Winter 2014

Bridging the gap between the hospital and alternate-site care Volume 3 • Number 1 • Winter 2014 • specialtypharmacycontinuum.com

In This Issue Clinical

6

This issue’s IVIG FAQ column addresses use of IVIG for Alzheimer’s disease.

Results deemed ‘potentially life-saving’

Hep C Rates Slashed In Liver Transplant Pts

Opinion

13

Avella’s Eric Sredzinski, PharmD, describes specialty pharmacy’s role in addressing adherence.

Operations & Mgmt

16

Supporting pharma with adverse event reporting can be tricky.

Policy

ACOs and SPs Can Benefit via Shared Risk Partnerships

A

ccountable care organizations (ACOs)—the trending new delivery model in which care is coordinated to achieve both cost efficiencies and improved quality—offer a rich new field of possible partnership opportunities for specialty pharmacy, suggested experts participating in the first of a series of webinars on ACOs and specialty pharmacy cosponsored by Avalere Health, Armada Health Care and the Specialty Pharmacy Association of America (SPAARx).

Whether they are part of the Centers for Medicare & Medicaid Services

•

21

Some newly credentialed specialty pharmacists share their views on certification.

22

Distribution networks announced for new cancer agents.

Educational Review Immune Globulins: Therapeutic, Pharmaceutical, Cost, and Administration Considerations See insert after page 24.

Corporate Spotlight Innovatix, LLC

See page 9.

see PARTNERSHIPS, page 18

Defining Standard Services Within Specialty Practice Washington—The outlook for patients with hepatitis C undergoing liver transplantation got a lot sunnier with the results of two studies presented at The Liver Meeting 2013. In one study, researchers showed that the combination of sofosbuvir (Sovaldi, Gilead Sciences) and ribavirin used prior to transplantation prevented recurrence of the hepatitis C virus (HCV) infection in 64% of patients. Used after transplantation, the regimen resulted in a sustained virologic response (SVR) rate of 77% four weeks after treatment completion.

“These studies are both very dramatic,” said Adrian Di Bisceglie, MD, the president elect of the American Association for the Study of Liver Diseases, who was not involved with the studies. “They signal a potential dramatic change in our practice of medicine related to hepatitis C and liver transplant.”

Sofosbuvir was approved to treat patients with HCV infection in December 2013, including patients with hepatocellular carcinoma awaiting liver transplantation to prevent HCV recurrence.

Reinfection of a transplanted liver is inevitable in patients who have HCV RNA-positive serum at the time of transplantation. Recurrence of HCV infection is the most common cause of mortality and graft loss following liver transplantation. Between 10% and 50% of transplant patients with recurrent HCV infection

Orlando, Fla.—Specialty pharmacists can find themselves in a challenging position between payors and manufacturers when it comes to defining services, according to a workshop discussion at the 2013 Therigy Specialty Pharmacy Leadership Congress.

Many specialty pharmacies, for example, strive to promote a wide range of services they can offer payors to secure a contract. At the same time, these pharmacies face a considerable disincentive to appear all-encompassing to manufacturers. From a business standpoint, the concern is that manufacturers might resist paying an additional amount for services specialty

see LIVER TRANSPLANT, page 7

see BASIC SERVICES, page 19

•

•

FDA Watch GSK’s combination melanoma therapy approved.

Tretten approved for congenital factor VIII A-subunit.

See specialtypharmacy continuum.com

See specialtypharmacy continuum.com

CIDP, PIDD, and ITP In the treatment of CIDP, PIDD, and ITP...

SEIZE THE DATA, SEIZE THE DAY Proven efficacy in 3 FDA-approved indications1 CIDP

PIDD

ITP

Chronic inflammatory demyelinating polyneuropathy

Primary immunodeficiency disease

Idiopathic thrombocytopenic purpura

All immune globulin (IG) formulations are not the same. Consider your patient’s risk factors when choosing an IG therapy.

Product features1 No sugar

Close to physiologic osmolality

Low infusion volume

Only trace amounts of sodium

Optimal pH

Low IgA content

Important Safety Information 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).

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

Reference: 1. GAMUNEX®-C (immune globulin injection [human], 10% caprylate/chromatography purified) Prescribing Information. Grifols; 2013.

© 2014 Grifols

All rights reserved.

January 2014

GX22-0114

GAMUNEXÂŽ-C

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C #52;3+ 5<+825'* E $3=:8-:>4> 8,y 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 vascular catheters, hyperviscosity, and cardiovascular risk factors.

E := ;,?409?> 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.

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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8;(+22' --------------------------INDICATIONS AND USAGE -------------------------

----------------------------CONTRAINDICATIONS ----------------------------

---------------------USE IN SPECIFIC POPULATIONS ---------------------

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3036427/3036428-BS Revised: 9/2013

4

Specialty Pharmacy Continuum • Winter 2014

LETTER TO THE EDITOR

Survey Reveals Gaps in Drug Temperature Tracking To the Editor:

I

commend you for bringing to light the importance of ensuring temperature integrity of specialty drugs during the “last mile” of delivery from the pharmacy to the patient. Until recently, tracking medication temperature was not a standard of operation when shipping packages from specialty pharmacy to patient.

At Pharmacy Advantage, Douglas Samojedny, RPh, manager of pharmacy operations, recognized this vital concept and brought its significance to our organization’s attention. Mr. Samojedny then designed and implemented a patientfocused study for our company.

Originally, the intent was to measure the effect that varying outside temperatures had on the efficacy of specialty medications en route to patient residences. However, the positive feedback received after initial studies drove our efforts to follow-up studies concentrating on temperature-sensitive shipments and alternative packaging.

Pharmacy Advantage conducted the

temperature monitoring investigation between April 4, 2013 and Nov. 30, 2013 using the TransTracker® device, including a questionnaire with the shipments. The questionnaire was available in two formats: a direct-mail version that was included in the patient’s medication package and an online version accessible through SurveyMonkey. To incentivize patient input, each respondent was given a free gift in return for completing a survey. The tokens of appreciation ranged from a logoed water bottle to a thermal beverage tumbler or small lunch tote.

In total, Pharmacy Advantage delivered 8,400 patient packages containing TransTracker® devices, surveys and prescribed specialty medications. By the end of the study, we experienced a cumulative response rate of 17.5% (1,472 surveys), 7.8% (115) of which were completed online and 92.2% (1,356) of which were completed and mailed (postage prepaid) directly to the data collection

and analysis company, Specialty Pharmacy Consumer Research. Pharmacy Advantage participants accounted for 25% of the entire aggregate responses received from all participating specialty pharmacies nationwide.

Additional key questionnaire results were as follows: • 52.4% of patients marked “yes” when asked if they had ever been concerned that the temperature of medication delivered was too warm or too cold during transit.

• 1.8% of patients completing the survey reported that the TransTracker® Indicator was marked red, meaning the contents of the shipment became too warm for recommended use. For these occurrences, instructions directed the patient to contact our pharmacy immediately so that replacement medication could be delivered to their home the same day free of charge through our private

delivery courier.

• 97.1% of the patients reported that they prefer a company that includes a TransTracker® temperature indicator in the package with their prescribed medication.

• 96.8% of participants “agreed” or “strongly agreed” that an organization that includes a temperature indicator with shipments of sensitive medications increases patient confidence in pharmaceutical products received from that facility.

After evaluating the post-study data/ feedback, we believe that standard policies and procedures utilized at Pharmacy Advantage are industry-leading.

We strive to assure specialty medications are just as safe during the last mile of their delivery journey as they are on our shelves.

Kindest regards, Daniel P. Kus, BS Pharm, RPh Vice President Pharmacy Advantage

Send us your comments Specialty Pharmacy Continuum appreciates your feedback.

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Volume 3 • Number 1 • Winter 2014

specialtypharmacycontinuum.com

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Managing a complex condition is hard We help make it easier Our integrated team of professionals works together to give patients and physicians the support they need.

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6

Specialty Pharmacy Continuum • Winter 2014

CLINICAL

IVIG for Alzheimer’s: A Glimmer of Hope?

I

’ve been involved with the development and management of intravenous immunoglobulin (IVIG) therapy for more than 30 years, and questions about the optimal use of IVIG are emailed to me on an almost daily basis. Many of those queries touch on safety issues, such as the review and monitoring of adverse reactions. I want to make this column as relevant as possible, so please send me your questions on IVIG therapy via email to Jerry.siegel.rx@gmail.com (cc: spceditor@ mcmahonmed.com), and I will do my best to answer them. Each quarter, we’ll choose the most compelling question or patient case and use it as the basis for my column.

T

he commercially available IVIG products produced in the United States are FDA-approved for only 6 indications—primary immune deficiencies, immune thrombocytopenic purpura (ITP), Kawasaki disease, chronic lymphocytic leukemia, chronic inflammatory demyelinating polyneuropathy (CIDP), and multifocal motor neuropathy. More than 100 potential uses of IVIG have been described in the literature, with varying degrees of evidence. One of those potential indications for IVIG therapy is Alzheimer’s disease (AD).

Beta-amyloid, a small protein, is considered the main component behind the amyloid hypotheses of AD. Once cleaved from its parent protein, amyloid precursor protein, beta-amyloid, can aggregate into small clusters and eventually block synaptic transmission of information in the brain.1 IVIG use in this disease is based on the idea that it may supplement endogenous antibodies with the ability to bind betaamyloid and lower the circulating levels, which may begin to reverse pathologic plaques in the brain.1-3 Over the past several years, various studies have evaluated the use of IVIG in patients with AD, with mixed results.

In 2008, Tsakanikas et al conducted a Phase II trial in patients with mild to moderate AD and found that IVIG therapy produced statistically significant improvements in cognitive function.4,5 Improvements in cognition scores (Alzheimer’s Disease Assessment Scalecognitive, or ADAS-cog) became significant 9 months into treatment, with an average change of 5.4 points.

In an open-label Phase I trial published in 2009, evaluating IVIG in patients with mild AD, Relkin et al observed an average increase of 2.5 points in Mini-Mental State Examination scores after 6 months of treatment.6 The scores returned to baseline during a 3-month washout period and remained stable with reintroduction of IVIG therapy.

More recently, in January 2013, Dodel et al conducted a Phase II trial using Octagam (Octapharma) and showed no apparent effects on cognitive or functional scores in AD patients.7 There also was no plasma increase in Aβ1-40 levels.

In May 2013, the Gammaglobulin Alzheimer’s Partnership (GAP) trial investigators also announced negative

Jerry Siegel, PharmD, FASHP Clinical Associate Professor The Ohio State University College of Pharmacy Columbus, Ohio

2. Weksler ME, Gouras G, Relkin NR, Szabo P. The immune system, amyloid-beta peptide, and Alzheimer’s disease. Immunol Rev. 2005;205:244-256.

3. Alzheimer’s Association. Experimental Alzheimer’s drugs targeting beta-amyloid and the “amyloid hypothesis.” http://www.alz.org/ national/documents/topicsheet_betaamyloid. pdf . Accessed January 28, 2014.

4. Weill Cornell Medical College. In preliminary study, NewYork-Presbyterian/Weill Cornell team finds IVIG therapy may improve cognitive function in Alzheimer’s patients: delivered antibodies bind to disease-causing amyloid proteins. April 11, 2005. http://weill.cornell.edu/ news/releases/wcmc/wcmc_2005/04_11_05. shtml. Accessed January 26, 2014.

Table. Primary End Point Results in GAP Trial End Point

IVIG 400 mg/kg

IVIG 200 mg/kg

Placebo

ADAS-cog score

7.4

8.9

8.4

ADCS-ADL score

–11.4

–12.4

–11.4

ADAS-cog, Alzheimer’s Disease Assessment Scale-cognitive subscale; ADCS-ADL, Alzheimer’s Disease Cooperative Study-Activities of Daily Living; GAP, Gammaglobulin Alzheimer’s Partnership

results.8 This Phase III, placebo-controlled trial included 390 patients who received 200 or 400 mg/kg of Gammagard (Baxter) or albumin every 2 weeks for 18 months. However, although the trial’s primary end points were not reached (Table), the study was not powered to show significant differences.

In a follow-up study in July 2013, investigators reported that a subgroup of the GAP patients who carried the APOEe4 allele and who received 400 mg/kg of IVIG had numerically superior results compared with placebo on the Modified Mini-Mental State Examination scores.9 There also was a reduction of brain fibrillar amyloid, as shown by positron emission tomography in this subset of patients.8 This analysis gives hope that certain AD patients with the genetic biomarker APOE-e4 may benefit from the use of IVIG. The question remains as to when AD patients should be treated with IVIG. If significant pathology has occurred already, it may be too late to gain benefit from IVIG; earlier treatment of certain patients may show better results.

Two additional studies using IVIG therapy in patients with AD are in progress: One is Phase III and is evaluating Flebogamma (Grifols), and the

other is Phase II and is evaluating an investigational product, NewGam (Octapharma). These studies are looking at patients with mild cognitive impairment and the ability of IVIG to influence the development of AD.8 The future use of IVIG therapy in AD has potential ramifications on the supply. According to data from the Alzheimer’s Association, in 2000 there were 411,000 new-onset cases of AD, with that number expected to increase to 454,000, 615,000, and 959,000 in 2010, 2030, and 2050, respectively.1 In contrast, the annual incidence of ITP has been reported to be from 1.8 to 3.8 cases per million people,10-12 and the annual incidence of CIDP has been reported to range from 1.9 to 7.7 cases per 100,000 people.13-15 The supply of IVIG was limited over the past decade and is affected by both use and the supply of blood. Use of IVIG should be prioritized to those indications with strong literature-based evidence. The long-term efficacy and safety of IVIG in patients with AD must be determined by additional research.

References 1. Alzheimer’s Association. 2008 Alzheimer’s disease facts and figures. Alzheimers Dement.

2008;4(2):110-133.

5. Weill Cornell Medical College. NewYork-Presbyterian/Weill Cornell announces results of 9-month Phase II study of Gammagard intravenous immunoglobulin (IGIV) in patients with Alzheimer’s disease. July 30, 2008. http://weill.cornell.edu/news/releases/wcmc/ wcmc_2008/07_30b_08.shtml. Accessed January 26, 2014.

6. Relkin NR, Szabo P, Adamiak B, et al. 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging. 2009;30(11):1728-1736.

7. Dodel R, Rominger A, Bartenstein P, et al.

Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer’s disease: a Phase 2 randomised, double blind, placebocontrolled, dose-finding trial. Lancet Neurol.

2013;12(3):233-243.

8. Science Daily. Updated results from Phase 3 trial of IVIG for Alzheimer’s disease. www.sciencedaily.com/releases/2103/07/130716092743. htm. Accessed January 26, 2014.

9. Loeffler DA. Intravenous immunoglobulin and Alzheimer’s disease: what now? J Neuroinflammation. 2013;10(1):70.

10. Török TJ, Holman RC, Chorba TL. Increasing mortality from thrombotic thrombocytopenic purpura in the United States—analysis of national mortality data, 1968-1991. Am J Hematol. 1995;50(2):84-90.

11. Miller DP, Kaye JA, Shea K, et al. Incidence of thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome. Epidemiology.

2004;15(2):208-215.

12. Schech SD, Brinker A, Shatin D, Burgess M. New-onset and idiopathic thrombotic thrombocytopenic purpura: incidence, diagnostic validity, and potential risk factors. Am J Hematol.

2006;81(9):657-663.

13. McLeod JG, Pollard JD, Macaskill P, Mohamed A, Spring P, Khurana V. Prevalence of chronic inflammatory demyelinating polyneuropathy in New South Wales, Australia. Ann Neurol.

1999;46(6):910-913.

14. Mygland A, Monstad P. Chronic polyneuropathies in Vest-Agder, Norway. Eur J Neurol.

2001;8(2):157-165.

15. Dalakas MC. Advances in the diagnosis, pathogenesis, and treatment of CIDP: immunopathogenesis. www.medscape.org/viewarticle/747804_4. Accessed January 28, 2014.

7

Specialty Pharmacy Continuum • Winter 2014

CLINICAL

LIVER TRANSPLANT

‘These studies are both very dramatic. They signal a potential dramatic change in our practice of medicine related to hepatitis C and liver transplant.’

continued from page 1

progress to cirrhosis within five years, and once cirrhosis is established, 42% of patients have graft failure within 12 months. Current therapies to treat HCV infection before and after liver transplantation have limited efficacy and are poorly tolerated, causing severe adverse reactions and significant interactions with immunosuppressive medications.

Post-Transplant Sofosbuvir Michael Charlton, MD, a professor of medicine at Mayo Clinic in Rochester, Minn., presented a late-breaking abstract on the topic at The Liver Meeting. In this study, Dr. Charlton and his colleagues enrolled 40 patients with HCV infection who underwent liver transplantation between six and 150 months before study enrollment.

Patients were given 24 weeks of treatment with ribavirin plus sofosbuvir, a nucleotide polymerase inhibitor with potent antiviral activity against HCV genotypes 1 to 6.

Both treatment-naive and treatmentexperienced patients were included in the study; individuals with decompensated liver disease were excluded. The majority of patients had HCV genotype 1 (55%, 1a and 28%, 1b); the remainder had HCV genotype 3 (15%) or 4 (3%).

At the time of study analysis, 77% of patients had achieved SVR four weeks after treatment completion, and 12 of 13 patients for whom data were available at 12 weeks still had SVR. Dr. Charlton reported that there were no interactions between sofosbuvir and any immunosuppressive agents, including cyclosporine and tacrolimus, and no deaths, graft losses or episodes of liver rejection.

Adverse events (AEs) included fatigue (28%), headache (25%), arthralgia (23%), diarrhea (23%), cough (18%), nausea (18%) and anemia (15%). Grade 3/4 laboratory abnormalities occurred in 53% of patients and included decreased levels of lymphocytes (33%) and hemoglobin (20%), and hyperglycemia (10%).

Pre-Transplant Sofosbuvir Michael Curry, MD, the medical director for liver transplantation at Beth Israel Deaconess Medical Center, in Boston, presented an abstract on pretransplantation treatment with sofosbuvir. In this study, 61 patients with HCV infection were enrolled to receive sofosbuvir plus ribavirin until the time of liver transplantation, or up to 48 weeks.

The patient population included those infected with HCV genotypes 1a (39%), 1b (34%), 2 (13%), 3a (12%) and 4 (2%).

At the time of analysis, 44 patients were scheduled to receive a liver transplant; of

—Adrian Di Bisceglie, MD

these, 41 (93%) were negative for HCV infection (undetectable HCV RNA) and three were positive. (The remaining 17

patients stayed on treatment, were posttreatment and awaiting a transplant, had discontinued treatment or had liver cancer progression.)

Post-transplant virologic response (pTVR) rate at 12 weeks was 64%. The

number of consecutive days with undetectable HCV RNA before transplantation was the strongest predictor of pTVR ( <0.0001). On-treatment HCV RNA (P suppression was rapid.

•

see LIVER TRANSPLANT, page 10

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10

Specialty Pharmacy Continuum â&#x20AC;˘ Winter 2014

CLINICAL

The Rise of Sofosbuvir Bostonâ&#x20AC;&#x201D;Many clinicians are ecstatic about the recent approval of sofosbuvir (Sovaldi, Gilead Sciences) for patients with hepatitis C virus (HCV) infection.

At The Liver Meeting 2013, several presentations provided new insight into just how sofosbuvir will perform in clinical practice. â&#x20AC;&#x153;I think sofosbuvir is the catâ&#x20AC;&#x2122;s meow,â&#x20AC;? said Sammy Saab, MD, MPH, a professor of medicine and surgery

and the head of outcomes research in hepatology at University of California, Los Angeles David Geffen School of Medicine. â&#x20AC;&#x153;Itâ&#x20AC;&#x2122;s a drug that has no resistance or incremental adverse effects. It is very well tolerated, very safe, very efficacious, and there are no significant drug interactions with it. I think it is going to revolutionize the way we treat hepatitis in this country and around the world.â&#x20AC;?

Traditional Risk Factors Fade Away According to studies presented at The Liver Meeting, many factors traditionally thought to portend poor outcomes in HCV patients may not have an effect with sofosbuvir. One study was a retrospective analysis of 982 patients with HCV infection (genotypes 1-6) from four Phase III trials: FISSION, POSITRON, FUSION and NEUTRINO. Patients were treated with sofosbuvir plus ribavirin, with or without pegylated interferon (IFN). Sustained virologic response

(SVR) rates were analyzed according to gender, age (<65 vs. â&#x2030;Ľ65 years), interleukin-28 B (IL28B) genotype, body mass index (<30 vs. â&#x2030;Ľ30 kg/m2), race (black vs. non-black), viral load (HCV RNA <107 vs. â&#x2030;Ľ107 copies/mL), opiate replacement status and cirrhosis. Of these factors, only male gender and the presence of cirrhosis were consistently predictive of worse outcomes; the difference between cirrhotics and noncirrhotics existed but was not large. In the NEUTRINO trial, for example, 80% of cirrhotics versus 92% of noncirrhotics achieved

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Dr. Curry characterized the treatment as safe and well tolerated. Although 18% of patients experienced a serious AE, none of the AEs were deemed related to sofosbuvir: Laboratory abnormalities and AEs observed pretransplantation were similar to those seen in the post-treatment study. Only 3% of patients discontinued treatment because of AEs.

â&#x20AC;&#x2DC;Potentially Lifesavingâ&#x20AC;&#x2122; Implications Dr. Di Bisceglie predicted that the studies will have an immediate effect on clinical practice. He called the pretransplant data â&#x20AC;&#x153;dramatic,â&#x20AC;? but said clinicians will be more likely to use the medications after transplantation at first. â&#x20AC;&#x153;Its availability, combined with these data, will probably mean we are going to start treating patients after liver transplantation very quickly. This is a potentially lifesaving therapy, and Iâ&#x20AC;&#x2122;m sure physicians will not want to wait until it is approved for this indication,â&#x20AC;? Dr. Di Bisceglie said. However, he added, until sofosbuvirâ&#x20AC;&#x2122;s label includes a posttransplant indication, clinicians â&#x20AC;&#x153;might meet resistance from third-party payors.â&#x20AC;?

Janet Nguyen, PharmD, BCPS, the vice president of network strategies at ModernHEALTH, a Los Angeles-based pharmacy services provider, agreed that third-party payors are looking closely at this. The duration of treatment for some transplant patients is a concern, she said. In clinical trials, post-transplant patients received 24 weeks of sofosbuvir, but pre-transplant patients received 48 weeks of treatment. â&#x20AC;&#x153;Transplant patients have to be on [sofosbuvir] for much longer,â&#x20AC;? she said, â&#x20AC;&#x153;and there is a huge concern among payors about the cost of therapy.â&#x20AC;? â&#x20AC;&#x201D;Kate Oâ&#x20AC;&#x2122;Rourke Dr. Curry reported a ďŹ nancial relationship with Gilead. Drs. Charlton and Di Bisceglie reported receiving support from and serving as a consultant for Gilead. Dr. Nguyen reported no relevant ďŹ nancial conďŹ&#x201A;icts of interest.

11

Specialty Pharmacy Continuum • Winter 2014

CLINICAL

SVR at week 12. Also, IL28B genotype status was only predictive of SVR in the NEUTRINO trial.

HIV Coinfection Sofosbuvir in combination with ribavirin also works well and causes less toxicity than IFN-based regimens in HCV patients who are coinfected with HIV. In the PHOTON-1 trial, 182 treatment-naive patients with HCV genotype 1 or 2/3 and stable HIV disease, some of whom had cirrhosis, were evaluated.

SVR rates 12 weeks after treatment were 81% in HCV genotype 2 patients and 67% in HCV genotype 3 patients. Among the 19 patients without SVR at week 12, relapse was confirmed in 12 patients and data were missing for six patients. HCV genotype 1 patients received 24 weeks of treatment and had an SVR rate of 76%.

Sofosbuvir was coadministered effectively with multiple HIV antiretroviral regimens, including inhibitors of HIV-1 protease, reverse transcriptase and integrase; it had no adverse effect on HIV status or antiretroviral therapy.

patients, the presence of cirrhosis did not affect outcomes, and 83% of patients achieved SVR at week 12.

Eric Lawitz, MD, the vice president of scientific and research development at The Texas Liver Institute and a clinical professor of medicine at the San Antonio University of Texas Health Science Center, who presented the LONESTAR-2 results, said, “Sofosbuvir plus pegylated IFN/ribavirin for 12 weeks demonstrated high efficacy in treatment-experienced genotype 2/3 patients, who have historically low response rates and limited treat-

Cirrhosis Results from the LONESTAR-2 trial echoed results of other trials showing the high efficacy of sofosbuvir in prior null responders and patients with cirrhosis. This trial tested 12 weeks of treatment with sofosbuvir plus pegylated IFN and ribavirin in treatment-experienced patients with HCV genotype 2/3 infection. HIV and HBV coinfected patients were excluded from the trial, but 50% of the study population had compensated cirrhosis. In patients with HCV genotype 2 (n=23), 93% of cirrhotics and 100% of noncirrhotics achieved SVR at week 12. In HCV genotype 3

Different Treatment Duration For HCV Genotypes 2 and 3 Although many of the traditional factors that predict treatment response in HCV patients do not seem to apply to sofosbuvir, there does seem to be a difference in response among HCV genotypes.

In general, clinicians are accustomed to treating patients with HCV genotype 2 or 3 similarly, but these two groups respond differently to sofosbuvir.

In Phase III trials, response rates have been higher in patients with HCV genotype 2 after 12 weeks of treatment with sofosbuvir plus ribavirin. The VALENCE trial originally set out to test 12 weeks of treatment with sofosbuvir plus ribavirin in patients with HCV genotype 2/3, but investigators amended the trial after recognizing that the two types of patients might respond to treatment differently; the 250 patients with HCV genotype 3 ultimately received 24 weeks of treatment.

Because Gammaplex has a viscosity similar to that of human plasma1* Mean Corrected Viscosity (cP) of IGIV Products

Mean Viscosity (cP)

3.0 2.5 2.0

1.64 cP

1.5 1.0 0.5

1.64

1.60

2.91

3.06

3.09

Plasma

Gammaplex 5%

Gammagard Liquid 10%

Gamunex 10%

Privigen 10%

•

see SOFOSBUVIR, page 12

is indicated for replacement therapy in adults with Primary Humoral Immunodeficiency (PI). Gammaplex is also indicated for the treatment of adults with chronic Immune Thrombocytopenic Purpura (ITP) to raise platelet counts.

3.5

Null Responders Data from the COSMOS trial suggested that HCV genotype 1 null responders may be a lot easier to treat with the combination of sofosbuvir plus simeprevir (Olysio, Janssen) than with first-generation directacting antiviral agents. In this Phase II trial, investigators evaluated 167 patients in two cohorts. In cohort 1, patients with METAVIR scores of F0 to F2 who were prior null responders to IFN with ribavirin received 12 or 24 weeks of treatment with sofosbuvir plus simeprevir, with or without ribavirin. In an intent-to-treat (ITT) analysis of the data, these patients achieved SVR rates of 79% to 96% at week 12. Cohort 2 included treatmentnaive patients and prior null responders with METAVIR scores of F3 to F4; they received 12 weeks of treatment with sofosbuvir plus simeprevir, with or without ribavirin. These patients achieved SVR rates of 96% to 100% at week 4, based on an ITT analysis. The treatments were characterized as generally well tolerated.

ment options. SVR rates were similar in patients with and without cirrhosis.”

0

* A 5% concentration may reduce the need for hydration compared to a 10% formulation

For more information visit www.gammaplex.com For medical information or reimbursement queries, please call 1-866-398-0825 or email BPLinfo@LashGroup.com To report side effects or adverse events, contact BPL by phone (1-866-398-0825) or email (adr@bpl.co.uk). You are also encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch, or call 1-800-FDA-1088

Infusion rate can be increased every 15 minutes to a maximum rate of 0.08 mL/kg/min2 Low IgA content (<10 μg/mL) 2 Can be pooled into IV infusion bags3 Liquid product / no reconstitution needed2 Bio Products Laboratory Limited (BPL) offers 60 years of plasma product heritage

Please see the Brief Summary of Prescribing Information, including boxed warning, on the reverse.

IMPORTANT SAFETY INFORMATION Gammaplex is indicated for the replacement therapy in adults with primary humoral immunodeficiency (PI). This includes, but is not limited to, the humoral immune defect in common variable immunodeficiency, X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome and severe combined immunodeficiencies.

Gammaplex is also indicated for treatment in adults with chronic immune thrombocytopenic purpura (ITP).

WARNING: Thrombosis may occur with immune globulin products, including Gammaplex. 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.

Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in predisposed patients who receive immune globulin intravenous (lGIV) products, including Gammaplex.

Patients predisposed to renal dysfunction include those with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs [see Warnings and Precautions (5.1)]. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. Gammaplex does not contain sucrose.

For patients at risk of thrombosis, renal dysfunction or acute renal failure, administer Gammaplex 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 [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].

See full prescribing information for complete boxed warning December 2013 US/Gx/1213/0036 Printed in USA

Gammaplex is contraindicated in patients who have had a history of anaphylactic or severe systemic reactions to human immune globulin; an hereditary intolerance to fructose and infants with undiagnosed fructose intolerance; and IgA deficient patients with antibodies to IgA and a history of hypersensitivity.

Thrombotic events may occur following treatment with Gammaplex and other IGIV products. Monitor patients with risk factors for thrombotic events, including a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization and/or known/ suspected hyperviscosity.

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

Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IGIV therapy.

Aseptic meningitis syndrome (AMS) may occur infrequently with IGIV treatment. AMS usually begins within several hours to 2 days following IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV. Hemolysis and hemolytic anemia can develop subsequent to IGIV treatments. Patient risk factors that may be associated with development of hemolysis include high dose (>2 g/kg), non-O blood group, and underlying inflammatory state. Noncardiogenic pulmonary edema may occur in patients following IGIV treatment (i.e. transfusionrelated acute lung injury [TRALI]). Monitor patients for pulmonary adverse reactions (TRALI). If TRALI is suspected, test product and patient’s serum for anti-neutrophil antibodies.

Gammaplex is made from human plasma and may contain infectious agents, e.g. viruses and, theoretically, the Creutzfeldt-Jakob disease agent. Based on effective donor screening and product manufacturing processes, Gammaplex carries an extremely remote risk of transmission

of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is considered to be extremely remote. No confirmed cases of transmission of viral diseases or CJD have been associated with the use of Gammaplex.

In clinical studies, the most common adverse reactions with Gammaplex were headache, pyrexia, vomiting, fatigue, pain, nausea, hypertension, chills and myalgia.

Please refer to the Gammaplex Prescribing Information for full prescribing details.

REFERENCES 1. Bio Products Laboratory Limited, Data on file, December 2011 2. Gammaplex US Prescribing Information, Revision Date: Sept 24 2013, version VSUS4PI V3 3. Bio Products Laboratory Limited, Pooling Study, Data on File, December 2013

Report adverse reactions to adr@bpl.co.uk The permanent HCPCS “J” code for Gammaplex is J1557, effective January 1, 2012

12

Specialty Pharmacy Continuum • Winter 2014

CLINICAL

SOFOSBUVIR continued from page 11

Among genotype 3 patients without cirrhosis, response rates were 94% in treatment-naive patients and 87% in treatment-experienced patients; genotype 3 patients with cirrhosis had a response rate of 60%.

More evidence that longer therapy is better for HCV genotype 3 patients came from data presented at a meeting of the FDA Sofosbuvir Review team in October 2013. The FDA analysis combined data

Gammaplex

®

Immune Globulin Intravenous (Human), 5% Liquid BRIEF SUMMARY CONSULT FULL PRESCRIBING INFORMATION FOR COMPLETE PRODUCT INFORMATION WARNING: ACUTE RENAL DYSFUNCTION THROMBOSIS, RENAL DYSFUNCTION and ACUTE RENAL FAILURE Thrombosis may occur with immune globulin products, including Gammaplex. 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. Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in predisposed patients who receive immune globulin intravenous (lGIV) products, including Gammaplex. Patients predisposed to renal dysfunction include those with any degree of pre-existing 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 IGIV products containing sucrose. Gammaplex does not contain sucrose. For patients at risk of thrombosis, renal dysfunction or acute renal failure, administer Gammaplex 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.

INDICATIONS AND USAGE Primary Humoral Immunodeficiency (PI) - Gammaplex is an Immune Globulin Intravenous (Human), 5% Liquid indicated for replacement therapy in adults with primary humoral immunodeficiency (PI).

Chronic Immune Thrombocytopenic Purpura (ITP) - Gammaplex is indicated for the treatment of adults with chronic immune thrombocytopenic purpura (ITP) to raise platelet counts.

CONTRAINDICATIONS Gammaplex is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. Gammaplex is contraindicated in patients with hereditary intolerance to fructose, also in infants and neonates for whom sucrose or fructose tolerance has not been established.

Gammaplex is contraindicated in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity.

WARNINGS AND PRECAUTIONS Renal Dysfunction / Failure: Acute renal dysfunction/failure, osmotic nephropathy, and death may occur upon use of human IGIV products. Ensure that patients are not volume depleted before administering Gammaplex. 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 blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Gammaplex and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing Gammaplex.

Thrombotic Events: Thrombosis may occur following treatment with immune globulin products, including Gammaplex. 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. 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.

For patients at risk of thrombosis, administer Gammaplex 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.

Hypersensitivity: Severe hypersensitivity reactions may occur. In case of hypersensitivity, discontinue Gammaplex infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions. Gammaplex contains trace amounts of IgA (<10 μg/ mL). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Gammaplex is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction.

from the FISSION, POSITRON, FUSION and VALENCE trials. In both treatment-naive and treatment-experienced patients with HCV genotype 3, SVR rates dramatically rose and relapse rates fell when treatment was increased from 12 weeks to 24 weeks (Table).

As a result, when the FDA approved sofosbuvir in December, the agency approved a 12-week treatment regimen in patients with HCV genotype 2 and a 24-week regimen in patients with genotype 3, both in combination with ribavirin. The FDA also approved a 12-week

Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia: Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IGIV therapy. It is critical to clinically distinguish true hyponatremia from a pseudohyponatremia that is associated with or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a possible predisposition to thrombotic events.

Aseptic Meningitis Syndrome (AMS): AMS may occur with IGIV treatment. AMS usually begins within several hours to 2 days following IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting.

Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL, but negative culture results. Conduct a thorough neurological examination on patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV. Hemolysis: Gammaplex may contain blood group antibodies that can act as hemolysins and induce in vivoo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin test (DAT) (Coombs’ test) result and hemolysis. Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration and acute hemolysis, consistent with intravascular hemolysis, has been reported. The following risk factors may be associated with the development of hemolysis following IGIV administration: high doses (e.g., *2 g/kg), given either as a single administration or divided over several days, and non-O blood group. Closely monitor patients for clinical signs and symptoms of hemolysis, particularly patients with risk factors noted above.

If clinical signs and symptoms of hemolysis or a significant drop in hemoglobin or hematocrit have been observed, perform confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching.

Transfusion-related Acute Lung Injury (TRALI): Noncardiogenic pulmonary edema may occur in patients following IGIV treatment. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function and fever. Symptoms typically appear within 1 to 6 hours following treatment. Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and the patient’s serum. TRALI may be managed using oxygen therapy with adequate ventilatory support.

Volume Overload: Carefully consider the relative risks and benefits before prescribing the high dose regimen (for chronic ITP) in patients at increased risk of volume overload.

Transmissible Infectious Agents: Because Gammaplex is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases or CJD have been associated with the use of Gammaplex. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare providers to BPL Inc. 1-866398-0825. Before prescribing Gammaplex, the physician should discuss the risks and benefits of its use with the patient.

Laboratory Tests: After infusion of immunoglobulin, 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. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test. Clinically assess patients with known renal dysfunction, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or those receiving nephrotoxic agents, and monitor as appropriate (BUN, serum creatinine, urine output) during therapy with Gammaplex. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with polycythemia, cryoglobulins, fasting chylomicronemia/markedly high triglycerides, or monoclonal gammopathies. Consider measuring hemoglobin or hematocrit at baseline and approximately 36 to 96 hours post infusion in patients at higher risk of hemolysis. If signs and/or symptoms of hemolysis are present after an infusion of Gammaplex, perform appropriate laboratory testing for confirmation. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient’s serum.

ADVERSE REACTIONS Serious adverse reactions (ARs) observed in clinical trial subjects with primary humoral immunodeficiency (PI) were thrombosis and chest pain. Serious ARs observed in clinical trial subjects with immune thrombocytopenic purpura (ITP) were headache, vomiting and dehydration. The most common ARs observed in the PI clinical trial were headache (18 subjects, 36%), pyrexia (8 subjects, 16%), fatigue (6 subjects, 12%), nausea (6 subjects, 12%), hypertension (3 subjects, 6%), chills (3 subjects, 6%), myalgia (3 subjects, 6%), pain (4 subjects, 8%), and vomiting (3 subjects, 6%). The most common ARs observed in the chronic ITP clinical trial were headache (12 subjects, 34%), vomiting (8 subjects, 23%), nausea (5 subjects, 14%), pyrexia (5 subjects, 14%), pruritus (2 subjects, 6%) and arthralgia (2 subjects, 6%).

regimen of sofosbuvir in combination with ribavirin and IFN for patients with HCV genotypes 1 and 4.

Janet Nguyen, PharmD, BCPS, the vice president of Network Strategies at ModernHEALTH, in Los Angeles, predicted that sofosbuvir’s approval would have an immediate impact. “A lot of physicians have been warehousing patients in anticipation of Sovaldi coming to market,” she said. “It will have a bigger impact for genotype 2, because it has been approved as an all-oral regimen with a short duration. The side-effect

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.

Treatment of Primary Humoral Immunodeficiency: In a multicenter, open-label, non-randomized clinical trial, 50 subjects with PI received doses of Gammaplex ranging from 279 to 799 mg/kg every 21 days (mean dose 465 mg/kg) or 28 days (mean dose 458 mg/kg), for up to 12 months. Twenty-four subjects (48%) had an AR at some time during the clinical trial that was considered product-related. The total number of ARs during infusion or within 72 hours of infusion was 237 (a rate of 0.34 ARs per infusion). The percentage of Gammaplex infusions with one or more ARs within 72 hours of infusion was 21%. The upper bound of the 1-sided 97.5% confidence interval for this percentage was 24%, which was below the pre-specified upper limit of 40% for this safety endpoint. The most common ARs observed in this clinical trial were headache (18 subjects, 36%), fatigue (6 subjects, 12%), nausea (6 subjects, 12%), pyrexia (6 subjects, 12%), pain (4 subjects, 8%), hypertension (3 subjects, 6%), chills (3 subjects, 6%), myalgia (3 subjects, 6%) and vomiting (3 subjects, 6%). Two subjects experienced serious ARs (thrombosis and chest pain).

Forty-seven of the 50 subjects enrolled in this clinical trial had a negative direct antiglobulin test (DAT) at baseline. Of these 47 subjects, 4 (9%) developed a positive DAT at some time during the clinical trial. However, no subjects showed evidence of hemolytic anemia.

Table 1: Adverse Reactions (ARs*) Occurring in >5% of Subjects with PI Adverse Reactions

Subjects (%) PI [n=50]

Infusions (%) PI [n=703]

Headache

18 (36%)

53 (7.5%)

Pyrexia

7 (14%)

10 (1.4%)

Sinusitis

8 (16%)

9 (1.3%)

Fatigue

6 (12%)

9 (1.3%)

Nausea

6 (12%)

7 (1.0%)

Nasal Congestion

5 (10%)

3 (0.4%)

Pain

4 (8%)

5 (0.7%)

Vomiting

3 (6%)

3 (0.4%)

Chills

3 (6%)

5 (0.7%)

Hypertension

3 (6%)

4 (0.6%)

Insomnia

3 (6%)

3 (0.4%)

Muscle spasms

3 (6%)

2 (0.3%)

Myalgia

3 (6%)

3 (0.4%)

Upper respiratory tract infection

3 (6%)

5 (0.7%)

*Adverse Reactions (ARs) are defined as treatment emergent adverse events which met any of the following criteria: (a) adverse events which began during an infusion of Gammaplex or within 72 hours of the end of an infusion, (b) adverse events considered by the investigator or sponsor to have been possibly, probably, or definitely related to administration of Gammaplex, (c) adverse events for which the investigator’s causality assessment was either missing or indeterminate.

Treatment of Chronic Immune Thrombocytopenic Purpura:: In a multicenter, open-label, non-randomized clinical trial, 35 subjects with chronic immune thrombocytopenic purpura were treated with a nominal dose of 1,000 mg/kg on each of two consecutive days (total dose 2,000 mg/kg). Doses of Gammaplex ranged from 482 to 1149 mg/kg on an infusion day. The median total dose per subject was 2035 mg/kg. All 35 subjects received at least one infusion of clinical trial drug, and all but one subject completed the first course of treatment. Twenty-four subjects (69%) reported at least one AR (103 in total); the most commonly reported being headache (12 subjects, 34%), vomiting (8 subjects, 23%), nausea (5 subjects, 14%), pyrexia (5 subjects, 14%), pruritus (2 subjects, 6%), dehydration (2 subjects, 6%) and arthralgia (2 subjects, 6%). Three subjects experienced a total of five serious ARs. Of the five serious ARs, one subject had three concurrently (vomiting, dehydration and headache) and two subjects each had one serious AR (headache). One of these latter two subjects discontinued from the clinical trial because of the severe headache. Table 2 lists the ARs in more than 5% of subjects. Based on a review of clinical and laboratory data, 4/35 subjects (11%) with drops in hemoglobin exceeding 2 g/dL following administration of Gammaplex were considered to have experienced suspected treatment-emergent hemolysis. Milder treatment-emergent hemolysis could not be excluded for an additional 7 subjects, giving a total of 11 of 35 subjects (31%) for whom hemolysis could not be excluded (not including an additional two subjects who lacked follow-up testing for hemolysis, so their hemolysis status was considered unassessable).

Table 2: Adverse Reactions (ARs ) Occurring in >5% of Subjects with ITP Adverse Reactions

Subjects (%) ITP [n=35]

Infusions (%) ITP [n=94]

Headache

12 (34%)

15 (16%)

Vomiting

8 (23%)

9 (9.6%)

Nausea

5 (14%)

5 (5.3%)

Pyrexia

5 (14%)

7 (7.4%)

Pain

2 (6%)

2 (2.1%)

Abdominal pain upper

2 (6%)

2 (2.1%)

Nausea

6 (12%)

7 (1.0%)

Nasal Congestion

5 (10%)

3 (0.4%)

Gastritis

2 (6%)

2 (2.1%)

Contusion

2 (6%)

2 (2.1%)

Arthralgia

2 (6%)

2 (2.1%)

Cough

2 (6%)

2 (2.1%)

Anemia

2 (6%)

1 (1.1%)

Ecchymosis

2 (6%)

3 (3.2%)

Pruritus

2 (6%)

2 (2.1%)

Dehydration

2 (6%)

2 (2.1%)

Hypertension

2 (6%)

1 (1.1%)

Neck pain

2 (6%)

1 (1.1%)

*Adverse Reactions (ARs) are defined as treatment emergent adverse events which met any of the following criteria: (a) adverse events which began during an infusion of Gammaplex or within 72 hours of the end of an infusion, (b) adverse events considered by the investigator or sponsor to have been possibly, probably, or definitely related to administration of Gammaplex, (c) adverse events for which the investigator’s causality assessment was either missing or indeterminate.

In neither of the above trials was there evidence of transmission of HBV, HCV, HIV and parvovirus B19.

Postmarketing Experience: Because adverse reactions are voluntarily reported post-approval from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure.

In addition to the adverse reactions identified in clinical studies, the following adverse reactions have been identified during postmarketing use of Gammaplex: Infusion reactions:: Dizziness, back pain, flushing; Respiratory:: Pulmonary embolism, dyspnea; Cardiovascular:: Myocardial infarction; Integumentary:: Rash, urticarial. The following adverse reactions have been identified during post-marketing use of intravenous immune globulins: Infusion reactions:: hypersensitivity (e.g., anaphylaxis), headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, urticaria or other skin reactions, wheezing or other chest discomfort, nausea, vomiting, rigors, back pain, myalgia, arthralgia, and changes in blood pressure; Renal:: Acute renal dysfunction/failure, osmotic nephropathy; Respiratory:: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm; Cardiovascular:: Cardiac arrest, thromboembolism, vascular collapse, hypotension; Neurological:: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome; Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g., bullous dermatitis); Hematologic:: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs’) test; Gastrointestinal:: Hepatic dysfunction, abdominal pain; General/ Body as a Whole:: pyrexia, rigors DRUG INTERACTIONS: Transitory rise of the various passively transferred antibodies in the patient’s blood after infusion of immunoglobulin may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test. Passive transfer of antibodies may transiently interfere with the immune response to live virus vaccines such as measles, mumps, rubella and varicella. Inform the immunizing physician of recent therapy with Gammaplex so that appropriate measures may be taken.

Manufactured by: Bio Products Laboratory Limited Dagger Lane Elstree Hertfordshire WD6 3BX United Kingdom.

US License No. 1811 U.S. Distributor: BPL Inc. 8601 Six Forks Road, Suite 400 Raleigh North Carolina 27615 U.S.A.

Table. FDA Analysis Of SVR Rates With Sofosbuvir–Ribavirin For HCV Genotype 3a Cohort

12 Weeks

24 Weeks

Treatment-naive patients SVR rate, %

56

93

Relapse rate, %

40

5

Treatment-experienced patients SVR rate, %

30

77

Relapse rate, %

66

20

HCV, hepatitis C virus; SVR, sustained virologic response a FISSION, POSITRON, FUSION and VALENCE trials

profile is very good, and the SVR rates are very good.”

A Focus on Early Intervention Dr. Nguyen said specialty pharmacists have the responsibility to make sure patients understand the importance of treatment adherence and the side-effect profile of their treatment, especially those with genotype 1 infection. She said she starts reaching out to patients a week after they start therapy with sofosbuvir to make sure there are no issues. “For genotype 1 patients, we are still going to see all of the impact from peginterferon and ribavirin, but the treatment duration will be much shorter,” said Dr. Nguyen.

“I think it is really critical for patients to understand the potential side effects they may have while they are on therapy, but if [patients with genotype 1/2] are able to tolerate the therapies for just three months, then there is a rainbow at the end of their treatment: They can be cured of their hepatitis C.” Although sofosbuvir carries a hefty price tag of $1,000 per day that is “certainly … concerning,” Dr. Nguyen said “there isn’t really anything that should cause payors to not pay for the regimen if it’s appropriately indicated.” However, she noted that some physicians were writing prescriptions for simeprevir in combination with sofosbuvir, possibly due to the positive findings from the COSMOS trial mentioned above. “There is obviously a significant cost of using those drugs together,” she said. “It’s not FDA-indicated, so I don’t think most payors will pay for it.”

Dr. Nguyen said that she expects to see an immediate uptick in sofosbuvir prescribing, but the real surge is several months away. “At the end of 2014, when we see an all-oral regimen with [sofosbuvir] for genotype 1,” she said, “we are going to see a lot more [sofosbuvir] prescribing.”

—Kate O’Rourke

13

Specialty Pharmacy Continuum • Winter 2014

OPINION

Specialty Pharmacist’s Role as Educator in Adherence Eric Sredzinski, PharmD, AAHIVP Vice President, Clinical Affairs Avella Specialty Pharmacy

Health care providers have long recognized nonadherence as a major barrier to positive patient health outcomes and a significant cause of increased health care costs.1,2 Nonadherence dates back to Hippocrates, who advised physicians “to keep watch for that fault in patients which makes them lie about the things prescribed.”3 Robert Koch, the 1905 Nobel Prize winner for his discovery of the bacterium that causes tuberculosis, described noncompliant patients as “vicious consumptives, careless and/or irresponsible.”4 Perhaps the most succinct and straightforward description of nonadherence is then-Surgeon General of the United States Dr. C. Everett Koop’s famous quote of the 1980s, “Drugs don’t work in patients who don’t take them.”

Although identified as a problem centuries ago, nonadherence continues to plague health care. Patients do not fill 20% to 30% of prescriptions written, and roughly 50% of medications prescribed for chronic conditions are not taken as prescribed.5,6 The cost of nonadherence ranges from $100 billion to $289 billion annually.7 Of the $289 billion, hospitalization resulting from nonadherence accounts for roughly $13 billion a year in the United States.8

Barriers to Adherence Several models are used to categorize nonadherence, including Andersen’s Behavioral Model and Leventhal’s Common Sense Model.9,10 A less complex approach identifies four main barriers to adherence: 1) physical/mental, 2) social, 3) perceptual and 4) logistical.11 1. Physical/mental barriers: The inability to open a prescription bottle is the most basic physical barrier to adherence. These barriers also include a patient’s emotional state, health beliefs and cognitive/mental disorders.

In one study, patients with depression were 76% more likely to be nonadherent to medications for diabetes and heart disease compared with patients without depression.12 Perceived disease severity also plays a role in this category. Research showed that HIV-positive patients with severe symptoms demonstrated increased adherence compared

with patients who had fewer or no physical symptoms of their disease.13 2. Social barriers: These include low literacy, the inability to read and comprehend prescription labels and literature, and poor communication between patients and prescribers. In some cases, the breakdowns in communication are due to prescribers’ attitudes. Specifically, studies have shown that physicians have biases toward less affluent patients

of minority races and ethnicies and communicate less with such patients.14 In one study, nonadherence was 19% higher in patients whose physicians exhibited poor communication skills.15 For some patients, the social stigma of their condition will affect their adherence. A study of HIV-positive urban youth found that 50% self-reported they skipped doses to conceal their status.16 Another social factor that can affect

compliance is marital status. Unmarried patients with a history of cardiac disease or events are more than twice as likely to be nonadherent as married patients.17 3. Perceptual barriers: Without comprehensive education about their prescribed drugs, patients may develop attitudes that lead to medication nonadherence. In a study of more than 300 patients with chronic renal, cardiac and

•

see ADHERENCE, page 14

For Uncompromised Living™

BIVIGAM® [Immune Globulin Intravenous (Human), 10% Liquid] is indicated for the treatment of primary humoral immunodeficiency (PI).

New J-Code - J1556 Effective January 1, 2014 Visit UncompromisedLiving.info WARNING: THROMBOSIS, RENAL DYSFUNCTION, AND ACUTE RENAL FAILURE See full Prescribing Information for complete boxed warning.

• Thrombosis may occur with immune globulin intravenous (IGIV) products, including BIVIGAM. Risk factors may include advanced age, prolonged immobilization, hypercoagulable conditions, a history of venous or arterial thrombosis, the use of estrogens, indwelling vascular catheters, hyperviscosity, and cardiovascular risk factors.

• Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with the administration of Immune Globulin Intravenous (Human) (IGIV) products in predisposed patients.

• Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. BIVIGAM does not contain sucrose.

• For patients at risk of thrombosis, renal dysfunction, or renal failure, administer BIVIGAM 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.

Please read the summary of full Prescribing Information on the adjacent page.

Customer Support: 1-800-458-4244 © 2014 Biotest Pharmaceuticals Corporation.

Low number of missed work or school days1 First newly approved IVIG* product with a validated thrombin generation assay (TGA) Sugar-free, 10% liquid preparation BIVIGAM is manufactured in the USA for US providers and patients BIOTEST and the BIOTEST & Design marks are trademarks and/or registered trademarks of BIOTEST AG. BIVIGAM is a registered trademark of Biotest Pharmaceuticals Corporation. This information is intended only for residents of the United States. *IVIG is also known as IGIV, Immune Globulin Intravenous (Human)

Reference: 1. Wasserman RL, Church JA, Stein M, et al. Safety, efficacy and pharmacokinetics of a new 10% liquid intravenous immunoglobulin (IVIG) in patients with primary immunodeficiency. J Clin Immunol. 2012; 32(4):663-669.

For more information, visit UncompromisedLiving.info All rights reserved.

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10190-90-IGG-040312_R05

14

Specialty Pharmacy Continuum • Winter 2014

OPINION

ADHERENCE continued from page 13

respiratory conditions, 17% were nonadherent because of unfounded beliefs about their medication, such as the drug having addictive properties.18 Such perceptual barriers also include patients’ lack of understanding of the prescribed therapy and lack of belief about its benefits.

4. Logistical: One of the most common logistical barriers is cost. A study found that more than 25% of patients with multiple sclerosis chose to leave their

prescribed specialty drugs at the pharmacy when annual copays cost between $201 and $250. That percentage reached nearly 30% when copays exceeded $500.19 Side effects also are categorized as logistical barriers. Upward of 25% of patients prescribed highly active antiretroviral therapy for HIV are nonadherent to their drug regimens because of side effects such as diarrhea.20

An Expanding Market Given the explosive growth of specialty medications, it is all the more

BIVIGAM® [Immune Globulin Intravenous (Human), 10% Liquid] Rx only Brief summary: Consult the full Prescribing Information for complete product information WARNING: THROMBOSIS, RENAL DYSFUNCTION, AND ACUTE RENAL FAILURE Thrombosis may occur with immune globulin (IGIV) products, including BIVIGAM. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, a history of venous or arterial thrombosis, the use of estrogens, indwelling central vascular catheters, hyperviscosity and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors. Use of Immune Globulin Intravenous (IGIV) products, particularly those containing sucrose, has been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death.

Patients at risk of acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. BIVIGAM does not contain sucrose. For patients at risk of thrombosis, renal dysfunction, or renal failure, administer BIVIGAM 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.

Indication and Usage: BIVIGAM is an Immune Globulin Intravenous (Human), 10% Liquid, indicated for the treatment of primary humoral immunodeficiency (PI).

Contraindications: BIVIGAM is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. BIVIGAM is contraindicated in IgA deficiency patients with antibodies to IgA and a history of hypersensitivity.

Warnings and Precautions: Thrombosis: Thrombosis may occur following treatment with IGIV products, including BIVIGAM. 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. 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. For patients at risk of thrombosis, administer BIVIGAM 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. Hypersensitivity: Severe hypersensitivity reactions may occur with IGIV products, including BIVIGAM. In case of hypersensitivity, discontinue BIVIGAM infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions.

BIVIGAM contains trace amounts of IgA ( 200 micrograms per milliliter). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. BIVIGAM is contraindicated in IgA deficient patients with antibodies against IgA and a history of hypersensitivity reaction. Acute Renal Dysfunction and Acute Renal Failure: Acute renal dysfunction/failure, osmotic nephrosis, and death may occur upon use of human IGIV products. Ensure that patients are not volume depleted before administering BIVIGAM. 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 blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of BIVIGAM and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing BIVIGAM. In patients who are at risk of developing renal dysfunction, because of pre-existing renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, hypovolemia, overweight, use of concomitant nephrotoxic medicinal products or age of >65 years), administer BIVIGAM at the minimum infusion rate practicable. Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia: Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IGIV therapy, including BIVIGAM. It is critical to clinically distinguish true hyponatremia from a pseudohyponatremia that is associated with or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a possible predisposition to thrombotic events. Aseptic Meningitis Syndrome (AMS): AMS may occur infrequently with IGIV treatments including BIVIGAM. AMS usually begins within several hours to 2 days following IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae.

AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting.

Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL, but negative culture results. Conduct a thorough neurological examination on patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV. Hemolysis: IGIV products, including BIVIGAM, may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis. Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration,13 and acute hemolysis, consistent with intravascular hemolysis, has been reported. Monitor patients for clinical signs and symptoms of hemolysis. If these are present after BIVIGAM infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis. Transfusion-Related Acute Lung Injury (TRALI): Noncardiogenic pulmonary edema may occur in patients following IGIV treatment including BIVIGAM. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following treatment. Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti- neutrophil antibodies in both the product and the patient’s serum. TRALI may be managed using oxygen therapy with adequate ventilatory support. Transmissible Oct 2013 [10760-90-IGG-032013_R01]

important for stakeholders to develop effective adherence programs for this burgeoning drug class. Specialty drugs have become a significant component of drug expenditures, accounting for 21% of all national pharmaceutical spending in 2010.21 Moreover, health care analysts project that specialty drugs will account for approximately 40% of a health plan’s drug spend by 2020, due in large part to hundreds of drugs in the pipeline.22 These trends are closely tied to the high cost of specialty medications: Accord-

Infectious Agents: Because BIVIGAM is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases or CJD have been associated with the use of BIVIGAM. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Biotest Pharmaceuticals Corporation at 1-800-458-4244. Before prescribing BIVIGAM, the physician should discuss the risks and benefits of its use with the patient. Monitoring Laboratory Tests: 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 blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of BIVIGAM and at appropriate intervals thereafter. Because of the potentially increased risk of thrombosis with IGIV treatment, 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. If signs and/or symptoms of hemolysis are present after an infusion of BIVIGAM, perform appropriate laboratory testing for confirmation. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient’s serum. Interference with Laboratory Tests: After infusion of immunoglobulin, 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. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test.

ADVERSE REACTIONS: Serious adverse reactions observed in clinical trial subjects receiving BIVIGAM were vomiting and dehydration in one subject. The most common adverse reactions to BIVIGAM (reported in 5% of clinical study subjects) were headache, fatigue, infusion site reaction, nausea, sinusitis, blood pressure increased, diarrhea, dizziness, and lethargy. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in clinical practice. In a multicenter, open-label, non-randomized clinical trial, 63 subjects with PI, on regular IGIV replacement therapy, received doses of BIVIGAM ranging from 254 to 1029 mg/kg (median dose 462.8 mg/kg) every 3 weeks or 4 weeks for up to 12 months (mean 317.3 days; range 66 – 386 days). The use of pre-medication was discouraged; however, if subjects required pre-medication (antipyretic, antihistamine, or antiemetic agent) for recurrent reactions to immune globulins, they were allowed to continue those medications for this trial. Of the 746 infusions administered, 41 (65%) subjects received premedication prior to 415 (56%) infusions. Fifty-nine subjects (94%) had an adverse reaction at some time during the study. The proportion of subjects who had at least one adverse reaction was the same for both the 3- and 4-week cycles. The most common adverse reactions observed in this clinical trial were headache (32 subjects, 51%), sinusitis (24 subjects, 38%), fatigue (18 subjects, 29%), upper respiratory tract infection (16 subjects, 25%), diarrhea (13 subjects, 21%), cough (14 subjects, 22%), bronchitis (12 subjects, 19%), pyrexia (12 subjects, 19%), and nausea (9 subjects, 14%). Adverse reactions (ARs) are those occurring during or within 72 hours after the end of an infusion. In this study, the upper bound of the 1-sided 95% confidence interval for the proportion of BIVIGAM infusions with one or more temporally associated adverse reactions was 31%. The total number of adverse reactions was 431 (a rate of 0.58 ARs per infusion).

Seven subjects (11.1%) experienced 11 serious ARs. Two of these were related serious Table: Adverse Reactions (ARs) (within 72 hours after the end of a BIVIGAM infusion) in 5% of Subjects No. Subjects No. Infusions With ARs Reporting ARs ARs (% of Subjects) (% of Infusions) [n=63] [n=746] Headache 27 (43%) 115 (15.4%) Fatigue 15 (24%) 59 (7.9%) Infusion Site Reaction 5 (8%) 5 (0.7%) Nausea 5 (8%) 8 (1.1%) Sinusitis 5 (8%) 5 (0.7%) Blood Pressure Increased 4 (6%) 5 (0.7%) Diarrhea 4 (6%) 4 (0.5%) Dizziness 4 (6%) 4 (0.5%) Lethargy 4 (6%) 4 (0.5%) Back Pain 3 (5%) 3 (0.4%) Blood Pressure Diastolic 3 (5%) 5 (0.7%) Decreased Fibromyalgiaa 3 (5%) 17 (2.3%) Migraine 3 (5%) 8 (1.1%) Myalgia 3 (5%) 4 (0.5%) Pharyngolaryngeal Pain 3 (5%) 3 (0.4%) a Symptoms occurring under pre-existing fibromyalgia ARs (vomiting and dehydration) that occurred in one subject. One subject withdrew from the study due to ARs related to BIVIGAM (lethargy, headache, tachycardia and pruritus). All 63 subjects enrolled in this study had a negative direct antiglobulin (Coombs’) test at baseline.

During the study, no subjects showed clinical evidence of hemolytic anemia. No cases of transmission of viral diseases or CJD have been associated with the use of BIVIGAM. During the clinical trial no subjects tested positive for infection due to human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). There was a single positive finding for parvovirus (B19 virus) during the study. This subject came in contact with acute B19 virus from working at a school greeting children where a child was reported to have symptomatic Fifth's disease. There was no cluster (no other cases in other subjects) of B19 virus transmission with the IGIV batch concerned.

DRUG INTERACTIONS Live Virus Vaccines Immunoglobulin administration may transiently impair the efficacy of live attenuated virus vaccines such as measles, mumps, rubella, and varicella because the continued presence of high levels of passively acquired antibody may interfere with an active antibody response. The immunizing physician should be informed of recent therapy with BIVIGAM so that appropriate measures may be taken.

ing to the 2012 Specialty Drug Benefit Report by the Pharmacy Benefit Management Institute, the average monthly cost for a specialty drug is $2,000—10 times greater than that for a non-specialty drug. (Specialty medications generally are defined as high-cost injectable, infused, oral or inhaled drugs that require close supervision and monitoring.23) In developing adherence programs, it is important to focus on therapeutic areas with high concentrations of specialty medications—for example, cancer and chronic conditions such as multiple sclerosis, rheumatoid arthritis, psoriasis and inflammatory bowel disease.24 Cancer medications can be particularly challenging in any effort to promote adherence. This is partly due to the fact that the treatment of many cancers has evolved from in-office IV therapies to oral oncolytics, an advancement that often negatively affects adherence.25 In a study of imatinib (Gleevec, Novartis) therapy, 22% of patients with chronic myelogenous leukemia and 27% of patients with gastrointestinal stromal tumors were noncompliant at month 14 of treatment.26

Counseling, Patient Education As noted, health literacy and patient knowledge play a vital role in adherence.27,28 Studies have shown, for example, that patients who did not understand the consequences of nonadherence were more likely to skip doses and often stop their therapy prematurely, especially if their symptoms disappearred or became not readily apparent, as in hyperlipidemia.29,30 Furthermore, a meta-analysis on various adherence tools showed that education-based counseling improved adherence more than patient reminders, packaging and support groups.31 Efforts to improve patient education and adherence can take many forms, but a successful outcome is more likely when pharmacists tailor their patient counseling to each patient’s condition.

Focusing on the specific benefits of adherence—as well as the consequences of nonadherence—can be an important component of such educational efforts.32

Avella’s Adherence Strategies Avella Specialty Pharmacy takes a patient-centric approach to medication adherence. Specialty pharmacists counsel every patient who is prescribed a new prescription, with the educational sessions occuring within two days of receipt of the prescription.

The pharmacists follow a prepared script that Avella’s Clinical Affairs Department develops for each specialty medication that Avella dispenses.

Key components of patient counseling include the following: 1. Introduction and purpose of call: Avella’s specialty pharmacists introduce

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Specialty Pharmacy Continuum • Winter 2014

OPINION

themselves immediately and determine if the person who answered the phone is the patient, or a spouse, parent, sibling, caregiver, etc. who is appropriate to engage for the medication counseling on the patient’s behalf. If the patient or appropriate person is not available or it is not a convenient time, Avella’s specialty pharmacists ascertain the best time to call again.

2. Baseline assessment and patient counseling: Avella specialty pharmacists use a series of open-ended questions that have been demonstrated to best help pharmacists assess patients’ baseline knowledge of their specialty medication therapy.33 Questions include: • What did the doctor tell you this medication is for?

• What dose of the medication did your doctor tell you to take?

• What did the doctor tell you about the importance of taking your medication as prescribed?

• What did the doctor tell you to do if you miss or forget a dose?

• Did your doctor tell you about the importance of lab work? (if appropriate for the medication prescribed) The specialty pharmacist notes the responses to each question in Avella’s proprietary clinical informatics platform. Depending on the correctness of the answers, the specialty pharmacist will confirm, clarify or correct specialty medication information for patients or their caregivers.

3. Drug interactions: Avella specialty pharmacists ask about patients’ use of OTC medications and herbal products as well as other prescription medications to identify potential drug interactions. If necessary, Avella’s specialty pharmacists contact the patient’s doctor to discuss and resolve potential drug interactions.

4. Side effects: Patients who are able to recognize and minimize their drug’s potential side effects tend to have increased adherence.34 During the counseling session, Avella’s specialty pharmacists review the potential side effects of the patient’s specialty medication and offer guidance on how to minimize the adverse reactions. In addition, specialty pharmacists develop educational materials that supplement personal conversations with patients. The materials are provided throughout a patient’s treatment.

5. Starter kits: During the counseling call, Avella specialty pharmacists review the contents of a manufacturer’s starter kit. If a starter kit is available, the pharmacist will arrange to have one shipped to the patient. Studies have shown that starter kits, in combination with patient education and disease-specific literature, can improve adherence rates.35

For example, a free text-messaging program provides medication reminders via two-way text messages, as well as refill reminders ensuring uninterrupted therapy, optional alerts to the caregiver when medication is not taken by the patient, and monthly educational and motivational messages.

Some programs are specific to a drug manufacturer. For example, patients who are prescribed specialty medications from Novartis are eligible to receive GlowCap® and GlowPack.™ GlowCap is a wireless prescription bottle cap and

light that remind patients to take their medication through sound and light signals. The gentle reminders from these innovative devices help trigger patients’ memory to take their medications each day, on time. The GlowPack will be available soon and will complement the GlowCap to monitor adherence for medications provided in blister packs.

2002-2003. Geneva: World Health Organization; 2003.

3.

Sterz R. Patient Compliance—The Misunderstood Problem of Healthcare: HCPC Conference, October 2006.

4.

Hugtenburg J, Timmers L, et al. Definitions, variants, and causes of non-adherence with medication: a challenge for tailored interventions. Patient Preference and Adherence. July 9, 2013.

5.

Peterson AM, Takiya L, Finley R. Meta-analysis of trials of interventions to improve medication adherence. Am J Health Syst Pharm. 2003;60:657-665.

6.

Haynes RB, Ackloo E, Sahota N, McDonald HP, Yao X. Interventions for enhancing medication adherence.

Cochrane Database Syst Rev. 2008:CD000011.

7.

Viswanathan M, Golin C, Jones, C, Ashok M, et al. Interventions to improve adherence to selfadministered medications for chronic diseases in the

References 1.

Osterberg L, Blaschke T. Adherence to medication.

N Engl J Med. 2005;353:487-497.

2.

World Health Organization. Noncommunicable Diseases and Mental Health: Progress Report

•

see ADHERENCE, page 21

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Specialty Pharmacy Continuum • Winter 2014

OPERATIONS AND MANAGEMENT

Supporting Pharma in AE Reporting Is Tricky Orlando, Fla.—Specialty pharmacies that agree to participate in patient assistance programs or other clinical support programs sponsored by drug manufacturers also may be required by the manufacturers to take on additional responsibilities related to supporting pharmacovigilance and adverse event (AE) reporting requirements.

A lack of standardization is one hurdle to overcome, as AE reporting protocols vary between pharmaceutical manufacturers and even for different agents made by the same manufacturer.

“Manufacturers and pharmacies have different requirements to report AEs. Manufacturers are held to a higher standard by FDA,” said Jon Hamrick, MBA, Therigy’s executive vice president of biotech and specialty services. “As a result, tension can occur when balancing the requirements for the specialty pharmacy versus those for the manufacturer.”

Beyond that, increasing globalization in the pharmaceutical industry presents another challenge, that of meeting both U.S. and international regulations, some of which cast a much wider net for AE reporting.

During a panel presentation at the 2013 Therigy Specialty Pharmacy Leadership Congress, Mr. Hamrick called on attendees to “work to figure out how to do this, how to solve these tensions.”

With increased industry globalization, European manufacturers are speaking with their counterparts in the United States “and advising that all adverse events need to be reported,” said Kevin G. Cast, MS, the vice president of global pharmaceutical business development at United BioSource Corporation (UBC), a pharmaceutical support services provider that is part of ExpressScripts.

“As specialty pharmacies interact with patients in a clinically complex man-

‘You have to be careful [if you] don’t want to screen for every adverse event under the sun. That can have a big impact on clinical operations.’

—Lily P. Duong, PharmD

ner on a frequent basis, imagine the influx of AEs that pharma is asking to be reported. This could result in a flood of adverse event reporting as required by manufacturers,” Mr. Cast added. However, he said, “specialty pharmacies and pharmacies [in general] don’t need to do that. We are held by specific state pharmacy laws to report significant adverse events, not [all] adverse events.”

Specialty pharmacies that conduct pharmacovigilance for a manufacturer sometimes “walk a fine line” between checking on a patient’s status and collecting any unsolicited, negative feedback as an AE, said Lily P. Duong, PharmD, Therigy’s vice president of outcomes and reporting. “When manufacturers approach a specialty pharmacy and award a purchasing contract, it usually includes language on adverse event reporting. As specialty pharmacies dis-

pensing products on [a manufacturer’s] behalf, the pharmacies … are obligated to report those adverse events,” she told Specialty Pharmacy Continuum.

“When you are on the phone with a patient administering a clinical program, we often ask a patient how they feel,” Dr. Duong said. “Patients might volunteer some information about an event that the pharmacy, on its own, would not have to report. But when working on behalf of a manufacturer, the same event must now be reported as an adverse event. You have to be careful [if you] don’t want to screen for every adverse event under the sun. That can have a big impact on clinical operations.”

Mr. Hamrick said, “It’s a real catch-22 for pharmacies and manufacturers because essentially any incident is reportable in terms of a manufacturer requirement, but at the same time, these

specialty patients are among the sickest. So, almost any interaction a pharmacy has with that patient could yield a reportable event.” rep Offering a potential solution for the O rep porting threshold, Mr. Cast suggested thaat specialty pharmacies discuss with maanufacturers precisely how much advverse event reporting they would likee. “What we see more and more in our manufacturer contracts is asko iing for adverse events to be includeed, for good and legitimate reasons.

We sit down with manufacturers to W dettermine what that really means to theem and how that affects our specialty phaarmacy operations.”

System enhancements to clinical S opeerations and staff training also will be needed to meet all the requirements, Dr.. Duong predicted. “Humans have som me limitations in remembering which advverse events need to be reported,” esp pecially when there are multiple sets of rrequirements” among different manufacturers f and regulatory bodies.

“What is really interesting is who the various manufacturers mandate … [must] be trained,” Mr. Cast said. “Some manufacturers only require training the clinicians who interact with patients, while others require non-clinicians like patient-care advocates [and] those on the phone scheduling refills. Other manufacturers look at this and think the entire call center has to be trained.

The concern spurring universal training comes from an interaction, for example, where a patient could say, ‘I don’t feel well today,’ and trigger an adverse event report,” he added. “When taken to an extreme, it could be a billing and reimbursement technician calling to secure payment, and then discovering that a patient has been hospitalized, which is a significant adverse event.”

—Damian McNamara

Drug Manufacturers Seek Innovative Specialty Pharmacies Orlando, Fla.—What pharmaceutical manufacturer executives seek from specialty pharmacies is changing as the overall industry landscape continues to shift and evolve. Despite considerable variation, complexity and customization in the contracts drawn up between manufacturers and pharmacies, several common themes emerged from a keynote panel presentation at the 2013 Therigy Specialty Pharmacy Leadership Congress.

Implementation of the Affordable Care Act is not the only factor driv-

‘Development on the tech side is now dwarfing the amount being spent on the drug development side.’

—Thomas Morrow, MD ing major changes in the industry.

For example, changes in distribution channels, data integration and patient adherence requirements have led many manufacturers to seek specific expertise from pharmacy partners. To this end, Therigy invited three representatives from various specialty and biotech

manufacturers to discuss exactly what they want from specialty pharmacy partners, during a session moderated

by Therigy’s executive vice president of biotech and specialty services, Jon Hamrick, MBA. Within the backdrop of the Affordable Care Act, “we’re going through a

period where change is creating the opportunities,” said George Oliver, the head of managed markets at Grifols. “We are seeing payors in these health care exchanges we didn’t know before. We’re going to have to add more resources to understand that market, to address it, and to figure out who the winners and losers are going to be.”

Partnerships, capabilities and entrepreneurship rank high, stressed Mr. Oliver. “The payor relationships are the key thing. The other thing I look at is the management team—are they

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Specialty Pharmacy Continuum • Winter 2014

OPERATIONS AND MANAGEMENT strategic thinkers? How entrepreneurial are they?”

Specialty pharmacies that “can show and quantify positive outcomes— those will be the specialty pharmacies and providers that pharma will tend to gravitate to,” according to Adele Wildermuth, the deputy director of hematology at Bayer Healthcare Pharmaceuticals. “As a marketing person, I spend more time with specialty pharmacy customers who are proactive and reach out to me with ideas, saying, ‘What do you think? Would you like to work with us on this?’”

Thomas Morrow, MD, the director of value-based health at Genentech, considered specialty pharmacies that can meet the challenge of increasing patient population complexity—particularly through technology—to have an advantage. “The terms ‘value-based outcome,’ ‘evidence-based medicine’ and ... ‘comparative effectiveness’ are aiming at the outcome for an individual patient in a very, very narrowing field for eversmaller populations, based potentially on a single genetic mutation.”

Although effectively addressing this level of specificity might appear daunting, Dr. Morrow said, “That is where technology comes in.” Technology could help facilitate the behavioral change required to convince patients to adhere to their prescribed therapy regimens, for example.

Whether through technology, in person or by other means, manufacturers need to demonstrate patient adherence to specialty therapies. “It’s the specialty pharmacy that can give the industry the level of adherence that we’re looking for because you do have that touchpoint with the patient,” Ms. Wildermuth said. Apps that download actual infusion times, and V-TAG technology that can track medication use in real time, are among the innovations that hold particular promise, she added.

Technology to track adherence also needs to yield data that manufacturers can use to meet regulations. “We need good, reliable, timely data,” Mr. Oliver said. “There are a lot of great technology solutions on the horizon. I think we will see more and more mobile reminders and RFID [radiofrequency identifica-

‘I spend more time with specialty pharmacy customers who are proactive and reach out to me with ideas, saying, “What do you think? Would you like to work with us on this?”’

deciding, “based on all the parameters, all the data and all the input, [whether] the product and … patients [are] best supported by an exclusive specialty pharmacy, a limited group, a managed group—or do you just open it up? It depends on the product, the patient population and how you think the payors are going to respond. It’s a very complex, very daunting process. It’s a great opportunity for [specialty pharmacy], but there are a lot of challenges.”

—Adele Wildermuth tion] technology. “It’s just a matter of being smart about it and choosing the solution that’s going to work.”

These efforts and others to enhance future technology are easily apparent, Dr.

Morrow said. “Development on the tech side is now dwarfing the amount being spent on the drug development side.”

From a manufacturer’s standpoint, Mr. Oliver said, one of the challenges is

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POLICY CY

PARTNERSHIPS continued from page 1

Shared Savings and Pioneer ACO programs, or a commercial ACO, all ACOs aim for three primary goals: improving the experience of care, improving the health of populations and reducing per capita costs of health care.

Those are goals that align well with the capabilities of specialty pharmacy, said webinar participants.

“Specialty pharmacies are positioned to support ACOs with key capabilities that are needed to manage risk: aggregating and capturing data, collaborations across providers and sites of care, patient care management and focus on cost and compliance with guidelines,” said Leigh Ann Bruhn, Avalere’s director of reimbursement. “All these are areas of focus that specialty pharmacies have, although to varying degrees of focus and sophistication.”

If your specialty pharmacy needs to ramp up that “focus and sophistication” to compete for those partnerships, the good news is you probably have some time, Ms. Bruhn said. “The early areas of focus for most ACOs are highprevalence, high-cost disease states like chronic obstructive pulmonary disease and diabetes—areas that are not big in specialty pharmacy,” she noted. “The good news is that it’s not a light switch.

You have time to prepare your organizations for these changes.”

cialty pharmacy is that we do have a lot of data. We are able to show improvements in therapy, possession rates, adherence.”

For these reasons, specialty pharmacies will fill a large niche in the ACO model moving forward, predicted Gary Freeman, RPh, MBA, the vice president of pharmacy at the national health care solutions company Amerinet. “Collaboration with providers across the various sites of care is what specialty pharmacies do. A good specialty pharmacy follows patients along the continuum of care, focusing on evidence-based outcomes. Those things are what ACOs want, what they need.”

Dr. Musil agreed that it makes perfect sense for specialty pharmacy to play an integral role in ACOs. “We’re able to touch the patients much more frequently than other providers, and ask the important questions, like whether adverse events are occurring, and appropriately managing them if they are,” Dr. Musil said. “How do we create value? By the open and regular communication we have with the patient and the providers.”

In contrast, “from a provider standpoint, when a prescription goes out the door, a lot of times there’s not a lot of touch with patients until they come in for another visit,” said Carrie Morton, PharmD, an ambulatory pharmacy supervisor at Deaconess Health System, in Evansville, Ind. “Callbacks and identifying adherence issues is important to

‘One of the great things about specialty pharmacy is that we do have a lot of data. We are able to show improvements in therapy, possession rates, adherence.’

—John Musil, PharmD, FACA And some of Medicare’s “focus areas of quality measures,” although not aimed at specialty conditions per se, are still right in specialty pharmacy’s wheelhouse: medication reconciliation, readmission rates and care transitions.

Avella Specialty Pharmacy, one of the nation’s fastest-growing companies, already has been approached by ACOs seeking help in engaging their patients to create a better health experience, said Avella’s founder John Musil, PharmD, FACA. “One of the great things about spe-

keeping the patient healthy and out of the hospital, and there’s a lot of opportunity there for specialty pharmacy.”

Specialty pharmacies can add further value and make themselves more attractive as ACO partners by enhancing their capabilities for data collection and tracking and analyzing trends, said SuAnn Stone, the director of business and product development for OmedaRx, and until recently the director of pharmacy services at RegenceRx. “ACOs are looking for ways to take

‘The physician has to stop thinking of the pharmacist in just a dispensing role: They offer opportunities for disease management and cost savings. But it’s taking time.’

—Carrie Morton, PharmD waste out of the system. Engaging with provider groups, as well as with health plans, to share that information back with them and improve adherence and side-effect management, as well as offering suggestions for lower-cost and clinically superior alternatives—that will be very important,” she said.

Ms. Bruhn offered examples of the potential role for specialty pharmacy providers in quality measure improvement. A Medicare ACO may have a target focused on risk-standardized allcondition readmission. “Readmissions may result from poor quality of care, inadequate coordination of care or lack of effective discharge planning and transitional care,” she said. “At the time of drug shipment, the specialty pharmacist can ask if the patient has been hospitalized recently, and ensure that the care team is notified so care coordination can be arranged to prevent readmission.”

But the ACO transition is not always an easy one, Dr. Morton said. Deaconess, which offers a specialty pharmacy for its employees, has been involved in a Medicare ACO pilot for about a year.

“It’s really a change in our culture,” Dr. Morton admitted. “A team-based approach sounds excellent—who wouldn’t buy into that? But the physicians are trained to deal with the patient by themselves, and to let others in is a

struggle. In our pilot, we’ve put a pharmacist in the physician’s office to collaborate with the physician, nurse and social worker. … The physician has to stop thinking of the pharmacist in just a dispensing role: They offer opportunities for disease management and cost savings. But it’s taking time.”

Pushing for Data Integration For specialty pharmacies that are already beginning to partner with ACOs, such as Avella, data integration is another key challenge. “A number of hospital systems have [electronic health records systems] that are often proprietary systems that don’t like the input of extraneous data,” Dr. Musil said.

“We’d like to see more open collaboration with [electronic health records] providers, for us to push [Health Level 7]-compliant data on, for example, the [effects] of a disease management program that we’re doing in specialty pharmacy that helps keep patients out of the hospital. That’s really going to drive the success of these models.”

Four more webinars on ACOs and specialty pharmacy are coming from the Avalere/Armada/SPAARx partnership in the coming months. Find out more online at http://bit.ly/1kdofqb.

—Gina Shaw

WEB EXCLUSIVES at SpecialtyPharmacyContinuum.com • Dick Schirber, VP of Excelera, on why hospitals are serious players in specialty pharmacy.

• Steve Kennedy of Walgreens makes the case for site of care optimization via home infusion.

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Specialty Pharmacy Continuum • Winter 2014

POLICY

continued from page 1

pharmacies already provide to payors.

“Pharmacists get caught because managed care expects them to provide a lot of services. Then manufacturers look at a big list of services and say, ‘We want those data, but we cannot pay for it,’” said Russel Allinson, RPh, MS, the chief executive officer and chief clinical officer at Therigy.

Additionally, “the contracts coming from manufacturers are very different,” said Brett Furchner, MBA, the vice president of sales and marketing at Acro Pharmaceutical Services, in Sharon Hill, Pa. “There is no standard core versus ancillary services. It’s a catch-22.”

Confirmation of medication shipping and patient receipt; medication refill reminders; 24/7 specialty pharmacy availability; and provision of a standard patient information and education packet (including rights and responsibilities as well as refill instructions) each could be defined as components of standard practice, according to general consensus at the workshop.

In contrast, suggestions to include drug utilization reviews, insurance investigations for patients and a standardized approach for reporting back to providers met with less certainty.

Although these and some other specialty pharmacy services are important, they might not be provided in every instance or warrant inclusion in a set of baseline practices. “Insurance investigation is the right thing to do, but it shouldn’t be a baseline standard. It takes a lot of FTEs [full-time equivalents] to do it right,” said Becky Rand, the senior director of trade relations at Premier Healthcare Alliance, in Charlotte, N.C. “Just because you can do it, doesn’t mean it should be standard,” said Mark Smith, the head of specialty services and channels at Novartis Pharmaceuticals, in East Hanover, N.J. “Manufacturers shouldn’t expect you to do more than you would with any other prescription.”

Without standardization, many specialty pharmacies struggle to find a solution. Therigy is working to find an answer, bringing industry leaders together at the Leadership Congress and in a series of meetings planned over the coming year to start defining services that fall into “standard practice” versus additional options.

Therigy’s initiative to define basic service elements for specialty pharmacy emerges from the recognition that the current contracting process remains complex, has little standardization and causes considerable confusion in the marketplace, Mr. Allinson said. Not all pharmacies offer the same level

of service, for instance, and a single manufacturer or payor often signs very different contracts from one specialty pharmacy to another.

Jay Bryant-Wimp, RPh, the owner and CEO of AccurateRx Pharmacy, echoed the idea that there are significant variations in the level of service provided at different specialty pharmacies. In an interview with Specialty Pharmacy Continuum, Mr. Bryant-Wimp said, “one of the biggest things” that should be added to those basic standard-ofcare services discussed during the

Therigy session, “is a patient-centric benefit investigation that allows for maximizing the benefit and minimizing the patients’ out-of-pocket cost.”

He said this has been a “huge miss” for specialty pharmacy, and “with patient copays going higher and higher,” the onus is on specialty pharmacies to do all they can to maximize patients’ benefits. Acknowledging that “it takes a lot of extra work,” he said that for drugs that could be billed through either the medical or the pharmacy benefit, such as many infused drugs, specialty phar-

macies should look at which payor path would be better for the patient. Then, if the pharmacy benefit is the way to go, they also should explore “pharmaceutical company loyalty programs to offset some of the increased costs to the patient” from copays, for example. “It’s really about being a good steward of the dollar from the patient’s perspective,” he said, “rather than going down the path of least resistance.”

—Damian McNamara, with additional reporting by Sarah Tilyou

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Specialty Pharmacy Continuum • Winter 2014

POLICY

Trials, Data Needed To Guide Biosimilar Adoption E

ffectively integrating biosimilar drugs into the U.S. market will require careful collaboration between manufacturers and regulators, according to clinicians who spoke during a recent web conference hosted by the Institute for Safe Medication Practices (ISMP).

For a number of blockbuster biologic drugs, the road ahead leads to the so-called patent cliff. Several drugs will lose their market protection within the next decade, including adalimumab in 2016 (Humira, Abbott) and trastuzumab in 2019 (Herceptin, Genentech). At the same time, the market for biologics is booming, with worldwide sales climbing from $46 billion in 2002 to $169 billion in 2012, an IMS Health report estimated.

As the demand for biologics continues to grow, physicians, regulators and patients are looking to biosimilars, the off-patent compounds that are comparable to biologics—although not identical copies—to help rein in costs.

“We definitely need biosimilars as a strategy to reduce our health care costs,” said Edward Li, PharmD, an associate professor in the Department of Pharmacy Practice at the University of New England, in Portland, Maine, who spoke during the ISMP seminar.

The pathways to approval for biosimilars and generic drugs run parallel, although there are a few important distinctions. Under the Biologics Price Competition and Innovation (BPCI) Act, part of the Affordable Care Act, a manufacturer can apply for a shortened approval process through the FDA. Previously, in 1984, the U.S. Drug Price Competition and Patent Term Restoration Act had paved the way for a standard method of approving nonbranded medication through an Abbreviated New Drug Application. At that time, however, Congress excluded biologic drugs from the abbreviated pathway, citing the difficulty of manufacturing these compounds.

“When you consider small molecule drugs,” Dr. Li said during the ISMP conference, “those are relatively simple [to produce] compared to a biologic manufacturing process.”

Big—but Not Easy Part of the challenge arises from the extreme disparity in size of the compounds. With a sequence of 165 amino acids, epoetin, for example, has a molecular mass of about 30,000 Da, hundreds of times larger than inorganic compounds such as the chemotherapy agent cisplatin. And unlike the chemical production of a small molecule compound, creating a large biologic drug requires living cells. “It’s not quite like synthesizing something in a test tube,” said Leonard Zwelling, MD, MBA, a clinical

oncologist and professor of medicine and pharmacology at the University of Texas MD Anderson Cancer Center, in Houston, who was not involved with the ISMP web seminar.

Because biosimilars are the product of living systems, it will be impossible for other manufacturers to perfectly match the structure of a brand-name biologic.

Although a biosimilar could have most of the same chemical constituents as a reference drug, post-translational modifications such as protein folding or other biological quirks of a cell line may affect a biosimilar agent’s efficacy.

Dr. Li noted that the complexity of producing biosimilars would keep the costs of these drugs higher than the price of traditional generic pharmaceuticals. “But we are going to see some savings compared to the reference product,” he said during the web conference.

“Hopefully, that will increase access to expensive therapies.”

John Mbagwu, PharmD, a clinical pharmacist for the medical consulting group Optum, told Specialty Pharmacy Continuum that, on the high end, estimates for the manufacture of a biosimilar would be about $250 million. Although he said this is a fraction of the average $1.2 billion cost of bringing a new drug to market, manufacturing is not the only expense that the biosimilar approval process will require. Compared with a generic drug, a biosimilar requires more rigorous safety and efficacy data to earn approval.

Ensuring Biosimilar Safety Approval for generic drugs must show bioequivalence in form, safety and route of administration, and the agents are not required by the FDA to undergo comparative clinical trials. Biosimilars, in contrast, must demonstrate that they are “highly similar” (Figure). To guide manufacturers looking to bring biosimilars to market, the FDA has released draft recommendations. In a 2012 draft guidance, the agency said that approval of a biosimilar must be based on “data derived from analytical studies, animal studies and a clinical study or studies,” under the BPCI Act. Because biologic drugs are manufactured in cells derived from hamsters, rabbits and other organisms, they pose varying risks for immunogenicity. A patient’s immune system may produce antibodies that neutralize the biologic, or develop antibodies that trigger antibody-mediated disease or other adverse reactions. Dr. Li cited an increase in the number of cases of pure red cell aplasia linked to biologic erythropoietin products in the 1990s.

“The whole point of this abbreviated biosimilar [approval] pathway is [to allow] the FDA [to] prospectively review these agents, so we don’t have

Figure. Biosimilar development approach.

Adapted from Clin Pharmacol Ther. 2012;91:409-417; http://1.usa.gov/L62id7.

immunogenicity issues in the future,” Dr. Li said. To that end, the FDA has recommended comparative parallel studies in its guidances.

But the requirement for clinical data increases the projected costs of biosimilars. Although generic drugs can be purchased at cost reductions of up to 80% of the price of branded versions, a 2011 review reported that estimates for biosimilars prices would be 15% to 30% less than the reference drug (Clinicoecon Outcomes Res 2011;3:29-36).

In June, the chief executive officer of Celltrion announced that the biosimilar version of infliximab, Remsima, would be more than 30% cheaper than Johnson & Johnson’s Remicade. Celltrion is seeking approval for Remsima in Europe, where more than a dozen biosimilars have been approved by the European Medicines Agency. In the European Union, biosimilars saved an estimated $2.6 billion (1.9 billion euros) in 2009, according to the European Generic Medicines Association.

Overcoming Prescriber Skepticism When biosimilars become available in the United States, a large body of clinical data will be needed to help overcome another hurdle—prescribers’ skepticism. Biosimilars of infliximab, such as Remsima, have been studied in patients with rheumatoid arthritis and may rely on “indication extrapolation” to be approved and/or used for inflammatory bowel disease and other indications. A 2013 study conducted by the market research firm BioTrends found

that about 70% of the 90 gastroenterologists surveyed would not prescribe a biosimilar that had only been tested in patients with rheumatoid arthritis.

Additional clinical data also will enable certain biosimilars to be labeled “interchangeable,” a term that has already come under fire in the United States.

Under a provision of the BPCI, biosimilars deemed interchangeable by the FDA can be substituted without a pharmacist notifying the prescribing physician.

A bill passed by California’s state Senate would have voided that provision, requiring pharmacists to notify prescribers which biosimilar drug they had dispensed. Responding to calls from the Generic Pharmaceutical Association and other critics, Gov. Edmund G. Brown vetoed the bill. In a letter to the state Senate, Mr. Brown pointed out that the FDA has not yet determined the standards for interchangeability, writing, “to require physician notification at this point strikes me as premature.”

At this point, Dr. Zwelling said, the question to ask is not when will biosimilars become available in the United States, but when will doctors prescribe them? “Until I see a trial in which the biosimilar and the [reference] drug are compared head to head, in real patients with real cancer,” he said, “I wouldn’t prescribe it, and I wouldn’t let my mother take it.”

—Ben Guarino Dr. Zwelling reported no relevant financial disclosures. Dr. Li has served on advisory boards for Amgen and Hospira.

21

Specialty Pharmacy Continuum • Winter 2014

POLICY

First Crop of Specialty Pharmacists Certified The Specialty Pharmacy Certification Board (SPCB) last fall announced that 49 specialty pharmacists were the first to take a new certification exam, earning them the distinction of becoming certified specialty pharmacists (CSPs). Specialty pharmacists involved in the development of the exam as well as those earning some of those first certifications predict that the process will be invaluable to the future of specialty pharmacy.

One of the newly credentialed pharmacists, Ray Tancredi, RPh, MBA, CSP, the vice president for specialty pharmacy development at Walgreens, took part in the behind-the-scenes certification development. “The specialty pharmacy space is really growing, yet there [had] been no credentialing to document specialty pharmacists’ expertise,” he said.

The new certification, he added, “allows specialty pharmacists to highlight their specific skill set, thereby proving [themselves] invaluable to their current and future employers.”

Rick Miller, RPh, MBA, CSP, the senior director of specialty clinical services at Walgreens, called the credential “a market differentiator for pharmacists in the specialty space. If you look at where we’re going, six to eight of the top 10 drugs to be prescribed in the next couple of years will be specialty medications, and there will be a need for clinicians to manage these patients. CSP is a vehicle to get them there.”

Pharmacy schools tend to focus on more prevalent diseases such as heart disease and asthma but not as much on hepatitis C, hemophilia, multiple sclerosis or other rare conditions requiring specialty pharmacy products, said Mr. Miller. So the specialty certification addresses a clinical knowledge gap, but

it also goes beyond that. “What I like about the program is it’s not just clinical in content,” Mr. Miller said. “You need to understand all aspects of specialty medications, which may include unique storage requirements, administration and reimbursement policies, in addition to the ongoing clinical monitoring and management of the patient.

All of this is touched on as part of the CSP curriculum.”

experience in the field before they can successfully take it.”

Mr. Tancredi agreed that experience is invaluable, noting that specialty pharmacists frequently ask him about “how to augment their clinical expertise and increase their business acumen. The answer,” he said, “is that being a credentialed specialty pharmacist isn’t just about paperwork but real-world experience as well.”

The SPCB developed the CSP certification “to provide independent, verifiable evidence of proficiency in specialty

management, fulfillment and outcomes, is offered twice a year in April and October at testing centers nationwide. Candidates are given two hours to complete the exam. A free handbook available on the SPCB’s website provides detailed information about the exam’s content, and candidates have the option to take continuing education training modules online.

To become CSP-certified, pharmacists must be a BSPharm, RPh or PharmD with a current, active pharmacy license in good standing, with no history of felony records or state board suspensions. They also must have 3,000 hours of specialty pharmacy practice within the previous three years and 30 hours of specialty pharmacy continuing education within the previous two years.

After passing the CSP examination, specialty pharmacists are expected to

The new certification ‘allows specialty pharmacists to highlight their specific skill set, thereby proving [themselves] invaluable to their current and future employers.’

—Ray Tancredi, RPh, MBA, CSP

Mike Crowe, PharmD, MBA, CSP, a clinical technology manager for Diplomat Pharmacy, said that getting the CSP credential enables him to show he has “a thorough understanding of specialty pharmacy.” He added that he “would certainly recommend [the exam], but pharmacists will need at least few years’

pharmacy practice,” said SPCB Executive Director Gary Cohen, BSPharm, RPh, CSP. Specialty pharmacy is one of the fastest-growing sectors of the pharmaceutical industry, he said, and “the demand for clear standards and guidelines continues to build.”

The 100-question computerized multiple-choice test, which covers the patient intake process, patient care

maintain their credential through continuing education and professional development activities. CSPs also will be required to adhere to a code of ethics and must be recertified every two years.

For more information, see www. spcboard.org or contact the SPCB at info@spcboard.org.

—Karen Blum

OPINION

ADHERENCE continued from page 15

United States: a systematic review. Ann Intern Med. 2012;157:785-795.

8. Sullivan S, Kreling DH, Hazlet TK. Noncompliance with medication regimens and subsequent hospitalizations: a literature analysis and cost of hospitalization estimate. J Res Pharmaco Econ. 1990;2:19-33.

9. Anderson R. Revisiting the behavioral model and access to medical care: does it matter? J Health Soc Behav. 1995;36:1.

10. Leventhal H, Brissette I, Leventhal EA. The Self-Regulation of Health and Illness Behaviour.

London: Routledge; 2003:42-65.

11. Boyle D, Bubalo J. Enhancing patient adherence to improve outcomes with oral chemotherapy. Proceedings from a symposium at the 2007 Hematology/ Oncology Pharmacy Association Annual Conference.

US Pharm. 2007;32:1-8. http://www.uspharmacist.com/ content/c/10216. Accessed February 6, 2014.

12. Grenard JL, Munjas BA, Adams JL, et al. Depression and medication adherence in the treatment of chronic diseases in the United States: a meta-analysis. J Gen Intern Med. 2011;26:1175-1182.

13. Gao X. The relationship of disease severity, health beliefs, and medication adherence among HIV patients. AIDS Care. 2000;12:387-398.

14. Medication adherence—improving health outcomes.

A resource from the American College of Preventive

Medicine. http://www.acpm.org/resource/resmgr/ timetools-files/adherenceclinicalreference.pdf.

Accessed February 6, 2014.

15. Haskard Zolnierek KB, DiMatteo MR. Physician communication and patient adherence to treatment: a meta-analysis. Med Care. 2009;47(8):826-834.

16. Rao D, Kekwaletswe TC, Hosek S, Martinez J, Rodriguez F. Stigma and social barriers to medication adherence with urban youth living with HIV. AIDS Care. 2007;19:28-33.

17. Wu JR, Lennie TA, Chung ML, et al. Medication adherence mediates the relationship between marital status and cardiac event-free survival in patients with heart failure. Heart Lung. 2012;41:107-114.

18. Horne R, Weinman J. Patients’ beliefs about prescribed medicines and their role in adherence to treatment in chronic physical illness. J Psychosom Res 1999; 47:555–567.

19. Kim YA, Rascati KL, Prasla K, Godley P, Goel N, Dunlop D. Retrospective evaluation of the impact of copayment increases for specialty medications on adherence and persistence in an integrated health maintenance organization system. Clin Ther. 2011;33:598-607.

20. Chesney MA. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis. 2000;30(suppl 2):s171-s176.

21. Kaiser Family Foundation. Prescription drug trends—May 2010 update. www.kff.org/rxdrugs/ upload/3057-08.pdf. Accessed February 6, 2014.

22. Pharmaceutical Research and Manufacturers of America. Medicines in development; 2012. http://www. phrma.org/sites/default/files/pdf/phrmamedicinesindevelopmentcancer2012.pdf. Accessed February 6, 2014.

23. Fontanez C, McDermott R, Whitehead D. 2004 Specialty Pharmacy Management Guide & Trend Report.

St. Louis, MO: CuraScript Pharmacy; June 2005.

24. Gleason PP, Alexander GC, Starner CI, et al.

Health plan utilization and costs of specialty drugs within 4 chronic conditions. J Manag Care Pharm. 2013;19(7):542-548.

25. Hede K. Increase in oral cancer drugs raises thorny issues for oncology practices. J Natl Cancer Inst. 2009;101:1534-1546.

26. Tsang J, Rudychev I, Pescatore SL, et al. Prescription compliance and persistency in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST) patients (pts) on imatinib (IM). J Clin Oncol.

2006;24(suppl):330s. Abstract 6119.

27. Jin J, Sklar G, Oh V, Li S. Factors affecting therapeutic compliance: a review from the patient’s perspective.

Ther Clin Risk Manag. 2008;4:269-286.

28. Ponnusankar S, Surulivelrajan M, Anandamoorthy N, Suresh B. Assessment of impact of medication counseling on patients’ medication knowledge and compliance in an outpatient clinic in South India.

Patient Educ Couns. 2004;54:55-60.

29. Alm-Roijer C, Stagmo M, Udén G, Erhardt L. Better knowledge improves adherence to lifestyle changes

and medication in patients with coronary heart disease. Eur J Cardiovasc Nurs. 2004;3:321-330.

30. Bender BG, Bender SE. Patient-identified barriers to asthma treatment adherence: responses to interviews, focus groups, and questionnaires. Immunol Allergy Clin N Am. 2005;25:107-130.

31. Gwadry-Sridhar F, Manias E, Lai L, et al. Impact of interventions on medication adherence and blood pressure control in patients with essential hypertension: a systematic review by the ISPOR Medication Adherence and Persistence Special Interest Group.

Value in Health. 2013;18:863-871.

32. Tanzi M. Counseling to enhance medication adherence. American Pharmacists Association, November 2012. http://www.pharmacist.com/node/84664.

Accessed February 6, 2014.

33. American Society of Health-System Pharmacists.

ASHP guidelines on pharmacist-conducted patient education and counseling. Am J Health Syst Pharm.

1997;54:431-444.

34. Oral therapy: managing side effects can aid adherence.

Oncology Nurse Advisor. November/December 2012. http://bit.ly/1lGpboz. Accessed Febraury 7, 2014.

35. New England Healthcare Institute. Thinking outside the pillbox: a system-wide approach to improving patient medication adherence for chronic disease. http://www.nehi.net/publications/44/thinking_outside_the_pillbox_a_systemwide_approach_to_improving_patient_medication_adherence_for_chronic_disease. Accessed February 6, 2014.

22

Specialty Pharmacy Continuum • Winter 2014

POLICY

Care Teams Are Hallmark of Ibrutinib Distribution Avella Specialty Pharmacy, Biologics, Diplomat Specialty Pharmacy, Onco360 and Total Life Care (TLC) are the exclusive distributors of ibrutinib, the once-daily oral Bruton tyrosine kinase (BTK) inhibitor recently approved for the treatment of mantle cell lymphoma (MCL).

Ibrutinib (Imbruvica, Pharmacyclics Inc. and Janssen Biotech Inc) won accelerated FDA approval in November for use in patients with MCL who have received at least one prior therapy. As of early February, the BTK inhibitor also was awaiting FDA approval for the treatment of chronic lymphocytic leukemia and small lymphocytic leukemia, following the termination of a large clinical trial that showed early and significant clinical benefits in these patients.

In the pivotal Phase II, open-label MCL trial, 65.8% of patients receiving the drug achieved clinical response, according to a Pharmacyclics press release (http://bit.ly/1inLxZQ).

However, with 9% of patients in the trial discontinuing ibrutinib due to adverse events (AEs), distributors such as Diplomat Specialty Pharmacy, which is headquartered in Flint, Mich., are focusing on preventing and managing drug-related complications at their earliest stages. “Like other oral oncolytics, ibrutinib has a fair amount of side effects,” said Gary Rice, RPh, MS, MBA, the vice president of clinical programs at Diplomat. “So, in addition to educating our patients on both the disease and the drug, we’re providing each patient with a compliance care pack.”

He said the package includes overthe-counter (OTC) treatments for some of the more common ibrutinib-related AEs, including diarrhea, rash, nausea

and vomiting. These events occurred in 51%, 25%, 31% and 23%, respectively, of MCL trial participants. “If a patient has diarrhea, they may not want to leave their home to get the appropriate OTC treatment,” Mr. Rice said. “By providing this package, we can help prevent some milder adverse events from progressing to grade 3/4 adverse events.”

Mr. Rice said Diplomat, which is the largest American distributor of ibrutinib, has assembled patient care teams to maintain frequent contact with recipients of the drug. Team members communicate safety concerns to physicians, who can decide whether to adjust the drug dose or discontinue the medication either temporarily or permanently. Mr. Rice said Diplomat is also sharing the collected data with the

drug’s manufacturer and noted there is no Risk Evaluation and Mitigation Strategies program in place.

Ibrutinib’s manufacturers have created a comprehensive program for patients to access the drug, according to Eric Sredzinski, PharmD, who is the vice president of clinical affairs at Avella Specialty Pharmacy, which is headquartered in Scottsdale, Ariz. Ibrutinib costs approximately $10,900 for a 30-day supply, according to figures cited during a Pharmacyclics corporate conference call held on Nov. 13, 2013.

Through the YOU&i Start Program ( (www.imbruvica.com/access.php ), eligible patients can obtain a free 30-day supply of ibrutinib if they have not secured insurer coverage within five days of receiving a prescription, Dr. Sredzinski explained. Patients are eligible for a second 30-day supply if they continue to experience coverage delays, he noted, adding that “both the launch of the drug and the processes to ensure access and distribution have been impressive.”

A separate service, the YOU&i Access Instant Savings program, subsidizes

‘Every [cancer] patient is different, and we take a very personal approach to our care, assigning a dedicated care team to each patient to support him or her throughout treatment.’

—Dan Duffy

copayments for commercially insured individuals, capping their copayments at $25 per month.

“Coverage is typically secured within a few hours,” Dr. Sredzinski said. “However, there are times we need to speak to the patient, which can result in delays.

These delays are infrequent and typically happen when patients have multiple insurance plans. At this time, we have only utilized the YOU&i program for a limited number of patients, as the payor delays have been minimal.”

Several third-party foundations and nonprofit groups, including the Johnson & Johnson Patient Assistance Foundation, an independent nonprofit organization that receives funding from Pharmacyclics, also offer patient assistance programs.

By mid-January, Biologics, Inc., another ibrutinib distributor, had secured more than $350,000 in copay assistance for its ibrutinib clients through these foundations or through the manufacturer. Dan Duffy, the chief business development officer at Biologics, Inc, which is headquartered in Cary, N.C., said the company follows “a holistic patient care model,” providing its ibrutinib clients not only with clinical and financial services but also with emotional support.

“With more than 20 years of experience supporting cancer patients, we understand that being diagnosed with cancer is a very overwhelming experience,” Mr. Duffy said. “Every patient is different, and we take a very personal approach to our care, assigning a dedicated care team to each patient to support him or her throughout treatment.”

—David Wild

CLL Drug Obinutuzumab Gets Network of Distributors

F

ollowing on the heels of the FDA’s approval of obinutuzumab late last year, the Flint, Mich., specialty pharmacy Diplomat has announced it will be part of an open network to distribute the chemotherapy drug, joining other distributers including ASD Healthcare, BioSolutions Direct, Cardinal Health Specialty Distribution and McKesson Specialty Health.

In combination with chlorambucil, obinutuzumab (Gazyva, Genentech) is indicated for use in treatment-naive patients with chronic lymphocytic leukemia (CLL). The CD20-directed cytolytic antibody is the first drug approved with the designation of a breakthrough therapy, as part of an accelerated pro-

cess for therapies aimed at serious or life-threatening conditions.

A recent study of 781 patients who were not previously treated for CLL compared obinutuzumab–chlorambucil treatment with rituximab–chlorambucil treatment ((N Engl J Med 2014; doi: 10.1056/NEJMoa1313984).

Patients in the obinutuzumab group had a significantly longer progression-free survival than patients who received rituximab (median progression-free survival, 26.7 vs. 15.2 months, respectively; P<0.001). The investigators reported a slightly lower rate of fatal medication events among patients treated with obinutuzumab– chlorambucil (4%) compared with

those who received rituximab–chlorambucil (6%), but they did not indicate that the difference was statistically significant.

Common adverse events associated with obinutuzumab, according to the drug’s label, include anemia, cough, musculoskeletal disorder, neutropenia, pyrexia and thrombocytopenia.

Additionally, obinutuzumab has been linked to hepatitis B virus reactivation, according to its boxed warning label, as well as progressive multifocal leukoencephalopathy, a potentially lethal inflammation of the brain’s white matter found in patients with decreased immune function.

A six-month treatment regimen of

obinutuzumab is estimated to cost $41,300 for a patient with CLL, according to a Genentech representative.

“We are pleased to partner with Genentech as a specialty pharmacy provider of Gazyva,” said Gary Kadlec, RPh, the president of Diplomat, in a press release. “[W]e are committed to providing Gazyva according to Diplomat’s high standards and industryleading protocols, enabling patients to obtain the best outcomes possible.”

Each year, 15,680 Americans are diagnosed with CLL, and the disease causes 4,580 deaths annually, according to the National Cancer Institute.

—Ben Guarino

2014 NHIA Annual Conference & Exposition

March 31 – April 3, 2014 Orlando, Florida Visit the 2014 NHIA Annual Conference & Exposition Website!

Explore every aspect of the conference before you arrive onsite—including all the robust education sessions and program highlights by utilizing the 2014 NHIA Session Planners and Schedule,at,a,Glance (located under the Education Program menu)…it’s all waiting for you at www.nhia.org/ac14. You can also scan the below QR code to get details on the many educational o erings NHIA 2014 has to o er!

Early-Bird Registration Discount Effective Through February 19, 2014 Early bird registration is now open…it’s fast, easy and secure—be sure to go to www.nhia.org/ac14/reg and reserve your spot today! Please mention this ad if registering by phone (703(838(2663) or enter code AC14(SPT in the “Other Advertisement” eld if registering online.

Bring More, Save Big! It really does pay to bring your whole team—learn more about NHIA’s company member discounts at: www.nhia.org/ac14/discounts Want to know more about NHIA Membership and how it can positively impact your specialty pharmacy? Contact Patricia Adair at 703(838(2668.

Questions? Call 703(549(3740 or email info@nhia.org Looking for a forum that provides numerous opportunities to connect with peers and industry experts on topics related to Specialty Pharmacy Infusions?

Search no further than the 2014 NHIA Annual Conference & Exposition—where you’ll find highly valuable educational and networking sessions focused on the compounding and administration of specialty pharmacy infusions in the home and alternate(site setting, including: • Extensive education on Sterile Compounding and the current regu, latory environment, including: ✔ A Breakfast Symposium titled “Achieving an Aseptic Compound ing State of Control,” supported by an educational grant from Hospira Worldwide and taught by industry,expert Eric Kastango, R.Ph., M.B.A., FASHP. ✔ Two Pharmacy Workshop Sessions, titled “Choosing the Right Certifier for Your Clean Room,” and “Clean Room Certification Re ports—Interpreting and Acting on the Good, Bad and the Ugly!” to guide you through the details and challenges inherent in this process, including tools you can use in your own facility.

• An always,popular Lunch Symposium, titled “New Drugs and Biologics— 2013,” returning for the 12th consecutive year at attendee requests, that will review key clinical and reimbursement considerations for the most re, cently approved parenteral drugs and biologic therapies—and also those oral agents with a potential to impact home infusion therapy services.

• An interactive Roundtables Program on two separate evenings that provide a venue for industry peers to gather and discuss a large array of specific topics related to home infusion therapy and specialty pharmacy—one of the most well,attended programs at the confer, ence each year!

• Topical Concurrent Track Sessions that provide insights into the complex care your specialty pharmacy infusion patients often re, quire, with strategies for successful management—including: ✔ Promoting Safe and Effective Transitions of Care—the Vital Role of the Home Infu sion Care Team ✔ Delivering Home Infusion Therapy to the Patient with an Addiction Disorder ✔ Effective Pain and Symptom Manage ment in Palliative Care

Acquire Indispensable Continuing Education Credit. . .

Earn up to 28 pharmacy and nursing continuing education (CE) credit contact hours—for complete continuing education information and educational objectives, please visit: www.nhia.org/ac14/ce

Thriving Amid the Turbulent Ride, Together. . .

Connect through productive and reciprocal fellowship—chances to network, strategize, innovate and collaborate with both friends and colleagues, as we all brave the turbulence from today’s health care environment and creatively pioneer opportunities that will enable home and specialty infusion therapy professionals to thrive.

Thriving Amid The Turbulent Ride

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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, the availability of immune globulin (Ig) products has been very good, so product shortages have not played a major role in product choice.

This allows clinicians to match the best product to the patient based on clinical condition and comorbidities.

New products have become available, providing more treatment options. For example, Bivigam (Biotest), a 10% liquid product for IV use, was released in early 2013. There now are 4 Ig products indicated for subcutaneous (SQ) use in patients with primary immunodeficiency: Gammagard Liquid (Baxter), Gammaked (Kedrion), and Gamunex-C (Grifols) come in 10% concentrations and can be administered 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. Two products, Gammaked and Gamunex-C, are approved for use in patients with chronic inflammatory demyelinating polyneuropathy (IV only). Gammagard Liquid is approved to treat multifocal motor neuropathy.

A common question regarding Ig products relates to whether they all are the same. 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 in nature and related to tolerability; they may be fiscal and based on contracting issues; or they 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

INDEPENDENTLY DEVELOPED BY MCMAHON PUBLISHING

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 widely 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 should be used as a general guide to help determine the product that is best suited for a particular patient population. 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 average numbers. When comparing administration rates, clinicians need to keep in mind that each patient has a maximum tolerated rate. This rate is based on patient tolerability and may be different for each product. Ig must be administered slowly initially and titrated as tolerated. The rate should be adjusted based on comorbidities as well. 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.)

SPECIALTY PHARMACY CONTINUUM •WINTER 2014

1

Table 1. Therapeutic Considerations FDAApproved IgA Indications 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 CIDP, ITP, for Kedrion Biopharma PIDf Customer service/medical info: (855) 353-7466; www.gammaked.com; www.kedrion.com

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 35 IQPP-certified plasma from FDA-registered sites

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

Octagam 5%

Octapharma Pharmazeutika 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

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 7; Key on page 8.

2

INDEPENDENTLY DEVELOPED BY MCMAHON PUBLISHING

40

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

CMV

HAV

HBV Herpes (Surface Simplex c Antibody) Type 1c

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

NA

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)

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

c

c

Polio Type 2c

INDEPENDENTLY DEVELOPED BY MCMAHON PUBLISHING

3

Table 2. Pharmaceutical Considerations

a

Product

Method of Preparation h

Available Dosing Forms

Form

Gamma Globulin, %

Monomers, %

Bivigam 10%

Cohn-Oncley, cold ethanol fractionation, SD

IV

Liquid

≥96

100 monomer + 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

Octagam 5%

Cold ethanol fractionation, ultrafiltration, anion-exchange chromatography, SD, pH 4.0 incubation

IV

Liquid

≥96

≥90 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 7; Key on page 8.

4

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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

≤0.1 mg/mL

0

0

≤30 mEq/L

10% maltosek

310-380 mOsm/kg

3 mg/L

Trace

0

Trace

Proline

240-440 mOsm/kg

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5

Table 3. Cost Considerations 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

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

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.

6

INDEPENDENTLY DEVELOPED BY MCMAHON PUBLISHING

Table 4. IVIG Administration Ratesm Initial Infusion Rate

Maintenance Infusion Rate

Bivigam 10%

0.3 mL/kg/h for 10 min

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

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 effectsp

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 eventsp

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/hp

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 eventsp

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 eventsp

Gamunex-C 10%

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

Increase gradually as 4.8 mL/kg/h tolerated to: 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 eventsp

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/minp

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 eventsp

IVIGa

Maximum Infusion Raten

Commentso

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.

ethanol fractionation; Kistler-Nitschmann is the specific cold ethanol fractionation method used by the manufacturer (CSL Behring). i

n

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.

o

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

p

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.

q

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

r

Data on file at Octapharma.

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

c

Average of sample lots.

d

Data on file at Grifols.

j

Data on file at Bio Products Laboratory.

e

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

k

Maltose does not significantly affect serum 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 GDH-PQQ and GDO can provide these false readings. See PI for full details.

f

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

g

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

l

Under appropriate storage conditions.

Cohn-Oncley is the original method of cold

m

Some infusion rates were converted from those

h

listed in the PI for consistency and reader convenience.

INDEPENDENTLY DEVELOPED BY MCMAHON PUBLISHING

7

Table 5. Log Reduction Factor Comparisonsq 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

Octagam 5%

≥14.6

≥16.7

NA

≥16.1

≥9.5 (MEV), ≥7.7 (PPV)

≥6.7r

Privigen 10%

≥16.0

NA

≥11.8

≥17.7

≥9.6 (EMCV), ≥7.8 (MMV)

≥14.8

Footnotes on page 7.

KEY BEV

bovine enterovirus (RNA model)

HCV

hepatitis C virus

NDC

National Drug Code

BGMS blood glucose monitoring systems

HH

inhibition of hemolysis

NS

normal saline

BPV

HIV

human immunodeficiency virus

NT

neutralization test

PEG

polyethylene glycol

PEI

Paul Ehrlich Institute International Units

bovine papillomavirus

BVDV bovine viral diarrhea virus

IFA

immunofluorescence assay

CF

complement fixation

IgA

immune globulin A

CIDP

chronic inflammatory demyelinating polyneuropathy

IgG

immune globulin G

PI

prescribing information

CLL

chronic lymphocytic leukemia

IgM

immune globulin M

PID

primary immunodeficiency

CMV

cytomegalovirus

IQPP

International Quality Plasma Program

PPV

porcine parvovirus

D5W

dextrose 5% in water

ITP

idiopathic thrombocytopenic purpura

PRV

pseudorabies virus

EIA

enzyme immunoassay

IU

international unit

RIA

radioimmunoassay

IVIG

intravenous immune globulin

RSS

reduced space symbology

SBV

Sindbis virus

SD

solvent detergent

SQ

subcutaneous

EMCV encephalomyocarditis virus (RNA model) FDA

Food and Drug Administration

GDH- glucose dehydrogenasePQQ pyrroloquinolone quinone

KD

Kawasaki disease

MEV

mouse encephalomyelitis virus

MMN

multifocal motor neuropathy

SV40 simian virus

MMV

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

TSE

transmissible spongiform encephalopathies

GDO

glucose-dye-oxidoreductase

HAI

heterologous anti-immunoglobulin

HAV

hepatitis A virus

NA

information not available

UIN

unique identifier number

HBV

hepatitis B virus

NaCl

sodium chloride

VZV

varicella zoster virus

8

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