MAVYRET: new dosage regimen and labeling updates
FDA | October 1, 2019
 

FDA recently approved changes to the MAVYRET (glecaprevir and pibrentasvir) product labeling to include:

  • Safety and efficacy data to support an 8-week dosing regimen for the treatment of genotypes 1, 2, 3, 4, 5, and 6, chronic hepatitis C virus infection in treatment-naïve subjects with compensated cirrhosis based on the results from the EXPEDITION-8 Study. MAYVRET is now the first eight-week treatment approved for all treatment-naïve adult and pediatric patients ages 12 years and older or weighing at least 45 kg with HCV genotypes 1-6 both without cirrhosis and with compensated cirrhosis

    • The SVR12 rates for an 8-week regimen of MAVYRET was 98% (all genotypes), 98% for genotype 1, 100% for genotype 2,4,5 and 6 and  95% for genotype 3

    • The safety of MAVYRET in HCV GT 1, 2, 3, 4, 5, or 6 adults with compensated cirrhosis is based on data from 288 subjects from the Phase 2/3 registrational trials treated with MAVYRET for 12 or more weeks and 343 subjects from EXPEDITION-8 treated with MAVYRET for 8 weeks. The adverse reactions observed were generally consistent with those observed in clinical studies of MAVYRET in non-cirrhotic subjects. In the Phase 2/3 registrational trials, the adverse reactions reported in greater than or equal to 5% of compensated cirrhotic subjects (n=288) treated across all durations of MAVYRET were fatigue (15%), headache (14%), nausea (8%), diarrhea (6%), and pruritus (6%).  In EXPEDITION-8, the adverse reactions reported in greater than or equal to 5% of compensated cirrhotic subjects (n=343) were fatigue (8%), pruritus (7%), and headache (6%). No subjects with compensated cirrhosis in the Phase 2/3 registrational trials (without severe renal impairment) or in EXPEDITION-8 discontinued treatment with MAVYRET due to an adverse reaction

    • Safety and efficacy data for subjects with genotype (GT) 5 and 6 Hepatitis C Virus (HCV) infection from the ENDURANCE-5,6 study

The product labeling was also updated to include:

  • A contraindication regarding the use of MAVYRET in patients with moderate hepatic impairment (Child-Pugh B) or those with any history of prior hepatic decompensation

  • A new subsection in WARNINGS AND PRECAUTIONS:  5.2, Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease

    • Postmarketing cases of hepatic decompensation/failure, including those with fatal outcomes, have been reported in patients treated with HCV NS3/4A protease inhibitor-containing regimens, including MAVYRET. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

    • The majority of patients with severe outcomes had evidence of advanced liver disease with moderate or severe hepatic impairment (Child-Pugh B or C) prior to initiating therapy with MAVYRET, including some patients reported as having compensated cirrhosis with mild liver impairment (Child-Pugh A) at baseline but with a prior decompensation event (i.e., prior history of ascites, variceal bleeding, encephalopathy). Rare cases of hepatic decompensation/failure were reported in patients without cirrhosis or with compensated cirrhosis (Child-Pugh A); many of these patients had evidence of portal hypertension. Events also occurred in patients taking a concomitant medication not recommended for coadministration, or in patients with confounding factors such as serious liver-related medical or surgical comorbidities. Cases typically occurred within the first 4 weeks of treatment (median of 27 days). 

    • In patients with compensated cirrhosis (Child Pugh A) or evidence of advanced liver disease such as portal hypertension, perform hepatic laboratory testing as clinically indicated; and monitor for signs and symptoms of hepatic decompensation such as the presence of jaundice, ascites, hepatic encephalopathy, and variceal hemorrhage. Discontinue MAVYRET in patients who develop evidence of hepatic decompensation/failure.

    • MAVYRET is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C) or those with any history of prior hepatic decompensation

  • A new subsection, 6.2, Post Marketing Experience

    • The following adverse reactions have been identified during post-approval use of MAVYRET. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

      • Skin and Subcutaneous Tissue Disorders: Angioedema

      • Hepatobiliary Disorders: Hepatic decompensation, hepatic failure

  • Information regarding INR fluctuations and dysglycemia to DRUG INTERACTIONS, Established and Other Potential Drug Interactions subsection

    • Clearance of HCV infection with direct-acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment.

    • Frequent monitoring of relevant laboratory parameters (e.g. International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as CYP P450 substrates with a narrow therapeutic index (e.g. certain immunosuppressants) is recommended effective use. Dose adjustments of concomitant medications may be necessary.

    • A new DRUG INTERACTIONS subsection 7.4, Medication-Assisted Treatment (MAT) for Opioid Use Disorder, to highlight drug interaction information.

      • No buprenorphine/naloxone or methadone dosage adjustment is required when used concomitantly with MAVYRET. There is insufficient information to make a recommendation regarding the concomitant use of naltrexone with MAVYRET.

The updated labels will soon be available at Drugs@FDA or DailyMed

 

Kimberly Struble

Division of Antiviral Products

Food and Drug Administration

 

Elizabeth Thompson

Division of Antiviral Products

Food and Drug Administration

 

Michael Stanfield Jr.

Division of Antiviral Products

Food and Drug Administration