Zepatier

Name: Zepatier

Zepatier Interactions

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

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 elbasvir and grazoprevir. 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.

Zepatier Overdose

If you take too much Zepatier, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

Zepatier FDA Warning

There is a risk of hepatitis B virus (HBV) becoming an active infection in those who have a current or previous infection with HBV and is treated with a certain antiviral medication (a direct-acting antiviral) to treat hepatitis C virus. Your healthcare provider will screen and monitor for HBV in those taking a direct-acting antiviral. Tell your healthcare provider if you have a history of hepatitis B infection or other liver problems before you are treated for hepatitis C. 

What other drugs will affect elbasvir and grazoprevir?

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 elbasvir and grazoprevir. 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.

Zepatier Dosage and Administration

General

  • For treatment of chronic HCV infection, elbasvir/grazoprevir is used alone or in conjunction with ribavirin.1 119

  • Base specific regimen and duration of treatment on HCV genotype and certain patient factors (e.g., previous treatment experience, presence of baseline polymorphisms).1 Relapse rates after treatment are affected by baseline patient and viral factors and differ between treatment regimens and treatment duration for certain subgroups.1

  • HCV genotype 1a infection: Screening for presence of HCV NS5A resistance-associated polymorphisms recommended prior to initiation of treatment to determine appropriate treatment regimen and treatment duration.1

  • Prior to and during treatment, perform appropriate laboratory tests to evaluate liver function.1 (See Hepatic Effects under Cautions.)

Administration

Oral Administration

Administer orally once daily without regard to food.1

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as fixed-combination tablets containing 50 mg of elbasvir and 100 mg of grazoprevir.1

Adults

Treatment of Chronic HCV Infection HCV Genotype 1a Infection Oral

1 tablet (elbasvir 50 mg and grazoprevir 100 mg) once daily.1

Use alone in patients without baseline NS5A polymorphisms who are treatment-naive or previously treated with peginterferon alfa and ribavirin;1 use in conjunction with ribavirin in those with baseline NS5A polymorphisms or in those previously treated with peginterferon alfa, ribavirin, and an HCV protease inhibitor.1 Treatment duration of 12 weeks recommended in most patients;1 treatment duration of 16 weeks recommended in those with baseline NS5A polymorphisms.1 (See Table 1.)

Previously treated defined as patients who failed treatment with peginterferon alfa and ribavirin.1

NS5A resistance-associated polymorphisms at amino acid positions 28, 30, 31, or 93.1

Use weight-based ribavirin dosage in patients with Clcr >50 mL/minute (800 mg daily in those <66 kg, 1 g daily in those 66–80 kg, 1.2 g daily in those 81–105 kg, 1.4 g daily in those >105 kg);1 give ribavirin daily dosage in 2 divided doses with food.1

Previously treated with an HCV protease inhibitor defined as patients who failed treatment with a regimen of peginterferon alfa, ribavirin, and an HCV NS3/4A protease inhibitor (e.g., boceprevir, simeprevir, telaprevir).1

The optimal elbasvir/grazoprevir-based regimen and duration of treatment not established for patients with HCV genotype 1a infection who were previously treated with peginterferon alfa, ribavirin, and an HCV protease inhibitor and have 1 or more baseline NS5A resistance-associated polymorphisms at positions 28, 30, 31, and 93.1

Table 1. Recommended Treatment Regimen and Duration of Elbasvir/Grazoprevir for HCV Genotype 1a Infection in Adults with or without Cirrhosis.1

Patient Type

Multiple-drug Regimen

Duration of Treatment

Treatment-naive or previously treated without baseline NS5A polymorphisms

Elbasvir/grazoprevir

12 weeks

Treatment-naive or previously treated with baseline NS5A polymorphisms

Elbasvir/grazoprevir with ribavirin

16 weeks

Previously treated with an HCV protease inhibitor,

Elbasvir/grazoprevir with ribavirin

12 weeks

HCV Genotype 1b Infection Oral

1 tablet (elbasvir 50 mg and grazoprevir 100 mg) once daily.1

Use alone in patients who are treatment-naive or previously treated with peginterferon alfa and ribavirin;1 use in conjunction with ribavirin in those previously treated with peginterferon alfa, ribavirin, and an HCV protease inhibitor.1 Treatment duration of 12 weeks recommended.1 (See Table 2.)

Previously treated defined as patients who failed treatment with peginterferon alfa and ribavirin.1

Previously treated with an HCV protease inhibitor defined as patients who failed treatment with a regimen of peginterferon alfa, ribavirin, and an HCV NS3/4A protease inhibitor (e.g., boceprevir, simeprevir, telaprevir).1

Use weight-based ribavirin dosage in patients with Clcr >50 mL/minute (800 mg daily in those <66 kg, 1 g daily in those 66–80 kg, 1.2 g daily in those 81–105 kg, 1.4 g daily in those >105 kg);1 give ribavirin daily dosage in 2 divided doses with food.1

Table 2. Recommended Treatment Regimen and Duration of Elbasvir/Grazoprevir for HCV Genotype 1b Infection in Adults with or without Cirrhosis.1

Patient Type

Multiple-drug Regimen

Duration of Treatment

Treatment-naive or previously treated

Elbasvir/grazoprevir

12 weeks

Previously treated with an HCV protease inhibitor

Elbasvir/grazoprevir with ribavirin

12 weeks

HCV Genotype 4 Infection Oral

1 tablet (elbasvir 50 mg and grazoprevir 100 mg) once daily.1

Use alone in patients who are treatment-naive;1 use in conjunction with ribavirin in those previously treated with peginterferon alfa and ribavirin.1 Treatment duration of 12 weeks recommended in treatment-naive patients;1 treatment duration of 16 weeks recommended in those previously treated with peginterferon alfa and ribavirin.1 (See Table 3.)

Previously treated defined as patients who failed treatment with peginterferon alfa and ribavirin.1

Use weight-based ribavirin dosage in patients with Clcr >50 mL/minute (800 mg daily in those <66 kg, 1 g daily in those 66–80 kg, 1.2 g daily in those 81–105 kg, 1.4 g daily in those >105 kg);1 give ribavirin daily dosage in 2 divided doses with food.1

Table 3. Recommended Treatment Regimen and Duration of Elbasvir/Grazoprevir for HCV Genotype 4 Infection in Adults with or without Cirrhosis.1

Patient Type

Multiple-drug Regimen

Duration of Treatment

Treatment-naive

Elbasvir/grazoprevir

12 weeks

Previously treated

Elbasvir/grazoprevir with ribavirin

16 weeks

HCV-infected with HIV Coinfection. Oral

HCV genotype 1 or 4: Use same elbasvir/grazoprevir dosage and same HCV genotype-specific multiple-drug regimen and duration of treatment recommended for HCV-infected patients without HIV coinfection.1 (See Table 1, Table 2, and Table 3.)

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustments not needed.1

Moderate or severe hepatic impairment (Child-Pugh class B or C): Contraindicated.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild, moderate, or severe renal impairment, including those requiring hemodialysis: Dosage adjustments not needed.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustments not needed.1 (See Geriatric Use under Cautions.)

Interactions for Zepatier

Elbasvir and grazoprevir are substrates of CYP3A;1 grazoprevir is a weak inhibitor of CYP3A.1 Elbasvir and grazoprevir inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, and 2D6.1

Elbasvir inhibits P-gp transport system;1 elbasvir and grazoprevir are substrates of P-gp.1

Elbasvir and grazoprevir inhibit intestinal breast cancer resistance protein (BCRP).1

Grazoprevir is a substrate and inhibitor of OATP1B1 and 1B3.1

The following drug interactions based on studies using elbasvir/grazoprevir, elbasvir alone, or grazoprevir alone, or are predicted drug interactions that may occur with elbasvir/grazoprevir.1 When elbasvir/grazoprevir is used, consider interactions associated with both drugs in the fixed combination.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potent CYP3A inducers: Possible pharmacokinetic interactions (decreased elbasvir and grazoprevir concentrations and possible loss of therapeutic effect);1 concomitant use contraindicated.1

Moderate CYP3A inducers: Possible pharmacokinetic interactions (decreased elbasvir and grazoprevir concentrations and possible reduced therapeutic effect);1 concomitant use not recommended.1

Potent CYP3A inhibitors: Possible pharmacokinetic interactions (increased elbasvir and grazoprevir concentrations);1 concomitant use not recommended.1

Drugs Affecting or Affected by Breast Cancer Resistance Protein

BCRP substrates: Possible pharmacokinetic interactions (increased concentrations of BCRP substrate).1

Drugs Affecting or Affected by Organic Anion Transport Polypeptides

OATP1B1 or 1B3 inhibitors: Possible pharmacokinetic interactions (increased grazoprevir concentrations);1 concomitant use contraindicated.1

Specific Drugs

Drug

Interaction

Comments

Abacavir

Clinically important pharmacokinetic interactions not expected1

Antacids

Dosage adjustments not needed if used concomitantly with antacids1

Anticonvulsants (carbamazepine, phenytoin)

Carbamazepine, phenytoin: Possible decreased elbasvir and grazoprevir concentrations;1 possible loss of virologic response to the HCV antiviral1

Carbamazepine, phenytoin: Concomitant use contraindicated1

Antifungals, azoles (ketoconazole)

Ketoconazole: Increased elbasvir and grazoprevir concentrations and AUC;1 may increase risk of hepatotoxicity1

Concomitant use not recommended1

Antimycobacterials, rifamycins (rifampin)

Rifampin: Multiple doses result in clinically important decreases in grazoprevir concentrations and is expected to result in clinically important decreases in elbasvir concentrations;1 12 may lead to loss of virologic response to the HCV antiviral1 12

Concomitant use contraindicated1

Atazanavir

Ritonavir-boosted atazanavir: Increased elbasvir concentrations and substantially increased grazoprevir concentrations;1 may increase risk of ALT elevations1

Ritonavir-boosted atazanavir: Concomitant use contraindicated1

Benzodiazepines (midazolam)

Midazolam: Increased midazolam exposures1

Bosentan

Possible decreased elbasvir and grazoprevir concentrations;1 possible reduced therapeutic effect of the HCV antiviral1

Concomitant use not recommended1

Buprenorphine

Fixed combination of buprenorphine and naloxone (buprenorphine/naloxone): No clinically important effects on elbasvir or grazoprevir pharmacokinetics1

Dosage adjustments not needed1

Corticosteroids (prednisone)

Prednisone: No clinically important effects on elbasvir, grazoprevir, or prednisone pharmacokinetics1

Dosage adjustments not needed1

Darunavir

Ritonavir-boosted darunavir: Increased elbasvir concentrations and substantially increased grazoprevir concentrations;1 may increase risk of ALT elevations1

Ritonavir-boosted darunavir: Concomitant use contraindicated1

Digoxin

No clinically important effects on digoxin pharmacokinetics1

Dosage adjustments not needed1

Dolutegravir

No clinically important effects on elbasvir, grazoprevir, or dolutegravir pharmacokinetics1

Dosage adjustments not needed1

Efavirenz

Substantially decreased elbasvir and grazoprevir concentrations;1 possible loss of virologic response to the HCV antiviral1

Concomitant use contraindicated1

Elvitegravir

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/c/FTC/TDF): Possible increased elbasvir and grazoprevir concentrations1

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (EVG/c/FTC/TAF): Possible increased elbasvir and grazoprevir concentrations1

EVG/c/FTC/TDF or EVG/c/FTC/TAF: Concomitant use not recommended1

Emtricitabine

Clinically important pharmacokinetic interactions not expected1

Entecavir

Clinically important pharmacokinetic interactions not expected1

Estrogens/progestins

Oral contraceptive containing ethinyl estradiol and levonorgestrel: No clinically important effects on pharmacokinetics of ethinyl estradiol or levonorgestrel1

Dosage adjustments not needed1

Etravirine

Possible decreased elbasvir and grazoprevir concentrations;1 possible reduced therapeutic effect of the HCV antiviral1

Concomitant use not recommended1

Histamine H2-receptor antagonists (famotidine)

Famotidine: No clinically important effects on elbasvir or grazoprevir pharmacokinetics1

Histamine H2-receptor antagonists: Dosage adjustments not needed1

HMG-CoA reductase inhibitors (statins)

Atorvastatin: Increased atorvastatin concentrations and AUC1

Fluvastatin, lovastatin, simvastatin: Possible increased statin concentrations1

Pitavastatin, pravastatin: No clinically important effects on pitavastatin or pravastatin pharmacokinetics1

Rosuvastatin: Increased rosuvastatin concentrations and AUC1

Atorvastatin: Do not exceed atorvastatin dosage of 20 mg once daily1

Fluvastatin, lovastatin, simvastatin: Use lowest necessary statin dosage;1 monitor for statin-associated adverse effects (e.g., myopathy)1

Pitavastatin, pravastatin: Dosage adjustments not needed1

Rosuvastatin: Do not exceed rosuvastatin dosage of 10 mg once daily1

Immunosuppressants (cyclosporine, tacrolimus)

Cyclosporine: Increased elbasvir concentrations and AUC;1 substantially increased grazoprevir concentrations and AUC;1 may increase risk of ALT elevations1

Tacrolimus: Increased tacrolimus concentrations;1 no effect on elbasvir and grazoprevir concentrations1

Cyclosporine: Concomitant use contraindicated1

Tacrolimus: Frequently monitor tacrolimus whole blood concentrations, renal function, and tacrolimus-associated adverse effects1

Lamivudine

Clinically important pharmacokinetic interactions not expected1

Lopinavir

Fixed combination of lopinavir and ritonavir (lopinavir/ritonavir): Increased elbasvir concentrations and substantially increased grazoprevir concentrations;1 may increase risk of ALT elevations1

Concomitant use contraindicated1

Methadone

No clinically important effects on elbasvir or grazoprevir pharmacokinetics1

Dosage adjustments not needed1

Modafinil

Possible decreased elbasvir and grazoprevir concentrations;1 possible reduced therapeutic effect of the HCV antiviral1

Concomitant use not recommended1

Montelukast

No clinically important effects on montelukast pharmacokinetics1

Mycophenolate mofetil

No clinically important effects on elbasvir, grazoprevir, or mycophenolic acid pharmacokinetics1

Dosage adjustments not needed1

Nafcillin

Possible decreased elbasvir and grazoprevir concentrations;1 possible reduced therapeutic effect of the HCV antiviral1

Concomitant use not recommended1

Phosphate binders (calcium acetate, sevelamer)

Calcium acetate, sevelamer: No clinically important effects on elbasvir or grazoprevir pharmacokinetics1

Phosphate binders: Dosage adjustments not needed1

Proton-pump inhibitors (pantoprazole)

Pantoprazole: No clinically important effects on elbasvir or grazoprevir pharmacokinetics1

Proton-pump inhibitors: Dosage adjustments not needed1

Raltegravir

No clinically important effects on elbasvir, grazoprevir, or raltegravir pharmacokinetics1

Dosage adjustments not needed1

Ribavirin

No clinically important effects on elbasvir or grazoprevir pharmacokinetics1

No in vitro evidence of antagonistic anti-HCV effects1

Dosage adjustments not needed1

Rilpivirine

No clinically important effects on elbasvir, grazoprevir, or rilpivirine pharmacokinetics1

Dosage adjustments not needed1

Ritonavir

Increased grazoprevir concentrations1

Saquinavir

Substantially increased grazoprevir concentrations expected;1 may increase risk of ALT elevations1

Concomitant use contraindicated1

Sofosbuvir

No clinically important effects on sofosbuvir pharmacokinetics1

Dosage adjustments not needed1

St. John's wort (Hypericum perforatum)

Substantially decreased elbasvir and grazoprevir concentrations;1 may lead to loss of virologic response to the HCV antiviral1

Concomitant use contraindicated1

Tenofovir

Tenofovir disoproxil fumarate (tenofovir DF): No clinically important effects on elbasvir, grazoprevir, or tenofovir pharmacokinetics1

Dosage adjustments not needed1

Tipranavir

Substantially increased grazoprevir concentrations expected;1 may increase risk of ALT elevations1

Concomitant use contraindicated1

Commonly used brand name(s)

In the U.S.

  • Zepatier

Available Dosage Forms:

  • Tablet

Therapeutic Class: Antiviral

Pharmacologic Class: Hepatitis C Virus NS5A Inhibitor

Before Using Zepatier

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of elbasvir and grazoprevir combination in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of elbasvir and grazoprevir combination in the elderly. However, elderly patients are more likely to have liver problems, which may require caution in patients receiving this medicine.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

  • Atazanavir
  • Carbamazepine
  • Cyclosporine
  • Darunavir
  • Efavirenz
  • Eltrombopag
  • Enzalutamide
  • Fosphenytoin
  • Lopinavir
  • Mitotane
  • Phenytoin
  • Rifampin
  • Ritonavir
  • Saquinavir
  • St John's Wort
  • Tipranavir

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Atorvastatin
  • Bosentan
  • Conivaptan
  • Etravirine
  • Modafinil
  • Nafcillin
  • Netupitant
  • Phenobarbital
  • Primidone
  • Rosuvastatin
  • Tacrolimus

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Hepatitis B, history of—Use with caution. May cause this condition to become active again.
  • Liver disease, moderate to severe—Should not be used in patients with this condition.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • Feeling very tired or weak.

How do I store and/or throw out Zepatier?

  • Store in the original container at room temperature.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.

Zepatier Dosage and Administration

Testing Prior to the Initiation of Therapy

Testing for HBV Infection

Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with Zepatier [see Warnings and Precautions (5.1)].

NS5A Resistance Testing in HCV Genotype 1a-Infected Patients

Testing patients with HCV genotype 1a infection for the presence of virus with NS5A resistance-associated polymorphisms is recommended prior to initiation of treatment with Zepatier to determine dosage regimen and duration [see Dosage and Administration (2.2)], Table 1. In subjects receiving Zepatier for 12 weeks, sustained virologic response (SVR12) rates were lower in genotype 1a-infected patients with one or more baseline NS5A resistance-associated polymorphisms at amino acid positions 28, 30, 31, or 93 [see Microbiology (12.4)], Table 11.

Hepatic Laboratory Testing

Obtain hepatic laboratory testing prior to and during treatment with Zepatier [see Warnings and Precautions (5.2)].

Recommended Dosage in Adults

Zepatier is a two-drug, fixed-dose combination product containing 50 mg of elbasvir and 100 mg of grazoprevir in a single tablet. The recommended dosage of Zepatier is one tablet taken orally once daily with or without food [see Clinical Pharmacology (12.3)]. Zepatier is used in combination with ribavirin in certain patient populations (see Table 1). When administered with Zepatier, the recommended dosage of ribavirin in patients without renal impairment is weight-based administered in two divided doses with food. For further information on ribavirin dosing and dosage modifications, refer to the ribavirin prescribing information.

Treatment Regimen and Duration of Therapy

Relapse rates are affected by baseline host and viral factors and differ between treatment regimens and durations for certain subgroups [see Clinical Studies (14)].

Table 1 below provides the recommended Zepatier treatment regimen and duration based on the patient population and genotype in HCV mono-infected and HCV/HIV-1 co-infected patients with or without cirrhosis and with or without renal impairment including patients receiving hemodialysis.

Table 1: Recommended Dosage Regimens and Durations for Zepatier for Treatment of HCV Genotype 1 or 4 in Patients with or without Cirrhosis
Patient Population Treatment Duration
* Patients who have failed treatment with peginterferon alfa (PegIFN) + ribavirin (RBV). † NS5A resistance-associated polymorphisms at amino acid positions 28, 30, 31, or 93. See section 2.1 Testing prior to the initiation of therapy, subsection NS5A resistance testing in HCV genotype 1a-infected patients. ‡ For patients with CrCl greater than 50 mL per minute, the recommended dosage of ribavirin is weight-based (less than 66 kg = 800 mg per day, 66 to 80 kg = 1000 mg per day, 81 to 105 kg = 1200 mg per day, greater than 105 kg = 1400 mg per day) administered in two divided doses with food. For patients with CrCl less than or equal to 50 mL per minute, including patients receiving hemodialysis, refer to the ribavirin tablet prescribing information for the correct ribavirin dosage. § The optimal Zepatier-based treatment regimen and duration of therapy for PegIFN/RBV/PI-experienced genotype 1a-infected patients with one or more baseline NS5A resistance-associated polymorphisms at positions 28, 30, 31, and 93 has not been established. ¶ Patients who have failed treatment with PegIFN + RBV + HCV NS3/4A protease inhibitor (PI): boceprevir, simeprevir, or telaprevir.
Genotype 1a: Treatment-naïve or PegIFN/RBV-experienced* without baseline NS5A polymorphisms† Zepatier 12 weeks
Genotype 1a: Treatment-naïve or PegIFN/RBV-experienced* with baseline NS5A polymorphisms† Zepatier + RBV‡ 16 weeks
Genotype 1b: Treatment-naïve or PegIFN/RBV-experienced* Zepatier 12 weeks
Genotype 1a§ or 1b: PegIFN/RBV/PI-experienced¶ Zepatier + RBV‡ 12 weeks
Genotype 4: Treatment-Naïve Zepatier 12 weeks
Genotype 4: PegIFN/RBV-experienced* Zepatier + RBV‡ 16 weeks

Renal Impairment

No dosage adjustment of Zepatier is recommended in patients with any degree of renal impairment including patients on hemodialysis. Administer Zepatier with or without ribavirin according to the recommendations in Table 1 [see Use in Specific Populations (8.8) and Clinical Studies (14.4)]. Refer to the ribavirin tablet prescribing information for the correct ribavirin dosage for patients with CrCl less than or equal to 50 mL per minute.

Hepatic Impairment

No dosage adjustment of Zepatier is recommended in patients with mild hepatic impairment (Child-Pugh A). Zepatier is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C) [see Contraindications (4), Use in Specific Populations (8.9), and Clinical Pharmacology (12.3)].

Adverse Reactions

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

  • Increased Risk of ALT Elevations [see Warnings and Precautions (5.2)].

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) [see Clinical Studies (14)].

Adverse Reactions with Zepatier in Treatment-Naïve Subjects

C-EDGE TN was a Phase 3 randomized, double-blind, placebo-controlled trial in 421 treatment-naïve (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-Naïve Subjects with HCV Treated 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-naïve 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 for 16 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 (14.4)]. 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-Naïve or PegIFN/RBV-Experienced Subjects with Stage 4 or 5 Chronic Kidney Disease and HCV Treated with Zepatier for 12 Weeks in C-SURFER
Zepatier
N=122
%
12 weeks
Placebo
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 (5.2)]. The frequency of late ALT elevations was higher in subjects with higher grazoprevir plasma concentrations [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. 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.

Zepatier Description

Zepatier is a fixed-dose combination tablet containing elbasvir and grazoprevir for oral administration.

Elbasvir is an HCV NS5A inhibitor, and grazoprevir is an HCV NS3/4A protease inhibitor.

Each tablet contains 50 mg elbasvir and 100 mg grazoprevir. The tablets include the following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, sodium chloride, sodium lauryl sulfate, and vitamin E polyethylene glycol succinate. The tablets are film-coated with a coating material containing the following inactive ingredients: carnauba wax, ferrosoferric oxide, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin.

Elbasvir:

The IUPAC name for elbasvir is Dimethyl N,N'-([(6S)-6-phenylindolo[1,2-c][1,3]benzoxazine-3,10-diyl]bis{1H-imidazole-5,2-diyl-(2S)-pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})dicarbamate.

It has a molecular formula of C49H55N9O7 and a molecular weight of 882.02. It has the following structural formula:

Elbasvir is practically insoluble in water (less than 0.1 mg per mL) and very slightly soluble in ethanol (0.2 mg per mL), but is very soluble in ethyl acetate and acetone.

Grazoprevir:

The IUPAC name for grazoprevir is (1aR,5S,8S,10R,22aR)-N-[(1R,2S)-1-[(Cyclopropylsulfonamido)carbonyl]-2-ethenylcyclopropyl]-14-methoxy-5-(2-methylpropan-2-yl)-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide.

It has a molecular formula of C38H50N6O9S and a molecular weight of 766.90. It has the following structural formula:

Grazoprevir is practically insoluble in water (less than 0.1 mg per mL) but is freely soluble in ethanol and some organic solvents (e.g., acetone, tetrahydrofuran and N,N-dimethylformamide).

How should I take Zepatier?

Take Zepatier exactly as prescribed by your doctor. Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Your doctor will perform blood tests to make sure you do not have conditions that would prevent you from safely using Zepatier.

You may take Zepatier with or without food.

Take the medicine at the same time each day.

You will need frequent blood tests to check your liver function.

Hepatitis C is often treated with a combination of drugs. Use all medications as directed by your doctor. Read all patient information, medication guides, and instruction sheets provided to you. Do not change your doses or medication schedule without your doctor's advice. Every person with chronic hepatitis C should remain under the care of a doctor.

You should not stop using this medicine suddenly. Stopping suddenly could make your condition harder to treat with hepatitis C antiviral medicine.

If you have ever had hepatitis B, elbasvir and grazoprevir can cause this condition to come back or get worse. You will need liver function tests during treatment and for several months after you stop using this medicine.

Store Zepatier at room temperature away from moisture and heat. Keep each tablet in the foil blister pack until you are ready to take it.

(web3)