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Pharmaceutical Approval Update October 2016
Obeticholic Acid (Ocaliva)
Manufacturer: Intercept Pharmaceuticals, Inc., New York, New York
Date of Approval: May 27, 2016
Indication: Obeticholic acid is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA.
Drug Class: Farnesoid X receptor agonist
Uniqueness of Drug: Obeticholic acid is the first agent in almost 20 years to be approved to treat PBC. The first agent, UDCA, was approved in 1997. Obeticholic acid was granted an accelerated Food and Drug Administration approval based on a reduction in alkaline phosphatase (ALP). An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Warnings and Precautions:
Liver-related reactions. A dose–response relationship was observed for liver-related adverse reactions (e.g., jaundice, worsening ascites, primary biliary cholangitis flare) with once-daily dosages of 10–50 mg (up to five times the highest recommended dosage) within the first month of therapy. Monitor patients for elevations in liver biochemical tests and for liver-related adverse reactions. The risk-versus-benefit should be weighed in all patients before continuing treatment. Do not exceed a dose of 10 mg once daily. Adjust the dose for patients with moderate or severe hepatic impairment, and stop the medication in patients who develop complete biliary obstruction.
Severe pruritus. Severe pruritus (defined as intense or widespread itching, interfering with activities such as sleep, or causing intolerable discomfort, and requiring medical intervention) occurred in up to 23% of obeticholic acid-treated patients. Management strategies include using bile acid binding resins, antihistamines, dose reductions, and/or temporary dose interruption.
HDL-C reduction. Patients with PBC generally have hyperlipidemia with significant total cholesterol elevations. In clinical trials, high-density lipoprotein-cholesterol (HDL-C) reductions of less than 40 mg/dL developed in 16 obeticholic acid-treated patients. Monitor serum lipid levels during treatment. If after year 1 there is no therapeutic response along with HDL-C reduction, continuation should be re-evaluated.
- Bile acid binding resins. Cholestyramine, colestipol, or colesevelam may reduce absorption, systemic exposure, and efficacy. Concomitant therapy with obeticholic acid should be administered at least four hours before or after the agent.
- Warfarin. International normalized ratios (INRs) should be closely monitored during concomitant treatment. INR has decreased during coadministration.
- CYP1A2 substrates with a narrow thera peutic index. Obeticholic acid may increase exposure to concomitant drugs that are cytochrome P450 iso-enzyme 1A2 (CYP1A2) substrates. Therapeutic monitoring of narrow therapeutic index CYP1A2 substrates (e.g., theophylline) is recommended.
Dosage and Administration: Start patients with 5 mg obeticholic acid orally once daily, with or without food. If an adequate ALP and/or total bilirubin reduction is not achieved after three months, the dose should be increased to 10 mg daily (the maximum recommended dose).
Commentary: The safety and efficacy of obeticholic acid 10 mg daily were evaluated in a randomized, double-blind, placebo-controlled, 12-month trial in 216 patients with PBC who were taking UDCA for at least 12 months (on a stable dosage for at least three months) or who were unable to tolerate UDCA and did not receive UDCA for at least three months. Patients were included in the trial if their ALP was 1.67 or more times the upper limit of normal (ULN) and/or if total bilirubin was one or more times, but less than two times, the ULN.
Patients were randomized (1:1:1) to receive obeticholic acid 10 mg once daily for 12 months (n = 73); obeticholic acid titration (5 mg once daily for the initial six months, with the option to increase to 10 mg once daily for the last six months if the patient was tolerating treatment but had ALP 1.67 times ULN or greater, and/or total bilirubin greater than ULN, or less than 15% ALP reduction)(n = 70); or placebo (n = 73). Obeticholic acid or placebo was administered with UDCA in 93% of patients during the trial and in 7% as monotherapy. The primary endpoint was a responder analysis at month 12, which was a composite of three criteria: ALP less than 1.67 times the ULN, total bilirubin less than or equal to the ULN, and an ALP decrease of at least 15%. Approximately 29% of the patients had ALP concentration levels more than three times the ULN. The mean baseline total bilirubin concentration was 0.65 mg/dL and was less than or equal to the ULN in 92% of the patients.
Sources: Intercept Pharmaceuticals, Inc., Ocaliva prescribing information
Sofosbuvir 400 mg/Velpatasvir 100 mg (Epclusa)
Manufacturer: Gilead Sciences, Foster City, California
Date of Approval: June 28, 2016
Indication: Sofosbuvir/velpatasvir is indicated for the 12-week treatment of adult patients with chronic hepatitis C virus (HCV) infection of genotypes 1, 2, 3, 4, 5, or 6. It is indicated for patients without cirrhosis and for patients with compensated cirrhosis; and in combination with ribavirin (RBV) for patients with decompensated cirrhosis.
Drug Class: HCV nucleotide analogue NS5B polymerase inhibitor (sofosbuvir)/HCV NS5A inhibitor (velpatasvir)
Uniqueness of Drug: Sofosbuvir/velpatasvir is the first novel oral combination product to treat the six major genotypes of HCV in a single tablet. It is also the first single-tablet regimen to treat HCV genotypes 2 and 3 without RBV. It is a fixed-dose combination containing 400 mg sofosbuvir (approved in 2013) and 100 mg velpatasvir, a new HCV NS5A inhibitor.
Warnings and Precautions:
Serious symptomatic bradycardia when sofosbuvir is coadministered with amiodarone and another HCV direct-acting antiviral. Post-marketing cases of symptomatic bradycardia, some requiring pacemaker intervention, have been reported when amiodarone is coadministered with sofosbuvir in combination with daclatasvir or simeprevir. A fatal cardiac arrest was reported in a patient taking ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) with amiodarone. Bradycardia generally occurs within hours to days, sometimes up to two weeks after initiating treatment. Patients taking beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministered amiodarone. Bradycardia generally resolves after HCV treatment discontinuation. Patients who must take amiodarone while taking sofosbuvir/velpatasvir should be counseled about the risk of symptomatic bradycardia. Cardiac monitoring in an inpatient setting for the first 48 hours of coadministration is recommended. Subsequently, heart rate monitoring should occur daily during at least the first two weeks of treatment. Patients who develop signs or symptoms of bradycardia should immediately seek medical attention.
P-glycoprotein inducers and/or moderate to potent inducers of CYP. Drugs that induce p-glycoprotein and/or are moderate to potent inducers of cytochrome P450 iso-enzyme 2B6 (CYP2B6), CYP2C8, or CYP3A4 may significantly decrease plasma concentrations of sofosbuvir/velpatasvir, leading to a potentially reduced therapeutic effect. The use of these agents with sofosbuvir/velpatasvir is not recommended.
Dosage and Administration: One tablet should be taken orally, once daily, with or without food. Treatment in patients with severe renal impairment or end-stage renal disease is not recommended.
Commentary: The safety and efficacy of 12 weeks of sofosbuvir/velpatasvir treatment were evaluated in three phase 3 clinical trials that included 1,558 total patients without cirrhosis or with compensated cirrhosis (mild cirrhosis). Results demonstrated that 95% to 99% of patients who received sofosbuvir/velpatasvir had no virus detected in the blood 12 weeks after finishing treatment, suggesting the patients’ infections had been cured.
The safety and efficacy of sofosbuvir/velpatasvir were also evaluated in a clinical trial of 267 patients with decompen-sated cirrhosis (moderate-to-severe cirrhosis), of whom 87 received treatment in combination with RBV for 12 weeks. Of the 267 total patients, 94% had no virus detected in the blood 12 weeks after finishing treatment.
Sources: Gilead Sciences, Epclusa prescribing information
Manufacturer: Biogen, Cambridge, Massachusetts
Date of Approval: May 27, 2016
Indication: Daclizumab is indicated for treating adults with relapsing forms of multiple sclerosis (MS). Due to its safety profile, daclizumab should generally be reserved for patients who have had an inadequate response to at least two prior MS drugs.
Drug Class: Interleukin-2 receptor blocking antibody
Uniqueness of Drug: MS is a chronic, inflammatory autoimmune disease of the central nervous system that disrupts communication between the brain and other parts of the body. MS is one of the most common causes of neurological disability in young adults, occurring more frequently in women than men. For most MS patients, relapses are initially followed by re missions. Over time, recovery may be in complete, leading to progressive functional decline and increased disability. Daclizumab is a monthly, long-acting, self-administered injection.
Warnings and Precautions:
Boxed warning: hepatic injury including autoimmune hepatitis. Daclizumab can cause life-threatening liver injury, including liver failure and autoimmune hepatitis. Transaminase and bilirubin levels should be obtained before initiation. These levels should be monitored and evaluated monthly and for up to six months after the last dose. Treatment modifications are recommended based on serum transaminase and total bilirubin values. Daclizumab is contraindicated in patients with pre-existing hepatic disease or impairment. Caution should be used when it is administered with other hepatotoxins, including nonprescription drugs and supplements.
Boxed warning: other immune-mediated disorders. Immune-mediated disorders, such as skin reactions, lymphadenopathy, and noninfectious colitis, can occur with daclizumab, and treatment increases the risk of these disorders. These conditions may require systemic corticosteroid or immunosuppressive drug treatment. In clinical trials, skin reactions occurred more often in patients treated with daclizumab (37%) compared with patients receiving Avonex (interferon beta-1a, Biogen)(19%) or placebo (13%). Eczema, rashes, and dermatitis were also more common in daclizumab-treated patients. One daclizumab-treated patient died from infectious complications following a serious cutaneous reaction. It is recommended that a specialist evaluate any patient who develops serious diffuse or inflammatory rashes prior to subsequent doses. Daclizumab discontinuation may be warranted.
Risk evaluation and mitigation strategy (REMS). Due to the serious safety risks of liver injury and immune conditions, daclizumab is only available through a REMS-restricted distribution program.
Acute hypersensitivity. Anaphylaxis, angioedema, and/or urticaria may occur following any daclizumab doses. If these or other allergic reactions occur, discontinue daclizumab.
Depression and suicide. Depression-related symptoms occurred more commonly in clinical trials in daclizumab-treated patients than in Avonex- or placebo-treated patients. Patients should immediately report depression and/or suicidal ideations to their health care provider. Drug discontinuation should be considered.
Infections. Daclizumab increases the risk for infections. Tuberculosis (TB) occurred in countries where TB is endemic. Daclizumab therapy should be avoided in patients with a severe active infection, and therapy may be restarted following infection resolution.
Immunogenicity. As with all therapeutic proteins, there is a risk for immunogenicity with the development of antidrug antibodies and neutralizing antibodies.
Vaccinations. Live virus vaccinations are not recommended during daclizumab treatment and for up to four months following discontinuation.
Dosage and Administration: The recommended daclizumab dose is 150 mg, which is self-injected subcutaneously once a month.
Commentary: The effectiveness of daclizumab was demonstrated in two clinical trials. One trial (N = 1,841) compared 150 mg of subcutaneous daclizumab every four weeks to 30 mcg of intramuscular Avonex once weekly for 144 weeks. Daclizumab-treated patients had fewer clinical relapses than Avonex-treated patients. A 45% relative reduction was noted. There was a 54% reduction in the mean number of new/newly enlarging T2 hyperintense lesions for daclizumab compared with Avonex (P < 0.0001). The second trial (N = 412) compared daclizumab to placebo for 52 weeks. Daclizumab-treated patients had fewer relapses compared with placebo-treated patients. Daclizumab had a statistically significant effect (P < 0.0001) on the annualized relapse rate, the proportion of patients who were relapse free, the number of new T1 gadolinium-enhancing lesions, and the number of new/newly enlarging T2 hyperintense lesions.
Sources: Biogen, Zinbryta prescribing information