Zepatier (Elbasvir Grazoprevir) is a combination of two direct-acting oral antiviral drugs used in the treatment of patients with chronic active hepatitis C Genotype 1 to 4.

Elbasvir and grazoprevir Uses:

• Chronic hepatitis C:

  • Treatment of chronic hepatitis C virus (HCV) genotype 1 or 4 infection in adults; though use it with ribavirin in certain patient populations.

• Off Label Use of Elbasvir and grazoprevir in Adults:

  • Chronic hepatitis C (genotype 3)

Zepatier (Elbasvir Grazoprevir) Dose in Adults

Zepatier (Elbasvir Grazoprevir) Dose in the treatment of Chronic hepatitis C (genotype 1a or 1b) (mono-infection or coinfection with HIV-1): Oral:

• Genotype 1a:

  • Treatment naive or peginterferon alfa + ribavirin treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) without baseline NS5A polymorphisms:
    • One tablet once a day for 12 weeks
  • Treatment naive or peginterferon alfa + ribavirin treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) with baseline NS5A polymorphisms (alternative agent):
    • One tablet once a day with concomitant ribavirin for 16 weeks (AASLD/IDSA 2017)
  • Peginterferon alfa + ribavirin + NS3/4A protease inhibitor treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) and without baseline NS5A polymorphisms (alternative agent):
    • One tablet once a day with concomitant ribavirin for 12 weeks.
  • Peginterferon alfa + ribavirin + NS3/4A protease inhibitor treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class) and with baseline NS5A polymorphisms (alternative agent):
    • One tablet once a day with concomitant ribavirin for 16 weeks.

• Genotype 1b:

  • Treatment naive or peginterferon alfa + ribavirin treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A):
    • One tablet once a day for 12 weeks
  • Peginterferon + ribavirin + NS3/4A protease inhibitor treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) (alternative agent):
    • One tablet once a day with concomitant ribavirin for 12 weeks.

Zepatier (Elbasvir Grazoprevir) Dose in the treatment of chronic hepatitis C (genotype 3) (off-label):

• Oral: Peginterferon alfa + ribavirin treatment-experienced with compensated cirrhosis (Child-Pugh class A):
  • One tablet once a day with concomitant sofosbuvir for 12 weeks.

Zepatier (Elbasvir Grazoprevir) Dose in the treatment of chronic hepatitis C (genotype 4): Oral:

• Treatment naive without cirrhosis or with compensated cirrhosis (Child-Pugh class A):
  • One tablet once on a daily basis for 12 weeks
• Peginterferon alfa + ribavirin treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) who experienced virologic relapse after earlier peginterferon/ribavirin therapy:
  • One tablet once on a daily basis for 12 weeks.
• Peginterferon alfa + ribavirin treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A) who experienced prior on-treatment failure while on peginterferon/ribavirin (alternative agent):
  • One tablet once a day with concomitant ribavirin for 16 weeks

Use in Children:

Not indicated.

Zepatier (Elbasvir Grazoprevir) Pregnancy Category: N

• Animal reproduction studies have shown that adverse events are rare.
• Hepatitis C treatment is not recommended for pregnant women.
• To reduce the risk of HCV transmission, HCV-infected women with childbearing potential may want to postpone pregnancy until treatment is completed.
• Treatment must be delayed until after birth if HCV infection is detected during pregnancy.
• Pregnant females should not be given antiviral medication that is directly effective without first undergoing clinical trials.
• If it is used with ribavirin in an amalgam, all warnings regarding ribavirin use and pregnancy/contraception must be observed.
• Refer to the ribavirin monograph for additional information.

Use of grazoprevir and elbasvir during lactation:

• It is not known if breast milk contains elbasvir and grazoprevir.
• According to the manufacturer, breastfeeding during therapy should be considered in light of the risks to the infant and the benefits to the mother.
• The spread of the hepatitis C viruses is not linked to breastfeeding.
• However, it is recommended that you stop breastfeeding if your baby has cracked or bleeding nipples.
• HIV co-infection means that breastfeeding is not recommended.

Zepatier (Elbasvir Grazoprevir) Dose in Kidney disease:

• CrCl >50 mL/minute:
  • No dosage adjustment is necessary.
• CrCl ≤50 mL/minute:
  • No dosage adjustment is necessary. If used with concomitant ribavirin, refer to ribavirin monograph for dosage adjustments.
• End-stage renal disease (ESRD) and hemodialysis (not removed by hemodialysis):
  • No dosage adjustment is necessary.

Zepatier (Elbasvir Grazoprevir) Dose in Liver disease:

• Mild impairment (Child-Pugh class A):
  • No dosage adjustment is necessary.
• Moderate or severe impairment (Child-Pugh class B or C):
  • Use is contraindicated.

Common Side Effects of Zepatier (Elbasvir Grazoprevir):

• Central nervous system:

  • Fatigue
  • Headache

• Gastrointestinal:

  • Nausea

Less Common Side Effects of Zepatier (Elbasvir Grazoprevir):

• Hepatic:

  • Increased serum alanine aminotransferase

Contraindications to Zepatier (Elbasvir Grazoprevir):

• Moderate to severe hepatic impairment (Child Puugh class B orC);
• Concurrent use with OATP1B1/3 (OATP1B1/3) inhibitors, which are expected to significantly increase grazoprevir plasma levels and induce strong cytochrome P4503A (CYP3A) activity.
• Concurrent use drugs that are contraindicated can include, but not necessarily:
  • Atazanavir,
  • carbamazepine,
  • Cyclosporine
  • darunavir,
  • efavirenz,
  • Lopinavir
  • phenytoin,
  • rifampin,
  • saquinavir,
  • St John's Wort,
  • tipranavir.
• Contraindications to ribavirin are also applicable if it is taken with ribavirin.

Canadian labeling (not US labeling).

• Hypersensitivity to elbasvir or grazoprevir, and any component of the formulation.
• If used with sofosbuvir, contraindications of sofosbuvir also apply.

Warnings and precautions

• Elevations of the ALT:

  • ALT elevations of >5 times the ULN have been seen generally in week 8 and beyond. However, these changes were mostly asymptomatic.
  • Patients over 65 years old, Asian patients and females may be at higher risk of ALT changes.
  • Patients should report weakness, fatigue, nausea/vomiting or discolored feces.
  • Perform liver function tests before and during treatment, at week 8 or as clinically indicated.
  • If ALT levels persist >10 times ULN, you should consider discontinuing therapy.
  • If you notice signs/symptoms such as hepatic inflammation, increased conjugated bilirubin, alkalinephosphatase or an international normalized rate (INR), discontinue the therapy.

• Diabetes:

  • A rapid reduction of hepatitis C viral loads during direct-acting antiviral therapy (DAA) for hepatitis C could lead to an improvement on glucose metabolism in patients suffering from diabetes.
  • If antidiabetic drugs are used at the same time, this may result in symptomatic hypoglycemia.
  • Monitor glucose tolerance changes and inform patients about the possibility of hypoglycemia while on DAA therapy, especially in the first three months.
  • Modifications to antidiabetic therapy might be necessary.

• Hepatic impairment

  • It is contraindicated in cases of severe or moderate impairment (Child-Pugh Class B or C).

• Hepatitis B virus activation: [US-Boxed Warning]

  • Hepatitis B virus reactivation (HBV), has been reported in HCV coinfected patients receiving or having completed treatment with direct-acting antivirals for HCV.
  • Some cases have led to fulminant liver disease, hepatic failure and even death.
  • Before initiating treatment, test all patients for evidences of HBV infection. Monitor HCV/HBV coinfected patients for flare-ups or HBV reactivation. Follow-up after treatment.
  • As soon as HBV infection is diagnosed, initiate treatment.
  • HBV reactivation was reported in HBsAg-positive patients and patients with confirmed HBV infection (e.g. HBsAg positive and anti-HBc negative. It is characterized as an abrupt increase of HBV replication, manifested by a rapid rise in serum HBV DNA levels; patients with resolved HBV infections may experience reactivation of HBsAg.
  • Patients who are taking immunosuppressants and chemotherapeutic agents may have a higher risk of HBV reactivation.

Elbasvir and grazoprevir: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Hepatic function (baseline, treatment week 8 and week 12 [if treatment duration is 16 weeks] and as clinically indicated).
• Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (antiHBc) prior to initiation;
• In patients with serologic evidence of hepatitis B virus (HBV) infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during treatment, and post-treatment follow-up.
• In genotype 1a patients, testing for the presence of virus with NS5A resistance-associated polymorphisms is suggested before the treatment initiation.
• Serum HCV-RNA at baseline, weeks 4, 8, 12, during treatment, follow up, and when clinically indicated.
• In patients with diabetes, monitor blood glucose and for signs/symptoms of hypoglycemia.

How to administer Zepatier (Elbasvir Grazoprevir)?

Oral: Administer without regard to meals.

Mechanism of action of Zepatier (Elbasvir Grazoprevir):

• Elbasvir is an HCV NS5A inhibitor, which is essential for virion assembly and viral replication.
• Grazoprevir, an inhibitor of HCV NS3/4A protease is necessary for the proteolytic cleavage (into mature forms the NS3A, NS4B and NS5A proteins) and is vital for viral replication.

Absorption:

• Not affected by meals.

Bioavailability:

• Elbasvir: 32%;
• Grazoprevir: 27%

Distribution:

• Elbasvir: Distribution into most tissue including hepatic;
• Grazoprevir: Predominantly hepatic distribution.

Protein binding:

• Elbasvir: >99.9% (albumin, alpha-1 acid glycoprotein);
• Grazoprevir: 98.8% (albumin, alpha-1 acid glycoprotein)

Metabolism:

• Elbasvir, Grazoprevir: Hepatic (partial oxidative metabolism via CYP3A); metabolites not detected in plasma.

Half-life elimination:

• Elbasvir: ~24 hours;
• Grazoprevir: ~31 hours

Time to peak:

• Elbasvir: Median: 3 hours (range: 3 to 6 hours);
• Grazoprevir: Median: 2 hours (range: 30 minutes to 3 hours)

Excretion:

• Feces (>90%);
• urine (<1%)

International Brands of Elbasvir Grazoprevir:

• Zepatier

Elbasvir Grazoprevir Brand Names in Pakistan:

No Brands Available in Pakistan.