Zepatier

Zepatier is a prescription medication used with or without ribavirin to treat chronic (long-lasting) hepatitis C virus (HCV) genotypes 1 or 4 infection in adults. It is a single product containing 2 medications elbasvir and grazoprevir. Zepatier belongs to a group of drugs called antiviral medications. These work by targeting certain proteins in the HCV to keep it from reproducing in the body.

This medication comes in tablet form and is typically taken once a day with or without food.

Common side effects of Zepatier include headache, nausea, and diarrhea.

Zepatier can also cause you to feel tired. Do not drive or operate heavy machinery until you know how Zepatier affects you.

Before taking Zepatier, tell your doctor about all of your medical conditions. Especially tell your doctor if you have liver problems other than hepatitis C/ 

• are allergic to Zepatier or to any of its ingredients 
• if you have a history of hepatitis B infection
• have ever taken any medicine for hepatitis C
• have HIV
• have had or are waiting for a liver transplant
• have any other medical conditions
• are pregnant or trying to get pregnant. Zepatier has not been studied in pregnant women. It is not known if Zepatier will harm your baby while you are pregnant.
• are breastfeeding or plan to breastfeed. It is not known if Zepatier gets in your breast milk and gets passed to your baby. Talk to your healthcare provider about the best way to feed your baby during treatment with Zepatier.

Males and females who take Zepatier and ribavirin should also read the ribavirin drug precautions for important pregnancy, contraception, and infertility information.
 

• Elbasvir/grazoprevir is a fixed combination of 2 HCV antivirals.1 Elbasvir is an HCV NS5A replication complex inhibitor (NS5A inhibitor)1 and grazoprevir is an HCV NS3/4A protease inhibitor.1

• Elbasvir and grazoprevir are both direct-acting antivirals (DAAs) with activity against HCV.1 No in vitro evidence of antagonistic anti-HCV effects between the drugs in HCV replicon studies.1

• Elbasvir targets HCV NS5A protein, which is required for viral replication and virion assembly.1 7 8 9 In vitro studies using cell-based replicon assays indicate elbasvir has activity against HCV genotypes 1a, 1b, and 4.1 7 8

• Grazoprevir inhibits HCV NS3/4A protease, which is required for viral replication.1 9 Inhibition of NS3/4A protease prevents proteolytic cleavage of the HCV-encoded polyprotein to form mature forms of NS3, NS4A, NS4B, NS5A, and NS5B.1 9 In vitro studies using cell-based replicon assays indicate grazoprevir has activity against HCV genotypes 1a, 1b, and 4.1

• Certain amino acid substitutions in NS5A of HCV genotypes 1a, 1b, and 4 selected in cell culture and associated with reduced susceptibility to elbasvir in vitro in replicon studies.1 8 Single M28A/G/T, Q30D/E/H/K/R, L31M/V, H28D, and Y93C/H/N substitutions in HCV genotype 1a replicons confer reduced susceptibility to elbasvir;1 8 single L28M, L31F, and Y93H substitutions in HCV genotype 1b replicons are associated with reduced susceptibility to elbasvir.1 8 In HCV genotype 4 replicons, single L30S, M31V, and Y93H substitutions are associated with reduced susceptibility to elbasvir.1 In general, combinations of elbasvir resistance-associated substitutions further reduce elbasvir antiviral activity in HCV genotypes 1a, 1b, and 4 replicons.1 In phase 2 and 3 clinical trials, treatment-emergent amino acid substitutions in NS5A were detected in patients with HCV genotype 1a infection (M28A/G/T, Q30H/K/R/Y, L31F/M/V, H58D, Y93H/N/S), HCV genotype 1b infection (L28M, L31F/V, Y93H), or HCV genotype 4 infection (L28S/T, M31I/V, P58D, Y93H) experiencing virologic failure.1

• Certain amino acid substitutions in NS3 of HCV genotypes 1a, 1b, and 4 selected in cell culture and associated with reduced susceptibility to grazoprevir in vitro in replicon studies.1 Single Y56H, R155K, A156G/T/V, and D168A/E/G/N/S/V/Y substitutions in HCV genotype 1a replicons confer reduced susceptibility to grazoprevir;1 single F43S, Y56F, V107I, A156S/T/V, and D168A/G/V substitutions in HCV genotype 1b replicons confer reduced susceptibility to grazoprevir.1 In HCV genotype 4 replicons, single D168A/V substitutions are associated with reduced susceptibility to grazoprevir.1 In general, combinations of grazoprevir resistance-associated substitutions further reduce grazoprevir antiviral activity in HCV genotypes 1a, 1b, and 4 replicons.1 In phase 2 and 3 clinical trials, treatment-emergent amino acid substitutions in NS3 were detected in patients with HCV genotype 1a infection (V36L/M, Y56H, V107I, R155I/K, A156G/T/V, V158A, D168A/G/N/V/Y), HCV genotype 1b infection (Y56F, V107I, A156T), or HCV genotype 4 infection (A156M/T/V, D168A/G, V170I) experiencing virologic failure.1

• Possible cross-resistance among HCV NS5A inhibitors and among HCV NS3/4A protease inhibitors.1 Efficacy of elbasvir/grazoprevir not established in patients who failed previous treatment with a regimen that included an HCV NS5A inhibitor.1 Only limited data available regarding efficacy of elbasvir/grazoprevir in patients who failed previous treatment with a regimen of peginterferon alfa, ribavirin, and an HCV NS3/4A protease inhibitor (e.g., boceprevir, simeprevir, telaprevir) and have HCV NS3 resistance-associated substitutions at baseline prior to administration of elbasvir/grazoprevir.1 Elbasvir and grazoprevir active against HCV with amino acid substitutions associated with resistance to HCV NS5B polymerase inhibitors.1

• It is used to treat long-term hepatitis C infections.
• This medicine may be used with other drugs to treat hepatitis C. If you are also taking other drugs to treat hepatitis C, talk with the doctor about the risks and side effects that may happen.

• If you have an allergy to Zepatier or any part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have liver problems other than hepatitis C.
• If you take any drugs (prescription or OTC, natural products, vitamins) that must not be taken with Zepatier, like certain drugs that are used for HIV, infections, or seizures. There are many drugs that must not be taken with this medicine.
• If you are taking St. John's wort. Do not take St. John's wort with Zepatier. This medicine may not work as well.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Zepatier with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• This medicine may affect how much of some other drugs are in your body. If you are taking other drugs, talk with your doctor. You may need to have your blood work checked more closely while taking Zepatier with your other drugs.
• Do not stop taking this medicine without calling the doctor who ordered it for you.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Zepatier while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• Do not take Zepatier (elbasvir and grazoprevir) out of the blister pack until you are ready to take it. Take this medicine right away after opening the blister pack. Do not store the removed drug for future use.
• Keep taking Zepatier as you have been told by your doctor or other health care provider, even if you feel well.
• It is important that you do not miss or skip a dose of this medicine during treatment.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.
• If you are not sure what to do if you miss a dose, call your doctor.

Zepatier® is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 or 4 infection in adults.

Zepatier is indicated for use with ribavirin in certain patient populations [see Dosage and Administration (2.2)].

Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.

HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.

Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with Zepatier. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with Zepatier and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Increased Risk of ALT Elevations

During clinical trials with Zepatier with or without ribavirin, 1% of subjects experienced elevations of ALT from normal levels to greater than 5 times the upper limit of normal (ULN), generally at or after treatment week 8. ALT elevations were typically asymptomatic and most resolved with ongoing or completion of therapy. Higher rates of late ALT elevations occurred in the following subpopulations: female sex (2% [10/608]), Asian race (2% [4/164]), and age 65 years or older (2% [3/177]) [see Adverse Reactions (6.1)].

Hepatic laboratory testing should be performed prior to therapy, at treatment week 8, and as clinically indicated. For patients receiving 16 weeks of therapy, additional hepatic laboratory testing should be performed at treatment week 12.

• Patients should be instructed to consult their healthcare professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, or discolored feces.
• Consider discontinuing Zepatier if ALT levels remain persistently greater than 10 times the ULN.
• Discontinue Zepatier if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR.

Risks Associated with Ribavirin Combination Treatment

If Zepatier is administered with ribavirin, the warnings and precautions for ribavirin, including the pregnancy avoidance warning, also apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of warnings and precautions for ribavirin [see Dosage and Administration (2.2)].

Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions

The concomitant use of Zepatier and certain drugs may result in known or potentially significant drug interactions, some of which may lead to:

• Possible clinically significant adverse reactions from greater exposure of concomitant drugs or components of Zepatier.
• Significant decrease of elbasvir and grazoprevir plasma concentrations which may lead to reduced therapeutic effect of Zepatier and possible development of resistance.

See Tables 2 and 6 for steps to prevent or manage these known or potentially significant drug interactions, including dosing recommendations [see Contraindications (4) and Drug Interactions (7.2)].

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

Call your doctor at once if you have:

• nausea, vomiting, upper stomach pain, loss of appetite;

• tiredness;

• dark urine, clay-colored stools;

• jaundice (yellowing of the skin or eyes); or

• (if you also take ribavirin) pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating.

Common Zepatier side effects may include:

• headache;

• nausea, diarrhea;

• sleep problems (insomnia); or

• feeling tired.

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.

Many drugs can interact with elbasvir and grazoprevir. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially:

• bosentan;

• modafinil;

• tacrolimus;

• antibiotic or antifungal medicine;

• antiviral medicine to treat hepatitis or HIV/AIDS;

• cholesterol medication;

• heart or blood pressure medicine; or

• tuberculosis medicine.

This list is not complete and many other drugs can interact with Zepatier. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Applies to elbasvir / grazoprevir: oral tablet

Along with its needed effects, elbasvir / grazoprevir may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking elbasvir / grazoprevir:

• Dark urine
• fever with or without chills
• light-colored stools
• loss of appetite
• nausea and vomiting
• unusual tiredness
• upper stomach pain
• yellow eyes or skin

Some side effects of elbasvir / grazoprevir may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Headache

Applies to elbasvir / grazoprevir: oral tablet

General

In clinical trials, the safety of this drug (with or without ribavirin) was assessed in patients with chronic hepatitis C virus (HCV) infection with compensated liver disease (with or without cirrhosis). Clinical trials included therapy-naive and therapy-experienced (peginterferon alfa/ribavirin-experienced, peginterferon alfa/ribavirin/HCV protease inhibitor-experienced) patients, with and without HCV/HIV-coinfection; at least 1 clinical trial included patients with severe renal dysfunction, including those on hemodialysis. The most common side effects reported with this drug were fatigue and headache.

If this drug is used with ribavirin, the manufacturer product information for ribavirin should be consulted for associated side effects.[Ref]

Other

Very common (10% or more): Fatigue (up to 25%)
Common (1% to 10%): Asthenia[Ref]

Nervous system

Very common (10% or more): Headache (up to 17%)
Common (1% to 10%): Dizziness[Ref]

Hematologic

Very common (10% or more): Anemia (up to 16%)
Common (1% to 10%): Decreased hemoglobin
Frequency not reported: CD4+ T-cell counts increased, CD4+ T-cell counts decreased[Ref]

The change from baseline in hemoglobin (Hgb) levels averaged about -2.2 g/dL in patients using this drug with ribavirin for 16 weeks and -0.3 g/dL in patients using this drug alone for 12 weeks. Hgb level decreased during the first 8 weeks of therapy, stayed low during the remainder of therapy, and normalized to baseline levels during follow-up. Less than 1% of patients using this drug with ribavirin had Hgb levels decrease to less than 8.5 g/dL during therapy; no patients using this drug alone had Hgb levels less than 8.5 g/dL.

In therapy-naive and therapy-experienced HCV/HIV-coinfected patients treated with this drug alone for 12 weeks, increase of CD4+ T-cell counts (of about 31 and 32 cells/mm3, respectively) was observed at the end of therapy. In therapy-experienced HCV/HIV-coinfected patients treated with this drug with ribavirin for 16 weeks, CD4+ T-cell counts decreased about 135 cells/mm3 by the end of therapy.[Ref]

Gastrointestinal

Very common (10% or more): Nausea (up to 12%)
Common (1% to 10%): Diarrhea, abdominal pain, dyspepsia, vomiting, constipation, upper abdominal pain, dry mouth[Ref]

Dermatologic

Common (1% to 10%): Pruritus, alopecia, rash[Ref]

Hepatic

Common (1% to 10%): Elevated bilirubin
Uncommon (0.1% to 1%): Elevated ALT[Ref]

During clinical trials with this drug (with or without ribavirin), regardless of duration of therapy, elevated bilirubin (greater than 2.5 x ULN) was reported in 6% and less than 1% of patients using this drug with ribavirin and alone, respectively. These increases were primarily indirect and generally associated with ribavirin coadministration. Elevated bilirubin was usually not associated with elevated serum ALT.

Based on pooled data in patients using this drug without ribavirin for 12 weeks, ALT of 5.1 to 10 x ULN, ALT of greater than 10 x ULN, total bilirubin of 2.6 to 5 x ULN, and total bilirubin of greater than 5 x ULN were reported in 0.7%, 0.7%, 0.4%, and 0% of patients, respectively.

During clinical trials with this drug (with or without ribavirin), regardless of duration of therapy, ALT in 13 of 1690 patients increased from normal levels to greater than 5 times the upper limit of normal (5 x ULN), usually at or after 8 weeks of therapy (mean onset: 10 weeks; range: 6 to 12 weeks). These late ALT elevations were generally asymptomatic and most resolved with continued use or after completion of therapy. Late ALT elevations occurred more often in patients with higher grazoprevir plasma levels (e.g., female, Asian, age at least 65 years). Incidence of late ALT elevations was not affected by duration of therapy and cirrhosis was not a risk factor. Less than 1% of patients treated with this drug (with or without ribavirin) had ALT elevations greater than 2.5 to 5 x ULN during therapy; therapy was not discontinued in these patients.[Ref]

Musculoskeletal

Common (1% to 10%): Arthralgia, myalgia[Ref]

Psychiatric

Common (1% to 10%): Insomnia, depression, irritability, anxiety[Ref]

Respiratory

Common (1% to 10%): Dyspnea, exertional dyspnea[Ref]

Metabolic

Common (1% to 10%): Decreased appetite

Some side effects of Zepatier may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.