soe-FOS-bue-vir/vel-PAT-as-vir

Therapeutic Classification: antivirals

Pharmacologic Classification: NS5A inhibitors

• Chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection in patients without cirrhosis or with compensated cirrhosis.
• Chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection in patients with decompensated cirrhosis (in combination with ribavirin).

• Sofosbuvir: inhibits the HCV NS5B RNA-dependent RNA polymerase, resulting in inhibition of viral replication.
• Velpatasvir: inhibits the HCV NS5A protein, resulting in inhibition of viral replication.

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

Sofosbuvir

Absorption: Rapidly metabolized following absorption (extensive first-pass effect).

Distribution: Unknown.

Metabolism/Excretion: Extensively metabolized primarily to GS-461203, an active antiviral moiety, then converted to 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: 25 hr.

Velpatasvir

Absorption: Well absorbed following oral administration.

Distribution: Unknown.

Protein Binding: >99.5%.

Metabolism/Excretion: Primarily metabolized in the liver via the CYP2B6, CYP2C8, and CYP3A4 isoenzymes. Primarily undergoes biliary excretion, with 94% excreted in feces and 0.4% eliminated in urine.

Half-life: 47 hr.

(plasma concentrations)

Contraindicated in:

• Situations when ribavirin is contraindicated (when ribavirin required)
• Concurrent use with other drugs/regimens containing sofosbuvir
• Receiving immunosuppressant or chemotherapy medications (↑ risk of hepatitis B virus [HBV] reactivation)
• 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:

• OB: Safety not established in pregnancy (when ribavirin not required)
• Lactation: Safety not established in breastfeeding (when ribavirin not required)
• Pedi: Children <3 yo (safety and effectiveness not established)
• Geri: Older adults may be more sensitive to drug's effects.

Without Ribavirin

Derm: rash.

GI: ↑lipase, HBV reactivation, nausea.

Neuro: fatigue, headache, insomnia, irritability.

With Ribavirin

Derm: rash.

GI: diarrhea, nausea, HBV reactivation, ↑ lipase.

Hemat: anemia.

Neuro: fatigue, headache, insomnia.

Drug-Drug:

• Concurrent use of P-glycoprotein inducers may ↓ levels and effectiveness of sofosbuvir and velpatasvir; concurrent use not recommended.
• Concurrent use of moderate to strong CYP2B6, CYP2C8, or CYP3A4 inducers may ↓ levels and effectiveness of velpatasvir; concurrent use not recommended.
• Amiodarone may ↑ risk of symptomatic bradycardia when used with sofosbuvir-containing regimens; 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/velpatasvir.
• Acid-reducing agents may ↓ levels and effectiveness of velpatasvir; separate administration from antacids, including magnesium hydroxide and aluminum hydroxide by 4 hr; administer H₂-receptor antagonists simultaneously or 12 hr apart from sofosbuvir/velpatasvir (dose of H₂ antagonist should not exceed famotidine 40 mg twice daily or equivalent); concurrent use with proton-pump inhibitors not recommended (if proton pump inhibitor necessary, administer sofosbuvir/velpatasvir with food and take 4 hr before omeprazole 20 mg; use with other proton pump inhibitors not studied).
• May ↑ levels and risk of toxicity of digoxin; therapeutic monitoring of serum digoxin concentrations recommended.
• May ↑ levels and risk of toxicity of topotecan; concurrent use not recommended.
• Carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifabutin, and rifampin may ↓ levels and effectiveness of sofosbuvir and velpatasvir; concurrent use not recommended.
• Efavirenz may ↓ levels and effectiveness of velpatasvir; concurrent use not recommended.
• May ↑ levels/toxicity of tenofovir disoproxil fumarate; monitor closely.
• Tipranavir/ritonavir may ↓ levels and effectiveness of sofosbuvir and velpatasvir; concurrent use not recommended.
• May ↑ levels and risk of toxicity of rosuvastatin and atorvastatin; rosuvastatin dose should not exceed 10 mg/day; monitor closely for atorvastatin-induced myopathy or rhabdomyolysis.
• 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:

• St. John's wort may ↓ levels and effectiveness of sofosbuvir and velpatasvir; concurrent use not recommended.

• PO (Adults): Patients without cirrhosis or with compensated cirrhosis (including liver transplant recipients): One 400-mg/100-mg tablet once daily for 12 wk; Patients with decompensated cirrhosis: One 400-mg/100-mg tablet once daily for 12 wk in combination with ribavirin.
• PO (Children 3 yr or 30 kg): Patients without cirrhosis or with compensated cirrhosis (including liver transplant recipients): One 400-mg/100-mg tablet once daily for 12 wk or two 200-mg/50-mg tablets once daily for 12 wk or two 200-mg/50-mg pellet packets once daily for 12 wk; Patients with decompensated cirrhosis: One 400-mg/100-mg tablet once daily for 12 wk in combination with ribavirin or two 200-mg/50-mg tablets once daily for 12 wk in combination with ribavirin or two 200-mg/50-mg pellet packets once daily for 12 wk in combination with ribavirin.
• PO (Children 3 yr or 17–<30 kg): Patients without cirrhosis or with compensated cirrhosis (including liver transplant recipients): one 200-mg/50-mg tablet once daily for 12 wk or one 200-mg/50-mg pellet packet once daily for 12 wk; Patients with decompensated cirrhosis: one 200-mg/50-mg tablet once daily for 12 wk in combination with ribavirin or one 200-mg/50-mg pellet packet once daily for 12 wk in combination with ribavirin.
• PO (Children 3 yr or <17 kg): Patients without cirrhosis or with compensated cirrhosis (including liver transplant recipients): one 150-mg/37.5-mg pellet packet once daily for 12 wk; Patients with decompensated cirrhosis: one 150-mg/37.5-mg pellet packet once daily for 12 wk in combination with ribavirin.

• Tablets: sofosbuvir 200 mg/velpatasvir 50 mg; sofosbuvir 400 mg/velpatasvir 100 mg;
• Oral pellets: sofosbuvir 150 mg/velpatasvir 37.5 mg per pkt; sofosbuvir 200 mg/velpatasvir 50 mg per pkt;

• 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.

• Measure hepatitis B surface antigen (HBsAg) and hepatitis core antibody (anti-HBc) in all patients before starting HCV therapy. May cause HBV 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.
  • May cause ↑ serum lipase and amylase levels.
  • May cause ↑ CK and indirect bilirubin levels.

• PO: Administer one tablet daily without regard to food for 12 wk.
  • Do not chew oral pellets; causes a bitter aftertaste. May be administered directly into mouth and swallowed whole or taken with food. In pediatric patients <6 years of age, administer oral pellets with food to increase tolerability and palatability. Sprinkle oral pellets on one or more spoonfuls of non-acidic soft food (pudding, chocolate syrup, ice cream) at or below room temperature. Take oral pellets within 15 min of gently mixing with food and swallow entire contents without chewing.
  • Administer antacids 4 hr apart from sofosbuvir/velpatasvir. May administer simultaneously or 12 hr apart with H₂-receptor antagonists at doses not to exceed famotidine 40 mg twice daily. Avoid administration with proton pump inhibitors; if medically necessary, administer sofosbuvir/velpatasvir with food and 4 hr before omeprazole 20 mg.

• Instruct patient to take Epclusa as directed. 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 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.
• Advise patients to notify health care professional if pregnancy is planned or suspected, or if breastfeeding. Advise females of reproductive potential who take Epclusa 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.

Epclusa