Does Zepatier (elbasvir and grazoprevir) cause side effects?
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:
Other side effects of Zepatier include:
- abdominal pain,
- 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:
- seizure medications,
- St. John's wort,
- antiretroviral medications to treat HIV/AIDS,
- etravirine, and
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.
What are the side effects of Zepatier (elbasvir and grazoprevir)?
Common side effects include:
Other side effects include:
- Abdominal pain
- Anemia (when combined with ribavirin)
- Elevations in levels of liver enzymes
- Increased bilirubin
- Joint pain
- Shortness of breath
- Reactivation of hepatitis B virus infection (HBV)
Zepatier (elbasvir and grazoprevir) side effects list for healthcare professionals
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
|Zepatier + Ribavirin|
|Rash or Pruritus||0%||4%|
- 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.
- 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.
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
What drugs interact with Zepatier (elbasvir and grazoprevir)?
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*
|Concomitant Drug Class: Drug Name||Effect on Concentration†||Clinical Comment|
|Antibiotics: nafcillin||↓ EBR|
|Co-administration of Zepatier with nafcillin may lead to reduced therapeutic effect of Zepatier. Coadministration is not recommended.|
|Antifungals: oral ketoconazole*||↑ EBR|
|Co-administration of oral ketoconazole is not recommended.|
|Endothelin Antagonists: bosentan||↓ EBR|
|Co-administration of Zepatier with bosentan may lead to reduced therapeutic effect of Zepatier. Coadministration 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.|
|Co-administration of Zepatier with etravirine may lead to reduced therapeutic effect of Zepatier. Coadministration is not recommended.|
|elvitegravir/ cobicistat/ emtricitabine/ tenofovir (disoproxil fumarate* or alafenamide)||↑ EBR|
|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|
|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|
|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 DRUG INTERACTIONS 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),
- mycophenolate mofetil,
- oral contraceptive pills,
- phosphate binders,
- tenofovir disoproxil fumarate, and
No clinically relevant drug-drug interaction is expected when Zepatier is co-administered with:
- entecavir, and
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. Common side effects of Zepatier include fatigue, headache, nausea, insomnia, and diarrhea. 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.
Multimedia: Slideshows, Images & Quizzes
Hepatitis: Surprising Things That Can Damage Your Liver
Alcohol and acetaminophen are well-known liver dangers, but what else can be harmful? WebMD says some of them may surprise you.
What Is Viral Hepatitis? How You Catch Hepatitis A, B, and C
Hepatitis C virus and hepatitis B can make an infected person very sick and they are risk factors for liver cancer, liver...
Liver Health: 14 Best and Worst Foods for Your Liver
Get some simple diet tips to keep your liver healthy, including the best veggies to keep disease away and some snacks you'll want...
Hepatitis C, Hep B, Hep A: Symptoms, Causes, Treatment
Hepatitis C, B, and A are viruses that cause liver inflammation. Hepatitis B vaccines and hepatitis A vaccines are available....
Hepatitis C (Hep C): Symptoms, Treatments, Antivirals
What is hepatitis C (Hep C, HVC)? Learn about hepatitis C symptoms, how you get Hep C, contagiousness, and treatment for...
Hepatitis A Quiz: Test Your Medical IQ
How many types of hepatitis are there, and what is different about hepatitis A? Take this quiz to find out!
Hepatitis C Quiz: What is Hepatitis C?
How many Americans have hepatitis C? Take this quiz to learn the facts about this chronic disease.
Picture of Hepatitis B
Inflammation of the liver due to the hepatitis B virus (HBV), once thought to be passed only through blood products. See a...
Related Disease Conditions
Hepatitis (Viral Hepatitis A, B, C, D, E, G)
Hepatitis is most often viral, due to infection with one of the hepatitis viruses (A, B, C, D, E, F (not confirmed), and G) or another virus (such as those that cause infectious mononucleosis, cytomegalovirus disease). The main nonviral causes of hepatitis are alcohol and drugs. Many patients infected with hepatitis A, B, and C have few or no symptoms of illness. For those who do develop symptoms of viral hepatitis, the most common are flu-like symptoms including: loss of appetite, nausea, vomiting, fever, weakness, tiredness, and aching in the abdomen. Treatment of viral hepatitis is dependent on the type of hepatitis.
Hepatitis C (HCV, Hep C)
Hepatitis C is an inflammation of the liver due to the hepatitis C virus (HCV), which is usually spread by blood transfusion, hemodialysis, and needle sticks, especially with intravenous drug abuse. Symptoms of chronic hepatitis include fatigue, fever, muscle aches, loss of appetite, and fever. Chronic hepatitis C may be cured in most individuals with drugs that target specific genomes of hepatitis C.
Is Hepatitis Contagious?
Hepatitis means "inflammation of the liver," and there are several different types of such as A, B, C, D, and E. Some types of hepatitis are contagious and some types are not. Hepatitis symptoms vary upon the type of disease; however, the following symptoms may develop in someone with hepatitis: fatigue, nausea and vomiting, abdominal pain and discomfort, jaundice (yellowing of the skin and whites of the eyes), and loss of appetite. Treatment for hepatitis depends upon the cause. Some types of hepatitis have a vaccine to prevent spread of disease such as hepatitis A and B.
Hepatitis A and B Vaccinations
Hepatitis A and hepatitis B are the two most commnon viruses that infect the liver. Hepatitis A and Hepatitis B can be prevented and treated with immunizations (vaccinations) such as Havrix, Vaqta, Twinrix, Comvax, Pediarix, and hepatitis b immune globulin (HBIG).
Is Hepatitis B Contagious?
Hepatitis B is a type of liver infection. Hepatitis B is spread through person-to-person contact or through personal items like razors, toothbrushes, etc. Symptoms of hepatitis B include fever, yellowish skin (jaundice), dark urine, fatigue, nausea, and vomiting. There is no drug to cure hepatitis B; however, there is a hepatitis B vaccine available.
Hepatitis B (HBV, Hep B)
The hepatitis B virus (HBV, hep B) is a unique, coated DNA virus belonging to the Hepadnaviridae family of viruses. The course of the virus is determined primarily by the age at which the infection is acquired and the interaction between the virus and the body's immune system. Successful treatment is associated with a reduction in liver injury and fibrosis (scarring), a decreased likelihood of developing cirrhosis and its complications, including liver cancer, and a prolonged survival.
Is Hepatitis C Contagious?
Hepatitis C or hep C causes acute and chronic liver disease. Hep C is a form of liver disease with symptoms like fatigue, jaundice, nausea and vomiting, anorexia, and abdominal discomfort. Hepatitis C is a contagious viral infection caused by people sharing drug needles, surgical instruments that have not been properly sanitized, and organ transplantation.
Hepatitis C Cure (Symptoms, Transmission, Treatments, and Cost)
Hepatitis is inflammation of the liver. There are a variety of toxins, diseases, illicit drugs, medications, bacterial and viral infections, and heavy alcohol use can case inflammation of the liver. Hepatitis C viral infection (HCV) is one type of hepatitis. According to the CDC, in 2014 there were an estimated 30,500 cases of acute hepatitis C infections in the US. An estimated 2.7-3.9 million people in the US have chronic hepatitis C. The virus is spread from person-to-person via blood-to-blood contact. Symptoms of HCV infection include joint pain, jaundice, dark urine, nausea, fatigue, fever, loss of appetites, clay colored stool. Hepatitis C can be cured with medications in most people. There is no vaccine against the hepatitis C virus.
Is Hepatitis A Contagious?
Hepatitis means inflammation of the liver. Hepatitis A is one type of hepatitis. Hepatitis is transmitted through person to person contact, contaminated ice, vegetables, fruits, and untreated water. Hepatitis A can be prevented by the hepatitis A vaccine. Symptoms of hepatitis A may include nausea and/or vomiting, fever, loss of appetite, abdominal pain, dark urine, clay-colored stools, jaundice (yellowish color to skin and/or eyes, or joint pain.
Hepatitis E Viral Infection
Hepatitis E (hep E) is a type of hepatitis viral infection that includes hepatitis A, B, C, D, F, which is caused by the hepatitis E virus. Usually, you get (transmitted) hepatitis E from eating or drinking dirty or contaminated water. Hepatitis E can be very serious, especially if a woman is pregnant. Up to ¼ of women who are pregnant with the hep E virus can die from the infection. The signs and symptoms of hepatitis E infection are nausea and vomiting, brown or dark urine, stool changes jaundice (yellow eyes and skin), pain in the right side of the abdomen, dark or brown urine, and light-colored stool. Some people with hep E don’t have any symptoms so they don’t know that they are contagious. It takes about 6 weeks to recover from hep E. A person who has any type of hepatitis, including hepatitis E, should not drink any alcohol. Hep E complications are rare, but when they do occur they include severe (“fulminant”) hepatitis, liver failure, and death. Currently, no specific drugs or treatments are available for hepatitis E. Moreover, the only hepatitis E vaccine currently is available in China. Avoid alcohol, keep hydrated, and getting rest are home remedies for hepatitis E. Talk to your doctor before taking any over-the-counter (medications), especially those containing acetaminophen (Tylenol and others). Usually, the prognosis and life expectancy for hepatitis E after recovery is good. Most people do not have long term liver problems from the infection.
Treatment & Diagnosis
- Hepatitis C FAQs
- Hepatitis A FAQs
- Hepatitis C News Release
- Chronic Viral Hepatitis, Alcoholism, Cirrhosis Linked to Liver Cancer
- Hepatitis A at Jam Band Concerts Alert
- Hepatitis C: Nightmare in Vegas
- IBS, GERD, Hepatitis C: Doctors Dialogue
- How common is Hepatitis C?
- How is diagnosis of Hepatitis C made?
- Hepatitis C : Can it be sexually transmitted?
- Hepatitis C: What blood tests?
- Hepatitis C genotypes
- Hepatitis C Treatments
- Hepatitis C: Most effective treatment
- Hepatitis C: Reasons for treating
- Hepatitis C: Interferon/ribavarin side effects
- Hepatitis C: Good candidates for treatment
- Do you treat hepatitis C patients with normal liver tests?
- Hepatitis C: Not Good Candidates for Treatment?
- Hepatitis C: Diet and Vitamins
- Hepatitis C: Should patients receive immunizations
- Hepatitis C treatment relapse
- What to do for relapsers after hepatitis C treatment?
- Hepatitis C: What is unique about hepatitis C?
- Can You Be Allergic to Ceclor for Hepatitis B?
- Can You Treat Hepatitis B With Aids Drug Lamivudine?
- Does Hepatitis B Cause Liver Cancer?
- What Kind of Doctor Do I See for Hepatitis C?
- Can The Hepatitis C Virus Survive Outside the Body?
Medications & Supplements
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.