giving them statins.”

Managing blood pressure in patients on dialysis poses a similar quandary.

“Usually dialysis patients are on two to five antihypertensive medications, taking them multiple times per day,” Dr. Kalantar-Zadeh said. “In relatively healthy people, lowering blood pressure is important. But studies have yielded mixed data about lowering blood pressure in people with ESRD. In fact, some indicate that lowering blood pressure can cause more harm than help for these people, leading to more compromised circulation and ischemia.”

Although β-blockers seem to be beneficial, Dr. Sekkarie said, the literature for other medications, such as angiotensinconverting enzyme (ACE) inhibitors, is conflicting. There are other unknowns as well, such as a lack of data to clearly establish the ideal blood pressure for the dialysis patient, as well as something as simple as when and how pressure should be monitored.

“There is some emerging consensus, although it’s not clearly shown, that it’s better for the patient to check blood pressure at home on non-dialysis days,” Dr. Sekkarie said. “Typically, when a patient comes in for dialysis, the blood pressure tends to be too high, and when they leave it tends to be too low— there’s a lot of variation because measurements aren’t standardized, people are wearing thick layers of clothing, and so on. But if the pressure’s high at the beginning of dialysis and you give too many antihypertensive [drugs], it drops by the end and you end up leaving too much fluid on.”

Instead, he urges working on blood pressure control by removing as much fluid as tolerated during the dialysis treatment and cutting down the salt load in the patient’s diet, thus minimizing the number of medications needed.

Growth Factors Another Tricky Area Erythropoiesis-stimulating agents (ESAs) for anemia also require vigilance in patients with ESRD. “We should use

great caution here,” Dr. Sekkarie said.

“Too much of these medications can lead to side effects, such as thrombosis.” In fact, he noted that normalizing hemoglobin levels with medication may not be as beneficial as achieving it naturally. “For

those people who don’t respond to treatment, it is better to settle for lower hemoglobin levels rather than give potentially harmful high doses of [ESAs].”

For many medications, prescribers are forced to generalize because there are

no studies specific to dialysis populations. “If you don’t give certain medications, you can be accused of undertreating, but at the same time, there are many patients exhausted by their pill burden,” Dr. Kalantar-Zadeh said.

“These questions need to be considered more carefully and [foster] an important dialogue for clinicians who care for these patients.”

—Gina Shaw The sources had no relevant financial conflicts of interest to disclose.

8

Specialty Pharmacy Continuum • February/March 2015

CLINICAL

Management Tips for Pulmonary Hypertension Anaheim, Calif.—Inhaled epoprostenol (iEPO) may be a less expensive alternative to inhaled nitric oxide (iNO) in the treatment of pulmonary arterial hypertension (PAH). Switching to the inhaled formulation was one of several innovative strategies for managing this challenging cardiopulmonary disease presented at the American Society of Health-System Pharmacists’ 2014 Midyear Clinical Meeting.

Other strategies included using combination versus stepwise therapy for PAH, and keeping informed about the newer FDA-approved PAH medications.

Gold Standard Loses Some Luster “Over the past decade, there has been increasing awareness that [iEPO] through a mechanical ventilator could be a more cost-effective alternative to inhaled nitric oxide,” said Mitchell Buckley, PharmD, FASHP, FCCM, FCCP, a clinical pharmacy specialist in critical care at Banner Good Samaritan Medical Center in Phoenix. iNO has been the gold standard, Dr. Buckley noted, but it requires special equipment for delivery, as well as monitoring for toxic metabolites. In cases where patients require additional therapy, choosing the next step can

be a tough call for clinicians, he said, because “there are no right or wrong answers.” He reviewed the literature for PAH treatment.

Among inhaled prostacyclins, more than a dozen studies have been conducted on iEPO, Dr. Buckley said, the vast majority of which demonstrated a significant decrease in pulmonary arterial pressures. Some studies also found an improvement in cardiac function, whereas others demonstrated no such changes.

There have been four major studies on inhaled treprostinil, most of which have been in class II and III patients. The studies found an increase in exercise capacity and a decrease in PAH symptoms, but no improvement in cardiac function.

In comparative trials of iNO and iEPO, a 2006 study found the two agents performed similarly, and better than IV vasodilators, in hospitalized

patients undergoing mitral valve surgery ((J Cardiovasc Med 2006;7:119-123).

Both agents significantly decreased mean pulmonary arterial pressure and improved cardiac index; and patients taking the drugs spent one less day in the ICU. Another study from 2013 also found similar performance among the two drugs in 105 patients with

Two Approaches to Patient Assistance

acute respiratory distress syndrome, with the only difference being that iNO cost 4.5 to 17 times more, depending on contract pricing ((J Crit Care 2013;28:844-848).

“If you’re looking for cost savings, work with your respiratory therapy department to see how much iNO you used last year and look at your contract prices,” Dr. Banner said. “Entertain the idea of substituting aerosolized epoprostenol.”

Stepwise vs. Front-Loaded Rx

P

AH is complex enough that it requires attention from specialty pharmacists.

At the University of Illinois-Chicago Medical Center (UIC), multidisciplinary teams including pharmacists manage PAH patients attending an outpatient clinic, said Rebekah Hanson, PharmD, a clinical assistant professor of ambulatory pharmacy.

‘With these critically ill patients, every day without treatment matters.’

—Rebekah Hanson, PharmD Dr. Hanson helps patients at all stages of therapy, including drug insurance approval, therapy initiation, dose titrations, tolerability assessment and drug safety. This approach “is particularly important for oral medications with REMS that require specific tests be completed prior to dispensing or infused therapies that have the associated risk of blood stream infections,” she said.

On clinic days, she interviews patients about medication usage, gets a medication history, does medication reconciliation, provides detailed PAH therapy education, updates electronic medical records and discusses any issues with the patient’s physician and others on the team. She performs therapy follow-up in collaboration with a nurse, helping patients with dose titrations, monitoring labs, renewing prior authorizations, coordinating refills as well as other services.

The clinic has a courier service that can deliver refrigerated medications from the pharmacy directly to patients’ homes.

One challenge has been accessing newer medications in a timely manner, some of which are available from just two specialty pharmacies, she said. “It’s really been a problem for

us.” In most circumstances, it takes a week or often longer to get patients started on therapy, she noted. “With these critically ill patients, every day without treatment matters.”

Accredo: a Focus on Speedy Access At Accredo, the specialty pharmacy recognizes the urgency with which PAH patients need their medicines, said Mary Dorholt, PharmD, the company’s vice president of clinical services. Accredo can get supplies to 90% of the United States within four hours, she said.

Accredo helps manage some 18,000 PAH patients per month, Dr. Dorholt noted, with a dedicated PAH team of 45 pharmacists (some who speak multiple languages) who only work with PAH patients, and 500 nurses, including 32 cardiopulmonary specialists, in the field. The pharmacy also has a 24/7 hotline staffed by clinicians who can provide emergency assistance while accessing a patient’s specific history; the hotline serves more than 6,000 patients monthly. Additionally, team members are available to manage patients who have worsening symptoms, or to advise patients on how to move past short-term medication-related headaches.

The company’s administrative and customer service representatives also have been trained in PAH management.

The criticality of the disease is challenging, Dr. Dorholt said. “Fortunately for patients, there are more drugs, more oral options and even more in the pipeline.” However, that makes management complex. “General pharmacists should not be dispensing these medications” because of the complexity of the disease state and the amount of patient counseling necessary, she said.

The company also mans an online support Web page, phneighborhood.com, with more than 2,000 message board users.

—K.B.

In terms of combination therapy, clinicians in the United States most often use a stepwise approach to initiating therapy; however, recent studies in Europe have demonstrated some efficacy and safety in using an up-front (i.e., front-loaded) approach, said Tiffany Pon, PharmD, an assistant professor of clinical pharmacy at the University of California, San Francisco School of Pharmacy. She practices at UC Davis Medical Center.

Dr. Pon discussed studies supporting each approach. Among five randomized controlled trials of stepwise therapy for PAH, only the PACES-1 (Pulmonary Arterial Hypertension Combination Study of Epoprostenol and Sildenafil) trial, which used long-term IV epoprostenol followed by sildenafil, showed a significant increase in six-minute walking distance ((J Heart Lung Transplant 2014;33:689-697). A handful of observational studies suggest the stepwise approach is effective, but none of the studies focused on safety. Adverse drug effects (ADEs) such as headaches, jaw pain, nausea and diarrhea also should be considered, Dr. Pon said, because these agents often overlap in terms of their side-effect profile.

9

Specialty Pharmacy Continuum • February/March 2015

CLINICAL

In a proposed updated treatment algorithm for PAH published in the Journal of the American College of Cardiology (2013;62:D60-D72), up-front initiation of combination therapy is suggested as a soft recommendation for class III or IV patients. This approach should be reserved for acutely ill patients who are younger and have fewer comorbidities, Dr. Pon said, because such patients are more likely to tolerate the regimen.

“It’s a soft recommendation because the evidence for the up-front approach is even more limited than what we have for sequential therapy,” Dr. Pon said.

There have been only one randomized controlled trial and two observational studies published. One observational study of up-front triple therapy (IV epoprostenol, bosentan and sildenafil) in 18 patients demonstrated an improvement in function that was maintained for three years, with 100% survival ((Eur Respir J 2014;43:1691-1697). Another randomized controlled trial pending publication, the AMBITION trial, evaluated the up-front initiation of two oral agents: ambrisentan (Letairis, Gilead) and tadalafil (Cialis, Lilly). A 50% relative reduction in clinical failure, mainly driven by decreased hospitalizations, was reported, she said.

Regardless of the approach to initiating combination therapy, it’s also important to include patients in these decisions, Dr. Pon said. “Some of these drugs, like the inhaled prostacyclins, are not easy to administer, and combination therapy requires consistent follow-up,” she explained. Thus, “clinicians need to consider if patients will be adherent to all aspects of their care. In addition, insurance companies require patients to meet certain criteria, such as failing monotherapy, to cover the cost of combination therapy as no drugs used for PAH are currently FDA-approved for combined use.”

Poor Five-Year Survival Rates New therapies for PAH are needed, added Andrew Berry, PharmD, a clinical pharmacy specialist with Banner Good Samaritan. Even using established medications, the average five-year survival for patients with PAH is only 60% (Chest 2012;142:448-456). The FDA approved three medications for PAH in fall 2013: riociguat (Adempas, Bayer), a novel class medication (an oral-soluble guanylate cyclase stimulator); macitentan (Opsumit, Actelion), an endothelin receptor antagonist; and oral treprostinil (Orenitram, United Therapeutics), an oral prostanoid. Selexipag (Uptravi, Actelion), an oral prostacyclin receptor agonist, is in Phase III trials, so far indicating a 39% reduction in morbidity and mortality, he said.

Riociguat improved exercise tolerance in patients with PAH and chronic thromboembolic pulmonary hypertension in

‘If you’re looking for cost savings, work with your respiratory therapy department to see how much iNO you used last year and look at your contract prices.’

—Mitchell Buckley, PharmD

published studies. It is generally well tolerated, with ADEs including increased headache, dyspepsia, peripheral edema, hypotension and anemia. Macitentan decreased PAH events in the SERAPHIN trial ((N Engl J Med d 2013;369:809-818), Dr.

Berry said, but so far it’s not clear if the drug is beneficial in combination with other therapies: “It’s tough to figure out its place in therapy versus other [endothelin receptor] antagonists,” he said.

ADEs include nasopharyngitis, head-

ache and anemia. Trials of oral treprostinil found high discontinuation rates because of side effects. About 85% of patients experience ADEs such as headache, diarrhea, flushing and pain, Dr. Berry noted. One trial (Circulation 2013; 5;127[5]:624-633) found significant improvements in six-minute walking distance but the trial lasted only 12 weeks.

—Karen Blum The sources had no relevant financial conflicts of interest to disclose.

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40 g VIAL

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Avoid potential IG waste—With the widest range of vial sizes, dispense IG according to prescription 1 g 2.5 g 5 g 10 g 20 g 40 g Important Safety Information

Visit gamunex-c.com to learn more.

GAMUNEX®-C (immune globulin injection [human], 10% caprylate/chromatography purified) is indicated for the treatment of primary humoral immunodeficiency disease (PIDD), idiopathic thrombocytopenic purpura (ITP), and chronic inflammatory demyelinating polyneuropathy (CIDP).

Thrombosis may occur with immune globulin products, including GAMUNEX-C. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors. For patients at risk of thrombosis, administer GAMUNEX-C at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.

Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IVIG) products in predisposed patients. Patients predisposed to renal dysfunction include those with any degree of preexisting renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IVIG products containing sucrose. GAMUNEX-C does not contain sucrose. For patients at risk of renal dysfunction or failure, administer GAMUNEX-C at the minimum concentration available and the minimum infusion rate practicable.

GAMUNEX-C is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin.

It is contraindicated in IgA-deficient patients with antibodies against IgA and history of hypersensitivity.

Severe hypersensitivity reactions may occur with IVIG products, including GAMUNEX-C. In case of hypersensitivity, discontinue GAMUNEX-C infusion immediately and institute appropriate treatment.

Monitor renal function, including blood urea nitrogen (BUN), serum creatinine, and urine output in patients at risk of developing acute renal failure.

Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IVIG treatment, including GAMUNEX-C. There have been reports of noncardiogenic pulmonary edema (transfusion-related acute lung injury [TRALI]), hemolytic anemia, and aseptic meningitis in patients administered with IVIG, including GAMUNEX-C. The high-dose regimen (1g/kg x 1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be a concern.

Because GAMUNEX-C is made from human blood, it may carry a risk of transmitting infectious agents, eg, viruses, and, theoretically, the CreutzfeldtJakob disease (CJD) agent.

Do not administer GAMUNEX-C subcutaneously in patients with ITP because of the risk of hematoma formation.

Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure.

Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of GAMUNEX-C and at appropriate intervals thereafter.

Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies, because of the potentially increased risk of thrombosis.

If signs and/or symptoms of hemolysis are present after an infusion of GAMUNEX-C, perform appropriate laboratory testing for confirmation.

If TRALI is suspected, perform appropriate tests for the presence of antineutrophil antibodies and anti-HLA antibodies in both the product and patient’s serum.

After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation.

In clinical studies, the most common adverse reactions with GAMUNEX-C were headache, fever, chills, hypertension, rash, nausea, and asthenia (in CIDP); headache, cough, injection-site reaction, nausea, pharyngitis, and urticaria with intravenous use (in PIDD) and infusion-site reactions, headache, fatigue, arthralgia and pyrexia with subcutaneous use (in PIDD); and headache, vomiting, fever, nausea, back pain, and rash (in ITP).

The most serious adverse reactions in clinical studies were pulmonary embolism (PE) in 1 subject with a history of PE (in CIDP), an exacerbation of autoimmune pure red cell aplasia in 1 subject (in PIDD), and myocarditis in 1 subject that occurred 50 days post-study drug infusion and was not considered drug related (in ITP). © 2014 Grifols Inc.

All rights reserved.

October 2014

GX239-1014

Please see brief summary of GAMUNEX-C full Prescribing Information on adjacent page.

GAMUNEXÂŽ-C

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E "09,7 /Csfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IGIV) products in predisposed patients.

E "09,7 /Csfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. GAMUNEX-C does not contain sucrose.

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C '99/<+ :8'49,+8 5, '4:/(5*/+9 3'? )54,5;4* 9+8525-/) :+9:/4- ----------------------------ADVERSE REACTIONS ---------------------------+8/5;9 '*<+89+ 8+'):/549 =./). 5));88+* /4 :.+ )2/4/)'2 :8/'29 =+8+ '4 +>')+8(':/54 5, ';:5/33;4+ 6;8+ 8+* )+22 '62'9/' /4 54+ 9;(0+): '4* 6;2354'8? +3(52/93 /4 54+ 9;(0+): =/:. ' ./9:58? 5, !.+ 359: )53354 '*<+89+ 8+'):/549 5(9+8<+* /4 âą&#x2013; 6':/+4:9 =+8+ PI 4tra<enous +'*').+ )5;-. /40+):/54 9/:+ 8+'):/54 4';9+' 6.'8?4-/:/9 '4* ;8:/)'8/' ;();:'4+5;9 4,;9/54 9/:+ 8+'):/549 .+'*').+ ,':/-;+ '8:.8'2-/' '4* 6?8+>/' ITP +'*').+ <53/:/4- ,+<+8 4';9+' (')1 6'/4 '4* 8'9.

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To report SUSPECTED ADVERSE REACTIONS, contact Grifols Therapeutics Inc. at 1-800-520-2807 or FDA at 1-800-FDA-1088 or GAMUNEX-C is an immune globulin injection (human), 10% liquid www.fda.gov/medwatch. indicated for treatment of: ----------------------------DRUG INTERACTIONS ---------------------------C 8/3'8? ;358'2 33;45*+A)/+4)?

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3036439/3036440-BS Revised: 7/2014

12

Specialty Pharmacy Continuum • February/March 2015

CLINICAL

As Orphan Drug Market Spikes, SPs Respond Philadelphia—The pace of approvals for orphan drugs— medications to treat conditions affecting less than 200,000 people in the United States—has accelerated dramatically over the past 10 years. From 2000 to 2013, 86 orphan drugs were approved in the United States, up from 65 during the previous 18 years, according to a recent study by the Tufts Center for the Study of Drug Development at Tufts University (http://goo.gl/drGrQi).

As the orphan/rare disease market becomes an increasing and costly chunk of the specialty drug space, manufacturers, specialty pharmacies, pharmacy benefit managers (PBMs) and payors are all struggling to define the most effective models for getting these new medications to patients in the most cost-effective way.

At the 2014 World Congress on Specialty Market Access, several speakers discussed the unique challenges of the “sub-subspecialty” market.

During the session, speakers set the stage by citing the latest figures on orphan drugs: In 2013, nine of the 27 new molecular entities approved by the FDA (33%) were considered to fit that designation—more than in any prior year.

Only one of these drugs costs less than $7,000 per month—which is the average monthly price for the hue-and-cry—gen-

erating hepatitis C medication sofosbuvir (Sovaldi, Gilead), and significantly more than other pricey specialty drugs such as dimethyl fumarate (Tecfidera, Biogen Idec), which costs about $4,980 per month, according to the Missouri Department of Social Services HealthNet Pharmacy Program (http://goo.gl/DhYlP).

The Manufacturers Given that pricing model, it’s not surprising that some manufacturers have chosen to focus on the orphan drug niche.

NPS Pharmaceuticals, for example, focuses its product portfolio on patients with rare gastrointestinal and endocrine disorders. In December 2012, it received FDA approval for Gattex (teduglutide), an injectable medication for adults with short

Table. The Orphan Drugs of 2013 and Their Prices Medication

Indication

Price, $

Afatinib (Gilotrif, Boehringer Ingelheim)

Metastatic non-small cell lung can- 6,180 cer with common EGFR mutations

Dabrafenib (Tafinlar, GlaxoSmithKline)

Advanced or unresectable melanoma expressing the BRAF V600E mutation, approved with companion diagnostic

6,240

Ibrutinib (Imbruvica, Pharmacyclics/Janssen)

Mantle cell lymphoma

11,282

Mekinist (Trametinib, GlaxoSmithKline)

Advanced or unresectable melanoma expressing the BRAF V600E or V600K mutation, approved with companion diagnostic

9,898

Mipomersen sodium (Kynamro, Genzyme)

Homozygous familial hypercholesterolemia

19,390

Obinutuzumab (Gazyva, Genentech)

Chronic lymphocytic leukemia

Cycle 1: 18,576 Cycles 2-6: 6,192

Macitentan (Opsumit, GlaxoSmithKline)

Pulmonary arterial hypertension

6,908

Pomalidomide (Pomalyst, Celgene)

Advanced multiple myeloma, refractory to at least 2 prior therapies

11,436

Riociguat (Adempas, Bayer Healthcare)

Pulmonary arterial hypertension

7,560

bowel syndrome who require parenteral nutrition. In September, an FDA panel recommended approval for the next drug in NPS’ pipeline, Natpara, a recombinant hormone replacement therapy for hypoparathyroidism.

Todd Hudson, the senior director for market access at NPS, explained the company’s distribution framework: “We ship via a third-party logistics [3PL] company to a local specialty/home infusion pharmacy, and they provide the drug to the patient,” he said. For example, he explained, Walgreens has 89 home infusion pharmacies around the country that manage patients in their local areas; NPS Pharma’s 3PL ships to those pharmacies, which then distribute the drug directly to patients.

“People with short bowel syndrome requiring parenteral support are receiving it from a local specialty pharmacy that provides home infusion, which has a pharmacist, a dietitian, a nurse and a case manager all working with the patient on a weekly basis to manage their care,” Mr. Hudson said. “If we drop this drug in from the sky, without involving the people who know what’s going on with that patient, it might compromise [patient] care. In the end, it all comes down to outcomes. We’ll give up some speed of delivery in exchange for better management of our patients’ care and improved outcomes.”

Defining what those improved outcomes are can be a challenge in itself. For a patient with short bowel syndrome, the primary goal is improving fluid levels. “If we can get them off TPN [total parenteral nutrition] entirely, that’s heaven for them,” Mr. Hudson said.

Mixed Reactions

T These figures do not include any discounts and are estimated on a per-month basis unless otherwise noted. Some of these medications, such as Imbruvica, are expected to expand into broader therapeutic designations and may not remain “orphan” drugs. Source: Missouri Department of Social Services HealthNet Pharmacy Program. Updated October 15, 2014. http://goo.gl/DhYlP.

When evaluating a new cystic fibrosis medication, like ivacaftor (Kalydeco, Vertex), the oral therapy that treats the underlying G551D gene mutation found in about 4% of people with cystic fibrosis, pulmonary function testing is the standard measure. “I’m not crazy about it, but it’s what we have to work with,” said Leslie Fish, PharmD, the senior director of pharmacy at Massachusetts’ Fallon Community Health Plan. But additional markers of improvement are beginning to emerge.

“We are beginning to see decreases in antibiotic use and decreases in pulmonary exacerbations among kids being treated with this drug,” Dr. Fish said. “It is trending in the right direction.”

Moreover, unlike with many medica-

tions for common diseases, it can take a long time to detect outcome trends for orphan conditions. “You may not know for a year or more whether your drug has a measurable effect in some patients,” said Pat Furlong, the founding president and CEO of Parent Project Muscular Dystrophy. And when you’re dealing with drugs that can cost up to half a million dollars annually, a year is a long time. The high cost of these medications (Table) means that patient assistance is a major issue for all players in the orphan drug space—manufacturers, specialty pharmacies, PBMs and third-party payors alike.

“We have a team in our [patient assistance] hub, called NPS Advantage, that will help you manage your insurance and other payment options so at least you know where to start,” Mr. Hudson said. “Genentech also does a great job with that. Some of the other biologics have taken these hubs inside because you really want to own that relationship with the patient, especially in the orphan space.” (For more details on PAPs, see the lead cover story in this issue.)

Shifting Costs to Patients Mr. Hudson predicted more “tiering” of drug copays, with plans shifting additional costs of orphan drugs to the patient.

“We’ve done the research, made the drug, gotten the outcomes data and the drug’s on the market—but what if the patients can’t get it? How can we make sure there’s access?” he asked. “There’s only so much we can do. And the costs are going to continue to go up. It’s harder to identify molecules that will treat these patients, and to accumulate 100 patients for a study in conditions like these can take five years.”

It can sound cold-blooded to talk about the bottom line when you’re dealing with rare, often devastating diseases, but sometimes it’s necessary, Mr. Furlong said. “Drugs for rare diseases are often expensive, anticipated to cost hundreds of thousands of dollars per year. The muscular dystrophies are progressive and debilitating and there is worry that insurers may refuse to cover individuals with significant muscle loss, or that the out-of-pocket cost may prevent some individuals from accessing therapies.

These are very difficult discussions to have with patients or parents.”

With price tags like these, adherence takes on a whole new level of importance. “Adherence is a goal for all medications, but if we’re going to be spending almost half a million dollars on a patient, we want to make sure we’re all doing our best to be effective with compliance,” Ms. Fish said.

With many rare conditions, the costs of lack of adherence—beyond simply wast-

•

see ORPHAN DRUGS, page 14

13

Specialty Pharmacy Continuum • February/March 2015

CLINICAL

Meeting the Challenge of Oral Cancer Agents Anaheim, Calif.—The past decade has seen a surge in oral cancer therapies. These agents—representing approximately 25% of all new anticancer drugs in development—provide benefits as well as present new challenges, and have increased the role that pharmacists play in cancer care.

Many of these oral agents are distributed through specialty pharmacies, in part because they require proof of Risk Evaluation and Mitigation Strategies compliance. Joseph Bubalo, PharmD, an oncology pharmacy specialist at Oregon Health & Science University, in Portland, estimates that almost half of all oral cancer agents move through specialty pharmacies. Thus, supply channel issues are often at the top of the list of challenges to resolve, not the least of which is access. For example, will a new oral chemotherapy drug even be available to patients at a given hospital or clinic, or do limited distribution networks pose barriers to access?

Assuming any access issues can be resolved, the next step is to meet clinical issues head on, including monitoring disease response, managing toxicities and ensuring treatment adherence.

At the American Society of Health-System Pharmacists 2014 Midyear Clinical Meeting, Ginah Nightingale, PharmD, an oncology pharmacy specialist at Thomas Jefferson University Hospital, in Philadelphia, and Susannah Koontz, PharmD, a pediatric clinical pharmacy specialist at Koontz Oncology Consulting, in Houston, addressed these issues, especially as they affect geriatric and pediatric patient populations.

They began by noting that pharmacists are uniquely positioned to navigate these often turbulent waters. “We have the opportunity to improve safe medication use and improve medication adherence,” Dr. Nightingale said, adding that the profession’s expertise isn’t limited to clinical areas. “We also are uniquely positioned to reduce drug spending,” she stressed.

Drug Safety and Effectiveness According to Dr. Koontz, one of the biggest challenges is that oral chemotherapy drugs haven’t been widely studied in pediatric patients. As a result, there are knowledge gaps regarding the pharmacodynamic or pharmacokinetic profile of the medications in children.

However, there are some useful clues on the literature. A study from Denmark, for example, showed that oral methotrexate and 6-mercaptopurine were more effective when children with acute lymphoblastic leukemia (ALL) took the medications in the morning or evening (J ( Pediatr Hematol Oncol 1997;119;19[2]:102-109).

Because older patients are underrepresented in clinical trials, just how new drugs will work in the elderly is also unclear. “In clinical trials, you have a superstar athlete, the most healthy and functionally fit patient, compared to an 82-year-old or 87-yearold who likely has several comorbidities, underlying organ impairment and declining functional status,” Dr. Nightingale said. “It is hard to generalize what you see in a clinical study to the patient in front of you.” Studies estimate that only 20% of patients in cancer clinical trials are 70 or older, and

age and functional age. Factors predicting treatment-related morbidity or mortality in elderly cancer patients include functional status, comorbid conditions, nutritional status, cognitive function, psychological state, social support and polypharmacy. Experts recommend that older patients undergo a comprehensive geriatric assessment before starting any oral cancer agent.

“A frail patient can be more at risk of cancer treatments causing harm than benefit,” Dr. Nightingale said. “We have all of our patients seen by a dietician to determine whether they have underlying malnutrition. Some of the new oral therapies are very specific in terms of dietary considerations—take the pills with food or high-fat food.” A patient with anorexia could run into problems, she added.

In the elderly population, managing patient prescriptions to avoid drug–

tol-Myers Squibb), are pH-sensitive, so over-the-counter antacids and proton pump inhibitors can impair drug absorption. Assessing nutritional supplements or herbal medicines as well as foods, such as grapefruit juice, that may interact with oral antineoplastic agents also is crucial.

All patients should have a portable medication list, on paper, as well as on their smartphone, to keep track of medications, Dr. Bubalo noted. Regular medication reconciliation is a must.

Treatment Adherence However, just because a drug is on a list doesn’t mean a patient is actually taking it. Suboptimal treatment adherence is one of the biggest obstacles to using oral therapies. Because studies measuring adherence use different definitions and different yardsticks (i.e., self-report, pill counts), it

Table 1. Selected Trials Evaluating Adherence to Oral Cancer Therapies Study

Patients, N

Drug

Adherence Metric

Adherence Rate

Time Period

J Clin Oncol 2012;30 (suppl): abstract e11067

666

Lapatinib (Tykerb, GlaxoSmithKline)

Medication possession ratio, ≥80%

78%

1y

J Clin Oncol 2008;26(4): 556-562

12,391

Anastrozole

Prescription refills, ≥80%

78%-86%, year 1; 62%-79%, year 3

3y

J Clin Oncol 2010;28(27): 4120-4128

5,979

Tamoxifen, letrozole

Medical claims, ≥80%

49%

5y

J Clin Oncol 40 2013;31(suppl 31): abstract 25

Sunitinib (Sutent, Pfizer), pazopanib (Votrient, GlaxoSmithKline), everolimus (Afinitor, Novartis)

Adherence questionnaire, eight-item Morisky Medication Adherence Scale

High adherence, 60%; Intermediate adherence, 30%; low adherence, 10%

60 d

J Clin Oncol 2011;29(suppl): abstract 7611

50

Erlotinib (Tarceva, Genentech)

Self-report, ≥95%

72%

2 mo

Arch Dis Child 2004;89(8): 785-788

39

Mercaptopurine

Patient interview, drug metabolite assay

54%

Conclusion of maintenance therapy

only 9% are 75 or older ((J Clin Oncol 2004;22[22]:4626-4631).

Age-related factors can influence the absorption, distribution and metabolism of oral agents ((Drug Agingg 2002;19[1]:2542). For example, older individuals often have reduced gastric acid secretion and gastrointestinal motility, and many are on concomitant medications, all of which can change drug absorption. The decreased plasma albumin and increased fat-to-muscle mass that comes with aging can hinder drug distribution. Reduced hepatic metabolism and cytochrome P450 enzymes can decrease drug metabolism.

Dr. Nightingale pointed out that there is a big difference between chronologic

drug interactions is another challenge.

“Most of the oral drugs are metabolized by liver enzymes that metabolize lots of other drugs, and some new agents change the metabolism of other drugs,” Dr. Bubalo explained. For example, sorafenib (Nexavar, Bayer) is partially metabolized by uridine diphosphate glucuronyltransferases 1A9 and cytochrome P450 3A4 isoform, both of which are involved in metabolizing many other drugs. The prostate cancer drug enzalutamide (Xtandi, Astellas/ Medivation) speeds up the metabolism of some medications, including those used to treat high cholesterol. Other oral agents, such as crizotinib (Xalkori, Pfizer) and dasatinib (Sprycel, Bris-

is difficult to get a clear picture of the problem, but some adherence rates are under 50% (Table 1).

Although a threshold of 80% often has been quoted as an adequate adherence rate, a study of imatinib (Gleevec, Novartis) in chronic myeloid leukemia demonstrated that an adherence rate of less than 90% greatly decreased the sixyear probability of a major molecular response compared with an adherence rate of 90% or greater (28.4% vs. 94.5%; P<0.001) ((J Clin Oncoll 2010;28[14]:23812388). A study of oral mercaptopurine in children with ALL showed that compared with a benchmark of at least 95% compliance, the risk for relapse rose

•

see ORAL AGENTS, page 14

14

Specialty Pharmacy Continuum • February/March 2015

CLINICAL

ORPHAN DRUGS continued from page 12

ed product—can be very high indeed. “If you have rheumatoid arthritis and you don’t like the side effects of one of your medications and you decide not to take it, you may be in more pain, and that’s up to you,” Ms. Fish said. “But with diseases where you’re going to be hospitalized if you don’t take the medication, that’s extremely significant both medically and financially. If children with inborn errors of metabolism, like PKU [phenylketonuria] and Pompe disease, are not taking their medications so that they’re working all the time, that’s not good for any of us.”

Without treatment, PKU results in permanent cognitive impairments, while untreated infantile-onset Pompe disease disables the heart and skeletal muscles and is ultimately fatal. The first drug therapies for these rare conditions—sapropterin dihydrochloride (Kuvan, Merck Serono) for PKU and alglucosidase alfa (Myozyme, Genzyme) for Pompe—were

ORAL AGENTS continued from page 13

with decreasing compliance ((J Clin Oncol 2012;30[17]:2094-2101).

When developing a plan to improve treatment adherence, Dr. Koontz said pharmacists can rely on the American College of Preventive Medicine’s mnemonic device, SIMPLE: • S, simplify the regimen; • I, impart knowledge; • M, modify patient beliefs and behavior; • P, provide communication and trust; • L, leave the bias; and • E, evaluate adherence.

To simplify, Dr. Koontz discusses schedules with patients and caregivers to identify the best time for medication administration, recommending that complex regimens be taken when a caregiver can devote more time. “For example, maybe first thing in the morning is not the best time for a child to take a lot of medications when a grandmother is coming over to take care of the kid,” she said. Pharmacists should be careful to avoid biases, such as assuming that single mothers will have the most problems managing a child’s medications; sometimes it is the two-parent family with a high income that struggles to comply.

Dr. Koontz provides regimen information in a chart that lists the drug names; what exactly each medication does; instructions on how to take the drug, such as time and food requirements; and information on managing the four or five most common side effects.

“It is not helpful to say these are 30 side effects that you might have; that can be overwhelming,” Dr. Koontz said. In

approved in 2006 and 2007, respectively.

NPS Pharma encourages its home infusion providers to communicate with patients—to a point. “If you reach out to patients too often, you can actually hurt adherence,” Mr. Hudson said. “They start to get annoyed that you’re calling them every day. That’s why we map communication so that we know who’s talking to them and when.”

Through patient market research, Mr. Hudson said, NPS Pharma has found that adherence is shaped during the first two to three months on therapy. “That’s when they see the side effects, and then they either get used to them, or the side effects go away. We are more intensive and hands-on during that period to drive persistency through the initial period of difficulty starting a new drug, and then we taper down.”

The orphan drug space is uniquely personal, said Wesley Winn, the vice president of commercial operations and market access for Hyperion Therapeutics, which markets Ravicti (glycerol

Table 2. Factors in Adherence to Oral Cancer Therapies

phenylbutyrate) and Buphenyl (sodium phenylbutyrate), which are both indicated for the treatment of urea cycle disorders. “We have 480 pharmacies and 2,000 patients, and I can count how many [of those patients] are in each [of those pharmacies],” he said.

A Challenging Trade Channel Although many patients prefer to pick up their medications at retail pharmacies, Mr. Winn noted, that poses some problems. Once the drug goes into that trade channel, “I don’t know what happens to the patient,” he explained. “I don’t get data on the back end. I’ve had retailers come to me and say, ‘I want to be in your network.’ But they couldn’t tell me the copays their patients were experiencing, and they didn’t know if patients were staying on the drug or falling off.

With specialty pharmacy, I know what’s going on every step of the way.”

In response, Hyperion started its model around two hubs that have significant experience with Risk Evaluation and

Table 3. Medication Reminder Apps

Patient-specific

MedSimple

Age

RxmindMe Prescription

Ethnicity/race

MyMeds

Cognitive capacity

Meds Agenda

Forgetfulness and ability to establish a medication routine Cultural health beliefs Financial resources Health knowledge literacy Physical factors Social support system Coping/adaptation skills Anxiety/self-esteem Caregiver beliefs and anxiety Treatment-specific Illness perception Side effects Cost/Access Polypharmacy Regimen complexity and administration Therapy duration Provider/system-specific Provider–patient relationship Fragmented continuity of care Insurance coverage Satisfaction with care Based on presentations by Ginah Nightingale, PharmD, a , and a d Susannah Susa a Koontz, oo t , PharmD a

contrast, empowering a patient with a manageable amount of knowledge can increase compliance.

There is no standard tool for measuring adherence to oncology medications, but Dr. Nightingale said she uses the eight-item Morisky Medication Adherence Scale, which has been validated in other diseases. Open-ended questions work better than “do you take” medicine X. “I say, ‘tell me how you are taking your mercaptopurine,’ and I let them verbalize it,” Dr. Koontz said.

Proactive patient education on adverse effects also can be helpful. According to Dr. Bubalo, one relatively new agent that can be challenging to manage is afatinib (Gilotrif, Boehringer Ingelheim). This lung cancer drug causes diarrhea in almost all patients and grade 3 diarrhea in roughly 15% ((J Clin Oncol 2013;31[27]:3327-3334). “There is a lot of patient education that goes into this drug. You need to tell patients what to expect, and how to manage the side effects and watch for the danger signs that indicate they should call back for medical support,” he said. “Patients are much more successful when you have

Mitigation Strategies. “We didn’t want someone else learning on our time,” he said. “We also wanted partners who were used to hand-holding patients in terms of adherence. But after launching, we realized that some of our patients have had good experiences with retail, so we’re always going back to the drawing board and assessing our pharmacy network.”

“We’re on a journey with our patients,” Mr. Hudson said. “We’re providing the product and the resources, but they have to communicate with the doctor and the infusion pharmacy to make sure they’re getting the outcome they want. Some patients just want a day off of TPN. Some just want a couple of hours. We had one mom on a PN [parenteral nutrition] backpack all day long, and she just wanted half an hour off in the morning while she helped her daughter get ready for school. That’s it. So we helped her get that half hour.”

—Gina Shaw The sources had no relevant financial conflicts of interest to disclose.

a preemptive side effect management process in place.”

Melanoma agents trametinib (Mekinist, GlaxoSmithKline) and vemurafenib (Zelboraf, Genentech) are associated with rash; patients need to be able to differentiate a normal rash from one that may require additional therapies, he pointed out.

Because the reasons that patients may be nonadherent to therapy are so varied (Table 2), adherence interventions must be individualized. Financial assistance programs can help those who may be noncompliant because they can’t afford their drugs, many of which run $8,000 to $12,000 per month. (See related story, page 1.) Even when a patient has insurance, he or she may have high copays.

Smartphone apps (Table 3) and automated texts may be helpful, but only for those comfortable with technology. Use of sticker books, with young patients being rewarded with a sticker every time they take their medication, is effective, especially for girls.

“There is a long history of pharmacists intervening to support patients with their medications,” Dr. Bubalo said.

“Sometimes it is a memory issue or figuring out how to integrate a medicine into the day. Some individuals have barriers such as cost, nutrition, the inability to swallow or side effects. You have to tailor an intervention to the patient.

Adherence issues are always individual.”

—Kate O’Rourke Drs. Bubalo and Nightingale reported no relevant financial conflicts of interest.

Dr. Koontz consults for Lexicomp and Sigma Tau Pharmaceuticals.

1+,$ $QQXDO &RQIHUHQFH ([SRVLWLRQ March 23-26, 2015

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Specialty Pharmacy Continuum • February/March 2015

CLINICAL

Guideline Development and Implementation David P. Reardon, PharmD, BCPS Senior Clinical Pharmacist – Critical Care

Paul M. Szumita, PharmD, BCPS Clinical Pharmacy Practice Manager Director, Critical Care Pharmacy Residency Brigham and Women’s Hospital Boston, Massachusetts

E

vidence-based medicine integrates clinical expertise with data from systematic research and national committee guidelines to provide individualized patient care.1 The incorporation of clinical evidence is meant to improve and sustain traditional health care values, which are centered on a clinician’s experience and clinical skills.2 Typically, it is the responsibility of each institution or health care system to determine what published research and consensus guidelines should shape its own practice guidelines, based on the specialties offered at that institution and the patient populations served. When determining the need for a local clinical practice guideline, three factors affecting uptake should be considered: 1. the type of change, 2. catalysts and barriers to change, and 3. implementation strategies.3

Get Buy-in From the Top Before a guideline is created and a change in practice is implemented, obtain support from departmental and institutional leadership, as well as high-level committees that may help influence staff to change (Figure). If a guideline imposes minor changes, such as conversion from one inhaled pulmonary vasodilator to another, there may be little need for political support or buy-in to facilitate effective implementation.4 If, in contrast, the

guideline imposes major changes, a large political campaign to get buy-in from the many stakeholders affected may be necessary. Examples of these types of guidelines include adoption of new pain, agitation and delirium management guidelines or an institution-wide guideline for treatment of hyperglycemic emergencies.5,6 Once leadership is on board with the proposed change, the next step is identifying champion(s) and creating a guideline development, implementation and sustainability team.

Creating Champions Change requires a strong individual or small group to accept the responsibility to model and encourage the new paradigm.6 It may be necessary to have such a champion from each discipline to positively reinforce the initiatives of the department team and overcome the inertia of current practice.7 These physicians, nurses, pharmacists, respiratory therapists, nutritionists, and/or other medical professionals are the core driving force behind achieving performance metrics and optimizing patient outcomes. These individuals are responsible for the formation and leadership of multidisciplinary committees charged with allocating institutional resources and providing continuous monitoring of implemented projects.

Building a Guideline Team Once these champions have been found, it is essential to pair them with “early adopters,” individuals who will spread change.8 Within the institution, this guideline team must be independent and have the authority to implement directives and conduct quality improvement projects for the enhancement of clinical care in the hospital. The team is composed of individuals pertinent to the goals and directives of that committee or guideline. For example, a team focused on implementation of a new nursing guideline

would want to include nurses from all affected care areas, and possibly physician and pharmacy representatives, to aid in educational efforts.

These individuals are needed to facilitate the integration of administrative, clinical, informational and laboratory resources through other multidisciplinary committees.9

Barriers to Change The guideline team should make an effort to anticipate the many barriers to effective implementation of the guideline. Common barriers include a lack of understanding about why a guideline is needed and how it will be incorporated into daily practice, as well as ineffective implementation strategies and a lack of urgency.10,11 Guideline team members must consider current clinical practice or local guidelines and the potential impact of the new or updated guideline on the daily practice of affected health care providers. The goal of a team should be to provide comprehensive direction, without excessively burdening staff with policies and guidelines.

In-person educational sessions focusing on improvement in patient care and ease of use by clinicians likely will result in more effective implementation and adoption of guidelines.

Implementation Once an area for improvement has been identified and the clinical practice guideline has been developed and vetted, the team needs to dettermine the best course of action for im mplementing change, based on the expeertise of its members and resources avaiilable in the institution.12 Many strategiees for implementation have been n explored, each with varyingg degrees of success. The usse of didactic training, traditional continuingg education formats and handouts aare a starting point. Used alo one, these techniques often are o unsuccessful. Hav-

Figure. Stepwise approach to guideline development and implementation. ing clinical experts target specific clinicians within the larger group and using concurrent audit and feedback education has been shown to be moderately effective. The most effective ways to implement a new guideline involve multiple-intervention strategies, the use of reminders, and patient-based interventions. The use of patient-based interventions, such as patient education, places responsibility on bedside clinicians for the adoption of the guideline. Reminders, such as posters or announcements at staff meetings, keep the idea of change and guideline implementation in the forefront of their minds.13

Quality Assurance And Sustainability Once a guideline has been developed and implemented, it is vital to assess its effect on quality improvement and determine its sustainability.

Each clinical practice guideline should have predetermined measurable outcomes. These outcomes are typically the driving force behind the change being implemented.

Use of a validated quality improvement tool, such as the “Model for Improvement” endorsed by the Institute for Healthcare Improvement, can accelerate and increase the efficiency

17

Specialty Pharmacy Continuum • February/March 2015

CLINICAL

of implementing change. The Model for Improvement focuses on the Plan, Do, Study, Act (PDSA) method of implementation. The PDSA method incorporates planning on all scales, trying the intended change (usually on a small scale), studying the results of the trial, and acting based on what is learned.

Once action has been taken, the cycle starts over and allows for perpetual development and improvement.14,15 Reaching the established target metrics of the clinical practice guideline often may require a few rounds of edits and reinforcement with end users. Periodic or ongoing assessment of these targets will help gauge sustainability and any deviation from the new practice.16 Sustainability often is the most difficult phase of implementation and may require a committee’s oversight.

6. White KE, Szumita PM, Gilboy N, et al. Implementation of a guideline for the treatment of pain, sedation, agitation, and neuromuscular blockage in the mechanically ventilated adult patient in the emergency department. Open Access Emerg Med. 2011;3:21-27.

7.

Zeimer DC, Doyle JP, Barnes CS, et al. An intervention to overcome clinical inertia and improve diabetes mellitus control in a primary care setting: Improving Primary Care of African Americans with Diabetes (IPCAAD) 8.

Arch Intern Med. 2006;166(5):507-513.

8. Berwick DM. Disseminating innovations in health care. JAMA. 2003;289(15):1969-1975.

9. Szumita PM, Greenwood B, Anger KE, Pendergrass M. Prevention and treatment of hyperglycemia in hospitalized patients.

Pharmacy Times. April 2007;110-120. http:// www.pharmacytimes.com/publications/iss ue/2007/2007-04/2007-04-6454. Accessed June 5, 2014.

10. Ahrens T. Evidence-based practice: priority and implementation strategies. AACN Clin Issues. 2005;16(1):36-42.

11. Anger KE, Szumita PM. Barriers to glucose control in the intensive care unit. Pharmacotherapy. 2006;26(2):214-228.

12. Miller MA, Bosk EA, Iwashyna TJ, Krein SL. Implementation challenges in the intensive care unit: the why, who, and how of daily interruption of sedation. J Crit Care.

2012;27:218e1-218e7.

13. Davis DA, Taylor-Vaisey A. Translating guide-

lines into practice: a systematic review of theoretic concepts, practical experience and research evidence in the adoption of clinical practice guidelines. CMAJ. J 1997;157(4):408-416.

14. Langley GL, Nolan KM, Nolan TW, et al. The Improvement Guide: A Practical Approach to Enhancing Organizational Performance. 2nd ed. San Francisco, CA: Jossey-Bass Publishers; 2009.

15. Deming WE. The New Economics for Industry, Government, and Education. Cambridge, MA: The MIT Press; 2000.

16. Blum RM, Stevens CA, Carter DM, et al.

Implementation of a dexmedetomidine stewardship program at a tertiary academic medical center. Ann Pharmacother.

2013;47(11):1400-1405.

Summary Development and implementation of a local clinical practice guideline should be based on the needs of the institution and should have support from institutional or health care system leadership. Guidelines champions and implementation teams are responsible for taking ownership of the process and anticipating barriers to change while implementing guidelines.

A validated process for continuous quality assurance should be put in place to promote sustainability and improvement of guidelines.

References 1. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn’t. BMJ. 1996;312(7023):71-72.

2. Oxman A, Flottorp S. An overview of strategies to promote implementation of evidencebased health care. In: Silagy C, Haines A, eds.

Evidence-based Practice in Primary Care. 2nd ed. London, England: BMJ Books; 2001.

3. Grol R, Grimshaw J. From best evidence to best practice: effective implementation of changes in patients’ care. Lancet.

2003;362(9391):1225-1230.

4. Torbic H, Szumita PM, Anger KE, Nuccio P, LaGambina S, Weinhouse G. Inhaled epoprostenol vs inhaled nitric oxide for refractory hypoxemia in critically ill patients. J Crit Care.

2013;28(5):844-848.

5. Beik N, Anger KE, Forni AA, Bawa K, Szumita PM. Evaluation of an institution-wide guideline for hyperglycemia emergencies at a tertiary academic medical center. Ann Pharmacother. 2013;47(10):1260-1265.

Enhance Patient Care While Realizing New Revenue Streams Specialty pharmaceuticals is one of the fastest growing segments within the pharmaceutical marketplace. According to future-trending reports, specialty drugs will account for the majority of new drug approvals in coming years and will consume approximately 40-50% of health plans’ pharmaceutical spending by 2020.

The cost of specialty drugs is growing at a rate of 20% per year and at a cost 50 times greater than traditional non-specialty drugs.

A PHS engagement can help your health system to address this opportunity. > Improved clinical outcomes and patient satisfaction by enhanced coordination of care

Follow us @SpecialtyPharm

> Decreased patient “leakage” from health system/ACO to maintain accompanying revenue streams > An employee-incentivized specialty benefit program > A consultative, scalable approach implemented to meet your specific health systems’ requirements

And send your Twitter handle to editor David Bronstein at davidb@mcmahonmed.com so we can follow you.

PHS assists clients to thoughtfully create a program to increase quality of care and deliver efficiency while realizing the substantial revenue streams and cost containment benefits it can provide.

For more information about Pharmaceutical Healthcare Solutions, contact us at 877-892-1254 or email solutions@amerisourcebergen.com

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SOARING PRICES continued from page 1

paperwork, getting approval, and we’ve occasionally had to alter treatment based on which agents are preferred by a person’s insurance plan. These things are happening with increasing frequency.”

Additionally, the margin of error for nonadherence can be vanishingly small. “Chronic myelogenous leukemia [CML] used to be a death sentence— your life expectancy was maybe two or three years after diagnosis. Then Gleevec [imatinib, Novartis] came along and made it into a chronic illness,” said Ivo Abraham, PhD, RN, the director of the Center for Health Outcomes & PharmacoEconomic Research, University of Arizona College of Pharmacy, in Tucson. “But with the high costs of these treatments, we see cancer patients lapsing into chronic illness behavior; they start skipping some doses. In [the] case of CML, if you start skipping doses, your chance of losing a cytogenetic response goes up real fast.”

Hence the growing importance of PAPs. Fortunately, “most manufacturers, and most branded cancer drugs, do have some form of patient assistance program,” said Darcy Malard Johnson, PharmD, the oncology pharmacy program manager for Fairview Pharmacy Services at the University of Minnesota Cancer Care, in Minneapolis. “If the drug is a generic, or a branded product that recently went to generic, they will usually eliminate the PAPs. We saw that with Xeloda [Genentech; capecitabine], where we used to have patients who could get assistance, and now they can’t.”

PAP Types There are two primary types of manufacturer PAPs: free or compensated cost drug programs for patients without insurance, and “copay coupon” programs for those who do have insurance. There are legal requirements associated with providing both types of assistance. For example, “copay coupons are not available to patients with insurance under a federal program, such as Medicare Part D,” said Shannon Wiley, a health care regulatory attorney with Bass, Berry, & Sims PLLC in Memphis, Tenn. (See sidebar.)

Aside from that important proscription, copay coupon programs are available to most patients, in part because they do not carry income requirements; “they are generally given to everyone who is not a federal program beneficiary,” Ms. Wiley noted.

However, it is important to understand that copay coupon programs don’t really use coupons anymore, Ms. Johnson pointed out. Instead, patients receive a copay card that resembles a credit card, which they present at the pharmacy to be processed and used to pay their copay

up to a certain limit. “Say your insurance copay for your drug is $125, and the company’s patient assistance program pledges that you have to pay no more than $25 out of pocket for it,” she explained. “You present the card to the pharmacy, and the program pays $100 so you only have to pay $25 when you pick it up.”

Free drug programs, in contrast, do have income requirements. Depending on the manufacturer, the drug and the type of assistance, there are different maximum income thresholds required for a person to qualify. For most free drug programs, a gross household income threshold of $100,000 per year is common, according to data from the national nonprofit NeedyMeds, which tracks thousands of assistance program across the country. “They may also have an annual cap, like $20,000 per person per year,” Dr. Johnson pointed out.

Once the patient qualifies, the manufacturer may ship the drug directly to the patient for a self-administered medication or to the physician or pharmacy for an IV medication, such as blinatumomab.

Specialty pharmacies must help their patients make the most of these programs, Dr. Johnson stressed. “That’s the kind of game you have to play,” she said.

“It’s different with each patient, each insurance, each deductible.”

The time frame for getting a patient approved into a PAP can vary, so Dr. Johnson advises specialty pharmacies to pull the necessary financial and clinical information together as early as possible

Patient Assistance Toolbox

F

or help finding resources for your patient—both PAP programs and others—the NeedyMeds.org website is about the best one-stop shopping resource around. Even large specialty pharmacies such as Fairview’s, with their own financial assistance departments, rely on NeedyMeds’ easily searchable databases. They track not only manufacturer PAPs, but also government-based assistance, private foundations and scholarships, and other resources. They also offer customizable, subscription-based PAPTracker software.

The Partnership for Prescription Assistance (www.pparx.org) is another useful resource. The organization is cosponsored by many leading biopharmaceutical companies and medical groups such as the American Academy of Family Physicians, American Cancer Society, American College of Emergency Physicians and National Association of Chain Drug Stores. It is “a single point of access to information on 475 public and private patient assistance programs, including nearly 200 programs offered by pharmaceutical companies,” according to the group’s website.

—G.S.

to avoid any interruption in therapy. “The key things you will need are the prescription, the indication and documentation of the patient’s income; usually they will want income tax returns,” she said. “They

will also require a patient’s signature as well, because when you send that information, you’re sending protected health information [PHI] and that signature is your HIPAA release.”

Copay Coupons and Legal Liability

P

roviding copay coupons to federal program beneficiaries, such as patients covered by Medicare Part D, is strictly prohibited, according to Shannon Wiley, a health care regulatory attorney with Bass, Berry & Sims PLLC in Memphis, Tenn. She explained that providing copay coupons to such beneficiaries raises problems for specialty pharmacies under the Anti-Kickback Statute, False Claims Act and the Civil Monetary Penalties law.

The prohibition arises from m a philosophy of cost sharing. Ms. Wiley pointed to reg gulatory guidance and Office of Inspector General (OIG) opinions o as the background for the prohibition. “The theory is that an invested consumer is a wise consumer, so by requiring the consumer to take on some out-of-pocket costs, it incentivizes her or him to make wise health decision ns,” she said.

As evidence that copay co oupons aren’t going away, Ms. Wiley pointed to the Sept. 19, 2014, OIG reporrt on copay coupons. The report n noted that coupon use by manufac cturers went from 86 in July 200 09 to 525 in December 2012. Despite thiss increase, commercial payors are also now putting copay coupon prohibitions in their payor agreem ments. Running afoul of commercial payor prohibitio ons can subject a specialty pharmacy to potential recou upment actions or contract terminations, Ms. Wiley warned. d “Many specialty pharmacies don’t have the leverage to keep copay coupon prohibitions out of payor

agreements,” she said, “so the real issue for SPs is to establish a protocol to honor the prohibition.” This can be problematic because SPs might not even realize these prohibitions are in place if the pharmacy contracts with payors through a pharmacy services administrative organization, because pharmacies must take the affirmative step to pull the individual provider manuals and comb through each to determine whether a prohibition exists.

Implementing the prohibitions is not always straightforward, Ms. Wiley noted. “For example, it may sseem like an SP could [prevent] a Part D ben neficiary from using a copay coupon by disallowing use by anyone over [age] 65 5; however, the September OIG report in ndicates that 17% of Part D beneficiariess are under 65.”

Ms. W Wiley urged SPs to involve their legal, compliance, business and op perations teams when dealin ng with copay coupons. “Good communication is essential. All relevant stakeholders need to be aware of these prohibitions as they are being negotiated an nd implemented.”

For more information on the copay coupon regulations regulations, see an in-depth article on the topic coauthored by Ms. Wiley at http://goo.gl/73XFRV. —G.S.

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Specialty Pharmacy Continuum • February/March 2015

OPERATIONS & MANAGEMENT

If the prescription is for an off-label diagnosis, PAP approval will be much more challenging to obtain. “We’ve seen it happen, but usually manufacturer assistance only covers on-label uses. If the use is off-label, or if the patient has Medicare or Medicaid, you will probably need to seek help from a private foundation instead,” Dr. Johnson said.

If you’ve submitted all the required paperwork and made sure that the patient meets the insurance and income parameters before applying, “you’re pretty much guaranteed to get the assis-

tance,” she stressed. A response should come within 48 hours in most cases.

Year after year, Fairview has been able to consistently increase the number of patients accepted into PAPs, as well as the dollar amount it obtains for these patients each year, she noted. “Talking with oncologists, they feel it’s been instrumental in ensuring that patients are getting on their medications in a timely fashion, and staying on them,” she said.

Back to Blincyto As for the example of blinatumomab’s

high cost, the drug underscores the complicated nature of the debate surrounding the pricing of cancer medications.

The price of the medication, which was approved for treatment-resistant acute lymphoblastic leukemia (ALL), “reflects the significant clinical, economic and humanistic value of the product to patients and the health care system, for an ultra-orphan population with a dramatic impact on a serious illness,” Amgen said in an emailed statement.

However, the upward price push of oncology drugs is harming patients, a

group of 120 cancer experts posited in a forum article published in Blood (2013;121[22]:4439-4442).

Noting that cost is the biggest factor for the approximately 10% of U.S. patients who fail to take prescribed drugs, they concluded, “This is reducing their chances of survival.”

—Gina Shaw Dr. Uy reported that he has served on an advisory board for Boehringer Ingelheim.

None of the other sources had any relevant financial conflicts of interest to disclose.

ASK THE EXPERT

HOTSPOTS continued from page 3

cialty to molecule to region, the biggest issues that physicians have with biosimilars are that their efficacy, safety and immunogenicity will be inferior to the reference product, according to a Decision Resources Group survey of more than 550 physicians across six different specialties in the United States, France and Germany. Generally, these concerns stem from the fact that they are aware that biosimilars do not go through the same number of clinical trials as innovative biologics. Our research shows that physician concerns about similarity off biosimilars to reference products are lowest among those who are very familiar with biosimilars. To reduce these apprehensions, physicians need access to clinical trial data for biosimilars, and they also need to be educated about the extent off the nonclinical analytics that biosimilars must go through.

Q: What is the next step for research with biosimilars?

A: We are focusing in particular on payor efforts to drive biosimilar uptake and physician opinion of these methods.

For example, a recent change in French law means that pharmacists will be able to dispense a biosimilar to a treatmentnaive patient who has a brand prescription, as long as the physician has not explicitly prohibited that switch. We are conducting research to assess how likelyy physicians are to prevent this pharmacy-level substitution.

—Paul Bufano

Web Exclusive For a PDF of worldwide biosimilar adoption, scan the adjacent 2D barcode or visit specialtypharmacy continuum.com/BiosimilarMap.

Now Available!

Our brand-new iPad app Scan here to download

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Specialty Pharmacy Continuum • February/March 2015

OPERATIONS & MANAGEMENT

One approach: tying the numbers to cost savings and improved patient care

Tips for Going From Data Donkey to Data Ninja Philadelphia— If there was one clear message resounding through the Specialty Pharmacy Data Optimization Summit organized by CBINet in December, it was that specialty drug manufacturers are intent on getting the most for their money in terms of data from specialty pharmacies and data aggregators— but just how to do that remains a challenge.

“When you have a product in a specialty pharmacy network and in retail, it’s very difficult to aggregate that data from two areas of business,” said the conference chairperson Stephen Lagano, a principal of the pharma/biotech consultancy Altometrixs Inc. “Especially the competitive data. You really have to think beyond aggregation and into integration—meaning that you have to have an overarching data strategy that continually extracts value.”

He called this process “moving from data donkey to data ninja.”

The basic challenges that pharmaceutical manufacturers face in achieving this ninja level are data fragmentation and diversity, John Giannouris, a specialty data integration practice leader with IMS Health, told Summit attendees. Big Pharma gets data from a huge array of sources—not just individual SPs and SP networks, but also wholesalers, group purchasing organizations, physician buyand-bill practices and direct sales, hubs and syndicated data providers, he noted.

patient care, and involve cold chain drug shipments and potentially costly temperature controls, data provision can be “very, very challenging,” she said. If, however, the product has a higher WAC, “we won’t run into that issue.”

The bottom line? “If we’re dealing with a losing margin situation, we’ll talk to the manufacturer about that and ask them to help support their drug in the specialty space,” she said.

Drug manufacturers need to be responsive to the margin pressures faced by specialty pharmacy providers, Ms. Allen noted. One way to do that is to get the feedback of multiple providers in the early phase of a product’s introduction, to determine the value of the requested data. She recalled, as an example, the dream panel of data “coopetition” set up by a pharmaceutical manufacturer, which included Diplomat.

“They started early on in the product launch with a face-to-face panel of five chosen specialty pharmacies as well as the manufacturer and the data aggre-

‘You need to be able to acquire master reference data that can bridge health care providers, payors and plans, and pharmacies.’

—John Giannouris that it’s maintaining those SVRs [sustained virologic responses] after those patients are treated?” she asked. “Did the manufacturer pay to gather outcomes data to prove that the drug is worth the price tag?”

Mr. Giannouris advised pharmaceutical manufacturers to seek out specialty pharmacy partners that have experience working with data aggregators and integrators. “Do they have

‘Manufacturers will be willing to pay more if the incremental gain from your data is substantial—particularly when it can be correlated back to compliance and persistency and cost savings in the form of utilization and health care outcomes.’

—Stephen Lagano

“Syndicated data alone may no longer support all the manufacturer’s commercial needs,” Mr. Giannouris said. “But competitive data are more limited and potentially cost-prohibitive if purchased from specialty pharmacies.”

Manufacturers face another challenge in gaining access to high-quality productrelated data: some SP providers may be feeling the pinch from shrinking margins and are looking to scale back on data provision, according to Cheryl Allen, RPh, the vice president of business development and industry relations for Diplomat Specialty Pharmacy.

“It’s a classic low WAC [wholesale acquisition cost] issue,” Ms. Allen told Summit attendees. “The core services we provide are paid for by the spread margin of the drug.”

If those services include high-touch

gator,” she said. “We went through the data set and had a discussion on the usefulness of that data, and the ability of the panel as a group to deliver the data. To date, they’re the only manufacturer that has asked us to do that.”

Making the Case for Value In the days of skyrocketing specialty drug prices, more and better data may be worth the investment. Manufacturers need to work with specialty pharmacies to carry the message of the value proposition of their products to the payor community, Ms. Allen said. She pointed to the recent example of Gilead’s hepatitis C behemoth Sovaldi (sofosbuvir), with its clinical trial–reported 90%-plus cure rate and $80,000 price tag.

“We’re hearing about this over90% cure rate, but where’s the proof

best practice project accelerators?” he asked. “Do they have a platform that’s flexible and scalable, and a HIPAAcompliant patient de-identification engine to track patients longitudinally across sources and time? You need to be able to acquire master reference data that can bridge health care providers, payors and plans, and pharmacies.”

Strategies for SP Providers The Summit speakers didn’t focus only on the manufacturer side of the data provision erquation; they also offered SP providers tips for proving their value as data partners. That process can begin, they noted, by addressing the following areas: • Education—“How many interventions are my patients receiving? How are my patients being contacted? What is

the contact frequency?”

• Support—“Are patient management programs improving patient adherence? How does this differ by contracted specialty pharmacy?”

• Managed Care—“Are patients experiencing high rejection rates? What plans are blocking access to my products? Are certain specialty pharmacies affected more than others?”

• Delivery—“Are patients experiencing high rejection rates? What plans are blocking access to my products? Are certain specialty pharmacies affected more than others?”

In a separate interview, Mr. Lagano also offered specialty pharmacies some tips to keep in mind when crafting their data provision strategies. He urged them, for example, to focus on “enhanced” data services. “Manufacturers will be willing to pay more if the incremental gain from your data is substantial,” he said, “particularly when it can be correlated back to compliance and persistency and cost savings in the form of utilization and health care outcomes. That’s not only important to manufacturers, but to the multiple audiences, like managed care, and all other critical players along the continuum.”

He called specialty pharmacy “a vector of opportunity” for data integration.

“There’s nobody who’s in a better position. They have a relationship with the payor, the physician, the patient and the manufacturer. Who could be in a better spot to ‘move the needle’ and get significant business results?”

—Gina Shaw The sources had no relevant financial conflicts of interest to disclose.

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OPERATIONS & MANAGEMENT

DATA CONTRACTING continued from page 1

SP1

STAR

Specialty Pharmacy Treatment Volume

tips he offered were focused primary on manufacturers—the lion’s share of the attendees at the conference—his suggestions are equally valuable to SP providers seeking insights into the fine points of contracting and data provision.

Mr. Duey urged drug manufacturers to hold their contracted SP partners accountable for a high level of performance when it comes to data delivery.

“Of course, your ideal partner is someone with high patient volume and who is strong on patient services and providing data, but you’ll have partners in all four quadrants,” he told attendees.

“You want to focus on the rising stars, and not be playing with the problem children—those with large volume, but who are low on overall performance— or the dogs, who not only have low patient volume but can’t deliver the data they promise or make errors.”

(See Figure 1.)

But what constitutes good data?

“Data strategies are complex and specific to disease states and therapies,” noted Jim McCann, the global information insights practice leader at Paragon. “You won’t find a complete set of data for every product and disease state you’re in.”

Generally speaking, Mr. Duey urged manufacturers to focus on patient-centered data, such as average time to fill, medication possession ratio, time on therapy and patients in queue.

Mr. Duey proposed some different options for manufacturers to use in scoring specialty pharmacies’ compliance with their contracted data obligations. They could, for example, rank each specialty pharmacy’s timeliness, completeness and accuracy percentages against national compliance rates (Figure 2). Or they could monitor data at a record level, scoring them “pass” or “fail” on everything from on-time delivery to inventory data completeness and Speed, Power, Agility, Reaction and Quickness (SPARQ) error rates.

600K

PROBLEM CHILD

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Specialty Pharmacy Performance Ranking

Figure 1. Specialty pharmacy network strategic mapping.

SP, specialty pharmacy

contract terms in the future.

Manufacturers can choose between carrots and sticks to get the data they want, Mr. Duey noted. He described strategies employed by three different clients—two sticks and one carrot.

On the stick side, one large pharmaceutical company, which spends $300,000 quarterly for data on its cancer drug, contractually specifies no payment if the specialty pharmacy doesn’t meet its minimum threshold for data provision. (The three key performance measures are timeliness, completeness and accuracy, with multiple methods for assessing levels of compliance.)

A mid-sized company, which spends $900,000 per quarter for data on its cancer drug, deducts a dollar figure per day from its fees for noncompliance with data provision requirements.

On the carrot side—another large pharmaceutical company that pays $500,000 quarterly for data on its central nervous system drug—sets low base fees for data but provides high financial rebates for performance.

Don’t Forget the Patient data breach, and of course the internal and specialty pharmacy legal and compliance review moves faster,” Mr. Duey said. “But that results in low data quality, inaccurate unique patient counts and length of therapy [data].”

Resistance Is Futile?

Conference chairman Stephen Lagano, principal of the pharma/biotech consultancy Altometrixs Inc., posed the obvious question: “What if somebody’s resistant to signing the contract and as the manufacturer you want those data elements?”

“Manufacturers who take the patientcentered approach to data very seriously go many rounds and eventually win,” Mr. Duey responded. “For example, we were recently in a negotiation where

most of the network of SPs had agreed to provide a complete patient-level data set with full PHI. But one of the large SPs said that they were unable to provide the full data set within the launch time. Round 1: No. Round 2: No. Round 3: The manufacturer asked for a little of this and a little of that, but the answer was still no. So finally the manufacturer said to the entity, ‘All right—we’re going to contract with you for a much smaller data set in Tier 2 instead of Tier 1.’

That’s the difference between $20,000 per month and $75,000 per month.”

In the scenario above, the SP provider had no choice but to accept the lower-tier contract, Mr. Duey said. But the negotiations were a lesson learned, he noted: the SP knew it had to improve its data aggregation skills to gain access to better

SP 5 compliance

Whatever the structure of the contract, Mr. Duey said, both manufacturers and specialty pharmacies, as well as hubs and data aggregators, need to look at data requirements from a patientcentric point of view. “How do we use this data to know when a patient’s not doing well? How do we know when their gap days are too long? We claim that adherence is better and compliance makes our product work better; we need to be able to show that. We want to help get the patient out of ‘disease’ and into ‘ease’—that’s what this data is ultimately for. Think about what the numbers mean for them.”

—Gina Shaw The sources had no relevant financial conflicts of interest to disclose.

National compliance

100

Skin in the Game But no matter how the scoring is done, Mr. Duey said, there must be stakes in the contract. “If you don’t have appropriate language in the contract [stipulating] that your specialty pharmacies will provide the data you want in a timely and accurate and complete fashion, and what it means and what happens if they don’t, the whole thing doesn’t work.”

Manufacturers will want full protected health information (PHI)–level data from their specialty pharmacies wherever possible. “When there’s no PHI, when the SPs and the hub send only de-identified data, there’s no risk for

75 50 25 0 Timely

Complete: Feed

Complete: Daily Stat

Complete: Inventory

Accurate: Inventory

Accurate: Patient ID

Figure 2. Monitor specialty pharmacy compliance: scorecard.

SP, specialty pharmacy; SPARQ, Speed, Power, Agility, Reaction and Quickness

No SPARQ Error Rates

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POLICY

Getting ACOs Up to Speed on Med Management Philadelphia—As of May 2014, at least 626 accountable care organizations (ACOs) were active in the United States, responsible for more than 20 million “covered lives,” according to a report from the health care consultancy Leavitt Partners.

ACO Pioneer in Houston There are lessons to be learned from some ACOs that embedded pharmacy and MTM deep within their DNA from the beginning. One of those is Kelsey-Seybold Clinic, in Houston, the first health care provider to be accredited as an ACO

by the National Committee for Quality Assurance. A multispecialty group practice with 420 physicians in 19 locations (12 of which include pharmacies), KelseySeybold “was an ACO before ACO was a term,” said Denise Jonathan, PharmD, the director of pharmacy services for KelseyCare Advantage, Kelsey-Seybold’s

It recently introduced a telephone postdischarge drug reconciliation program similar to Kelsey-Seybold’s, as well as a program to identify patients who are not achieving therapeutic goals—such as lower hemoglobin (Hb) A1c levels—and targets them for intervention.

Data fragmentation remains a major challenge for smaller operations, said Mark Shinmoto, PharmD, the director of pharmacy at HealthCare Partners. “For many ACOs, it is much more difficult to integrate data, with significant lag time,” he said. “And for those who still have

100

Percentage

But as ACOs continue to grow, some are struggling with medication therapy management (MTM), noted Leigh Ann Bruhn, a health director with Avalere Health in Washington, D.C., at the World Congress on Specialty Market Access.

Although a June 2014 report from Leavitt Partners predicted, “ACOs will quickly begin focusing on optimizing medication and addressing drug spend as central parts of their care management programs,” that time has not yet come, Ms. Bruhn pointed out. She cited, as an example, research published in the Journal of Managed Care Pharmacy (2014;20[1]:17-21), which showed that less than 25% of ACOs report high levels of readiness in several critical MTM areas.

Of 46 ACOs surveyed, only 22% involved pharmacists in direct patient care; 17% had protocols in place to avoid medication duplication; 9% notified the treating physician that a prescription had been filled; and just 7% were able to quantify cost offsets and demonstrate the value of appropriate medication use (Figure).

“That’s surprisingly low,” Ms. Bruhn said, adding that the gap offers specialty pharmacies the opportunity to define their role within this dynamic market. In most ACOs today, she explained, specialty pharmacy is on the outside of a central circle that may include the hospitals, the primary care physician groups, the multispecialty groups and post-acute care.

Going forward, specialty pharmacy should be more central to an ACO, Ms. Bruhn urged.

“The changing environment requires consideration of the entire health care system; SPPs [specialty pharmacy providers] can help by coordinating care and increasing patient adherence throughout this continuum,” she said. That’s an understatement: a study published in the August 2012 edition of Health Affairs (http://goo.gl/nI1SZc) found that a typical ACO with 10,000 Medicare beneficiaries might save up to $1.1 million annually in emergency department and hospitalization costs by improving medication adherence for patients with diabetes alone. (Think how much more might be saved for costly specialty conditions.)

explained. “First, a pharmacy technician calls the patient and asks them what’s going on with their medication regimen.

Sixty percent of the time, lack of adherence is attributable to forgetfulness, but the other 40%, there’s something else playing a role: the patient believes the drug isn’t working, there are side effects, and so on. When the patient reports a problem with the medication, a pharmacist follows up with the patient and their physician to devise a solution.”

Most recently, Kelsey-Seybold created a hospital discharge program; within

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Notified the treating physician that a prescription had been filled

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Figure. ACO readiness to deliver MTM services.

MTM, medication therapy management

‘If you can demonstrate that your medication therapy management program has improved adherence by this percentage, or HbA1c management by this much, then others will buy in. Conquer one [physician] group at a time.’

—Denise Jonathan, PharmD Medicare Advantage plan.

Medication therapy management was one of the Centers for Medicare & Medicaid Services’ (CMS) required admission tickets to the Medicare Advantage program for KelseyCare Advantage, launched in 2008. “After we had the MTM program created, we launched our RxQI program, where we focus on brand-name medications that can be switched to a generic alternative,” Dr. Jonathan said. In 2011, the first year after the program was in place, KelseySeybold saved more than $1 million by switching members to cost-effective alternative therapies; savings in 2012 totaled $800,000, and in 2013, $700,000.

“From there, we created our adherence clinic, which includes any patient who is not taking their medications at least 80% of the time,” Dr. Jonathan

48 hours after discharge, a pharmacist speaks with high-risk patients about managing their disease state at home, and reconciles the discharge medications with those previously prescribed by the primary care provider, ensuring that there are no gaps in care, therapeutic duplications or drug–drug interactions.

Kelsey-Seybold stands out precisely because of its success. “Nationwide, 15% of patients enrolled in a medication therapy management program have actually spoken to a pharmacist,” Dr. Jonathan said. “Our average is 85%.”

Calling on Patients California’s HealthCare Partners, one of the first 23 pioneer ACOs designated

by CMS, is an integrated mixed-practice group that employs 13 full-time pharmacists and serves about 750,000 patients.

open access to specialists, it is difficult to steer utilization to preferred products and preferred delivery models.”

Another barrier is “skin in the game”—or the lack of it. At this point, Dr. Jonathan said, most ACOs are led by physician groups, which are at “medical risk” for their outcomes, but not at “pharmacy risk.” “Doctors are not contracted on how they prescribe,” she said.

“When the ACO itself has some kind of pharmacy risk, or a contract driven by pharmacy-related measures, then medication therapy management will go to the top of their list of priorities.”

Dr. Jonathan acknowledged that Kelsey-Seybold has a particular advantage in MTM as a closed network. “But it starts with one group,” she said. “If you don’t have a closed system, then find one physician group that’s willing to take this step with you—one small group of doctors and patients to create a prototype and show others. If you can demonstrate that your medication therapy management program has improved adherence by this percentage, or HbA1c management by this much, then others will buy in.

Conquer one group at a time.”

—Gina Shaw The sources had no relevant financlal conflicts of interest to disclose.

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Immune Globulins: Therapeutic, Pharmaceutical, Cost, and Administration Considerations JERRY SIEGEL, PHARMD, FASHP Clinical Associate Professor The Ohio State University College of Pharmacy Columbus, Ohio

F

or the past several years, immune globulin (Ig) product shortages ha ave e not played a major role in productt choice. This allows clinicians to match the best product to the patient based on clinical condition and comorbidities.

New products also provide more treatment options. ns There now are 5 Ig products indicated for subcutaneous (SQ) use in patients with primary immunodeficiency: Gammagard Liquid (Baxter), Gammaked (Kedrion), GamunexC (Grifols) come in 10% concentrations and can be given intravenously or subcutaneously; Hizentra (CSL Behring) comes in a 20% concentration and can be administered subcutaneously. It should be noted that dosing adjustments are required for all SQ agents when converting from IV. HyQvia (Baxter) is the newest SQ Ig product, which became available in 2014. While the IgG portion of the product is identical to Gammagard Liquid 10%, it is to be used with recombinant human hyaluronidase (HY). This combination product allows for SQ administration of a large amount of Ig, equivalent in dose to that of IVIG, in one site and equivalent in conversion ratio on a 1:1 basis. It is FDA-approved for primary immunodeficiency in adults. This is the first product of its type. In the chart it will look identical to Gammagard Liquid 10%, but will be distributed as a dual package with the 5 mL vial of HY. Instructions for administration are unique and specific to this product.

Two products, Gammaked and Gamunex-C, are approved for patients with chronic inflammatory demyelinating polyneuropathy (IV only). Gammagard Liquid is approved to treat multifocal motor neuropathy.

Although clinicians have considered all Ig products to have comparable efficacy, they are not pharmaceutically equivalent. It is imperative that Ig products not be interchanged without full consideration of the pharmaceutical differences. The reasons for switching products may be clinical; they may be based on contracting issues; or they

S P E C I A LT Y P H A R M A C YC O N T I N U U M . C O M

may be due to product availability. It is best to consider product changes as if the patient is naive to Ig use, with increased monitoring and conservative infusion times.

Whereas Tables 1 to 5 may help facilitate these decisions, it is important to understand the clinical impact of changing products. Although all of the products contain primarily IgG, trace amounts of other Igs—IgA and IgM—as well as different stabilizing agents, may affect tolerability. The differences in salt, sugar, and overall osmolarity of these products are particularly important when patients have various comorbidities, such as renal dysfunction, diabetes mellitus, vascular disease, or heart failure. Differences between lyophilized and liquid products may result in changes in product concentration and infusion rate, as well as tolerability.

The tables in this review may be helpful for providing optimal care for patients receiving Ig products. They are presented as a general guide to help determine the product that is best suited for a particular patient group.

Because there is variation from batch to batch, the exact numbers represent averages of selected batches; any one batch of any Ig product may have ranges outside these averages. When comparing administration rates, clinicians need to keep in mind that each patient has a maximum tolerated rate. This rate may be different for each Ig product. Ig must be administered slowly initially and titrated as tolerated. The rate also should be adjusted based on comorbidities. The infusion should be slowed or stopped if adverse events (AEs) become evident during the infusion. See the prescribing information for each agent for more information about AEs.

S P E C I A LT Y P H A R M A C Y C O N T I N U U M • F E B R U A R Y/ M A R C H 2 0 1 5

1

Table 1. Therapeutic Considerations FDAApproved Indications

IgA Content

pH (after reconstitution) Plasma Source

Halflife, db

Pathogen Inactivation/Removal

Producta

Manufacturer

Bivigam 10%

Biotest Pharmaceuticals Medical info: (800) 458-4244 www.biotestpharma.com www.bivigam.com

PID

≤200 mcg/mL

4.0-4.6

Plasmapheresis, 30 US donors

Precipitation and removal of fraction III from resuspended fraction II+III, SD, 35 nm filtration

Carimune NF

CSL Behring Customer service: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com

ITP, PID

1,000-2,000 6.4-6.8 mcg/mL (6%)

Plasmapheresis, 23 US donors (>16,000)

pH 4.0/pepsin, nanofiltration, TSE removal

Flebogamma 5% DIF Flebogamma 10% DIF

Instituto Grifols SA Barcelona, Spain Customer service: (888) GRIFOLS www.grifols.com

PID

<3.2 mcg/mLc,d

5.6±0.1 (5%)c,d 5.5±0 (10%)c,d

US source IQPP-certified plasma from FDA-registered sites

4-week dosing: 32±5 (5%) 37±13 (10%)

Pasteurization (60°C, 10 h), SD, 20 nm nanofiltration, fraction I precipitation, fraction II+III incubation, PEG precipitation, acid treatment, TSE removal

Gammagard Liquid 10%

Baxter Healthcare Corp Direct inquiries: (800) 423-2090 www.baxter.com

MMN, PID

37 mcg/mL

4.6-5.1

Plasma from FDA-registered sites

35

SD, low pH, nanofiltration

Gammagard S/D 5%

Baxter Healthcare Corp Direct inquiries: (800) 423-2090 www.baxter.com

CLL, ITP, KD, PID

<1 mcg/mLe

6.4-7.2

Plasmapheresis, 37.7±15 10,000 donors

Gammaked 10%

Manufactured by Grifols Therapeutics Inc for Kedrion Biopharma Customer service/medical info: (855) 353-7466; www.gammaked.com; www.kedrion.com

CIDP, ITP, PIDf

47±13 mcg/mLc,d

4.0-4.5c,d US source IQPP-certified plasma from FDA-registered sites

35

Caprylate precipitation/depth filtration, caprylate incubation, depth filtration, column chromatography, low pH incubation, TSE removal

Gammaplex 5%

Bio Products Laboratory (distributed by FFF Enterprises) Customer service: (800) 843-7477 www.fffenterprises.com

ITP, PID

<10 mcg/mL

4.8-5.1

Plasma from FDA-registered sites

4-week dosing: 41±14

SD, nanofiltration, terminal low pH incubation

Gamunex-C 10%

Grifols Therapeutics Inc Customer service: (800) 243-4153 Medical info: (800) 520-2807 www.gamunex-c.com

CIDP, ITP, PIDf

51±1.4 mcg/mLc,d

4.0-4.5c,d

US source IQPP-certified plasma from FDA-registered sites

35

Caprylate precipitation/depth filtration, caprylate incubation, depth filtration, column chromatography, low pH incubation, TSE removal

Hizentra 20%

CSL Behring Customer service: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com www.hizentra.com

PID

≤50 mcg/mL

4.6-5.2

Plasmapheresis, NA US donors

pH 4.0 incubation, nanofiltration, depth filtration, virus filtration, TSE reduction

HyQvia (IgG 10% + HY 5%)

Baxter Healthcare Corp Direct inquiries: (800) 423-2090 www.baxter.com

PID

37 mcg/mL

4.6-5.1

Plasma from FDA-registered sites

35

SD, low pH, nanofiltration

Octagam 5%

Octapharma USA Customer service: (866) 766-4860 www.octapharma.com

PID

<200 mcg/mLg

5.1-6.0

US source and recovered plasma from FDA-registered sites

40

Cold ethanol, pH 4.0 incubation, SD

Octagam 10%

Octapharma USA Customer service: (866) 766-4860 www.octapharma.com

Chronic ITP

106 mcg/mL

4.5-5.0

US source and recovered plasma from FDA-registered sites

36-40

Cold ethanol, pH 4.0 incubation, SD

Privigen 10%

CSL Behring Customer service: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com; www.privigen.com

ITP, PID

≤25 mcg/mL

4.6-5.0

Plasmapheresis, 36.6 US donors (≥60,000)

Footnotes on page 6; Key on page 8.

2

S P E C I A LT Y P H A R M A C YC O N T I N U U M . C O M

SD

pH 4.0 incubation, 20 nm virus filtration, depth filtration, TSE removal

IgG Subclass,c %

Type 1

Type 3

Haemophilus influenzae Type Bc

Streptococcus pneumoniaec

Streptolysin Oc

CMVc

HAVc

HBV Herpes (Surface Simplex Antibody)c Type 1c

Polio Type 2c

IgG1

IgG2

IgG3

IgG4

Diphtheria Toxinc

62.5

30.1

6

1.4

18.2 IU/mL

NA

NA

NA

NA

NA

NA

17 IU/mL

NA

Type 1: 0.99 x Ref (176)

60.5

30.2

6.6

2.8

3.6 IU/mL (NT)

313 (EIA)

180 (EIA)

1:60 (CF)

300 IU/mL (HAI)

1:512 (IFA); 1:2,560 (EIA)

1:348 (RIA)

1:64 (RIA)

1:128 (CF)

1:64 (NT)

66.6

28.5 (5%) 27.9 (10%)

2.7 (5%) 3.0 (10%)

2.2 (5%) 2.5 (10%)

7.0±1.0 NA IU/mL (5%); 13.7±1.4 IU/mL (10%)

NA

15±1 mg/L (5%)

NA

30±6 PEI U/mL (5%); 36±7 IU/mL (10%)

21±4 IU/mL (5%)

88.0±41.8 IU/g Ig (5%); 80.7±23.0 IU/g Ig (10%)

NA

NA

60.9

32.1

5

2.1

4.0 units/mL (NT)

NA

21.2 mcg/mL (EIA)

1:2,320 (EIA)

NA

68 PEI U/mL (EIA)

16.4 IU/mL (RIA)

≥0.20 IU/mL (EIA)

VZV: 32 U/mL (NT)

Type 1: 1:190 mIU/mL (NT)

67

25

5

3

2-5 IU/ mL (NT); J5 lipid A 1:273

17.5 mcgAbN/ mL (EIA)

8.5 mcg/mL (EIA)

11 mcg/mL (EIA)

1,150 IU (HH)

37 PEI mcg/mL (EIA), 1:2,480 (NT)

1:267 (RIA)

820 mIU/mL (RIA)

1:1,000 (EIA)

1:305 (NT)

62.8

29.7

4.8

2.7

7±2 AU/mL

87.4±22.2 mcg/mL

26.1±7.7 mcg/mL

13.0±2.4 mcg/mL

16,846± 13,648 Todd units/mL

57 PEI U/mL

1:139

65±19 IU/g Ig

NA

1:22±0.35

64

30

5

1

2.2 IU/mL

2.3 mcg/mL

NA

791 mcg/mL

185 IU/mL

431 U/mL

20 IU/mL

4.7 IU/mL

5,129 AU/mL

NA

62.8

29.7

4.8

2.7

7±2 AU/mL

87.4±22.2 mcg/mL

26.1±7.7 mcg/mL

13.0±2.4 mcg/mL

16,846± 13,648 Todd units/mL

57 PEI U/mL

1:139

65±19 IU/g Ig

NA

1:22±0.35

68.7

26.6

2.7

2

≥2.5 IU/mL

NA

NA

NA

≥1,000 IU/mL

NA

NA

≥0.4 IU/mL NA

60.9

32.1

5

2.1

4.0 units/mL (NT)

NA

21.2 mcg/mL (EIA)

1:2,320 (EIA)

NA

68 PEI U/mL (EIA)

16.4 IU/mL (RIA)

≥0.20 IU/mL (EIA)

VZV: 32 U/mL (NT)

Type 1: 1:190 mIU/mL (NT)

65

30

3

2

5-30 IU/mL

NA

NA

NA

600-800 IU/mL

33-40 IU/mL

21-25 IU/mL

51 IU/g

1:8,192

1:160-1:320 (NT)

65

30

3

2

67.8

28.7

2.3

1.2

4.9 (3.8-7.3) IU/mL

NA

NA

36.1 1,746 (26.4-45.0) (1,310IU/mL 2,010) IU/mL

76.4 (51.2-116.8) IU/mL

NA

5.3 (3.0-10.1) IU/mL

NA

NA

NA

S P E C I A LT Y P H A R M A C Y C O N T I N U U M • F E B R U A R Y/ M A R C H 2 0 1 5

3

Table 2. Pharmaceutical Considerations

Producta

Method of Preparation

Available Dosing Forms

Bivigam 10%

Cohn-Oncley,h cold ethanol fractionation, SD

IV

Liquid

≥96

100 monomers + dimers

Carimune NF

Kistler-Nitschmann,h pH 4.0 + trace pepsin, nanofiltration

IV

Lyophilized

≥96

92

Flebogamma 5% DIF Flebogamma 10% DIF

Cohn-Oncley,h ion-exchange chromatography, acid pH treatment, PEG precipitation, SD, pasteurization, dual nanofiltration (35+20 nm)

IV

Liquid

≥99c,d

>99.95 monomers + dimers (5%)c,d >99.89 monomers + dimers (10%)c,d

Gammagard Liquid 10%

Cohn-Oncley,h anion-exchange chromatography, SD, nanofiltration, ultrafiltration, low pH incubation

IV, SQ (SQ for PID only)

Liquid

≥98

≥95 monomers + dimers

Gammagard S/D 5%

Cohn-Oncley,h ultrafiltration, anion-exchange chromatography, SD

IV

Lyophilized

≥90

96.4

Gammaked 10%

Cold ethanol fractionation, anion-exchange chromatography, caprylate chromatography purified, low pH incubation

IV, SQ (SQ for PID only)

Liquid

100

100 monomers + dimersc,d

Gammaplex 5%

Cold ethanol fractionation, ion-exchange chromatography, SD, nanofiltration (20 nm), ultrafiltration, terminal low pH incubation

IV

Liquid

>99

≥99 monomers + dimers

Gamunex-C 10%

Cold ethanol fractionation, anion-exchange chromatography, caprylate chromatography purified, low pH incubation

IV, SQ (SQ for PID only)

Liquid

100

100 monomers + dimersc,d

Hizentra 20%

Cold ethanol fractionation, anion-exchange chromatography, octanoic acid fractionation, pH 4.0 incubation, depth filtration, nanofiltration (20 nm)

SQ

Liquid

≥98

≥90 monomers + dimers

HyQvia (IgG 10% + HY 5%)

Cohn-Oncley,h anion-exchange chromatography, SD, nanofiltration, ultrafiltration, low pH incubation

SQ

Liquid

≥98

≥95 monomers + dimers

Octagam 5%

Cold ethanol fractionation, ultrafiltration, chromatography, SD, pH 4.0 incubation

IV

Liquid

≥96

≥90 monomers + dimers

Octagam 10%

Cold ethanol fractionation, ultrafiltration, chromatography, SD, pH 4.0 incubation

IV

Liquid

≥96

≥94 monomers + dimers

Privigen 10%

Cold ethanol fractionation, octanoic acid fractionation, anion-exchange chromatography, pH 4.0 incubation, depth filtration, nanofiltration (20 nm)

IV

Liquid

≥98

≥98 monomers + dimers

Footnotes on page 6; Key on page 8.

4

S P E C I A LT Y P H A R M A C YC O N T I N U U M . C O M

Form

Gamma Globulin, %

Monomers, %

IgM Content

Albumin

PEG

Sodium Content

Stabilizer

Osmolality/Osmolarity

2.3 mcg/mL

<0.5%

NA

100-140 mEq/L

Glycine

≤510 mOsm/kg

Trace

0

0

0% water, 0.9% NS

5% sucrose

In sterile water: 3%, 192 mOsm/kg; 6%, 384 mOsm/kg; 12%, 768 mOsm/kg In NS: 3%, 498 mOsm/kg; 6%, 690 mOsm/kg; 12%, 1,074 mOsm/kg

Trace

<2 mcg/mL (5%)c,d <5 mcg/mL (10%)c,d

Not detectable

Trace (<3.2 mEq/L)c,d

5% sorbitol (polyol)

326±5.1 mOsm/kg (5%)c,d 343±6.1 mOsm/kg (10%)c,d

Trace

NA

Not detectable

No sodium added

Glycine

240-300 mOsm/kg

Trace

<3 mg/mL

<2 mg/mL

0.85%

2% glucose, glycine

636 mOsm/L (5%), 1,250 mOsm/L (10%)i

Trace

<2 mcg/mLc,d

0

Trace (<7 mEq/L)c,d

Glycine

264±3 mOsm/kgc,d

<0.02 mcg/mLj

0j

0j

30-50 mEq/L

Sorbitol, glycine, and polysorbate 80

420-500 mOsm/kg, but not less than 240 mOsm/kg

Trace

<2 mcg/mLc,d

0

Trace (<7 mEq/L)c,d

Glycine

264±3 mOsm/kgc,d

Trace

≤2 mcg/mL

NA

Trace

Proline

380 mOsm/kg

Trace

NA

Not detectable

No sodium added

Glycine

240-300 mOsm/kg

≤0.1 mg/mL

0

0

≤30 mmol/L

10% maltosek

310-380 mOsm/kg

<106 mcg/mL

0

0

≤30 mmol/L

Maltose (90 mg/mL)

310-380 mOsm/kg

3 mg/L

Trace

0

Trace

Proline

240-440 mOsm/kg

S P E C I A LT Y P H A R M A C Y C O N T I N U U M • F E B R U A R Y/ M A R C H 2 0 1 5

5

Table 3. Cost Consideration Criteria Producta

Supply

Storagel

Distribution

Return Policy Warranty

Packaging or Labeling Enhancements

Bivigam 10%

5, 10 g

2°C-8°C, 24 mo; do not freeze

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Tamper-evident seal, peel-off label with name, latex-free packaging, lot number, expiration date

Carimune NF

3, 6, 12 g

≤30°C, 24 mo

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Tamper-evident seal, RSS bar code, peel-off label with lot number, expiration date

Flebogamma 5% DIF Flebogamma 10% DIF

2.5, 5, 10, 20 g (5%); 5, 10, 20 g (10%)

2°C-25°C, 24 mo; do not freeze

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Tamper-evident seal with hologram, prior handling recognition, integral suspension band, laser-etched vials with UIN, bar code, peel-off label with product lot number

Gammagard Liquid 10%

1, 2.5, 5, 10, 20, 30 g

2°C-8°C, 36 mo; ≤25°C, 24 mo; do not freeze

Wholesaler or direct

No

Latex-free packaging, tamper-evident cap, RSS bar code, peel-off label with lot number, expiration date

Gammagard S/D 5%

2.5, 5, 10 g

≤25°C, 24 mo; do not freeze

Wholesaler or direct

No

Tamper-evident cap, peel-off label with lot number, expiration date

Gammaked 10%

1, 2.5, 5, 10, 20 g

2°C-8°C, 36 mo; ≤25°C, 6 mo; do not freeze

Wholesaler

Shipping error; defective or damaged product; no out-of-date products

Tamper-evident cap, laser-etched vials with UIN, NDC bar code, integral suspension band on larger vial sizes, peel-off label with product lot number, vial stopper not made with natural rubber latex

Gammaplex 5%

5, 10 g

2°C-25°C, 24 mo; do not freeze

Wholesaler

Shipping error; defective or damaged product; no out-of-date products

Latex-free, single-use vial, tamperevident cap, peel-off label with lot number, expiration date

Gamunex-C 10%

1, 2.5, 5, 10, 20 g

2°C-8°C, 36 mo; ≤25°C, 6 mo; do not freeze

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Tamper-evident cap, laser-etched vials with UIN, NDC bar code, integral suspension band on larger vial sizes, peel-off label with product lot number, vial stopper not made with natural rubber latex

Hizentra 20%

1, 2, 4, 10 g

≤25°C, 30 mo

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Latex-free packaging, single-use tamper-evident vials, peel-off label with lot number, expiration date

HyQvia (IgG 10% + HY 5%)

2.5, 5, 10, 20, 30 g

2°C-8°C, 36 mo; do not freezem

Wholesaler or direct

No

Latex-free packaging, tamper-evident cap, RSS bar code, peel-off label with lot number, expiration date

Octagam 5%

1, 2.5, 5, 10, 25 g

2°C-25°C, 24 mo; do not freeze

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Tamper-evident, latex-free packaging, peel-off label with lot number, expiration date

Octagam 10%

2, 5, 10, 20 g

2°C-8°C, 24 mo; ≤25°C, 6 mo; do not freeze

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Tamper-evident, latex-free packaging, peel-off label with lot number, expiration date

Privigen 10%

5, 10, 20 g

≤25°C, 36 mo

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Latex-free, single-use vial, tamperevident seal, RSS bar code, peel-off label with lot number, expiration date

Key on page 8.

FOOTNOTES a

All agents are contraindicated for IgA deficiency with antibodies to IgA.

b

Varies with disease state, immune status, and age of the patient.

c

Average of sample lots.

d

Data on file at Grifols.

e

As of Dec. 2012, Baxter has discontinued Gammagard S/D 5%; the low IgA product will

6

remain available for patients with known reactions to IgA or IgA deficiency with antibodies; all Gammagard S/D will be manufactured with IgA <1; special request only.

h

Cohn-Oncley is the original method of cold ethanol fractionation; Kistler-Nitschmann is the specific cold ethanol fractionation method used by the manufacturer (CSL Behring).

f

DO NOT USE Gammaked or Gamunex-C subcutaneously for ITP or CIDP.

i

Limit infusion rate to <3.3 mg IgG/kg per minute (2 mL/kg per hour) for 10% solutions.

g

With additional purification steps added in 2010, current release lots contain <100 mcg/mL. Data on file at Octapharma.

j

Data on file at Bio Products Laboratory.

k

Maltose does not significantly affect serum.

S P E C I A LT Y P H A R M A C YC O N T I N U U M . C O M

Table 4. IVIG Infusion Ratesn Initial Infusion Rate

Maintenance Infusion Rate

Maximum Infusion Rateo

Bivigam 10%

0.3 mL/kg/h for 10 min

Increase by 0.48 mL/kg/h every 20 min if tolerated, up to 3.6 mL/kg/h

3.6 mL/kg/h

No filter required; for patients at risk for renal dysfunction or failure, administer at the minimum dose recommended and the minimum infusion rate practicableq

Carimune NF 3%-12%

0.48 mL/kg/h

1-2 mL/kg/h

3 mL/kg/h

Reconstitution time is several minutes; no filter required; compatible with NaCl, D5W; increased risk for renal and thrombotic adverse effectsq

Flebogamma 5% DIF Flebogamma 10% DIF

0.6 mL/kg/h

Increase gradually as tolerated to 6 mL/kg/h (5%), 4.8 mL/kg/h (10%)

6 mL/kg/h (5%), 4.8 mL/kg/h (10%)

No filter required; administer at the minimum infusion rate practical to patients >65 and those at risk for renal failure or thrombotic eventsq

Gammagard Liquid 10%

0.5 mL/kg/h for 30 min (PID)

Increase every 30 min if tolerated, up to 5 mL/kg/h (PID)

5 mL/kg/h (PID)

No filter required; patients at risk for renal dysfunction or thrombotic events should be gradually titrated up to a more conservative maximum rate <2 mL/kg/hq

Gammagard S/D 5%

0.5 mL/kg/h for 30 min

Increase gradually as tolerated to 4 mL/kg/h

4 mL/kg/h (5%)

Reconstitution time is <5 min at RT & >20 min if cold; 15-micron filter required and supplied with administration set; compatible with sterile water

Gammaked 10%

0.6 mL/kg/h, 1.2 mL/kg/h (CIDP)

Increase gradually as tolerated to 4.8 mL/kg/h

4.8 mL/kg/h

No filter required; do not dilute with NaCl, but NaCl flush is fine; incompatible with heparin (refer to full PI for details); administer at minimum infusion rate practical to patients >65 or at risk for renal or thrombotic eventsq

Gammaplex 5%

0.6 mL/kg/h, for 15 min

Increase gradually as tolerated every 15 min to 4.8 mL/kg/h

4.8 mL/kg/h

15- to 20-micron in-line filter recommended; ensure that patients with pre-existing renal insufficiency are not volume depleted; discontinue Gammaplex if renal function deteriorates; administer at minimum infusion rate practical to patients at risk for renal dysfunction or thrombotic eventsq

Gamunex-C 10%

0.6 mL/kg/h, 1.2 mL/kg/h (CIDP)

Increase gradually as tolerated to 4.8 mL/kg/h

4.8 mL/kg/h

No filter required; do not dilute with NaCl, but NaCl flush is fine; incompatible with heparin (refer to full PI for details); administer at minimum infusion rate practical to patients >65 or at risk for renal or thrombotic eventsq

Octagam 5%

0.6 mL/kg/h for 30 min

1.2 mL/kg/h for 30 min, then 2.4 mL/kg/h for 30 min, then as tolerated, up to maximum rate

<4.2 mL/kg/h

No filter required or supplied; if an in-line filter is used, the pore size should be 0.2-200 microns; for patients at risk for renal dysfunction or thrombotic events, administer at the minimum infusion rate practical, not to exceed 0.07 mL/kg/minq

Octagam 10%

0.01 mL/kg/ min for 30 min

Increase gradually as tolerated every 30 min to: 0.12 mL/kg/min

â&#x2030;¤0.12 mL/kg/min

No filter required or supplied; if an in-line filter is used, the pore size should be 0.2-200 microns; for patients at risk for renal dysfunction or thrombotic events, administer at the minimum infusion rate practical, not to exceed 0.03 mL/kg/minq

Privigen 10%

0.3 mL/kg/h

As tolerated, up to maximum recommended rate

2.4 mL/kg/h (ITP), No filter required; administer at minimum 4.8 mL/kg/h (PID) infusion rate practical to patients at risk for renal dysfunction or thrombotic eventsq

IVIGa

glucose or insulin levels and can be safely administered to diabetic patients. Certain BGMS falsely interpret maltose, icodextrin, galactose, and xylose as glucose and can provide falsely elevated glucose readings. If insulin is administered as a result of these readings, hypoglycemia can occur.

The BGMS that use test strips containing GDHPQQ and GDO can provide these false readings.

See PI for full details. l

Under appropriate storage conditions.

m

Must be used within 3 mo after removal from

Commentsp

refirgerator to room temperature or less if expiration date is shorter. n

Some infusion rates were converted from those listed in the PI for consistency and reader convenience.

0

Certain severe adverse drug reactions may be related to the rate of infusion. Slowing or stopping the infusion usually allows the symptoms to disappear promptly.

p

Unless specific compatibility information is available, do not mix with other drugs or solutions.

q

Patients at high risk for thromboembolic events include patients who are elderly, overweight, or immobilized; patients with a history of hypertension, cardiovascular disease, or thrombotic disorders; and those who are >65 or dehydrated.

r

Log reduction factor values obtained from those listed in the PI; most are available on respective websites.

s

Data on file at Octapharma.

S P E C I A LT Y P H A R M A C Y C O N T I N U U M â&#x20AC;˘ F E B R U A R Y/ M A R C H 2 0 1 5

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Table 5. Log Reduction Factor Comparisonsr Enveloped Viruses

HIV Producta

Models for HCV

Model for Large DNA

SBV

BVDV

PRV

Nonenveloped Virus

TSE (Prion)

Bivigam 10%

>9.62

>7.11

>11.79

>8.65

5.29 (MEV), 6.18 (BPV), 4.0 (PPV), 7.02 (SV40)

NA

Carimune NF

≥26

≥19

≥9

≥25

≥19 (BEV)

NA

Flebogamma 5% DIF, 10% DIF

≥25.11

≥6.49

≥21.28

≥27.78

≥15.04 (PPV), ≥19.25 (EMCV)

≥11.64

Gammagard Liquid 10%

>14.8

NA

>16.8

>16.9

>5.7 (HAV), >7.7 (EMCV), >5.1 (MMV)

NA

Gammagard S/D 5%

>15 (HIV-1)

NA

>7.5

>9.3

>5.2 (HAV), >5.0 (EMCV), >5.3 (MMV)

NA

Gammaked 10%

≥14

NA

≥16.3

≥12.2

≥5.0 (HAV), 8.2 (PPV)

≥6.6

Gammaplex 5%

>12.9

>20.2

>11.7

NA

>5.9 (HAV), >7.5 (EMCV)

NA

Gamunex-C 10%

≥14

NA

≥16.3

≥12.2

≥5.0 (HAV)

≥6.6

Hizentra 20%

≥16.0

NA

≥11.8

≥17.7

≥9.6 (EMCV), ≥7.8 (MMV)

≥14.8

HyQvia IgG 10% + HY 5%

>14.8

NA

>16.8

>16.9

>5.7 (HAV), >7.7 (EMCV), >5.1 (MMV

NA

Octagam 5%

≥14.6

≥16.7

NA

≥16.1

≥9.5 (MEV), ≥7.7 (PPV)

≥6.7s

Octagam 10%

≥14.7

≥20.61

NA

≥18.22

≥20.20 (MEV), ≥6.53 (PPV)

NA

Privigen 10%

≥16.0

NA

≥11.8

≥17.7

≥9.6 (EMCV), ≥7.8 (MMV)

≥14.8

Footnotes on page 6.

KEY BEV

bovine enterovirus (RNA model)

BGMS blood glucose monitoring systems BPV

bovine papillomavirus

BVDV bovine viral diarrhea virus

HCV

hepatitis C virus

NDC

National Drug Code

HH

inhibition of hemolysis

NS

normal saline

NT

neutralization test

PEG

polyethylene glycol

PEI

Paul Ehrlich Institute International Units

HIV

human immunodeficiency virus

IFA

immunofluorescence assay

IgA

immune globulin A

CF

complement fixation

CIDP

chronic inflammatory demyelinating polyneuropathy

IgG

immune globulin G

PI

prescribing information

CLL

chronic lymphocytic leukemia

IgM

immune globulin M

PID

primary immunodeficiency

cytomegalovirus

International Quality Plasma Program

porcine parvovirus

CMV

IQPP

PPV PRV

pseudorabies virus

D5W

dextrose 5% in water

ITP

idiopathic thrombocytopenic purpura

RIA

radioimmunoassay

EIA

enzyme immunoassay

IU

international unit

RSS

reduced space symbology

IVIG

intravenous immune globulin

RT

room temperature

KD

Kawasaki disease

SBV

Sindbis virus

SD

solvent detergent

SQ

subcutaneous

EMCV encephalomyocarditis virus (RNA model) FDA

Food and Drug Administration

GDH- glucose dehydrogenasePQQ pyrroloquinolone quinone

MEV

mouse encephalomyelitis virus

MMN

multifocal motor neuropathy

MMV

mouse minute virus (model for non-lipid DNA virus)

TSE

transmissible spongiform encephalopathies

SV40 simian virus

GDO

glucose-dye-oxidoreductase

HAI

heterologous anti-immunoglobulin

HAV

hepatitis A virus

NA

information not available

UIN

unique identifier number

HBV

hepatitis p B virus

NaCl

sodium chloride

VZV

varicella zoster virus

8

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