ZEPATIER® (elbasvir + grazoprevir)

• ACRONYMS AND DEFINITIONS

• AASLD - American Association for the Study of Liver Diseases
• CP - Child-Pugh liver failure classification
• GT - Genotype
• HBV - Hepatitis B virus
• HCV - Hepatitis C virus
• IDSA - Infectious Diseases Society of America
• PegIFN - Pegylated interferon
• RBV - Ribavirin
• ULN - Upper limit of normal

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• DRUGS IN CLASS

• Zepatier is part of a new generation of antiviral medications that are highly effective against hepatitis C
• Zepatier is a combination pill that contains 2 medications - elbasvir and grazoprevir
• See Hepatitis C treatment for a list of other HCV drugs

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• MECHANISM OF ACTION

• Elbasvir
• Elbasvir is an inhibitor of HCV NS5A protein, which is essential for viral RNA replication and virion assembly


• Grazoprevir
• Grazoprevir is HCV NS3/4A protease inhibitor
• HCV NS3/4A protease cleaves HCV-encoded polyprotein into the individual proteins NS3, NS4A, NS4B, NS5A, and NS5B. These proteins form a complex that is necessary for viral replication.
• Illustration of mechanism of action of hepatitis C drugs

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• FDA-APPROVED INDICATIONS

• Treatment of HCV genotype 1 (with and without ribavirin) - in adults and patients ≥ 12 years of age weighing at least 30 kg (66 lbs) without cirrhosis or with Child-Pugh A
• Treatment of HCV genotype 4 (with and without ribavirin) - in adults and patients ≥ 12 years of age weighing at least 30 kg (66 lbs) without cirrhosis or with Child-Pugh A

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• HEPATITIS C TREATMENT

• HCV genotype 1
• in trials, Zepatier ± ribavirin was > 90% effective in eradicating HCV genotype 1
• HCV genotype 4
• In trials, Zepatier ± ribavirin was > 90% effective in eradicating HCV genotype 4

• NS5A polymorphism
• Certain strands of the HCV genotype 1 have different amino acid sequences (polymorphisms) in their NS5A protein. These polymorphisms can confer resistance to medications.
• The effectiveness of Zepatier was reduced in patients with HCV genotype 1a NS5A polymorphisms (M28, Q30, L31, or Y93)
• The manufacturer of Zepatier recommends testing for NS5A polymorphisms in HCV genotype 1a-infected patients before starting therapy
• Patients who are positive for resistance-associated polymorphisms should have ribavirin added to their therapy and be treated for 16 weeks

• SVR - sustained virological response 12 weeks after treatment ended (cure)
• RBV was weight based - see ribavirin dosing
• References [1]

HCV genotype 1a response to therapy
Treatment	Polymorphism (M28, Q30, L31, or Y93)	SVR at 12 weeks
Zepatier for 12 weeks	No	98% (441/450)
Zepatier + RBV for 16 weeks	No	100% (49/49)
Zepatier for 12 weeks	Yes	70% (39/56)
Zepatier + RBV for 16 weeks	Yes	100% (6/6)

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• SIDE EFFECTS

• General
• In trials, the incidence of side effects with Zepatier was similar to placebo
• The two most commonly reported side effects were fatigue (Zepatier - 11% | Placebo - 10%) and headache (Zepatier - 10% | Placebo - 9%)
• In the Zepatier and placebo groups, only 1% of patients discontinued treatment because of adverse reactions

• Elevated liver enzymes
• In trials, 1% of Zepatier-treated patients experienced ALT elevations > 5 X ULN
• Elevations were typically asymptomatic and most resolved with ongoing therapy or at the completion of therapy
• The manufacturer recommends checking LFTs prior to therapy, at treatment week 8, and when clinically indicated
• Consider stopping Zepatier if ALT elevations are persistently > 10 X ULN
• Discontinue Zepatier if ALT elevations are accompanied by signs of liver failure (e.g. fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, discolored feces, elevated bilirubin, increased INR, etc.)

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• CONTRAINDICATIONS

• Child-Pugh B or C - may lead to significantly increased grazoprevir plasma concentration and increased risk of ALT elevations
• History of hepatic decompensation - patients with a history of hepatic decompensation should not take Zepatier because the risk of recurrent decompensation is increased.
• Concomitant OATP1B1/3 inhibitors - grazoprevir is a sensitive OATP1B1/3 substrate
• Concomitant CYP3A4 strong inducers - elbasvir and grazoprevir are both sensitive CYP3A substrates
• Concomitant efavirenz (Sustiva®) - efavirenz is a moderate CYP3A4 inducer
• Other medications - the Zepatier PI contains a list of other medications that are contraindicated with Zepatier - see Zepatier PI [sec 4] for a complete list

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• PRECAUTIONS

• Kidney disease
• No dose adjustment is necessary for any degree of renal impairment including patients receiving hemodialysis

• Liver disease
• Child Pugh A: no dose adjustment necessary
• Child-Pugh B or C: DO NOT USE
• History of hepatic decompensation: DO NOT USE
• Rare cases of worsening liver function or liver failure have occurred in patients with moderate to severe liver disease who took Zepatier. Zepatier should also not be used in patients with a history of hepatic decompensation.
• 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 Zepatier in patients who develop evidence of hepatic decompensation.

• Asian patients
• In trials, higher levels of elbasvir and grazoprevir were observed in Asian patients
• Asian patients also had a higher incidence of ALT elevations (2% of Asians vs 1% overall)
• No dose adjustment is recommended

• Female patients
• In trials, higher levels of elbasvir and grazoprevir were observed in female patients
• Female patients also had a higher incidence of ALT elevations (2% of females vs 1% overall)
• No dose adjustment is recommended

• Elderly patients (≥ 65 years)
• In trials, higher levels of elbasvir and grazoprevir were observed in elderly patients
• Elderly patients also had a higher incidence of ALT elevations (2% of elderly vs 1% overall)
• No dose adjustment is recommended

• Hepatitis B coinfection
• In October 2016, the FDA placed a boxed warning on all new hepatitis C drugs about the possible reactivation of hepatitis B infection in coinfected patients who are taking direct-acting antiviral hepatitis C drugs
• At the time of the warning, the FDA had identified 24 cases of hepatitis B reactivation in patients taking these drugs. Reactivation occurred in patients who were HBsAg positive and in those who were HBsAg negative and anti-HBc positive (see interpreting HBV screening results for more).
• The FDA recommends that providers check all patients for hepatitis B coinfection (HBsAg and anti-HBc) before starting therapy and that they monitor patients for reactivation during and after therapy
• See AASLD guidelines for HBV coinfected patients for more

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• MONITORING THERAPY

• Manufacturer's recommendation
• The manufacturer recommends checking LFTs prior to therapy, at treatment week 8, and when clinically indicated
• Consider stopping Zepatier if ALT elevations are persistently > 10 X ULN
• Discontinue Zepatier if ALT elevations are accompanied by signs of liver failure (e.g. fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, discolored feces, elevated bilirubin, increased INR, etc.)


• AASLD recommendations
• See AASLD lab recommendations for HCV treatment

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• DRUG INTERACTIONS

• NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.

• Drug interactions
• Elbasvir and Grazoprevir are metabolized and eliminated through a number of pathways that can lead to significant drug interactions
• Zepatier is contraindicated with a number of medications, and it has the potential to interact with many others
• See the Zepatier PI for a list of drug contraindications [sec 4] and drug interactions [sec 7]

• Metabolism and clearance
• Elbasvir
• CYP3A - sensitive substrate
• P-glycoprotein - substrate
• BCRP - inhibitor
• Grazoprevir
• OATP1B1/3 - sensitive substrate
• CYP3A - sensitive substrate, weak inhibitor
• P-glycoprotein - substrate
• BCRP - inhibitor

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• DOSING

• Dosage form
• Zepatier tablet contains elbasvir 50 mg and grazoprevir 100 mg
• Comes in a carton that contains 2 blister pack cards with 14 pills on each card

• Dosing (adults and patients ≥ 12 years of age weighing at least 30 kg (66 lbs))
• One tablet once daily with or without food

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• HEPATITIS C TREATMENT RECOMMENDATIONS

• Hepatitis C treatment recommendations

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• LONG TERM SAFETY

• Zepatier® was FDA-approved in 2014
• There is no long-term safety data available

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• BIBLIOGRAPHY

• 1 - Zepatier® PI