Sofosbuvir, Velpatasvir, and Voxilaprevir

Name: Sofosbuvir, Velpatasvir, and Voxilaprevir

How should this medicine be used?

The combination of sofosbuvir, velpatasvir, and voxilaprevir comes as a tablet to take by mouth. It is usually taken with food once daily for 12 weeks. Take sofosbuvir, velpatasvir, and voxilaprevir at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take sofosbuvir, velpatasvir, and voxilaprevir exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Continue to take sofosbuvir, velpatasvir, and voxilaprevir even if you feel well. The length of your treatment depends on your condition, how well you respond to the medication, and whether you experience severe side effects. Do not stop taking sofosbuvir, velpatasvir, and voxilaprevir without talking to your doctor.

Ask your pharmacist or doctor for a copy of the manufacturer's information for the patient.

In case of emergency/overdose

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

What is sofosbuvir, velpatasvir, and voxilaprevir?

Sofosbuvir, velpatasvir, and voxilaprevir are antiviral medications that prevent hepatitis C virus (HCV) from multiplying in your body.

Sofosbuvir, velpatasvir, and voxilaprevir is a combination medicine used to treat chronic hepatitis C in adults with HCV genotype 1, 2, 3, 4, 5, or 6.

This medicine is usually given after other antiviral medicines have been tried without success.

Sofosbuvir, velpatasvir, and voxilaprevir may also be used for purposes not listed in this medication guide.

Actions and Spectrum

Mechanism Of Action

Sofosbuvir, velpatasvir, and voxilaprevir is a fixed combination of 3 direct-acting antiviral (DAA) agents each with a different mechanism of action against hepatitis C virus.1

Spectrum

Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a, and 4a with an IC50 value ranging from 0.36 to 3.3 µM. GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.1

Velpatasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication. Resistance selection in cell culture and cross-resistance studies indicate velpatasvir targets NS5A as its mode of action.1

Voxilaprevir is a noncovalent, reversible inhibitor of the NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical inhibition assay, voxilaprevir inhibited the proteolytic activity of recombinant NS3/4A enzymes from clinical isolates of HCV genotypes 1b and 3a with Ki values of 38 and 66 pM, respectively.1

Evaluation of sofosbuvir in combination with velpatasvir or voxilaprevir, as well as the combination of velpatasvir and voxilaprevir, showed no antagonistic effect in reducing HCV RNA levels in replicon cells.1

Resistance

In Cell Culture: HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with the nucleotide analog NS5B polymerase inhibitor resistance substitution, S282T, in all replicon genotypes examined. An M289L substitution emerged along with the S282T substitution in genotypes 2a, 5 and 6 replicons. Site-directed mutagenesis of the S282T substitution in replicons of genotype 1 to 6 conferred 2- to 18-fold reduced susceptibility to sofosbuvir.1

HCV genotype 1a, 1b, 2a, 3a, 4a, 5a, and 6a replicon variants with reduced susceptibility to velpatasvir were selected in cell culture. The replicon variants developed amino acid substitutions at NS5A inhibitor resistance-associated positions 24, 28, 30, 31, 32, 58, 92, and 93. Phenotypic analysis of site-directed mutant replicons of the selected NS5A substitutions showed that single Y93H/N and the combination of L31V + Y93H/N in genotype 1a, the combination of L31V + Y93H in genotype 1b, the single substitution Y93H/S in genotype 3a, and single substitutions L31V and P32A/L/Q/R in genotype 6 conferred greater than 100-fold reduction in velpatasvir susceptibility. In the genotype 2a replicon, the single substitutions F28S and Y93H showed 91-fold and 46-fold reduced susceptibility to velpatasvir, respectively. The single substitution Y93H conferred 3-fold reduced susceptibility to velpatasvir in genotype 4a replicons. Combinations of these NS5A substitutions often showed greater reductions in susceptibility to velpatasvir than single substitutions alone.1

HCV genotype 1a, 1b, 2a, 3a, 4a, 5a, and 6a replicon variants with reduced susceptibility to voxilaprevir were selected in cell culture. Amino acid substitutions were selected at NS3/4A protease inhibitor resistance-associated positions 41, 156, and 168. Site-directed mutagenesis of NS3 resistance-associated substitutions showed that substitutions conferring a greater than 100-fold reduction in voxilaprevir susceptibility were A156L/T in genotype 1a, A156T/V in genotype 1b, A156L/V in genotype 2a, A156T/V in genotype 3a, and A156L/T/V in genotype 4. Combinations of these NS3 substitutions often showed greater reductions in susceptibility to voxilaprevir than single substitutions alone.1

In Clinical Trials: Of the 263 NS5A inhibitor-experienced subjects treated with sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks in POLARIS-1, 7 of 263 (3%) subjects (2 with genotype 1a, 4 with genotype 3a, and 1 with genotype 4d) did not achieve sustained virologic response at 12 weeks after the end of treatment (SVR12) and qualified for resistance analysis; 6 relapsed and 1 experienced virologic breakthrough. All the virologic failures had cirrhosis and all had a previous DAA regimen containing sofosbuvir; 3 were previously treated with ledipasvir/sofosbuvir, 2 were previously treated with sofosbuvir/velpatasvir, and 2 were previously treated with daclatasvir and sofosbuvir. Six of the 7 virologic failures had baseline NS5A inhibitor resistance-associated substitutions at position 30 or 93. All 7 virologic failures had NS5A resistance-associated substitutions at failure using a sensitivity threshold of 1% of the viral population.1

Of the 2 genotype 1a virologic failure subjects, one subject with virologic breakthrough at Week 12 had virus with the NS5A resistance-associated substitution Q30T at baseline and failure and emergent NS5A resistance-associated substitutions L31M and Y93H at breakthrough; the other subject had virus with the NS5A resistance-associated substitution Y93N at baseline and relapse and emergence of low-level K24R (1.2%) in NS5A and V36A (2%) in NS3 at relapse.1

Of the 4 genotype 3a virologic failure subjects, one subject had virus with emergent NS5A resistance-associated substitution E92K. Two subjects had virus with Y93H at relapse that was enriched from baseline. The remaining subject had virus with the NS5A resistance-associated substitution A30K at baseline and relapse and emergence of low-level Q41K (2%), V55A (3%) and R155M (1%) substitutions in NS3 at relapse.1

The genotype 4d subject who relapsed had virus with emergent NS5A resistance-associated substitution Y93H.1

No NS5B nucleotide analog inhibitor resistance-associated substitutions emerged among the virologic failure subjects from POLARIS-1. 1

In POLARIS-4, of the 182 DAA-experienced subjects who had not received an NS5A inhibitor treated with sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks, 1 subject (genotype 1a) of 182 (1%) subjects relapsed and qualified for resistance analysis. The NS5A resistance-associated substitution M28T (7.5%) emerged in this subject at relapse. No NS3/4A protease inhibitor or nucleotide analog NS5B inhibitor substitutions were observed in this subject at relapse.1

Cross Resistance

Cross-resistance is possible between HCV NS3/4A protease inhibitors and between HCV NS5A inhibitors by class. Sofosbuvir, velpatasvir, and voxilaprevir were each active against substitutions associated with resistance to other classes of DAAs with different mechanisms of action (e.g., voxilaprevir was fully active against virus with NS5A resistance-associated substitutions and nucleotide analog NS5B inhibitor resistance-associated substitutions).1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV

Inform patients that HBV reactivation can occur in patients coinfected with HBV during or after treatment of HCV virus infection. Advise patients to tell their healthcare provider if they have a history of hepatitis B infection.1

Serious Symptomatic Bradycardia When Coadministered with Amiodarone

Advise patients to seek medical evaluation immediately for symptoms of bradycardia such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, or memory problems.1

Drug Interactions

Inform patients that sofosbuvir, velpatasvir, and voxilaprevir may interact with other drugs. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort.1

Administration

Advise patients to take the fixed combination of sofosbuvir, velpatasvir, and voxilaprevir once daily on a regular dosing schedule with food. Inform patients that it is important not to miss or skip doses and to take the drug for the duration that is recommended by the physician.1

Commonly used brand name(s)

In the U.S.

  • Vosevi

Available Dosage Forms:

  • Tablet

Therapeutic Class: Antiviral

Pharmacologic Class: Hepatitis C Virus NS5A Inhibitor

What are some things I need to know or do while I take Sofosbuvir, Velpatasvir, and Voxilaprevir?

  • 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 does not stop the spread of diseases like HIV or hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors. Talk with your 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 sofosbuvir, velpatasvir, and voxilaprevir with your other drugs.
  • Slow heartbeat and the need to get a pacemaker have happened when amiodarone was given with sofosbuvir and certain other hepatitis C drugs. Sometimes, this has been deadly. Slow heartbeat has happened up to 2 weeks after starting hepatitis C treatment. You will need to be watched closely if you will be taking amiodarone with hepatitis C treatment. Follow what your doctor has told you to do. Call your doctor right away if you have signs of slow heartbeat like chest pain, confusion, dizziness, passing out or near-passing out, memory problems, shortness of breath, tiredness, or weakness.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
  • Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Pronunciation

(soe FOS bue vir, vel PAT as vir, & vox i LA pre vir)

ALERT U.S. Boxed Warning

Hepatitis B virus reactivation:

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with sofosbuvir/velpatasvir/voxilaprevir. HBV reactivation has been reported in hepatitis C virus (HCV)/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals 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.

Renal Dose Adjustments

Mild or moderate renal dysfunction: No adjustment recommended.
Severe renal dysfunction (estimated glomerular filtration rate less than 30 mL/min/1.73 m2): Data not available

Comments:
-Safety and efficacy not established in patients with severe renal dysfunction; dose not established due to higher exposures of the main sofosbuvir metabolite.

Precautions

US BOXED WARNING:
-RISK OF HBV REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV: All patients should be tested for evidence of current/prior HBV infection before starting this drug. HBV reactivation has been reported during or after completion of HCV direct-acting antiviral therapy in HCV/HBV-coinfected patients who were not receiving HBV antiviral therapy; some cases resulted in fulminant hepatitis, hepatic failure, and death. HCV/HBV-coinfected patients should be monitored for hepatitis flare or HBV reactivation during HCV therapy and posttherapy follow-up; appropriate patient management for HBV infection should be started as clinically indicated.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Sofosbuvir / velpatasvir / voxilaprevir Pregnancy Warnings

The manufacturer makes no recommendation regarding use during pregnancy. US FDA pregnancy category: Not assigned. Risk summary: No adequate data available on use of this drug in pregnant women to inform a drug-related risk.

Animal studies have failed to reveal evidence of fetal harm. There are no controlled data in human pregnancy. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Sofosbuvir / velpatasvir / voxilaprevir Breastfeeding Warnings

The manufacturer makes no recommendation regarding use during lactation. Excreted into human milk: Unknown Excreted into animal milk: Yes (GS-331007 [main circulating metabolite of sofosbuvir], velpatasvir, voxilaprevir) Comments: -Developmental and health benefits of breastfeeding should be considered as well as the mother's clinical need for this drug. -The effects in the nursing infant are unknown; potential side effects in the breastfed child due to this drug or the mother's underlying condition should be considered.

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