Side Effects of Zepatier (elbasvir and grazoprevir)

Zepatier (elbasvir and grazoprevir) is a combination of two direct-acting antiviral agents used to treat chronic infection with the hepatitis C virus (HCV), genotype 1 and 4 in adults.

• Elbasvir directly blocks replication of HCV by interfering with a hepatitis C virus enzyme called NS5A.
• Grazoprevir is an inhibitor of another hepatitis C virus enzyme called NS3/4A, which also is needed for viral replication.
• Both drugs in Zepatier interfere with enzymes needed by hepatitis C virus to multiply and make new viruses, thus reducing the overall viral load.
• The efficacy of Zepatier has been established in subjects with hepatitis C virus genotypes 1 and 4.
• Zepatier may be administered with or without ribavirin.
• In clinical studies, 95% of patients who were not previously treated for their hepatitis C virus were cured after 12 weeks of Zepatier treatment. 

Common side effects of Zepatier include:

• fatigue,
• headache,
• nausea,
• insomnia, and
• diarrhea.

Other side effects of Zepatier include:

• abdominal pain,
• irritability,
• depression,
• anemia (when combined with ribavirin),
• elevations in levels of liver enzymes,
• increased bilirubin,
• joint pain,
• shortness of breath,
• rash, and
• reactivation of hepatitis B virus infection (HBV).

Drug interactions of Zepatier include the following, which may reduce blood levels of Zepatier: 

• nafcillin,
• bosentan,
• seizure medications,
• rifampin,
• St. John's wort,
• antiretroviral medications to treat HIV/AIDS,
• efavirenz,
• etravirine, and
• modafinil.

Combining Zepatier with cyclosporine or ketoconazole may increase the risk of liver enzyme elevations.

Zepatier increases blood levels of some statins.

Zepatier has not been adequately evaluated in pregnant women. However, ribavirin which may be combined with this drug should not be used by pregnant women or their male partners.

It is unknown if Zepatier is secreted into breast milk. Consult your doctor before breastfeeding. 

Common side effects include:

• Fatigue
• Headache
• Nausea
• Insomnia
• Diarrhea

Other side effects include:

• Abdominal pain
• Irritability
• Depression
• Anemia (when combined with ribavirin)
• Elevations in levels of liver enzymes
• Increased bilirubin
• Joint pain
• Shortness of breath
• Rash
• Reactivation of hepatitis B virus infection (HBV)

The following adverse reaction is described below and elsewhere in the labeling:

• Increased Risk of ALT Elevations.

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• If Zepatier is administered with ribavirin, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions.
• The safety of Zepatier was assessed based on 2 placebo-controlled trials and 7 uncontrolled Phase 2 and 3 clinical trials in approximately 1700 subjects with chronic hepatitis C virus infection with compensated liver disease (with or without cirrhosis).

Adverse Reactions With Zepatier In Treatment-Naive Subjects

• C-EDGE TN was a Phase 3 randomized, double-blind, placebo-controlled trial in 421 treatment-Naive (TN) subjects with HCV infection who received Zepatier or placebo one tablet once daily for 12 weeks.
• Adverse reactions (all intensity) occurring in C-EDGE TN in at least 5% of subjects treated with Zepatier for 12 weeks are presented in Table 3.
• In subjects treated with Zepatier who reported an adverse reaction, 73% had adverse reactions of mild severity.
• The type and severity of adverse reactions in subjects with compensated cirrhosis were comparable to those seen in subjects without cirrhosis.
• No subjects treated with Zepatier or placebo had serious adverse reactions.
• The proportion of subjects treated with Zepatier or placebo who permanently discontinued treatment due to adverse reactions was 1% in each group.

Table 3: Adverse Reactions (All Intensity) Reported in ≥5% of Treatment-Naive Subjects with HCV Treated with Zepatier for 12 Weeks in C-EDGE TN

• C-EDGE COINFECTION was a Phase 3 open-label trial in 218 treatment-Naive HCV/HIV co-infected subjects who received Zepatier one tablet once daily for 12 weeks.
• Adverse reactions (all intensity) reported in C-EDGE COINFECTION in at least 5% of subjects treated with Zepatier for 12 weeks were fatigue (7%), headache (7%), nausea (5%), insomnia (5%), and diarrhea (5%).
• No subjects reported serious adverse reactions or discontinued treatment due to adverse reactions.
• No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression.
• Median increase in CD4+ Tcell counts of 31 cells per mm³ was observed at the end of 12 weeks of treatment.

Adverse Reactions With Zepatier With Or Without Ribavirin In Treatment-Experienced Subjects

• C-EDGE TE was a Phase 3 randomized, open-label trial in treatment-experienced (TE) subjects.
• Adverse reactions of moderate or severe intensity reported in C-EDGE TE in at least 2% of subjects treated with Zepatier one tablet once daily for 12 weeks or Zepatier one tablet once daily with ribavirin for 16 weeks are presented in Table 4.
• No subjects treated with Zepatier without ribavirin for 12 weeks reported serious adverse reactions or discontinued treatment due to adverse reactions.
• The proportion of subjects treated with Zepatier with ribavirin for 16 weeks with serious adverse reactions was 1%.
• The proportion of subjects treated with Zepatier with ribavirin for 16 weeks who permanently discontinued treatment due to adverse reactions was 3%.
• The type and severity of adverse reactions in subjects with cirrhosis were comparable to those seen in subjects without cirrhosis.

Table 4: Adverse Reactions (Moderate or Severe Intensity) Reported in ≥2% of PegIFN/RBVExperienced Subjects with HCV Treated with Zepatier for 12 Weeks or Zepatier + Ribavirin for 16 Weeks in C-EDGE TE

• The type and severity of adverse reactions with Zepatier with or without ribavirin in 10 treatmentexperienced subjects with HCV/HIV co-infection were comparable to those reported in subjects without HIV co-infection. Median increase in CD4+ T-cell counts of 32 cells/mm³ was observed at the end of 12 weeks of treatment with Zepatier alone.
• In subjects treated with Zepatier with ribavirin for 16 weeks, CD4+ T-cell counts decreased a median of 135 cells per mm³ at the end of treatment.
• No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. No subject experienced an AIDS-related opportunistic infection.
• C-SALVAGE was a Phase 2 open-label trial in 79 PegIFN/RBV/PI-experienced subjects. Adverse reactions of moderate or severe intensity reported in C-SALVAGE in at least 2% of subjects treated with Zepatier once daily with ribavirin for 12 weeks were fatigue (3%) and insomnia (3%).
• No subjects reported serious adverse reactions or discontinued treatment due to adverse reactions.

Adverse Reactions With Zepatier In Subjects With Severe Renal Impairment Including Subjects On Hemodialysis

• The safety of elbasvir and grazoprevir in comparison to placebo in subjects with severe renal impairment (Stage 4 or Stage 5 chronic kidney disease, including subjects on hemodialysis) and chronic hepatitis C virus infection with compensated liver disease (with or without cirrhosis) was assessed in 235 subjects (C-SURFER).
• The adverse reactions (all intensity) occurring in at least 5% of subjects treated with Zepatier for 12 weeks are presented in Table 5. In subjects treated with Zepatier who reported an adverse reaction, 76% had adverse reactions of mild severity.
• The proportion of subjects treated with Zepatier or placebo with serious adverse reactions was less than 1% in each treatment arm, and less than 1% and 3% of subjects, respectively, permanently discontinued treatment due to adverse reactions in each treatment arm.

Table 5: Adverse Reactions (All Intensity) Reported in ≥5% of Treatment-Naive or PegIFN/RBVExperienced Subjects with Stage 4 or 5 Chronic Kidney Disease and HCV Treated with Zepatier for 12 Weeks in C-SURFER

Laboratory Abnormalities In Subjects Receiving Zepatier With Or Without Ribavirin

Serum ALT Elevations

• During clinical trials with Zepatier with or without ribavirin, regardless of treatment duration, 1% (12/1599) of subjects experienced elevations of ALT from normal levels to greater than 5 times the ULN, generally at or after treatment week 8 (mean onset time 10 weeks, range 6-12 weeks).
• These late ALT elevations were typically asymptomatic.
• Most late ALT elevations resolved with ongoing therapy with Zepatier or after completion of therapy.
• The frequency of late ALT elevations was higher in subjects with higher grazoprevir plasma concentrations.
• The incidence of late ALT elevations was not affected by treatment duration.
• Cirrhosis was not a risk factor for late ALT elevations.

Serum Bilirubin Elevations

• During clinical trials with Zepatier with or without ribavirin, regardless of treatment duration, elevations in bilirubin at greater than 2.5 times ULN were observed in 6% of subjects receiving Zepatier with ribavirin compared to less than 1% in those receiving Zepatier alone.
• These bilirubin increases were predominately indirect and generally observed in association with ribavirin co-administration. Bilirubin elevations were typically not associated with serum ALT elevations.

Decreased Hemoglobin

• During clinical trials with Zepatier with or without ribavirin, the mean change from baseline in hemoglobin levels in subjects treated with Zepatier for 12 weeks was -0.3 g per dL and with Zepatier with ribavirin for 16 weeks was approximately -2.2 g per dL.
• Hemoglobin declined during the first 8 weeks of treatment, remained low during the remainder of treatment, and normalized to baseline levels during follow-up.
• Less than 1% of subjects treated with Zepatier with ribavirin had hemoglobin levels decrease to less than 8.5 g per dL during treatment.
• No subjects treated with Zepatier alone had a hemoglobin level less than 8.5 g per dL.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Zepatier. 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

Potential For Drug Interactions

• Grazoprevir is a substrate of OATP1B1/3 transporters. Co-administration of Zepatier with OATP1B1/3 inhibitors that are known or expected to significantly increase grazoprevir plasma concentrations is contraindicated.
• Elbasvir and grazoprevir are substrates of CYP3A and P-gp, but the role of intestinal P-gp in the absorption of elbasvir and grazoprevir appears to be minimal.
• Co-administration of moderate or strong inducers of CYP3A with Zepatier may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of Zepatier.
• Co-administration of Zepatier with strong CYP3A inducers or efavirenz is contraindicated. Coadministration of Zepatier with moderate CYP3A inducers is not recommended.
• Co-administration of Zepatier with strong CYP3A inhibitors may increase elbasvir and grazoprevir concentrations.
• Co-administration of Zepatier with certain strong CYP3A inhibitors is not recommended.
• Fluctuations in INR values may occur in patients receiving warfarin concomitantly with HCV treatment, including treatment with Zepatier.
• Frequent monitoring of INR values is recommended during treatment and post-treatment follow-up.

Established And Other Potentially Significant Drug Interactions

• If dose adjustments of concomitant medications are made due to treatment with Zepatier, doses should be readjusted after administration of Zepatier is completed.
• Table 6 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either Zepatier, the components of Zepatier (elbasvir [EBR] and grazoprevir [GZR]) as individual agents, or are predicted drug interactions that may occur with Zepatier.

Table 6: Potentially Significant Drug Interactions: Alteration in Dose May Be Recommended Based on Results from Drug Interaction Studies or Predicted Interactions*

Drugs Without Clinically Significant Interactions With Zepatier

The interaction between the components of Zepatier (elbasvir or grazoprevir) or Zepatier and the following drugs were evaluated in clinical studies, and no dose adjustments are needed when Zepatier is used with the following drugs individually:

• acid reducing agents (proton pump inhibitors, H2 blockers, antacids),
• buprenorphine/naloxone,
• digoxin,
• dolutegravir,
• methadone,
• mycophenolate mofetil,
• oral contraceptive pills,
• phosphate binders,
• pitavastatin,
• pravastatin,
• prednisone,
• raltegravir,
• ribavirin,
• rilpivirine,
• tenofovir disoproxil fumarate, and
• sofosbuvir.

No clinically relevant drug-drug interaction is expected when Zepatier is co-administered with:

• abacavir,
• emtricitabine,
• entecavir, and
• lamivudine.