Elbasvir and grazoprevir

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

• Zepatier^®

You should not use this medicine if you are allergic to elbasvir or grazoprevir, or if you have:

• moderate or severe liver disease.

Some medicines can cause unwanted or dangerous effects when used with elbasvir and grazoprevir. Your doctor may need to change your treatment plan if you use any of the following drugs:

• cyclosporine;

• rifampin;

• St. John's wort;

• HIV or AIDS medication--atazanavir, darunavir, efavirenz, lopinavir, saquinavir, tipranavir; or

• seizure medicine--carbamazepine, phenytoin.

To make sure elbasvir and grazoprevir is safe for you, tell your doctor if you have:

• a history of hepatitis B;

• liver problems other than hepatitis, or if you have had a liver transplant;

• HIV (human immunodeficiency virus); or

• if you are waiting to have a liver transplant.

It is not known whether this medicine will harm an unborn baby. Elbasvir and grazoprevir is sometimes used in combination with ribavirin. Ribavirin can cause birth defects or death in an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant. You may need to have a negative pregnancy test before using these medications together, and every month during your treatment.

• If you are a woman, do not use elbasvir and grazoprevir with ribavirin if you are pregnant.

• If you are a man, do not use this drug combination if your sexual partner is pregnant. An unborn baby could also be harmed if a man fathers the child while he is taking ribavirin.

• Use at least 2 effective forms of non-hormonal birth control (condom, diaphragm with spermicide) while either sexual partner is using these medications together. Keep using 2 forms of birth control for at least 6 months after treatment ends. Tell your doctor right away if a pregnancy occurs while either the mother or the father is using elbasvir and grazoprevir with ribavirin.

It is not known whether elbasvir and grazoprevir passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Elbasvir and grazoprevir is not approved for use by anyone younger than 18 years old.

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.

Chronic HCV Infection

Treatment of chronic HCV genotype 1 or genotype 4 infection in treatment-naive (previously untreated) or previously treated adults, including those with compensated liver disease (with or without cirrhosis) and those with HIV coinfection.1 2 3 4 5 6 10 119

Used alone or in conjunction with ribavirin, depending on HCV genotype and certain patient factors (e.g., previous treatment experience, presence of baseline polymorphisms).1 119

Efficacy of 12-week elbasvir/grazoprevir regimen for treatment of HCV genotype 1a infection reduced when 1 or more NS5A resistance-associated polymorphisms at certain amino acid positions (28, 30, 31, 93) are present at baseline.1 Screening for NS5A resistance-associated polymorphisms recommended prior to initiation of treatment in patients with HCV genotype 1a infection.1 (See General under Dosage and Administration.)

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information.119 Information from the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and International Antiviral Society–USA (IAS–USA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at .119

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

• 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 elbasvir and grazoprevir 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 elbasvir and grazoprevir while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

(ELB as vir & graz OH pre vir)

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl ≤50 mL/minute: No dosage adjustment necessary. If used with concomitant ribavirin, refer to ribavirin monograph for dosage adjustments.

End-stage renal disease (ESRD) and hemodialysis (not removed by hemodialysis): No dosage adjustment necessary.

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate or severe impairment (Child-Pugh class B or C): Use is contraindicated.

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 elbasvir / grazoprevir may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Hemodialysis: No adjustment recommended.
Peritoneal dialysis: Data not available

Comments:
-The manufacturer product information for ribavirin tablets should be consulted regarding use in patients receiving hemodialysis (if applicable).