Zepatier Side Effects Center

Last updated on RxList: 1/3/2022
Zepatier Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

What Is Zepatier?

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

What Are Side Effects of Zepatier?

Common side effects of Zepatier include:

  • fatigue,
  • headache,
  • nausea,
  • abdominal pain,
  • diarrhea,
  • shortness of breath,
  • rash or itching,
  • irritability,
  • joint pain,
  • depression, or
  • anemia.

Dosage for Zepatier

The recommended dosage of Zepatier is one tablet taken orally once daily with or without food.

What Drugs, Substances, or Supplements Interact with Zepatier?

Zepatier may interact with nafcillin, ketoconazole, bosentan, tacrolimus, HIV/AIDS medications, statin drugs, and modafinil. Tell your doctor all medications and supplements you use. During pregnancy, Zepatier should be taken only if prescribed. Its effects on a fetus are unknown.

Zepatier During Pregnancy or Breastfeeding

If Zepatier is administered with ribavirin, the combination regimen is not recommended in pregnant women and in men whose partners are pregnant. Consult your doctor. It is unknown if Zepatier passes into breast milk. If Zepatier is administered with ribavirin, the combination regimen is not recommended in nursing mothers. Consult your doctor before breastfeeding.

Additional Information

Our Zepatier (elbasvir and grazoprevir) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

QUESTION

Hepatitis C virus causes an infection of the ______________. See Answer
Zepatier Consumer Information

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

In rare cases, elbasvir and grazoprevir may cause serious liver injury. Tell your doctor right away if you have symptoms such as:

  • right-sided upper stomach pain or swelling;
  • nausea, vomiting, loss of appetite;
  • confusion, tiredness, feeling light-headed;
  • easy bruising or bleeding, vomiting blood;
  • diarrhea, black or bloody stools;
  • dark urine, clay-colored stools; or
  • yellowing of your skin or eyes.

If you also take ribavirin, tell your doctor if you have symptoms of low red blood cells (anemia):

  • pale skin, cold hands and feet;
  • unusual tiredness, feeling light-headed; or
  • shortness of breath.

Common side effects may include:

  • headache;
  • tiredness;
  • anemia; or
  • nausea.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

SLIDESHOW

Hepatitis: How Do You Get Hepatitis A, B, and C? See Slideshow
Zepatier Professional Information

SIDE EFFECTS

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

  • Increased Risk of ALT Elevations [see WARNINGS AND PRECAUTIONS].

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.

Clinical Trials In Adult Subjects

The safety of ZEPATIER in adult subjects 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) [see Clinical Studies].

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 HCVTreated with ZEPATIER for 12 Weeks in C-EDGE TN

C-EDGE TN
ZEPATIER
N=316
%
12 weeks
Placebo
N=105
%
12 weeks
Fatigue 11% 10%
Headache 10% 9%

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+ T-cell 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/RBV-Experienced Subjects with HCV Treated with ZEPATIER for 12 Weeks or ZEPATIER + Ribavirin for16 Weeks in C-EDGE TE

C-EDGE TE
ZEPATIER
N=105
%
12 weeks
ZEPATIER + Ribavirin
N=106
%
16 weeks
Anemia 0% 8%
Headache 0% 6%
Fatigue 5% 4%
Dyspnea 0% 4%
Rash or Pruritus 0% 4%
Irritability 1% 3%
Abdominal pain 2% 2%
Depression 1% 2%
Arthralgia 0% 2%
Diarrhea 2% 0%

The type and severity of adverse reactions with ZEPATIER with or without ribavirin in 10 treatment-experienced 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) [see Clinical Studies]. 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/RBV-Experienced Subjects with Stage 4 or 5 Chronic Kidney Disease and HCV Treated with ZEPATIERfor 12 Weeks in C-SURFER

ZEPATIER
N=122
%
12 weeks
ZEPATIER + Ribavirin
N=113
%
12 weeks
Nausea 11% 8%
Headache 11% 5%
Fatigue 5% 8%

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 [see WARNINGS AND PRECAUTIONS]. The frequency of late ALT elevations was higher in subjects with higher grazoprevir plasma concentrations [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY]. 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.

Clinical Trial In Pediatric Subjects

Adverse Reactions in Pediatric Subjects 12 Years of Age and Older

The safety of ZEPATIER was assessed in pediatric subjects 12 years of age and older based on data from 22 subjects, without cirrhosis, who were treated with ZEPATIER for 12 weeks in a Phase 2b, open-label clinical trial (MK-5172-079). The adverse reactions observed were consistent with those observed in clinical trials of ZEPATIER in adults [see Clinical Studies]. The adverse drug reactions observed in greater than or equal to 5% of subjects receiving ZEPATIER were headache (14%) and nausea (9%).

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

Hepatobiliary Disorders

Hepatic decompensation, hepatic failure [see WARNINGS AND PRECAUTIONS]

DRUG INTERACTIONS

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 [see CONTRAINDICATIONS, CLINICAL PHARMACOLOGY], and Table 2.

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 [see CONTRAINDICATIONS, CLINICAL PHARMACOLOGY], and Table 2. Co-administration of ZEPATIER with moderate CYP3A inducers is not recommended [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY], and Table 6. 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 [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY], and Table 6.

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.

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 CYP450 substrates with a narrow therapeutic index (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary.

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 [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].

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

Concomitant Drug
Class: Drug Name
Effect on Concentration Clinical Comment
Antibiotics:
Nafcillin
↓ EBR
↓ GZR
Co-administration of ZEPATIER with nafcillin may lead to reduced therapeutic effect of ZEPATIER. Co-administration is not recommended.
Antifungals:
oral Ketoconazole
↑ EBR
↑ GZR
Co-administration of oral ketoconazole is not recommended.
Endothelin
Antagonists:

Bosentan
↓ EBR
↓ GZR
Co-administration of ZEPATIER with bosentan may lead to reduced therapeutic effect of ZEPATIER. Co-administration is not recommended.
Immunosuppressants:
Tacrolimus
↑ tacrolimus Frequent monitoring of tacrolimus whole blood concentrations, changes in renal function, and tacrolimus-associated adverse events upon the initiation of co-administration is recommended.
HIV Medications:
Etravirine ↓ EBR
↓ GZR
Co-administration of ZEPATIER with etravirine may lead to reduced therapeutic effect of ZEPATIER. Co-administration is not recommended.
Elvitegravir/ cobicistat/ emtricitabine/ tenofovir (disoproxil fumarate or alafenamide) ↑ EBR
↑ GZR
Co-administration of cobicistat-containing regimens is not recommended.
HMG-CoA Reductase Inhibitors§:
Atorvastatin ↑ atorvastatin The dose of atorvastatin should not exceed a daily dose of 20 mg when co-administered with ZEPATIER.§
Rosuvastatin ↑ rosuvastatin The dose of rosuvastatin should not exceed a daily dose of 10 mg when co-administered with ZEPATIER.§
Fluvastatin
Lovastatin
Simvastatin
↑ fluvastatin
↑ lovastatin
↑ simvastatin
Statin-associated adverse events such as myopathy should be closely monitored. The lowest necessary dose should be used when co-administered with ZEPATIER.§
Wakefulness-
Promoting Agents:

Modafinil
↓ EBR
↓ GZR
Co-administration of ZEPATIER with modafinil may lead to reduced therapeutic effect of ZEPATIER. Co-administration is not recommended.
*This table is not all inclusive.
↓ = decrease, ↑ = increase
These interactions have been studied in healthy adults.
§See Drugs Without Clinically Significant Interactions With ZEPATIER for a list of HMG Co-A reductase inhibitors without clinically relevant interactions with ZEPATIER.

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 [see CLINICAL PHARMACOLOGY].

No clinically relevant drug-drug interaction is expected when ZEPATIER is co-administered with abacavir, emtricitabine, entecavir, and lamivudine.

Read the entire FDA prescribing information for Zepatier (Elbasvir and Grazoprevir Tablets)

© Zepatier Patient Information is supplied by Cerner Multum, Inc. and Zepatier Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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