Drug information of Sofosbuvir and velpatasvir

Sofosbuvir and velpatasvir

Drug group:

Sofosbuvir and velpatasvir is a combination antiviral medicine used to treat chronic hepatitis C in adults.

Mechanism of effect

Sofosbuvir: Inhibitor of HCV NS5B RNA-dependent polymerase; its inhibition, in turn, suppresses viral replication

Velpatasvir: Pangenotypic HCV NS5A inhibitor; the NS5A protein is required for viral replication

Pharmacodynamic

Velpatasvir is a small molecule direct-acting antiviral used in the treatment of hepatitis C in combination with sofosbuvir. Velpatasvir prevents viral replication by inhibiting non-structural protein 5A (NS5A).

At a dose 5 times the recommended dose, velpatasvir does not prolong QTc interval to any clinically relevant extent.

Sofosbuvir acts against HCV and is categorized as a direct-acting antiviral agent (DAA).

At a dose 3 times the recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent.

Pharmacokinetics

Absorption

Velpatasvir solubility decreases as gastric pH increases; practically insoluble (<0.1 mg/mL) at pH >5

Peak concentration time

  • Sofosbuvir: 0.5-1 hr
  • Velpatasvir: 3 hr

Peak plasma concentration

  • Sofosbuvir: 567 ng/mL
  • Velpatasvir: 259 ng/mL

AUC

  • Sofosbuvir: 1268 ng· hr/mL
  • Velpatasvir: 2980 ng·hr/mL

Protein bound

  • Sofosbuvir: 61-65%
  • Velpatasvir: >99.5%

Metabolism

Sofosbuvir

  • Liver metabolism by cathepsin A, CES1, and HINT1
  • Substrate of P-gp transporter and breast cancer resistance protein (substrate for sofosbuvir but not metabolite GS-331007)

Velpatasvir

  • Substrate of P-gp transporter, CYP2B6, 2C8, and 3A4

Half-life

  • Sofosbuvir: 0.5 hr; GS-33107 25 hr (active metabolite)
  • Velpatasvir: 15 hr

Excretion

  • Major route of elimination
    • Sofosbuvir: Metabolism
    • GS-33107: Glomerular filtration and active tubular secretion
    • Velpatasvir: Biliary excretion as parent compound (77%)
  • Urine
    • Sofosbuvir: 80%
    • Velpatasvir: 14%
  • Feces
    • Sofosbuvir: 0.4%
    • Velpatasvir: 94%

Dosage

Adult         

Chronic Hepatitis C

Indicated for adults with chronic hepatitis C virus (HCV) infection genotypes 1, 2, 3, 4, 5, and 6

1 tablet (400 mg sofosbuvir/ 100 mg velpatasvir) PO qDay

Treatment duration

  • Patients without cirrhosis or with compensated cirrhosis (Child-Pugh A): Sofosbuvir/velpatasvir for 12 weeks
  • Patients with decompensated cirrhosis (Child-Pugh B or C): Sofosbuvir/velpatasvir plus weight-based ribavirin with food for 12 weeks
  • The above regimens also apply to patients coinfected with HIV-1
  • Weight-based ribavirin dose
    • <75 kg: 1000 mg/day PO divided BID
    • ≥75 kg: 1200 mg/day PO divided BID
    • Ribavirin starting dose and on-treatment dosage should be modified based on hemoglobin and creatinine clearance

Pediatric

Safety and efficacy not established

Alerts

If administered with ribavirin, warnings and precautions for ribavirin apply to this combination; see ribavirin prescribing information

Bradycardia

  • Coadministration with amiodarone is not recommended
  • Serious symptomatic bradycardia may occur if sofosbuvir is coadministered with amiodarone in combination with another direct-acting antiviral (eg, daclatasvir, simeprevir)
  • Bradycardia has generally occurred within hours to days, but reports have been observed up to 2 weeks after initiating HCV treatment
  • Patients also taking beta blockers, or those with underlying cardiac comorbidities, and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone
  • If no alternative exists for amiodarone, inpatient cardiac monitoring is recommended for the first 48 hr and then daily home monitoring for at least the first 2 weeks
  • Because of amiodarone’s long half-life, patients discontinuing amiodarone just prior to starting therapy should also undergo similar cardiac monitoring

Drug interaction overview

  • Drugs affecting sofosbuvir/velpatasvir
    • Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 (the predominant circulating metabolite of sofosbuvir) is not
    • In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed
    • Drugs that are potent P-gp inducers and/or moderate-to-potent inducers of CYP2B6, CYP2C8, or CYP3A4 (eg, rifampin, carbamazepine, St. John’s wort) may significantly decrease sofosbuvir and/or velpatasvir plasma concentrations, leading to potentially reduced therapeutic effect; avoid coadministration
  • Drugs that increase gastric pH
    • Coadministration with drugs that increase gastric pH are expected to decrease velpatasvir serum concentration
  • Sofosbuvir/velpatasvir effect on other drugs
    • Velpatasvir inhibits drug transporters P-gp, BCRP, OATP1B1, OATP1B3, and OATP2B1
    • Coadministration with drugs that are substrates of these transporters may increase the exposure of such drugs

Black Box Warnings

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HCV direct acting antivirals (DDAs)

HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with DDAs and were not receiving HBV antiviral therapy

Some cases have resulted in fulminant hepatitis, hepatic failure, and death

Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up

Initiate appropriate patient management for HBV infection as clinically indicated

Points of recommendation

Follow all directions on your prescription label and read all medication guides or instruction sheets. Use the medicine exactly as directed.

You may take this medicine with or without food.

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

You should not stop using sofosbuvir and velpatasvir suddenly. Stopping suddenly could make your hepatitis C harder to treat with antiviral medicine.

If you have ever had hepatitis B, using sofosbuvir and velpatasvir can cause this virus to become active or get worse. You may need frequent liver function tests while using this medicine and for several months after you stop.

Store this medicine in the original container at room temperature away from moisture and heat.

Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.

Get your prescription refilled before you run out of medicine completely.

If you also take omeprazole or an antacid, do not take it for at least 4 hours after you have taken your dose of sofosbuvir and velpatasvir (with food).

Using sofosbuvir and velpatasvir will not prevent your disease from spreading. Do not have unprotected sex or share razors or toothbrushes. Talk with your doctor about safe ways to prevent HCV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Related drugs

Daclatasvir , Sofosbuvir


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