ELB-as-vir/graz-OH-pre-vir

Therapeutic Classification: antivirals

Pharmacologic Classification: NS5A inhibitors, protease inhibitors

• Chronic hepatitis C virus (HCV) genotypes 1 or 4 infection (with or without ribavirin).

• Elbasvir: inhibits the HCV NS5A protein, resulting in inhibition of viral replication; Grazoprevir: inhibits the HCV NS3/4A protease, resulting in inhibition of viral replication.

• Decreased levels of HCV with sustained virologic response and lessened sequelae of chronic HCV infection.

Elbasvir

Absorption: Well absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Protein Binding: >99.9%.

Metabolism/Excretion: Partially metabolized by the CYP3A4 isoenzyme. >90% excreted in feces and <1% eliminated in urine.

Half-life: 24 hr.

Grazoprevir

Absorption: Well absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Protein Binding: >98.8%.

Metabolism/Excretion: Partially metabolized by the CYP3A4 isoenzyme. >90% excreted in feces and <1% eliminated in urine.

Half-life: 31 hr.

(blood levels)

Contraindicated in:

• Moderate or severe hepatic impairment (Child-Pugh B or C) or history of hepatic decompensation (↑ risk of hepatic decompensation)
• Concurrent use of organic anion transporting polypeptides 1B1/3 (OATP1B1/3) inhibitors, strong CYP3A inducers, or efavirenz
• Situations when ribavirin is contraindicated (when ribavirin required)
• OB: Pregnant women or men whose partners are pregnant (when ribavirin is required; ribavirin may cause fetal harm)
• Lactation: Lactation (when ribavirin required).

Use Cautiously in:

• Patients who are female or of Asian ancestry (↑ risk of liver enzyme elevation)
• Patients awaiting liver transplantation or liver transplant recipients (safety and effectiveness not established)
• Receiving immunosuppressant or chemotherapy medications (↑ risk of hepatitis B virus reactivation)
• OB: Safety not established in pregnancy (when ribavirin not required)
• Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant (when ribavirin not required)
• Pedi: Children <12 yr or <30 kg (safety and effectiveness not established)
• Geri: ↑risk of liver enzyme elevation in older adults.

GI: ↑liver enzymes, abdominal pain, diarrhea, HEPATIC DECOMPENSATION/FAILURE, nausea.

Neuro: headache, insomnia.
Misc: fatigue, ANGIOEDEMA, hepatitis B virus reactivation.

Drug-Drug:

• OATP1B1/3 inhibitors, including atazanavir, cyclosporine, darunavir, lopinavir, or tipranavir may ↑ levels/toxicity of grazoprevir; concurrent use contraindicated.
• Strong CYP3A inducers, including phenytoin, carbamazepine, or rifampin may ↓ levels/effectiveness of elbasvir and grazoprevir; concurrent use contraindicated.
• Efavirenz may ↓ levels/effectiveness of elbasvir and grazoprevir; concurrent use contraindicated.
• Moderate CYP3A inducers, including nafcillin, bosentan, etravirine, and modafanil may ↓ levels/effectiveness of elbasvir and grazoprevir; concurrent use not recommended.
• Strong CYP3A inhibitors, including ketoconazole and cobicistat-containing regimens may ↑ levels/toxicity of elbasvir and grazoprevir; concurrent use not recommended.
• May ↑ levels/toxicity of tacrolimus; frequent monitoring of tacrolimus whole blood concentrations recommended.
• May ↑ levels/toxicity of atorvastatin, fluvastatin, lovastatin, rosuvastatin, and simvastatin; rosuvastatin dose should not exceed 10 mg/day; atorvastatin dose should not exceed 20 mg/day; use lowest possible dose of fluvastatin, lovastatin, and simvastatin and monitor closely for myopathy.
• May cause fluctuations in INR when used with warfarin; closely monitor INR.

Drug-Natural Products:

• St. John's wort may ↓ levels/effectiveness of elbasvir and grazoprevir; concurrent use contraindicated.

Patients with HCV genotype 1a infection should be tested for the presence of virus with NS5A resistance-associated polymorphisms prior to initiation of therapy to determine the most appropriate dosage regimen and duration of therapy

• PO (Adults and Children 12 yr or 30 kg): Genotype 1a: Treatment-nave or Peg-interferon/ribavirin-experienced without baseline NS5A polymorphisms: 1 tablet once daily for 12 wk; Genotype 1a: Treatment-nave or Peg-interferon/ribavirin-experienced with baseline NS5A polymorphisms: 1 tablet once daily for 16 wk in combination with ribavirin; Genotype 1b: Treatment-nave or Peg-interferon/ribavirin-experienced: 1 tablet once daily for 12 wk; Genotype 1a or 1b: Peg-interferon/ribavirin/ HCV NS3/4A protease inhibitor-experienced: 1 tablet once daily for 12 wk in combination with ribavirin; Genotype 4: Treatment-nave: 1 tablet once daily for 12 wk; Genotype 4: Peg-interferon/ribavirin-experienced: 1 tablet once daily for 16 wk in combination with ribavirin.

• Tablets: elbasvir 50 mg/grazoprevir 100 mg;

• Monitor for signs and symptoms of hepatitis B reactivation or hepatitis (jaundice, dark urine, light colored stools, fatigue, weakness, loss of appetite, nausea, vomiting, stomach pain) during therapy.
• Monitor for signs and symptoms of hepatic decompensation (jaundice, ascites, hepatic encephalopathy, variceal hemorrhage). Discontinue therapy if hepatic decompensation/failure occurs.

• Measure hepatitis B surface antigen (HBsAg) and hepatitis core antibody (anti-HBc) in all patients before starting hepatitis C virus therapy. May cause hepatitis B virus reactivation. Monitor for clinical and laboratory signs of hepatitis flare (↑ AST, ALT, bilirubin, liver failure, death) or HBV reactivation (rapid ↑ in serum HBV DNA level) during HCV treatment and post-treatment follow-up.
  • Test all patients for current or prior hepatitis B virus (HBV) infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before starting therapy. Monitor for HBV reactivation during and following therapy.Test patient with HCV genotype 1a infection for presence of virus with NS5A resistance-associated polymorphisms prior to starting therapy with Zepatier to determine dose regimen and duration.
  • Monitor liver function tests (AST, ALT, bilirubin, alkaline phosphatase) prior to, at treatment wk 8, at treatment wk 12 if patient receiving 16 wk therapy, and as clinically indicated during therapy. If persistently ALT ↑ >10 times upper limit of normal, consider discontinuing elbasvir/grazoprevir. Discontinue therapy if ↑ ALT and signs and symptoms of liver inflammation or ↑ conjugated bilirubin, alkaline phosphatase, or INR.

• PO: Administer one tablet daily without regard to food.

• Instruct patient to take Zepatier as directed. Keep tablet in blister pack until ready to take dose. Do not skip or miss doses, or stop medication without consulting health care professional. Advise patient to read Patient Information before starting and with each Rx refill in case of changes.
• Advise patient to notify health care professional promptly if signs and symptoms of liver inflammation (fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, discolored feces) occur.
• Advise patient to notify health care professional if they have a history of HBV. May cause reactivation.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's wort.
• May cause fetal harm. Advise patients to notify health care professional if pregnancy is planned or suspected or if breastfeeding. Advise females of reproductive potential and males with a female partner of reproductive potential who take Zepatier with ribavirin to use effective contraception during and for 6 mo after therapy is completed. Notify health care professional immediately if pregnancy is suspected.

• Decreased levels of HCV with sustained virologic response and lessened sequelae of chronic HCV infection.

Zepatier