soe-FOS-bue-vir

Therapeutic Classification: antivirals

Pharmacologic Classification: polymerase inhibitors

• Chronic hepatitis C virus (HCV) infection (genotypes 1 or 4) in patients without cirrhosis or with compensated cirrhosis (in combination with ribavirin and peginterferon alfa).
• Chronic HCV infection (genotypes 2 or 3) in patients without cirrhosis or with compensated cirrhosis (in combination with ribavirin).

• Inhibits RNA-dependent RNA polymerase, resulting in inhibition of viral replication.

• Decreased HCV RNA levels with decreased severity and sequelae of HCV.

Absorption: Rapidly absorbed following oral administration.

Distribution: Unknown.

Metabolism/Excretion: Extensively metabolized with much conversion to GS-461203, an active antiviral moiety, then converted GS-331007, which does not have antiviral activity. 80% excreted in urine mostly as GS-331007 (3.5% as unchanged drug), 14% excreted in feces, 2.5% excreted in expired air.

Half-life: Sofosbuvir: 0.4 hr; GS-331007: 27 hr.

(plasma concentrations)

† Sofosbuvir (2–4 hr for GS-331007).

Contraindicated in:

• Contraindications for ribavirin and/or peginterferon alfa
• Severe renal impairment or end-stage renal disease
• OB: Pregnant women or men whose partners are pregnant (ribavirin may cause fetal harm).

Use Cautiously in:

• Receiving immunosuppressant or chemotherapy medications (↑ risk of hepatitis B virus [HBV] reactivation)
• Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant
• Women and men of reproductive potential
• Pedi: Children <3 yr (safety and effectiveness not established).

In combination with ribavirin

Derm: pruritus.

GI: diarrhea, HBV reactivation, nausea.

MS: myalgia.

Neuro: fatigue, headache, insomnia, irritability, weakness.
Misc: chills, fever.

In combination with ribavirin and peginterferon alfa

Derm: rash, pruritus.

GI: diarrhea, nausea, HBV reactivation.

Hemat: anemia.

MS: myalgia.

Neuro: fatigue, headache, insomnia, irritability, weakness.
Misc: chills, fever.

Drug-Drug:

• Levels and effectiveness may be ↓ by concurrent use of carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifabutin, rifampin, rifapentine, and tipranavir/ritonavir; avoid concurrent use.
• Amiodarone may ↑ risk of symptomatic bradycardia when used with sofosbuvir; concurrent use not recommended; if amiodarone necessary, monitor patients in inpatient setting for first 48 hr of concomitant use and then monitor heart rate on outpatient basis for at least the first 2 wk of treatment (follow same monitoring procedure if discontinuing amiodarone immediately before initiation of sofosbuvir therapy).
• May cause fluctuations in INR when used with warfarin; closely monitor INR.
• May ↑ risk of hypoglycemia when used with certain antidiabetic agents.

Drug-Natural Products:

• Levels and effectiveness may be ↓ by concurrent use of P-gp inducers, including St. John's wort; avoid concurrent use.

• PO (Adults): Genotypes 1 or 4 (treatment-naive without cirrhosis or with compensated cirrhosis [Child-Pugh A]): 400 mg once daily for 12 wk in combination with peginterferon alfa and ribavirin; Genotype 2 (treatment-naive and treatment-experienced without cirrhosis or with compensated cirrhosis [Child-Pugh A]): 400 mg once daily for 12 wk in combination with ribavirin; Genotype 3 (treatment-naive and treatment-experienced without cirrhosis or with compensated cirrhosis [Child-Pugh A]): 400 mg once daily for 24 wk in combination with ribavirin; Patients with hepatocellular carcinoma awaiting liver transplantation: 400 mg once daily in combination with ribavirin for up to 48 wk or until transplantation, whichever occurs first.
• PO (Children 3 yr and 35 kg): Genotype 2 (treatment-naive and treatment-experienced without cirrhosis or with compensated cirrhosis [Child-Pugh A]): 400 mg (as one 400-mg tablet, two 200-mg tablets, or two 200-mg packets of oral pellets) once daily for 12 wk in combination with ribavirin; Genotype 3 (treatment-naive and treatment-experienced without cirrhosis or with compensated cirrhosis [Child-Pugh A]): 400 mg (as one 400-mg tablet, two 200-mg tablets, or two 200-mg packets of oral pellets) once daily for 24 wk in combination with ribavirin.
• PO (Children 3 yr and 17–<35 kg): Genotype 2 (treatment-naive and treatment-experienced without cirrhosis or with compensated cirrhosis [Child-Pugh A]): 200 mg (as one 200-mg tablet or one 200-mg packet of oral pellets) once daily for 12 wk in combination with ribavirin; Genotype 3 (treatment-naive and treatment-experienced without cirrhosis or with compensated cirrhosis [Child-Pugh A]): 200 mg (as one 200-mg tablet or one 200-mg packet of oral pellets) once daily for 24 wk in combination with ribavirin.
• PO (Children 3 yr and <17 kg): Genotype 2 (treatment-naive and treatment-experienced without cirrhosis or with compensated cirrhosis [Child-Pugh A]): 150 mg (as one 150-mg packet of oral pellets) once daily for 12 wk in combination with ribavirin; Genotype 3 (treatment-naive and treatment-experienced without cirrhosis or with compensated cirrhosis [Child-Pugh A]): 150 mg (as one 150-mg packet of oral pellets) once daily for 24 wk in combination with ribavirin.

(Generic available)

• Oral pellets: 150 mg/pkt; 200 mg/pkt;
• Tablets: 200 mg; 400 mg;

• Monitor for signs and symptoms of chronic HCV.
• Monitor for signs and symptoms of HBV reactivation (jaundice, dark urine, light-colored stools, fatigue, weakness, loss of appetite, nausea, vomiting, stomach pain) during therapy.

• A negative pregnancy test must be obtained immediately before beginning therapy and monthly thereafter.
  • Determine current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating therapy. In patients with HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation (rapid ↑ in serum HBV DNA level) during HCV therapy and during post-therapy follow-up.
  • Monitor CBC periodically during therapy. If Hgb <10 g/dL in patients with no cardiac disease, reduce ribavirin dose to 600 mg/day. If Hgb <8.5 g/dL, discontinue ribavirin. If 2 g/dL decrease in Hgb during any 4 wk treatment period in patient with history of stable cardiac disease, decrease ribavirin dose to 600 mg/day. If Hgb <12 g/dL despite 4 wk at reduced dose, discontinue ribavirin.
  • May cause pancytopenia and thrombocytopenia.
  • May cause ↑ bilirubin, CK, and serum lipase levels.

• Must be administered in conjunction with ribavirin or ribavirin plus peginterferon alfa. If ribavirin or ribavirin plus peginterferon alfa is/are discontinued, sofosbuvir must be discontinued.
• PO: Administer once daily without regard to food.
  • For patients with difficulty swallowing, sprinkle pellets on one or more spoonfuls of nonacidic soft food (pudding, chocolate syrup, mashed potato, ice cream) at or below room temperature. Take pellets within 30 min of gently mixing with food and swallow entire contents without chewing to avoid a bitter aftertaste. Do not chew pellets.

• Instruct patient to take sofosbuvir with ribavirin or ribavirin plus PEG-interferon alfa as directed. Take missed doses on same day on one day as soon as remembered; do not double doses. Advise patient to read Patient Information before starting and with each refill in case of changes.
• 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.
• Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception due to risks for birth defects and fetal death and avoid breastfeeding. Women and male partners must use 2 forms of nonhormonal contraception during and for at least 6 mo after discontinuation of therapy. Encourage patients with HCV/HIV-1 coinfection taking antiretrovirals to enroll in the Antiviral Pregnancy Registry at 1-800-258-4263.

• Decreased HCV RNA levels with decreased severity and sequelae of HCV.
  • Patients with genotype 1 and 4 chronic HCV should be treated with sofosbuvir, peginterferon alfa, and ribavirin for 12 wk.
  • Patients with genotype 2 chronic HCV should be treated with sofosbuvir and ribavirin for 12 wk.
  • Patients with genotype 3 chronic HCV should be treated with sofosbuvir and ribavirin for 24 wk.
  • Patients with hepatocellular cancer awaiting liver transplantation may be treated with sofosbuvir and ribavirin for up to 48 wk.

Sovaldi