Stacey Ness, PharmD, RPh, MSCS

Therapy approvals significantly changed the landscape of treatment for hepatitis C and it is anticipated that the drugs in the treatment pipeline will mark significant advances in therapy as well.

There was much anticipation surrounding the new hepatitis C treatment options that were granted FDA approval in May 2011. Victrelis (boceprevir, Merck) and Incivek (telaprevir, Vertex) are both direct-acting protease inhibitors that were approved for the treatment of chronic hepatitis C genotype 1 infection in combination with peginterferon alfa and ribavirin in adult patients (18 years or older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon or ribavirin therapy.

Just as those therapy approvals significantly changed the landscape of treatment, it is anticipated that the drugs in the hepatitis C treatment pipeline will mark significant advances in therapy as well. Hepatitis C virus (HCV) is a leading cause of chronic liver disease. It is estimated that 180 million people are infected worldwide. In the United States, the prevalence of HCV infection is estimated to be 1.6%, or approximately 4.1 million people. Hepatitis C is the primary cause of death from liver disease and the leading cause of liver transplantation in the United States. The American Association for the Study of Liver Diseases (AASLD) suggests that mortality related to HCV infections will rise over the next 2 decades.

Current Treatment of HCV Genotype 1 Infection

The goal of HCV therapy is to prevent complications and death from HCV infections. This is achieved through a sustained virologic response (SVR), which refers to no detectable HCV RNA being found in the blood 24 weeks after stopping treatment. SVR is associated with long-term clearance of HCV infection and improved morbidity and mortality.

The AASLD released an updated practice guideline in 2011 to address the addition of boceprevir and telaprevir to the HCV genotype 1 armamentarium. According to the 2011 AASLD guidelines, the optimal therapy for genotype 1 chronic HCV infection is the use of boceprevir or telaprevir in combination with peg-interferon alfa (either Pegasys or Peg-Intron) and ribavirin.

 Now that boceprevir and telaprevir have been on the market for almost 19 months, there has been wide adoption of the 2011 guideline update in clinical practice, leading to significant clinical experience for those pharmacies that treat patients with hepatitis C. One such pharmacy with experience in treating hepatitis C patients is MedCart Specialty Pharmacy.

MedCart Specialty Pharmacy Hepatitis C Program

MedCart Specialty Pharmacy applies the knowledge, experience, and skills of its clinical staff to help optimize drug therapy outcomes for its HCV patients. At their state-of-the-art facility in Livonia, Michigan, MedCart Specialty employees help patients in the fight against hepatitis C by placing emphasis on the patient’s ability to access medication and maintain a high quality of life during pharmacotherapy. MedCart Specialty has developed a patient-centric model of care that addresses the coordination of benefits as well as the maintenance of an open and reliable channel of communication among all stakeholders. In addition, MedCart Specialty has created a taskforce within its patient care department that is dedicated to the mitigation of drug side effects that are often experienced by patients embarking on hepatitis C therapy.

Because out-of-pocket costs for HCV therapy can create considerable barriers to accessing treatment, MedCart Specialty Pharmacy’s Patient Financial Resources Department employs funding specialists to help reduce the risk of nonadherence due to financial considerations. The funding specialists coordinate with third party payers, drug manufacturers, community-based social work organizations, nonprofit groups, and disease foundations to help devise individualized yet comprehensive strategies to minimize the financial burden of HCV therapy to the patient.

Another important way that MedCart Specialty Pharmacy promotes a high level of medication adherence and persistency is through proactive clinical intervention by the pharmacy care staff for the duration of HCV treatment. This is accomplished throughout the treatment regimen and begins with motivational interviewing prior to a patient starting on therapy. Patients receive one-on-one educational training on the disease, the treatment regimen, expectations from treatment, and what to anticipate during the therapeutic journey. Another key component to the MedCart Specialty HCV program is empowering the patient to know to whom they can reach out for direction, clinical support, and questions that may arise.

Continued outreach during HCV treatment allows for the creation of a therapeutic relationship between the pharmacy staff and the patient—and it also allows for various data sets to be obtained throughout treatment. This enables further analysis of the patient’s treatment experience and provides alerts to pharmacy staff of those patients who may need escalated levels of intervention by MedCart’s clinical staff to optimize therapy outcomes.

MedCart Specialty clinical and patient care staff utilize a variety of resources to carry out this creative approach to outcome-based care. Patient care may be supplemented by the use of adherence tools such as TextMed, a custom text messaging medication reminder service; MedPac compliance packaging; or by communicating with the physician regarding any complementary and adjunct therapies that may help mitigate therapy side effects. Furthermore, these patients also may be referred to support groups to deal with the emotional toll of this disease and to connect with other patients who are going through similar experiences.

To provide outstanding care to patients and providers and to recognize additional savings and services that positively impact the bottom line, MedCart Specialty works with collaborative partners such as Managed Health Care Associates, Inc (MHA), a leading health care services company. MHA’s Specialty Pharmacy Solutions program supports MedCart Specialty with clinical information to enhance disease state and specialty product knowledge as well as contract analytics and reporting to facilitate understanding of therapy- specific and population metrics. MHA’s Specialty Pharmacy Solutions also provides consistent tracking and analysis of trends in specialty pharmaceuticals to help MedCart Specialty anticipate what might be on the horizon and how to be in the best position to grow business and expand opportunities in the marketplace. MHA Specialty Pharmacy Solutions clinical services help MedCart Specialty keep apprised of the pipeline so that its hepatitis C clinical practice and expertise can evolve along with new therapy developments.

Just as the addition of boceprevir and telaprevir altered the HCV treatment paradigm, the current pipeline agents are anticipated to shift the HCV treatment landscape once again. Many agents are being developed with the goal of eliminating concomitant therapy with interferon in an effort to reduce the overall side effect burden of hepatitis C therapy (Table 1).

It is anticipated that most of the new agents will initially come to market approved for combination therapy with pegylated interferon and ribavirin, and then gain approval in interferon-free regimens. Additional agents are looking at finding better regimens for treating HIV/HCV coinfected patients. There is some notion in the marketplace that physicians are again opting to defer treatment until newer regimens become available, much like what was seen prior to the approvals of telaprevir and boceprevir.

 Several hepatitis C investigational agents are highlighted below.

 is being evaluated as a once-daily oral NS3/4A protease inhibitor in combination with pegylated interferon and ribavirin, as well as in an interferon-sparing regimen both with and without ribavirin in combination with another investigational agent, 

 (an NS5B RNA-dependent polymerase inhibitor).

 Boehringer Ingelheim’s hepatitis C virus clinical development program is referred to as HCVerso

, from Bristol-Myers Squibb, is a once-daily NS5A replication complex inhibitor being studied for use up to 24 weeks in combination with pegylated interferon and ribavirin. It is also being studied with the investigational agent 

 (BMS-650032, a twice-daily NS3 protease inhibitor) in a quadruple regimen consisting of daclatasvir, asunaprevir, pegylated interferon, and ribravirin, and in an all-oral regimen consisting of asunaprevir plus daclatasvir.

 is a once-daily oral NS3/4A protease inhibitor being studied in phase III trials in combination with pegylated interferon and ribavirin. It is also being studied with other direct-acting antiviral agents as part of interferon-free regimens, both with and without ribavirin.

 is Giliead’s once-daily oral NS5B polymerase inhibitor. It is being studied in phase III to treat HCV genotype 2 or 3 in combination with ribavirin for 12 weeks and is also being studied in Phase III in a combination including ribavirin plus a fixed-dose combination of sofosbuvir plus 

 (an NS5A inhibitor) for 12 or 24 weeks to treat genotype 1 HCV.

Abbott’s hepatitis C treatment pipeline consists of 

, a protease inhibitor that requires boosting with ritonavir; 

, a nonnucleoside polymerase inhibitor. These experimental agents have been studied with and without ribavirin for either 12 or 24 weeks in all-oral treatment regimens. Abbott announced that phase III clinical trials for these agents would begin in October 2012.

 (a nucleotide analogue inhibitor of hepatitis C polymerase) and 

 (an oral nonnucleoside inhibitor of hepatitis C polymerase) currently in phase II development and is exploring opportunities to partner with other manufacturers to create an efficacious regimen.

 for hepatitis C treatment. The human interferon lambda proteins are generated by the immune system in response to viral infection and signal through a different receptor than interferon alpha. This particular receptor is found on fewer cells throughout the human body than the receptor for interferon alpha; therefore it is thought that interferon lambda may be able to offer an improved safety and tolerability profile.

 (KD024, viramidine), which is a prodrug of ribavirin. The goal of this drug is to preferentially target the liver while significantly reducing the anemia associated with ribavirin.

 Phase III trials from 2006 did not meet the noninferiority efficacy end point on an intentto-treat basis, but did confirm the safety advantages of taribavirin. Valeant has since entered into a strategic agreement with Kadmon to pursue additional clinical trials with higher or weight-based dosing.

 (DEB025) is Novartis’ cyclophilin blocker that showed promising efficacy, but development was placed on hold when a small number of patients developed pancreatitis in trials. Additional analysis is being conducted to determine if the increased risk of pancreatitis was caused by alisporivir.

The above information is a selective summary of publicly available information and is accurate as of the date of writing. Please consult the sources for complete reference information. The views expressed in this article are those of the author alone and not of Managed Health Care Associates, Inc, or MedCart Specialty Pharmacy. Any patient care, treatment, dosing or other decisions related to the subject matter of this article should be based on an independent evaluation of the patient’s condition and medical history by his/her treating physician.

Ed Saleh, RPh, is the cofounder and chief executive officer of MedCart Specialty Pharmacy. An alumnus of the Wayne State University School of Pharmacy in Detroit, Michigan, Mr. Saleh began his career at Sigmapharm Co, a community-based independent pharmacy group serving the needs of both the Hispanic and indigent populations of Detroit, where he held the position of president. He has also worked alongside many regional and national non-profit organizations to help increase access to health care resources for Michigan’s senior citizen community. Mr. Saleh has held leading positions within Goldberg Int and Worldpharm Inc, in the latter of which he still serves as chairman of the board. The extensive community outreach and dedication to the fight against chronic diseases by Mr. Saleh has afforded MedCart Specialty Pharmacy national peer recognition.

Stacey Ness, PharmD, RPh, MSCS, has worked in both national specialty pharmacy and payer organizations and has experience in clinical management, adherence, and persistency programs, as well as chronic disease cost optimization strategies. Dr. Ness is active in the Consortium of Multiple Sclerosis Centers, Academy of Managed Care Pharmacy, National Home Infusion Association, and Hematology and Oncology Pharmacy Association, and has served on the Minnesota Medicaid Drug Formulary Committee since 2008. She is a multiple sclerosis certified specialist and currently serves as the director of specialty clinical services at Managed Health Care Associates, Inc, a health care services organization based in Florham Park, New Jersey.

		     Incivek prescribing information. Vertex October 2012.  

http://pi.vrtx.com/files/uspi_telaprevir.pdf

		     Victrelis prescribing information. Schering Corporation, a subsidiary of Merck and Co. July 2012.  

www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

		     AASLD practice guidelines: diagnosis, management, and treatment of hepatitis C: an update. 

www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/Diagnosis_of_HEP_C_Update.Aug%20_09pdf.pdf

		     An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. 

www.aasld.org/practiceguidelines/Documents/2011UpdateGenotype1HCVbyAASLD24641.pdf. Published October 2011

		     Clinical Trials Registry. United States National Institutes of Health, 2012.  

		     Gilead Sciences’ hepatitis C drug candidate may have first mover advantage. iStock Analyst, August 2012.  

www.istockanalyst.com/finance/story/5983419/gilead-sciences-hepatitis-c-drug-candidate-may-have-first-mover-advantage

		     Wanted: premier hepatitis C drug developer to partner with Vertex. Fierce Biotech, October 19, 2012.  

www.fiercebiotech.com/story/wanted-premier-hepatitis-c-drug-developer-partner-vertex/2012-10-19

		     Hepatitis C: interferon-free combination of BI 201335 plus BI 207127 and ribavirin shows up to 76% of patients achieve a virological response at week 12, and 59% achieve SVR12 with 16 weeks treatment. Boehringer Ingelheim, November 2011.  

www.boehringer-ingelheim.com/news/news_releases/press_releases/2011/07_november_2011hepc.html

		     Simeprevir (TMC435) data in hepatitis C to be presented at the annual meeting of the American Association for the Study of Liver Diseases. PRN Newswire, October 16, 2012.  

www.prnewswire.com/news-releases/simeprevir-tmc435-data-in-hepatitis-c-to-be-presented-at-the-annual-meeting-of-the-american-association-for-the-study-of-liver-diseases-174342921.html

		  Vertex research and development pipeline. Vertex 2012.  

www.vrtx.com/research-development/pipeline

		  Pipeline asset update for PEG-Interferon Lambda. Bristol-Myers Squibb 2012.  

www.bms.com/research/investigational/hepatitis/Pages/PEG_interferon_lambda.aspx

		  Valeant Pharmaceuticals reports VISER2 results for Viramidine(R); company initiates phase 2b weight-based dose-ranging study. Business Wire, 2006.  

		  Viramidine fails to show non-inferiority to ribavirin at tested doses, but causes less anemia.  

www.hivandhepatitis.com/hep_c/news/2010/011910_a.html

		Hepatitis C drug alisporivir is effective, but pancreatitis a concern. Aidsmap,

www.aidsmap.com/Hepatitis-C-drug-alisporivir-is-effective-but-pancreatitis-a-concern/page/2326524/

Articles

MedCart Specialty Pharmacy: Preparing for the Next Advancements in Hepatitis C Therapy

The latest advances in HIV treatment  and care include new drug therapies, a new at-home test, and updates guidelines for antiretroviral therapy for pregnant women. 

2012 marked the 31st year since the first cases of AIDS were reported in the United States. 

 Extraordinary advances in understanding HIV and its treatment have been made in the last 3 decades—and that momentum continues with several recent advances and the development of best practices, new drugs, and new technologies. Some of the current HIV topics highlighted in this article include preexposure prophylaxis, a newly approved “quad” tablet, approval of an in-home HIV test, and updated guidelines for the treatment of perinatal HIV.

On July 16, 2012, the FDA approved Gilead’s Truvada (emtricitabine and tenofovir disoproxil fumarate) as the first drug to reduce the risk of HIV infection in uninfected individuals who are at high risk of HIV infection and who may engage in sexual activity with HIV-infected partners.

Truvada is to be used for preexposure prophylaxis (PrEP) in combination with safer sex practices to reduce the risk of sexually acquired HIV infection in adults at high risk. Truvada for PrEP was approved with a Risk Evaluation and Mitigation Strategy (REMS) to minimize the risk to uninfected individuals of acquiring HIV infection and to reduce the risk of developing HIV resistance. The REMS program aims to train and educate prescribers when counseling individuals who are taking or considering Truvada for PrEP.

The training and education program will not restrict distribution of the drug, but will provide information about the importance of adhering to the recommended dosing regimen and understanding the serious risks of becoming infected with HIV while taking Truvada for PrEP. It will also include an agreement form documenting the completion of patient education and an understanding of risks and responsibilities when initiating Truvada for PrEP.

The form will need to be signed by both the prescriber and uninfected individual and placed in the individual’s medical record. Furthermore, Gilead will be required to collect information from individuals who acquire HIV despite using Truvada for PrEP, in order to evaluate for resistance. Gilead will also be required to collect data on pregnancy outcomes, drug adherence, and the characteristics of patients using PrEP. At the FDA’s request, Gilead will be developing an adherence questionnaire that will help prescribers to identify individuals at risk for low adherence.

In response to the Truvada PrEP approval, the CDC issued an “Interim Guidance for Clinicians Considering the Use of Preexposure Prophylaxis for the Prevention of HIV Infection in Heterosexually Active Adults” on August 10, 2012. In addition, previous interim guidance was issued on January 28, 2011, to address “Preexposure Prophylaxis for the Prevention of HIV Infection in Men Who Have Sex with Men.”

The CDC and other public health agencies are developing a full set of guidelines on the use of PrEP as part of a comprehensive group of HIV prevention strategies. Those full guidelines are anticipated later this year.

On August 27, 2012, the FDA approved Gilead’s Stribild, which contains 4 antiretroviral medications in 1 tablet (sometimes referred to as the “quad” pill) given once a day with food. Stribild contains the previously approved nucleoside reverse transcriptase inhibitors (NRTIs) emtricitabine and tenofovir disoproxil fumarate as well as the novel agents elvitegravir and cobicistat. Elvitegravir is an HIV integrase inhibitor and cobicistat inhibits an enzyme that metabolizes elvitegravir and thereby boosts elvitegravir’s effect.

Efficacy was evaluated in 1408 treatment-naïve patients who were randomized to receive Stribild (emtricitabine/ tenofovir/elvitegravir/cobicistat), Atripla (emtricitabine/tenofovir/efavirenz), or Truvada (emtricitabine/tenofovir) plus atazanavir and ritonavir. After 48 weeks of therapy, between 88% and 90% of patients treated with Stribild had an undetectable amount of HIV in their blood, compared with 84% treated with Atripla and 87% treated with Truvada plus atazanavir and ritonavir.

Common side effects of Stribild noted in clinical trials included nausea and diarrhea. A boxed warning states that there is a risk of lactic acidosis and the potential for severe liver problems. Additional warnings and precautions noted are renal impairment, decreases in bone mineral density, redistribution of body fat, and immune reconstitution syndrome.

FIRST OVER-THE-COUNTER AT HOME RAPID HIV TEST KIT 

In July 2012, the FDA approved the OraQuick In-Home HIV Test, which is the first over-the-counter rapid HIV test kit to be used at home. The OraQuick In-Home HIV Test detects antibodies to HIV-1 and HIV-2. Patients swab their upper and lower gums for an oral fluid sample with the testing device provided. The testing device is then placed in a tube with developing solution for 20 to 40 minutes. After that time, 1 line on the testing device indicates a negative test, while 2 lines indicate that HIV antibodies were detected and that a 

 performed by a health care professional is required. Clinical trials showed that approximately 1 false positive can be expected out of every 5000 test results in uninfected patients.

In addition, trials of the OraQuick test showed that approximately 1 false negative can be expected out of every 12 test results in HIV-infected patients. The test is not a reliable indicator of infection until at least 3 months after the initial HIV infection. The OraQuick customer support center has counselors available 24 hours a day to answer questions and provide local referrals for follow-up testing and HIV care.

It is anticipated by the FDA that the availability of the OraQuick In-Home HIV test will contribute to public health by offering another testing option to people who may not participate in standard HIV screenings. Helping more infected individuals become aware of their HIV status is a key in helping to reduce HIV transmission.

DEPARTMENT OF HEALTH AND HUMAN SERVICES PERINATAL ANTIRETROVIRAL GUIDELINES UPDATED 

On July 31, 2012, the Health and Human Services Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission updated its guidelines, entitled “Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1- Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States.” Selected notable updates include:

		A preconception counseling and care section discussing reproductive options for HIV concordant and serodiscordant couples.

		An updated table of drug interactions between hormonal contraceptives and antiretroviral agents.

		An antepartum care section discussing general principles regarding the use of antiretroviral drugs during pregnancy and specific modified recommendations for preferred regimens, alternative regimens, or those regimens to use in special circumstances.

		An enhanced discussion of intrapartum and postpartum care, including infant antiretroviral prophylaxis and postnatal management of the HIV- exposed neonate

1.    Valdiserri R. Commentary: thirty years of AIDS in America: a story of infinite hope. Office of HIV/AIDS and Infectious Disease Policy, US Department of Health and Human Services. http://aids.gov/news-and-events/thirty-years-of-aids/. Published June 2011. Accessed September 9, 2012.

2.    FDA approves first drug for reducing the risk of sexually acquired HIV infection [press release]. US Food and Drug Administration website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312210.htm. Published July 16, 2012. Accessed September 9, 2012.

3.     Truvada for PrEP fact sheet: ensuring safe and proper use. US Food and Drug Administration, US Department of Health and Human Services. www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM312290.pdf. Published July 2012. Accessed September 9, 2012.

4.    Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults. Centers for Disease Control and Prevention website. www.cdc.gov/Mmwr/preview/mmwrhtml/mm6131a2.htm. Published August 10, 2012. Accessed September 9, 2012.

5.    FDA approves new combination pill for HIV treatment for some patients [press release]. US Food and Drug Administration website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm317004.htm. Published August 27, 2012. Accessed September 9, 2012.

6.    Stribild prescribing information, Gilead Sciences. www.stribild.com/Content/pdf/stribild_prescribing_information.pdf. Published August 2012. Accessed September 9, 2012.

7.    FDA approves first over-the-counter home-use rapid HIV test [press release]. US Food and Drug Administration website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm310542.htm. Published July 3, 2012. Accessed September 9, 2012.

8.    First rapid home-use HIV kit approved for self-testing [press release]. US Food and Drug Administration website. www.fda.gov/ForConsumers/ConsumerUpdates/ucm310545.htm. Published July 2012. Accessed September 9, 2012.

9.    Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed September 9, 2012.

Stacey Ness, PharmD, RPh, MSCS, is director of specialty clinical service, Managed Health Care Associates, Inc, and has worked in both national specialty pharmacy and payer organizations and has experience in clinical management, adherence, and persistency programs, as well as chronic disease cost optimization strategies. Dr. Ness is active in the Consortium of Multiple Sclerosis Centers, Academy of Managed Care Pharmacy, National Home Infusion Association, and Hematology and Oncology Pharmacy Association, and has served on the Minnesota Medicaid Drug Formulary Committee since 2008. She is a multiple sclerosis certified specialist and currently serves as the director of specialty clinical services at Managed Health Care Associates, Inc, a health care services organization based in Florham Park, New Jersey. Dr. Ness is an associate editor of

Timely Topics in HIV

Newly approved drugs represent marked advances in treatment for this rare but deadly disease, and they were deemed to be among the top game changers in oncology in 2011.

Last year proved to be a significant milestone for advances in the treatment of melanoma with the FDA approval of 3 new drugs to treat this rare but deadly form of skin cancer. Bristol-Myers Squibb’s Yervoy (ipilimumab) was approved in March 2011, Merck’s Sylatron (peginterferon alfa-2b) was approved in April 2011, and Roche’s Zelboraf (vemurafenib) was approved in August 2011.

 These newly approved drugs represent marked advances in treatment and were deemed to be among the top game changers in oncology in 2011.

Melanoma is a cancer that develops from cells called melanocytes, which make the brown pigment of the skin referred to as melanin. Melanoma can occur on any location on the skin but is most likely to appear on the trunk in males and on the legs in females in addition to common sites such as the face and neck. Because of the melanin, melanoma tumors are likely to be black or brown, although they can also be flesh colored, pink, red, purple, blue, or white. Melanoma is typically caused by intense occasional ultraviolet light exposure.

Although melanoma accounts for less than 5% of all skin cancers, it is among the most deadly. The American Cancer Society Estimates that in 2012 about 76,000 new melanomas will be diagnosed and approximately 9100 people are expected to die of melanoma. The rate of melanoma is highest among those in their 80s; however, melanoma can occur at almost any age and is one of the more common cancers in young adults.

Self-exam is critical to spotting melanoma and it is important to check skin frequently (at least once per month) for any changes in the size, shape, or color of spots on the skin (Table). Any changes or unusual markings should be brought to the attention of a physician. A skin biopsy is typically used to determine if melanoma is present. The prognosis of melanoma can be predicted and staged based on the following: the depth of the tumor, presence or absence of ulceration, and whether or not there are lymph nodes involved at the time of diagnosis. Patients with stage I melanoma have a 5-year survival rate of >90% while those that present with metastatic disease have a 5-year survival rate of <20%.

Treatment of early-stage melanoma consists of surgery to remove the local tumor. Removal of local lymph nodes can also be considered. Because surgery is the mainstay of treatment for melanoma, pharmacotherapy is typically only used for patients with advanced melanoma. Dacarbazine, interleukin-2, carboplatin, and paclitaxel have been used with somewhat limited success for advanced-stage melanoma. Although each of the agents approved for melanoma in 2011 has a unique and specific indication, the FDA approvals of Yervoy (ipilimumab), Sylatron (peginterferon alfa-2b), and Zelboraf (vemurafenib) represent needed additional options in the treatment of melanoma.

On March 25, 2011, the FDA announced the approval of the monoclonal antibody ipilimumab for the treatment of unresectable or metastatic melanoma. Ipilimumab was the first agent shown to increase survival time in patients with advanced melanoma.

Iplimumab is a targeted T-cell antibody. It blocks cytoxic T-lymphocyte associated antigen-4 (CTLA-4), an antigen on the surface of T-cells which acts to inhibit T-cell activity. By blocking CTLA-4, T-cells can be activated to attack cancer cells associated with melanoma.

The FDA based its approval of iplimumab on a phase III, randomized, doubleblind active control study in 676 patients with stage III or stage IV melanoma who had previously received treatment. As there is currently no otherSpecialtyPharmacyTimes.com Specialty Pharmacy Times | 08.12 n 29 accepted standard of care for advanced metastatic melanoma, the active control in this study was the experimental cancer vaccine gp100. Gp100 has been shown to induce immune response and increase the efficacy of interleukin-2 and ipilimumab. The study was designed to show if treatment with iplimumab, either alone or in combination with gp100, improved survival compared with treatment with gp100 alone in patients with metastatic melanoma who had undergone previous treatment. The study design consisted of ipilimumab dosed at 3 mg/kg and infused intravenously over 90 minutes every 3 weeks for 4 treatments.

The primary end point was median overall survival, which showed that treatment with iplimuab+gp100 or ipilimumab alone led to a statistically significant increase in median overall survival versus gp100 alone (10 months [95% CI, 8.5-11.5], 10.1 months [95% CI, 8.0- 13.8], and 6.4 months [95% CI, 5.5-8.7], respectively). The effect of iplimumab on survival was independent of age, sex, disease stage, or previous interleukin therapy. The most common reason for discontinuation during the study was disease progression.

Serious immune-related adverse events were associated with iplimumab therapy, prompting the FDA to require a REMS program for drug approval, which Bristol-Myers Squibb has developed and implemented. Iplimumab prescribing information includes a boxed warning stating that potentially life-threatening immune-mediated reactions can affectany organ system but most commonly include enterocolitits, hepatitis, dermatitis, neuropathy, and endocrinopathy. Immune reactions were mostly seen during treatment with iplimumab, but some occurred weeks to months after drug discontinuation. Patients should be assessed for signs and symptoms of immune-mediated reactions and have blood chemistries, including liver function tests and thyroid function tests, at baseline and before each ipilimumab dose. Discontinuation of ipilimumab and initiation of high-dose corticosteroids are recommended for severe immune reactions.

On March 29, 2011, the FDA approved Sylatron (peginterferon alfa-2b) for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy. Peginterferon alfa-2b first gained approval in the United States in 2001 under the trade name PegIntron for the treatment of chronic hepatitis C in combination with ribavirin at an adult dose of 1.5 mcg/kg/week. The FDA-approved dosing for Sylatron use in melanoma is 6 mcg/kg/week subcutaneously for 8 doses, followed by 3 mcg/kg/week subcutaneously for up to 5 years.

The FDA approval was granted based on a single open-label, multi-center trial that enrolled 1256 patients who had been adequately surgically resected for their primary cutaneous melanoma and affected regional lymph nodes. These patients were randomized in a 1:1 ratio to receive either treatment with Sylatron or observation for 5 years. Patients were assessed for local and regional recurrence or distant metastases every 3 months for the first 2 years and then every 6 months through the end of the trial. The primary efficacy end point was relapse-free survival (RFS) and was defined as the time to the earliest of local or regional recurrence, distant metastases, or death. There were 696 relapse events in the study. The estimated median RFS was 34.8 months for the Sylatron arm and 25.5 months in the observational arm (HR 0.82, CI, 0.71-0.96, p = 0.011). There were 525 deaths during the course of the study and there were no differences in the overall survival rate detected between the 2 treatment groups.

The most common adverse reactions seen with Sylatron therapy were fatigue, increased alanine transaminase, increased aspartate aminotransferase, pyrexia, headache, anorexia, myalgia, nausea, chills, and injection site reactions. A total of 33% of patients treated with Sylatron in the clinical trial discontinued therapy due to adverse reactions. Peginterferon alfa-2b can cause life-threatening or fatal neuropsychiatric reactions which may include suicide, suicidal and homicidal ideation, depression, and an increased risk of relapse of recovering drug addicts. Sylatron should be permanently discontinued if the patient develops new onset ventricular arrhythmia, cardiovascular decompensation, new or worsening retinopathy or other serious ocular adverse reactions, if there is evidence of severe (grade 3) hepatic injury or hepatic decompensation (Child-Pugh score >6 [class B and C]), or if the patient develops hypothyroidism, hyperthyroidism, or diabetes mellitus that cannot be effectively managed.

On August 17, 2011, the FDA approved vemurafenib for the treatment of patients with unresectable or metastatic melanoma with the BRAF

 mutation as detected by an FDA-approved test. Confirmation of BRAF

 mutation-positive melanoma using an FDA-approved test is required before treatment with vemurafenib. Vemurafenib is not recommended for use in patients with wildtype BRAF melanoma. Vemurafenib approved dosing is 960 mg orally twice daily administered approximately 12 hours apart, with or without a meal.

One of the studies that the FDA considered consisted of 337 patients who were assigned to vemurafenib 960 mg twice daily and 338 who were assigned to dacarbazine 1000 mg/m2 intravenous every 3 weeks. It was found that overall survival was significantly improved in patients receiving vemurafenib compared with those receiving dacarbazine. The median survival of patients receiving vemurafenib had not yet been reached at the data cutoff point (95% CI, 9.6 months, not reached) and was 7.9 months (95% CI, 7.3-9.6) for those patients receiving dacarbazine. Progression-free survival was also significantly improved in patients treated with vemurafenib compared with dacarbazine. The median progression-free survival was 5.3 months (95% CI, 4.9-6.6) for vemurafenib and 1.6 months (95% CI, 1.6-1.7) in the dacarbazine arm.

The most common adverse reactions (≥30%) in patients treated with vemurafenib were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea. Cutaneous squamous cell carcinomas (cuSCC), including squamous cell carcinomas of the skin, were detected in approximately 24% of patients treated with vemurafenib. CuSCCs were managed with excision in clinical trials, and patients were able to continue treatment without dose adjustment. A Medication Guide must be dispensed to inform health care professionals and patients of vemurafenib’s potential risks.

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2.    FDA Approves Merck's Sylatron (peginterferon alfa-2b) for Injection, a New Adjuvant Treatment for Melanoma with Microscopic or Gross Nodal Involvement. Drugs.com, April 11, 2011. Available at http://www.drugs.com/newdrugs/fda-approves-merck-s-sylatron-peginterferon-alfa-2b-new-adjuvant-melanoma-microscopic-gross-nodal-2602.html Accessed June 27, 2012.

3.    FDA approves Zelboraf and companion diagnostic test for late-stage skin cancer. United States Food and Drug Administration, August 17, 2011. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm268241.htm  Accessed June 27, 2012.

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10.  Yervoy prescribing information. March 2011. Bristol-Myers Squibb. Princeton, New Jersey. Available at http://packageinserts.bms.com/pi/pi_yervoy.pdf. Accessed July 2, 2012.

11.   Sylatron Prescribing Inforamation. Schering Corporation, 2011. Available at  http://www.merck.com/product/usa/pi_circulars/s/sylatron/sylatron_pi.pdf  Accessed July 2, 2012.

12.   Long Term Pegylated Interferon Alfa-2b Therapy in Stage III Melanoma Demonstrated Significant and Sustained Impact on Relapse-Free Survival. Medical News Today, July 12, 2008. Available at http://www.medicalnewstoday.com/articles/114772.php Accessed July 2, 2012.

13.   PegIntron Prescribing Information. Schering Corporation, 2011. Available at http://www.spfiles.com/pipeg-intron.pdf Accessed July 2, 2012.

14.   Zelboraf Prescribing Information. Hoffman-LaRoche, August 2011. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202429s000lbl.pdf Accessed July 2, 2012.

15.   Vemurafenib. US Food and Drug Administration, August 17, 2011. Available at http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm268301.htm  Accessed July 2, 2012.

The above information is a selective summary of publicly available information and is accurate as of the date of writing. Please consult the sources for complete reference information. The views expressed in this article are those of the author alone and not of Managed Health Care Associates, Inc. Any patient care, treatment, dosing, or other decisions related to the subject matter of this article should be based on an independent evaluation of the patient’s condition and medical history by his/her treating physician.

Stacey Ness, PharmD, RPh, MSCS, has worked in both national specialty pharmacy and payer organizations and has experience in clinical management, adherence and persistency programs, as well as chronic disease cost optimization strategies. Dr. Ness is active in the Consortium of Multiple Sclerosis Centers, Academy of Managed Care Pharmacy, National Home Infusion Association, and Hematology and Oncology Pharmacy Association, and has served on the Minnesota Medicaid Drug Formulary Committee since 2008. She is a multiple sclerosis certified specialist and currently serves as the director of specialty clinical services at Managed Health Care Associates, Inc, a health care services organization based in Florham Park, NJ. Dr. Ness is associate editor of Specialty Pharmacy Times.