FDA approves Zepatier for treatment of chronic hepatitis C genotypes 1 and 4.

zep1
Image- Merck & Co. Inc

January 28, 2016

The U.S. Food and Drug Administration approved Zepatier (elbasvir and grazoprevir) with or without ribavirin for the treatment of  chronic hepatitis C virus (HCV) genotypes 1 and 4 infections in adult patients.

DESCRIPTION

  • ZEPATIER is a fixed-dose combination tablet containing elbasvir and grazoprevir for oral administration.
  • Elbasvir is an HCV NS5A inhibitor, and grazoprevir is an HCV NS3/4A protease inhibitor.
  • Each tablet contains 50 mg elbasvir and 100 mg grazoprevir.

Elbasvir:

It has a molecular formula of C49H55N9O7 and a molecular weight of 882.02. It has the following structural formula:

ebas
ELBASVIR

Grazoprevir:

It has a molecular formula of C38H50N6O9S and a molecular weight of 766.90. It has the following structural formula:

grazo
GRAZOPREVIR

CLINICAL PHARMACOLOGY

 Mechanism of Action

  • ZEPATIER is a fixed-dose combination of elbasvir and grazoprevir which are direct-acting antiviral agents against the hepatitis C virus.
  • ZEPATIER combines two direct-acting antiviral agents with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle.
  • Elbasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of elbasvir has been characterized based on cell culture antiviral activity and drug resistance mapping studies.
  • Grazoprevir is an inhibitor of the HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication.
  • In a biochemical assay, grazoprevir inhibited the proteolytic activity of the recombinant HCV genotype 1a, 1b, and 4a NS3/4A protease enzymes with IC50 values of 7pM, 4 pM, and 62 pM, respectively.

Combination Antiviral Activity

  • Evaluation of elbasvir in combination with grazoprevir or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells.
  • Evaluation of grazoprevir in combination with ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells.

INDICATIONS AND USAGE

ZEPATIER is a fixed-dose combination product containing elbasvir, a hepatitis C virus (HCV) NS5A inhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor, and is indicated with or without ribavirin for treatment of chronic HCV genotypes 1 or 4 infection in adults.

DOSAGE AND ADMINISTRATION

Testing Prior to the Initiation of Therapy

NS5A Resistance Testing in HCV Genotype 1a-Infected Patients Testing patients with HCV genotype 1a infection for the presence of virus with NS5A resistance associated polymorphisms is recommended prior to initiation of treatment with ZEPATIER to determine dosage regimen and duration.

In subjects receiving ZEPATIER for 12 weeks, sustained virologic response (SVR12) rates were lower in genotype 1a-infected patients with one or more baseline NS5A resistance-associated polymorphisms at amino acid positions 28, 30, 31, or 93.

Hepatic Laboratory Testing

Obtain hepatic laboratory testing prior to and during treatment with ZEPATIER.

Recommended Dosage in Adults

ZEPATIER is a two-drug, fixed-dose combination product containing 50 mg of elbasvir and 100 mg of grazoprevir in a single tablet. The recommended dosage of ZEPATIER is one tablet taken orally once daily with or without food.

Treatment Regimen and Duration of Therapy

Table 1 below provides the recommended ZEPATIER treatment regimen and duration based on the patient population and genotype in HCV mono-infected and HCV/HIV-1 co-infected patients with or without cirrhosis and with or without renal impairment including patients receiving hemodialysis.

ZEP

  • Renal Impairment : No dosage adjustment of ZEPATIER is recommended in patients with any degree of renal impairment including patients on hemodialysis.
  • Hepatic Impairment: No dosage adjustment of ZEPATIER is recommended in patients with mild hepatic impairment (Child-Pugh A). ZEPATIER is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C).

DOSAGE FORMS AND STRENGTHS

  • Tablets: 50 mg elbasvir and 100 mg grazoprevir.

Safety and Efficacy

  • The safety and efficacy of Zepatier with or without ribavirin was evaluated in clinical trials of 1,373 participants with chronic HCV genotype 1 or 4 infections with and without cirrhosis.
  • The participants received Zepatier with or without ribavirin once daily for 12 or 16 weeks.
  • The studies were designed to measure whether a participant’s hepatitis C virus was no longer detected in the blood 12 weeks after finishing treatment (sustained virologic response or SVR), suggesting a participant’s infection had been cured.

CONTRAINDICATIONS

  • Patients with moderate or severe hepatic impairment (Child-Pugh B or C).
  • OATP1B1/3 inhibitors, strong CYP3A inducers, and efavirenz.
  • If ZEPATIER is administered with ribavirin, the contraindications to ribavirin also apply.

 WARNINGS AND PRECAUTIONS

  • ALT elevations: Perform hepatic laboratory testing prior to therapy, at treatment week 8, and as clinically indicated. For patients receiving 16 weeks of therapy, perform additional hepatic laboratory testing at treatment week 12.
  • Risk associated with ribavirin combination treatment: If ZEPATIER is administered with ribavirin, the warnings and precautions for ribavirin also apply.

ADVERSE REACTIONS

  • In subjects receiving ZEPATIER for 12 weeks, the most commonly reported adverse reactions of all intensity (greater than or equal to 5% in placebo-controlled trials) were fatigue, headache, and nausea.
  • In subjects receiving ZEPATIER with ribavirin for 16 weeks, the most commonly reported adverse reactions of moderate or severe intensity (greater than or equal to 5%) were anemia and headache.

 

Zepatier carries a warning alerting patients and health care providers that elevations of liver enzymes to greater than five times the upper limit of normal occurred in approximately 1 percent of clinical trial participants, generally at or after treatment week eight. Liver-related blood tests should be performed prior to starting therapy and at certain times during treatment.

Zepatier was granted breakthrough therapy designation for the treatment of chronic HCV genotype 1 infection in patients with end stage renal disease on hemodialysis and for the treatment of chronic HCV genotype 4 infection.

Breakthrough therapy designation is a program designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint.

Zepatier is marketed by Merck & Co. Inc. based in Whitehouse Station, New Jersey.

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