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Clinical Alert JULY 2016 Hot Topic: FDA Approves Epclusa®: First Pangenotypic Agent to Treat Chronic Hepatitis C Virus (HCV) On June 28, 2016, under a priority review, the Food and Drug Administration (FDA) approved the first pangenotypic oral direct-acting antiviral agent to treat chronic HCV infection, targeting genotypes 1-6. Approximately 70-75% of people infected with HCV in the United States (U.S.) have genotype 1; about 15-20% have genotype 2; and 10-12% are infected with genotype 3. Only a small proportion of patients in the U.S. have genotypes 4, 5, or 6. Genotype 3 is considered to be the most difficult genotype to treat. Gilead’s new breakthrough therapy, Epclusa, is a once daily fixed-dose combination of 400 mg sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor, and 100 mg velpatasvir, an HCV NS5A inhibitor. Epclusa is indicated alone for use in adults with HCV, without cirrhosis or with compensated cirrhosis; it is also indicated in combination with weight-based ribavirin in those with decompensated cirrhosis (Child-Pugh B or C). The recommended dose of Epclusa is one 400/100 mg tablet once daily, taken without regard to food, for 12 weeks. The approval of Epclusa was supported by the ASTRAL phase 3 clinical trials that reported high sustained viral response (SVR) rates with Epclusa. Pooled data from ASTRAL-1, -2, and -3, with a total of 1,558 patients with HCV genotypes 1-6, without cirrhosis or with compensated cirrhosis, revealed SVR rates of 95% or above with Epclusa (12-week duration) for all genotypes regardless of the presence of cirrhosis, high baseline HCV RNA level, prior treatment experience, or presence of NS5A RAV mutations. Relapse rates of 1% or less were reported. ASTRAL-4 studied Epclusa with and without ribavirin in 267 patients with HCV genotypes 1-6 and decompensated cirrhosis. The overall SVR rate was 94% in patients treated for 12 weeks with Epclusa + ribavirin compared to 83% with Epclusa alone. However, in patients with genotype 3 and decompensated cirrhosis, SVR rates as low as 50% and 85%, were reported with Epclusa alone and with Epclusa + ribavirin, respectively. The most common adverse effects with Epclusa were headache and fatigue; anemia, nausea, insomnia, and diarrhea were also reported when ribavirin was included. Ribavirin contraindications apply when taken in combination with Epclusa. Epclusa has also been studied in HIV-coinfected patients with HCV genotypes 1 through 4 in the ASTRAL-5 trial; results have not been published. Currently, there are several all-oral antiviral regimens, with and without ribavirin, that provide SVR rates over 90% when treating HCV genotype 1 infection, the most common genotype in the U.S. Sofosbuvir/velpatasvir (Epclusa) provides a single tablet oral option without ribavirin for all genotypes, including genotypes 2 and 3. In the U.S., fewer patients are infected with genotypes 4, 5, and 6, so the greater impact on these genotypes will be realized globally in countries where these specific genotypes are far more prevalent. LEADER Trial Reports Cardiovascular Outcomes of Liraglutide Type 2 diabetes is associated with a high risk of cardiovascular (CV) complications. Studies have confirmed that glycemic control leads to decreased risk of microvascular complications; however, the same has not been proven regarding macrovascular risks, such as CV disease. Recently, the New England Journal of Medicine published results Drug Information Highlights • In 2013, the FDA removed indications for the treatment of fungal infections of the skin and nails from ketoconazole oral tablet labeling due to reports of serious liver damage, adrenal insufficiency, and serious drug interactions. Since that time, 1 death due to oral ketoconazole use to treat a fungal infection of the nails has been reported. The agency is again warning healthcare professionals (HCPs) to avoid prescribing ketoconazole oral tablets for this off-label use. Oral ketoconazole should only be used when other antifungal therapies are either not available or not tolerated. Topical ketoconazole formulations have not been linked to these serious adverse effects. Other treatment options, available overthe-counter (OTC) or with a prescription, have their unique risks. This, coupled with the fact that, in otherwise healthy patients, fungal infections of the skin and nails are not a life-threatening condition, should prompt prescribers to consider the risks and benefits of any antifungal agent when treating fungal infections of the skin and nails. • Since 2009, current labeling of OTC aspirincontaining antacids includes warnings of bleeding risks. However, since then, the FDA has received 8 reports of serious bleeding, all requiring hospitalization. The FDA continues to monitor this safety concern and advises consumers to always read the label before taking any OTC product and to consider antacid products that do not contain aspirin to relieve symptoms of heartburn, indigestion, or upset stomach. Factors that increase the risk for bleeding include: age over 60 years, history of stomach ulcers or bleeding problems, use of other blood thinning agents, consuming 3 or more alcoholic drinks every day, and taking an aspirin-containing antacid at higher dosages or durations than recommended in the label. • The Centers for Disease Control and Prevention (CDC) advises against the use of FluMist® Quadrivalent (live attenuated influenza vaccine [LAIV]) intranasal spray during the 2016-2017 influenza season. This stance is based on data showing that, during the 2015-2016 flu season, the LAIV was only 3% effective against any flu virus in children 2 to 17 years of age. Data from the prior 2 seasons also showed lower than expected results. The CDC continues to recommend Editorial Staff Maryam Tabatabai, PharmD Carole Kerzic, RPh Editor in Chief Executive Editor 1 July 2016 Lara Frick, PharmD, BCPS, BCPP, CGP Deputy Editor Raquel Holmes, RPh, MHM, AAHIV Deputy Editor Leslie Pittman, PharmD Eileen Zimmer, PharmD, MBA Deputy Editor Deputy Editor of the highly anticipated LEADER trial, a large study evaluating the CV outcomes of the glucagon-like peptide-1 (GLP-1) agonist, liraglutide (Victoza®; Novo Nordisk). The study followed 9,340 patients with type 2 diabetes over a median of 3.8 years and found that liraglutide was associated with a significant 13% relative reduction in the first occurrence of a major coronary event (death from CV cause, nonfatal myocardial infarction [MI], or nonfatal stroke) as compared to placebo. While the rate of death from CV or other causes was lower with liraglutide, the rates of nonfatal MI, nonfatal stroke, and hospitalization for heart failure (HF) were not significantly lower than reported with placebo. The LEADER trial is the second study to assess the CV benefit and safety of an antidiabetic agent. In November 2015, results of the EMPA-REG OUTCOME trial, which evaluated the CV benefit and safety of the sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin (Jardiance®; Boehringer Ingelheim), as add-on to standard-of-care were published. Empagliflozin led to a 14% reduction in the first occurrence of a major CV event (composite of CV death, nonfatal MI, nonfatal stroke) and was deemed superior to placebo. This reduction was almost entirely due to an impact on CV death, as it did not reduce nonfatal MI or nonfatal stroke. Focused Guidelines for the Treatment of Heart Failure The American College of Cardiology (ACC) along with the American Heart Association (AHA) and the Heart Failure Society of America (HFSA) published a focused guideline on new pharmacologic therapy for HF, which is an update to the 2013 American College of Cardiology Foundation (ACCF)/AHA guideline on the management of HF. The new guidance highlights 2 new agents, valsartan/sacubitril (Entresto®) and ivabradine (Corlanor®). Entresto is a new combination known as an angiotensin-neprilysin inhibitor (ARNI). Specifically, an ARNI is an angiotensin receptor blocker (ARB) plus a new class of drug, a neprilysin inhibitor; neprilysin is an enzyme that degrades vasoactive peptides in the body. The guidelines recommend, in select patients with chronic HF with reduced ejection fraction (HFrEF), treatment with an angiotensin-converting enzyme inhibitor (ACEI), ARB, or ARNI in conjunction with an evidence-based beta-blocker and an aldosterone antagonist (Class I, Level A [ACEI, ARB] and Level B-R [ARNI] evidence). Patients with chronic symptomatic HFrEF (NYHA class II or III) who tolerate an ACEI or an ARB should be switched to an ARNI to further reduce morbidity and mortality (Class I, Level B-R evidence). ARNI should not be administered concomitantly or within 36 hours of an ACEI or in patients with a history of angioedema. Entresto is currently the only ARNI agent on the market. The consensus group also determined that ivabradine, a sinoatrial node modulator, may be beneficial to reduce HF hospitalization for patients with symptomatic stable chronic HFrEF (left ventricular ejection fraction [LVEF] ≤ 35%) who are receiving guidelinedirected care, including a beta-blocker at the maximum tolerated dose, and who are in sinus rhythm (heart rate ≥ 70 bpm at rest) (Class IIa, Level B-R evidence). yearly flu vaccination for everyone 6 months and older, with either the inactivated or recombinant vaccine injections, which conferred an estimated 63% efficacy against any flu virus during 2015-2016 among children 2 to 17 years of age. In recent years, FluMist, the only non-injectable flu vaccine, accounted for about one-third of child flu vaccinations. The CDC is working with manufacturers to ensure an adequate vaccine supply in the upcoming season. Pipeline News: Upcoming Prescription Drug User Fee Acts (PDUFA) Dates •July, 2016: Lyxumia®; lixisenatide; subcutaneous (SC) GLP-1 agonist; type 2 diabetes; Sanofi/ Zealand. •July, 2016: pegfilgrastim; biosimilar to Neulasta®; SC colony stimulating factor; neutropenia in cancer patients receiving myelosuppressive chemotherapy; Sandoz. •July, 2016: Viekira Pak™ (once daily); ombitasvir/ paritaprevir/ritonavir + dasabuvir; oral hepatitis C antiviral; chronic hepatitis C genotype 1; Abbvie. •July, 2016: iDegLira; insulin degludec/liraglutide; SC long-acting insulin and GLP-1 agonist; type 2 diabetes; Novo Nordisk. •July 1, 2016: Syndros®; dronabinol; cannabinoid oral spray; chemotherapy-induced nausea and vomiting, cachexia or unexplained weight loss due to HIV/AIDS; Insys. •July 19, 2016: Relistor®; methylnaltrexone; oral peripheral opioid antagonist; opioid-induced constipation; Salix. •July 21, 2016: Vesneo™; latanoprostene bunod; ophthalmic prostaglandin analog; glaucoma, ocular hypertension; Bausch + Lomb/NicOx. •July 22, 2016: lifitegrast; ophthalmic DC11a/ DC18 antagonist; dry eye; Shire. •August, 2016: iGlarLixi; insulin glargine/ lixisenatide; SC insulin analog/GLP-1 agonist; type 2 diabetes; Sanofi/Zealand. •Quarter 3, 2016: immune globulin subcutaneous (human), 20%; immunoglobulin; primary immunodeficiency; Baxalta/Shire. FDA Strengthens Warnings for Canagliflozin and Dapagliflozin The FDA strengthened existing warnings for antidiabetic agents containing the SGLT2 inhibitors canagliflozin (Invokana®, Invokamet®) or dapagliflozin (Farxiga®, Xigduo XR®) regarding the risk of acute kidney injury. The agency received reports of 101 confirmed cases of acute kidney injury in patients treated with either canagliflozin or dapagliflozin; some patients required hospitalization and dialysis. In approximately half of the cases, acute kidney injury occurred within 1 month of starting therapy. Most patients improved after stopping the drug. Possible contributing factors reported in some patients were dehydration, hypotension, or concurrent use of other medications that can affect the kidneys. Manufacturers of canagliflozin and dapagliflozin are required to update their labels. Providers should consider factors predisposing patients to kidney injury, such as decreased blood volume, chronic renal impairment, congestive heart failure, and concurrent medications (diuretics, ACE inhibitors, ARBs, and NSAIDs), prior to prescribing these agents; use should be discontinued if kidney injury occurs. Patients should seek immediate medical attention if they experience decreased urine output or swelling of the lower extremities. 2 July 2016 Whole Health Rx Corner Provided on a quarterly basis, compliments of Magellan’s Whole Health Rx, a behavioral health center of excellence, ensuring appropriate prescribing pracces Smartphones for Bipolar Disorder Monitoring Bipolar disorder has a recurrent and chronic nature that results in impaired functioning of daily life. Patients often have poor insight into their disease state which further complicates the ability to recognize changing moods and other symptoms, increasing the risk and rate of relapses. A German pilot study hypothesized that improved availability of daily patient data to patients and their prescribers via a smartphone would provide for earlier intervention during bipolar relapse. Smartphones have been suggested as a low cost device that may be able to measure patient information on a daily basis; most patients already use these devices on a daily basis, they are easy to use, and most have built-in sensor capabilities (e.g., global positioning system [GPS]). Safety of Varenicline and Bupropion The smoking cessation agents, varenicline (Chantix®) and bupropion sustained-release (Zyban®), carry boxed warnings of increased risk for neuropsychiatric adverse effects (agitation, hostility, depressed mood, changes in behavior). Bupropion also carries a boxed warning of suicidal thinking and behavior in children, adolescents, and young adults. However, a study published in The Lancet that included 8,144 smokers, half of which had a psychiatric disorder that was either stable or in remission, suggests otherwise. The study randomized subjects to varenicline, bupropion, nicotine patch, or placebo and found that the incidence of moderate to severe neuropsychiatric events was similar for all groups, except varenicline, which was associated with a lower risk compared to placebo (1.3% versus 2.4%) in the non-psychiatric cohort only. In addition, varenicline was favored in achieving abstinence from smoking compared to other agents. This study was funded by Pfizer and GlaxoSmithKline, manufacturers of Chantix and Zyban, respectively. The investigators aimed to determine if smartphone data can predict impending clinical symptoms in bipolar disorder. Adults with bipolar I or bipolar II disorder, according to DSM-IV criteria, and with basic skills using a smartphone, were recruited from an outpatient psychiatric department. Thirteen participants were given a smartphone with a pre-installed application, or app, for the 12-month study period. The phone had an unlimited call, text, and data plan and patients were encouraged to use it as their primary mobile device. The app, Social Information Monitoring for Patients with Bipolar Affective Disorder (SIMBA), is able to record data through questionnaires and GPS sensors. Patients self-reported mood (affect and energy level) once a day through a random time 2-item questionnaire that notified them via a beep. Patients met every 8 weeks with the treating clinician who completed assessments of manic and depressive symptoms using clinical rating scales (e.g., Young Mania Rating Scale [YMRS] and Hamilton Depression Scale [HAM-D]); the treating clinicians were blinded to the smartphone data. The results suggested that overall symptom changes were related to smartphone measures. Lower self-reported mood measured by the smartphone app, a decrease in social communication (e.g., outgoing calls or texts), and a decline in physical activity (measured by cell tower movement or distance traveled) predicted higher overall levels of clinical depressive symptoms. Likewise, decreased physical activity and increased social communication predicted higher overall levels of clinical manic symptoms. However, self-reported mood did not predict manic symptoms. While the authors hypothesized that physical activity would increase prior to or during clinical mania, the results suggest that activity decreased with both clinical depression and mania. This study had several limitations: small sample size, self-reported data, and low compliance rates (55.7%). Smartphones may have the potential to monitor symptoms for bipolar patients, but larger studies are needed to confirm their benefit. New Guidance on the Management of Chronic Insomnia Approximately 6-10% of adults suffer from insomnia, particularly women and older adults. Treatments include psychological and pharmacological therapies, or a combination of both. Medications approved by the FDA for the treatment of insomnia include: benzodiazepine hypnotics; nonbenzodiazepine hypnotics (zaleplon, zolpidem, and eszopiclone); the orexin receptor antagonist, suvorexant (Belsomra®); the melatonin receptor agonist, ramelteon (Rozerem®); and the antidepressant doxepin. Select antidepressants, antihistamines, antipsychotics, and melatonin have also been used for the treatment of insomnia. The American College of Physicians (ACP) recently developed a guideline for the treatment of adults with chronic insomnia. ACP recommends nonpharmacologic therapy, specifically cognitive behavioral therapy (CBT), as initial therapy for all patients. CBT for insomnia consists of a combination of education and treatments targeting behaviors, such as sleep restriction to improve sleep efficiency, stimulus control to establish consistency, and sleep hygiene. For those in whom CBT alone did not provide adequate relief, clinicians and patients should decide if pharmacologic therapy is appropriate only after a full discussion of the risks, benefits, and costs of short-term drug therapy. Potential benefits of pharmacologic treatment include improved sleep outcomes (e.g., sleep onset latency, total sleep). ACP’s review found that evidence is insufficient to evaluate the balance of the benefits and harms of long-term use of pharmacologic treatments in adults with chronic insomnia disorder. However, most studies evaluated by ACP focused on newer medications; there is a paucity of data with older and off-label medications. Another notable finding from ACP’s literature evaluation is that serious adverse effects, such as dementia and fractures, may be associated with hypnotic drugs. Product labels of hypnotics warn about cognitive and behavioral changes, such as possible driving impairment and motor vehicle accidents. The FDA also recommends short-term use and lower doses of hypnotics in older or debilitated adults who may be more susceptible to adverse effects. Ultimately, while short-term pharmacologic therapy may be appropriate for some individuals, the skills learned through CBT can manage insomnia over the longer term. 3 July 2016 Recent FDA Approvals Generic Name Trade Name buprenorphine FDA Status Description Applicant Probuphine® A buprenorphine implant (Probuphine), was FDA-approved for the maintenance treatment of opioid dependence in patients who have achieved and sustained prolonged clinical stability on low-to-moderate doses (≤ 8mg/day) of a transmucosal buprenorphine-containing product. It is not recommended for use in new patients who have not established prolonged clinical stability. It is only available through a Risk Evaluation and Mitagation Strategies (REMS) program due to risks associated with removal and insertion of the implant. Four rod-shaped implants are inserted subdermally by a HCP in the upper arm to remain in place for 6 months. There are no data on the use of this implant beyond 1 dose in each arm. Each implant contains 74.2 mg of buprenorphine (80mg buprenorphine HCl) for a total of 296.8 mg per dose. It is a scheduled III controlled drug. Titan FDA NDA priority approval 05/26/2016 daclizumab Zinbryta™ An interleukin-2 receptor blocking antibody, daclizumab (Zinbryta), has received approval for the treatment of relapsing forms of multiple sclerosis (MS). It carries a boxed warning for the potential risk of severe hepatic injury including autoimmune hepatitis and other immune mediated disorders. The use of daclizumab should be reserved for patients with inadequate response to 2 or more MS medications. It will be available though the restricted distribution Zinbryta REMS program. Daclizumab is a long-acting subcutaneous injection self-administered at a recommended dose of 150 mg once monthly. The injection is approved as a 150 mg/mL solution in a single-dose prefilled syringe. Biogen FDA BLA approval 05/27/2016 linagliptin/ metformin Jentadueto XR® Jentadueto XR, a fixed-dose combination of the dipeptidyl peptidase 4 inhibitor, linagliptin, with metformin extended-release (ER), has been approved in a once daily formulation. It is indicated as adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. It carries a boxed warning for the potential risk for lactic acidosis, due to the metformin component. Jentadueto XR is dosed once a day based on the patient’s current regimen, but not to exceed a total daily dose of linagliptin 5 mg and metformin 2,000 mg. It is approved as tablets containing 2.5 mg linagliptin/1,000 mg metformin ER and 5 mg linagliptin/1,000 mg metformin ER. Boehringer Ingelheim FDA NDA approval 05/27/2016 obeticholic acid Ocaliva™ The FDA granted accelerated approval and breakthrough therapy designation for the first in class farnesoid X receptor agonist, obeticholic acid (Ocaliva). It is indicated for the treatment of primary biliary cholangitis (PBC) in adults with inadequate response to ursodeoxycholic acid (UDCA), to be used in combination with UDCA, or as monotherapy in those intolerant to UDCA. PBC is a rare autoimmune cholestatic liver disease. Obeticholic acid received accelerated approval based on the reduction in alkaline phosphate (ALP). It will be available through a specialty pharmacy network. Approved as 5 mg and 10 mg oral tablets, the starting dose is 5 mg daily and may be increased to a maximum of 10 mg daily if there is inadequate reduction in ALP and/or total bilirubin after 3 months of therapy. It is contraindicated in patients with complete biliary obstruction. Intercept FDA NDA priority approval 05/27/2016 nebivolol/ valsartan Byvalson™ A fixed-dose combination of nebivolol, a beta adrenergic blocker, and valsartan, an angiotensin II receptor blocker (ARB), has been approved for the treatment of hypertension. It carries a boxed warning regarding use in pregnant patients which may cause fetal harm. The recommended dose is 5 mg nebivolol and 80 mg valsartan once daily. It is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), or severe hepatic impairment, and patients who are hypersensitive to any component of the product. In patients with diabetes, it should not be co-administered with aliskiren. Byvalson is approved as an oral tablet containing 5mg nebivolol and 80 mg valsartan. Actavis/ Forest FDA NDA approval 06/03/2016 ANDA = Abbreviated New Drug Application; BLA = Biologics License Application; NDA = New Drug Application; sNDA = Supplemental New Drug Application References Contact: Dona Jones, Executive Assistant, [email protected] https://www1.magellanrx.com/magellan-rx/publications/pharmacy-clinical-alerts.aspx © 2016, Magellan Health, All Rights Reserved. 4 July 2016 www.fda.gov www.hfsa.org www.thelancet.com www.nejm.org www.ncbi.nlm.nih.gov www.regulations.gov