Sofosbuvir / velpatasvir / voxilaprevir

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# Black Box Warning

# Overview
Sofosbuvir / velpatasvir / voxilaprevir is a fixed-dose combination of Sofosbuvir, a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor, Velpatasvir, an HCV NS5A inhibitor, and Voxilaprevir, an HCV NS3/4A protease inhibitor that is FDA approved for the treatment of treatment of adult patients with chronic HCV infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen containing an NS5A inhibitor or genotype 1a or 3 infection and have previously been treated with an HCV regimen containing Sofosbuvir without an NS5A inhibitor. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include headache, fatigue, diarrhea, and nausea.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Sofosbuvir/Velpatasvir/Voxilaprevir is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have:
- genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen containing an NS5A inhibitor.
- genotype 1a or 3 infection and have previously been treated with an HCV regimen containing Sofosbuvir without an NS5A inhibitor.
- Additional benefit of Sofosbuvir/Velpatasvir/Voxilaprevir over Sofosbuvir/Velpatasvir was not shown in adults with genotype 1b, 2, 4, 5, or 6 infection previously treated with Sofosbuvir without an NS5A inhibitor.
- The recommended dosage of Sofosbuvir/Velpatasvir/Voxilaprevir is one tablet, taken orally, once daily with food . One tablet of Sofosbuvir/Velpatasvir/Voxilaprevir contains 400 mg of Sofosbuvir, 100 mg of Velpatasvir, and 100 mg of Voxilaprevir. Table 1 shows the recommended treatment regimen and duration based on patient population.
- No dosage recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate  less than 30 mL/min/1.73 m2) or with end stage renal disease (ESRD), due to higher exposures (up to 20-fold) of the predominant Sofosbuvir metabolite.
- Sofosbuvir/Velpatasvir/Voxilaprevir is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C) due to higher exposures of Voxilaprevir in these patients.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Sofosbuvir/Velpatasvir/Voxilaprevir Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding Sofosbuvir/Velpatasvir/Voxilaprevir Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Sofosbuvir / velpatasvir / voxilaprevir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Sofosbuvir/Velpatasvir/Voxilaprevir Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding Sofosbuvir/Velpatasvir/Voxilaprevir Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
- Sofosbuvir/Velpatasvir/Voxilaprevir is contraindicated with rifampin.

# Warnings
- Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.
- HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.
- Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with Sofosbuvir/Velpatasvir/Voxilaprevir. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with Sofosbuvir/Velpatasvir/Voxilaprevir and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.
- Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with a Sofosbuvir-containing regimen. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a Sofosbuvir-containing regimen (HARVONI (ledipasvir/Sofosbuvir)). Bradycardia has generally occurred within hours to days, but cases 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. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown.
- Coadministration of amiodarone with Sofosbuvir/Velpatasvir/Voxilaprevir is not recommended. For patients taking amiodarone who have no other alternative viable treatment options and who will be coadministered Sofosbuvir/Velpatasvir/Voxilaprevir:
- Counsel patients about the risk of symptomatic bradycardia.
- Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.
- Patients who are taking Sofosbuvir/Velpatasvir/Voxilaprevir who need to start amiodarone therapy due to no other alternative viable treatment options should undergo similar cardiac monitoring as outlined above.
- Due to amiodarone's long half-life, patients discontinuing amiodarone just prior to starting Sofosbuvir/Velpatasvir/Voxilaprevir should also undergo similar cardiac monitoring as outlined above.
- Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion, or memory problems.
- Drugs that are inducers of P-gp and/or moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., St. John's wort, carbamazepine) may significantly decrease plasma concentrations of Sofosbuvir, Velpatasvir, and/or Voxilaprevir, leading to potentially reduced therapeutic effect of Sofosbuvir/Velpatasvir/Voxilaprevir. The use of these agents with Sofosbuvir/Velpatasvir/Voxilaprevir is not recommended.

# Adverse Reactions

## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse Reactions in HCV-Infected Subjects without Cirrhosis or with Compensated Cirrhosis
- The adverse reactions data for Sofosbuvir/Velpatasvir/Voxilaprevir were derived from two Phase 3 clinical trials (POLARIS-1 and POLARIS-4) that evaluated a total of 445 subjects infected with genotype 1, 2, 3, 4, 5, or 6 HCV, without cirrhosis or with compensated cirrhosis (Child-Pugh A), who received Sofosbuvir/Velpatasvir/Voxilaprevir for 12 weeks. Sofosbuvir/Velpatasvir/Voxilaprevir was studied in placebo- and active-controlled (Sofosbuvir/Velpatasvir) trials.
- The proportion of subjects who permanently discontinued treatment due to adverse events was 0.2% for subjects who received Sofosbuvir/Velpatasvir/Voxilaprevir for 12 weeks.
- The most common adverse reactions (adverse events assessed as causally related by the investigator and at least 10%) were headache, fatigue, diarrhea, and nausea in subjects treated with Sofosbuvir/Velpatasvir/Voxilaprevir for 12 weeks.
- Table 2 lists adverse reactions (adverse events assessed as causally related by the investigator, all grades) observed in at least 5% of subjects receiving 12 weeks of treatment with Sofosbuvir/Velpatasvir/Voxilaprevir in the Phase 3 clinical trials. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.
- In POLARIS-1, of the subjects receiving Sofosbuvir/Velpatasvir/Voxilaprevir who experienced adverse reactions, 99% were mild or moderate (Grade 1 or 2) in severity. In POLARIS-4, of the subjects receiving Sofosbuvir/Velpatasvir/Voxilaprevir who experienced adverse reactions, all the reported adverse reactions were mild or moderate (Grade 1 or 2) in severity.
Less Common Adverse Reactions Reported in Clinical Trials
- The following adverse reactions occurred in less than 5% of subjects without cirrhosis or with compensated cirrhosis treated with Sofosbuvir/Velpatasvir/Voxilaprevir for 12 weeks and are included because of a potential causal relationship.
- Rash: In the POLARIS-1 and POLARIS-4 trials, rash occurred in less than 1% and 2% of subjects treated with Sofosbuvir/Velpatasvir/Voxilaprevir, respectively. Rash was reported in 1% of subjects treated with placebo in POLARIS-1, and was not reported by any subject taking Sofosbuvir/Velpatasvir in POLARIS-4. No serious adverse reactions of rash occurred and all rashes were mild or moderate in severity.
- Depression: In the POLARIS-1 and POLARIS-4 trials, depressed mood occurred in less than 1% and 1% of subjects treated with Sofosbuvir/Velpatasvir/Voxilaprevir, respectively. Depressed mood was not reported by any subject taking placebo in POLARIS-1 and was reported in 1% of subjects treated with Sofosbuvir/Velpatasvir in POLARIS-4. No serious adverse reactions of depressed mood occurred and all events were mild or moderate in severity.
Laboratory Abnormalities
- Lipase Elevations: Isolated, asymptomatic lipase elevations of greater than 3ULN were observed in POLARIS-1 in 2% of subjects treated with Sofosbuvir/Velpatasvir/Voxilaprevir and 3% of subjects treated with placebo, and in POLARIS-4 in 2% of subjects treated with Sofosbuvir/Velpatasvir/Voxilaprevir and less than 1% of subjects treated with Sofosbuvir/Velpatasvir.
- Creatine Kinase: Isolated, asymptomatic creatine kinase elevations greater than or equal to 10ULN were reported in POLARIS-1 in 1% of subjects treated with Sofosbuvir/Velpatasvir/Voxilaprevir and 1% of subjects treated with placebo, and in POLARIS-4 in less than 1% of subjects treated with Sofosbuvir/Velpatasvir/Voxilaprevir and no subjects treated with Sofosbuvir/Velpatasvir.
- Total bilirubin: Increases in total bilirubin less than or equal to 1.5ULN were observed in subjects treated with Sofosbuvir/Velpatasvir/Voxilaprevir due to inhibition of OATP1B1 and OATP1B3 by Voxilaprevir: 4% and 6% of subjects without cirrhosis in POLARIS-1 and POLARIS-4, respectively; and 7% and 13% of subjects with compensated cirrhosis in POLARIS-1 and POLARIS-4, respectively. No subjects experienced jaundice and total bilirubin levels decreased after completing Sofosbuvir/Velpatasvir/Voxilaprevir treatment.

## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of Sofosbuvir-containing regimens. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cardiac Disorders
- Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiated treatment with a Sofosbuvir-containing regimen.
Skin and Subcutaneous Tissue Disorders
- Skin rashes, sometimes with blisters or angioedema-like swelling.
- Angioedema.

# Drug Interactions
- Potential for Other Drugs to Affect Sofosbuvir/Velpatasvir/Voxilaprevir
- Potential for Sofosbuvir/Velpatasvir/Voxilaprevir to Affect Other Drugs
- Established and Potentially Significant Drug Interactions
- Drugs without Clinically Significant Interactions with Sofosbuvir/Velpatasvir/Voxilaprevir
- Sofosbuvir, Velpatasvir, and Voxilaprevir are substrates of drug transporters P-gp and BCRP while GS-331007 (predominant circulating metabolite of Sofosbuvir) is not. Voxilaprevir is also a substrate of OATP1B1 and OATP1B3. In vitro, slow metabolic turnover of Velpatasvir by CYP2B6, CYP2C8, and CYP3A4 and of Voxilaprevir by CYP1A2, CYP2C8, and primarily CYP3A4 was observed.
- Drugs that are inducers of P-gp and/or moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., St. John's wort, carbamazepine) may significantly decrease plasma concentrations of Sofosbuvir, Velpatasvir, and/or Voxilaprevir leading to reduced therapeutic effect of Sofosbuvir/Velpatasvir/Voxilaprevir. The use of these agents with Sofosbuvir/Velpatasvir/Voxilaprevir is not recommended. Sofosbuvir/Velpatasvir/Voxilaprevir may be coadministered with P-gp, BCRP, and CYP inhibitors. The use of OATP inhibitors which may substantially increase exposure of Voxilaprevir (e.g., cyclosporine) with Sofosbuvir/Velpatasvir/Voxilaprevir is not recommended.
- Velpatasvir and Voxilaprevir are inhibitors of drug transporters P-gp, BCRP, OATP1B1, and OATP1B3. Velpatasvir is also an inhibitor of OATP2B1. Coadministration of Sofosbuvir/Velpatasvir/Voxilaprevir with drugs that are substrates of these transporters may alter the exposure of such drugs. Coadministration of Sofosbuvir/Velpatasvir/Voxilaprevir with BCRP substrates (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) is not recommended.
- Fluctuations in INR values may occur in patients receiving warfarin concomitant with HCV treatment, including treatment with Sofosbuvir/Velpatasvir/Voxilaprevir. Frequent monitoring of INR values is recommended during treatment and post-treatment follow-up.
- Table 3 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with Sofosbuvir/Velpatasvir/Voxilaprevir, or are predicted drug interactions that may occur with Sofosbuvir/Velpatasvir/Voxilaprevir.
- Based on drug interaction studies conducted with Sofosbuvir/Velpatasvir/Voxilaprevir, no clinically significant drug interactions have been observed with the following drugs:
- Sofosbuvir/Velpatasvir/Voxilaprevir: cobicistat, darunavir, elvitegravir, emtricitabine, ethinyl estradiol/norgestimate, gemfibrozil, rilpivirine, ritonavir, tenofovir alafenamide, voriconazole.
- Sofosbuvir/Velpatasvir: dolutegravir, ketoconazole, raltegravir.
- Sofosbuvir: methadone, tacrolimus.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Risk Summary
- No adequate human data are available to establish whether or not Sofosbuvir/Velpatasvir/Voxilaprevir poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of Sofosbuvir/Velpatasvir/Voxilaprevir (Sofosbuvir, Velpatasvir, or Voxilaprevir) at exposures greater than those in humans at the recommended human dose (RHD). During organogenesis in the mouse, rat, and rabbit, systemic exposures (AUC) of Velpatasvir were approximately 23 (mice), 4 (rats), and 0.5 (rabbits) times the exposure in humans at the RHD, while exposures of Voxilaprevir were approximately 141 (rats) and 4 (rabbits) times the exposure in humans at the RHD. Exposures of the predominant circulating metabolite of Sofosbuvir (GS-331007) were approximately 6 (rats) and 16 (rabbits) times the exposure in humans at the RHD. In rat pre/postnatal development studies, maternal systemic exposures (AUC) for each component of Sofosbuvir/Velpatasvir/Voxilaprevir were approximately 7 (Sofosbuvir metabolite GS-331007), 3 (Velpatasvir), and 238 (Voxilaprevir) times the exposure in humans at the RHD.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 24% and 1520%, respectively.
Data
- Sofosbuvir: Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day) and rabbits (up to 300 mg/kg/day) on gestation days 6 to 18 and 6 to 19, respectively, and also to rats (oral doses up to 500 mg/kg/day) from gestation day 6 to lactation/post-partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. The systemic exposures (AUC) of the predominant circulating metabolite of Sofosbuvir (GS-331007) during gestation were approximately 6 (rats) and 16 (rabbits) times the exposure in humans at the RHD.
- Velpatasvir: Velpatasvir was administered orally to pregnant mice (up to 1000 mg/kg/day), rats (up to 200 mg/kg/day) and rabbits (up to 300 mg/kg/day) from gestation days 6 to 15, 6 to 17, and 7 to 20, respectively, and also to rats (oral doses up to 200 mg/kg) on gestation day 6 to lactation/post-partum day 20. No significant effects on embryo-fetal (mice, rats, and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. The systemic exposures (AUC) of Velpatasvir during gestation were approximately 23 (mice), 4 (rats), and 0.5 (rabbits) times the exposure in humans at the RHD.
- Voxilaprevir: Voxilaprevir was administered orally to pregnant rats (up to 100 mg/kg/day) and rabbits (up to 600 mg/kg/day) from gestation days 6 to 17, and 7 to 19, respectively, and also to rats (oral doses up to 100 mg/kg) on gestation day 6 to lactation/post-partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. The systemic exposures (AUC) of Voxilaprevir during gestation were approximately 141 (rats), and 4 (rabbits) times the exposure in humans at the RHD.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sofosbuvir / velpatasvir / voxilaprevir in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Sofosbuvir / velpatasvir / voxilaprevir during labor and delivery.

### Nursing Mothers
Risk Summary
- It is not known whether the components of Sofosbuvir/Velpatasvir/Voxilaprevir and its metabolites are present in human breast milk, affect human milk production, or have effects on the breastfed infant. When the components of Sofosbuvir/Velpatasvir/Voxilaprevir were administered to lactating rats, GS-331007 (the predominant circulating metabolite of Sofosbuvir) and Velpatasvir were detected in milk, while Voxilaprevir was detected in the plasma of nursing pups likely due to the presence of Voxilaprevir in milk. No significant effects of any of the drugs were observed in nursing rat pups.
- The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Sofosbuvir/Velpatasvir/Voxilaprevir and any potential adverse effects on the breastfed child from Sofosbuvir/Velpatasvir/Voxilaprevir or from the underlying maternal condition.
Data
- Sofosbuvir: No significant effects of Sofosbuvir on growth or postnatal development were observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure (AUC) of the predominant circulating metabolite of Sofosbuvir (GS-331007) was approximately 7 times the exposure in humans at the RHD, with exposure of approximately 2% that of maternal exposure observed in nursing pups on lactation day 10. In a lactation study, Sofosbuvir metabolites (primarily GS-331007) were excreted into the milk of lactating rats following administration of a single oral dose of Sofosbuvir (20 mg/kg) on lactation day 2, with milk concentrations of approximately 10% that of maternal plasma concentrations observed 1 hour post-dose.
- Velpatasvir: No significant effects of Velpatasvir on growth or postnatal development were observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure (AUC) of Velpatasvir was approximately 3 times the exposure in humans at the RHD. Velpatasvir was present in the milk (approximately 173% that of maternal plasma concentrations) of lactating rats following a single oral dose of Velpatasvir (30 mg/kg), and systemic exposure (AUC) in nursing pups was approximately 4% that of maternal exposure on lactation day 10.
- Voxilaprevir: No significant effects of Voxilaprevir on growth or postnatal development were observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure (AUC) of Voxilaprevir was approximately 238 times the exposure in humans at the RHD, with exposure of approximately 58% that of maternal exposure observed in nursing pups on lactation day 10.

### Pediatric Use
- Safety and effectiveness of Sofosbuvir/Velpatasvir/Voxilaprevir have not been established in pediatric patients.

### Geriatic Use
- Clinical trials of Sofosbuvir/Velpatasvir/Voxilaprevir included 74 subjects aged 65 and over (17% of total number of subjects in the POLARIS-1 and POLARIS-4 Phase 3 clinical trials). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment of Sofosbuvir/Velpatasvir/Voxilaprevir is warranted in geriatric patients.

### Gender
There is no FDA guidance on the use of Sofosbuvir / velpatasvir / voxilaprevir with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Sofosbuvir / velpatasvir / voxilaprevir with respect to specific racial populations.

### Renal Impairment
- No dosage adjustment of Sofosbuvir/Velpatasvir/Voxilaprevir is required for patients with mild or moderate renal impairment. The safety and efficacy of Sofosbuvir/Velpatasvir/Voxilaprevir have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or ESRD requiring hemodialysis. No dosage recommendation can be given for patients with severe renal impairment or ESRD due to higher exposures (up to 20-fold) of the predominant Sofosbuvir metabolite in these patients.

### Hepatic Impairment
- No dosage adjustment of Sofosbuvir/Velpatasvir/Voxilaprevir is required for patients with mild hepatic impairment (Child-Pugh A). Sofosbuvir/Velpatasvir/Voxilaprevir is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C) due to the higher exposures of Voxilaprevir (up to 6-fold in non-HCV infected subjects); the safety and efficacy have not been established in HCV-infected patients with moderate or severe hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sofosbuvir / velpatasvir / voxilaprevir in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Sofosbuvir / velpatasvir / voxilaprevir in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Administer with food.

### Monitoring
- Hepatitis C virus genotype: Prior to initiation of therapy.
- Reduction in HCV-RNA viral load and improvement in signs/symptoms of chronic hepatitis C genotype 1 infection may indicate efficacy.
- Hepatitis B virus (HBV) current or prior infection: Prior to initiation.
- Clinical and laboratory signs of hepatitis flare or HBV reactivation, in patients with evidence of current or prior HBV infection: During treatment and post-treatment follow-up.
- Cardiac monitoring in in-patient setting: First 48 hours during concomitant therapy with amiodarone or if discontinuing amiodarone just prior to treatment initiation.

# IV Compatibility
There is limited information regarding the compatibility of Sofosbuvir / velpatasvir / voxilaprevir and IV administrations.

# Overdosage
- No specific antidote is available for overdose with Sofosbuvir/Velpatasvir/Voxilaprevir. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Sofosbuvir/Velpatasvir/Voxilaprevir consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Hemodialysis can efficiently remove the predominant circulating metabolite of Sofosbuvir, GS-331007, with an extraction ratio of 53%. Hemodialysis is unlikely to result in significant removal of Velpatasvir or Voxilaprevir since Velpatasvir and Voxilaprevir are highly bound to plasma protein.

# Pharmacology

## Mechanism of Action
- Sofosbuvir/Velpatasvir/Voxilaprevir is a fixed-dose combination of Sofosbuvir, Velpatasvir, and Voxilaprevir which are DAA agents against the hepatitis C virus.

## Structure
- Sofosbuvir
- Velpatasvir
- Voxilaprevir

## Pharmacodynamics
Cardiac Electrophysiology
- The effect of Sofosbuvir 400 mg (recommended dosage) and 1200 mg (3 times the recommended dosage) on QTc interval was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT trial. At a dose 3 times the recommended dose, Sofosbuvir does not prolong QTc to any clinically relevant extent.
- The effect of Velpatasvir 500 mg (5 times the recommended dosage) was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT trial. At a dose 5 times the recommended dose, Velpatasvir does not prolong QTc interval to any clinically relevant extent.
- The effect of Voxilaprevir 900 mg (9 times the recommended dosage) was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT trial. At a dose 9 times the recommended dose, Voxilaprevir does not prolong QTc interval to any clinically relevant extent.

## Pharmacokinetics
- The pharmacokinetic properties of the components of Sofosbuvir/Velpatasvir/Voxilaprevir are provided in Table 4. The multiple dose pharmacokinetic parameters of Sofosbuvir and its metabolite GS-331007, Velpatasvir, and Voxilaprevir are provided in Table 5.
- Sofosbuvir and GS-331007 AUC024 and Cmax were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=137), Velpatasvir AUC024 and Cmax were 41% lower and 39% lower, respectively, in HCV-infected subjects. Relative to healthy subjects (N=63), Voxilaprevir AUC024 and Cmax were both 260% higher in HCV-infected subjects.
- Sofosbuvir and GS-331007 AUCs are near dose-proportional over the dose range of 200 mg to 1200 mg. Velpatasvir AUC increases in a greater than proportional manner from 5 to 50 mg and in a less than proportional manner from 50 to 450 mg in healthy volunteers. However, Velpatasvir exhibited near dose-proportional increase in exposures 25 mg to 150 mg in HCV-infected patients. Voxilaprevir AUC increases in a greater than proportional manner over the dose range of 100 to 900 mg when administered with food.
Specific Populations
- Pediatric Patients: The pharmacokinetics of Sofosbuvir/Velpatasvir/Voxilaprevir in pediatric patients has not been established.
- Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 85 years) analyzed, age did not have a clinically relevant effect on the exposure to Sofosbuvir, GS-331007, Velpatasvir, or Voxilaprevir.
Patients with Renal Impairment:
- The pharmacokinetics of Sofosbuvir were studied in HCV-negative subjects with mild (eGFR between 50 to less than 80 mL/min/1.73 m2), moderate (eGFR between 30 to less than 50 mL/min/1.73 m2), severe renal impairment (eGFR less than 30 mL/min/1.73 m2), and subjects with ESRD requiring hemodialysis following a single 400 mg dose of Sofosbuvir. Relative to subjects with normal renal function (eGFR greater than 80 mL/min/1.73 m2), the Sofosbuvir AUC0inf was 61%, 107%, and 171% higher in subjects with mild, moderate, and severe renal impairment, while the GS-331007 AUC0inf was 55%, 88%, and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, Sofosbuvir and GS-331007 AUC0inf was 28% and 1280% higher when Sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when Sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4-hour hemodialysis session removed approximately 18% of administered dose of Sofosbuvir.
- The pharmacokinetics of Velpatasvir were studied with a single dose of 100 mg Velpatasvir in HCV-negative subjects with severe renal impairment (eGFR less than 30 mL/min by Cockcroft-Gault). No clinically relevant differences in Velpatasvir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.
- The pharmacokinetics of Voxilaprevir were studied with a single dose of 100 mg Voxilaprevir in HCV-negative subjects with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault). No clinically relevant differences in Voxilaprevir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.
Patients with Hepatic Impairment:
- The pharmacokinetics of Sofosbuvir were studied following 7-day dosing of 400 mg Sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh B and C). Relative to subjects with normal hepatic function, the Sofosbuvir AUC024 was 126% and 143% higher in subjects with moderate and severe hepatic impairment, respectively, while the GS-331007 AUC024 was 18% and 9% higher, respectively. Population pharmacokinetic analysis in HCV-infected subjects indicated that compensated cirrhosis (Child-Pugh A) had no clinically relevant effect on the exposure of Sofosbuvir and GS-331007.
- The pharmacokinetics of Velpatasvir were studied with a single dose of 100 mg Velpatasvir in HCV-negative subjects with moderate and severe hepatic impairment (Child-Pugh B and C). Velpatasvir plasma exposure (AUCinf) was similar in subjects with moderate hepatic impairment, severe hepatic impairment, and control subjects with normal hepatic function. Population pharmacokinetic analysis in HCV-infected subjects indicated that compensated cirrhosis (Child-Pugh A) had no clinically relevant effect on the exposure of Velpatasvir.
- The pharmacokinetics of Voxilaprevir were studied with a single dose of 100 mg Voxilaprevir in HCV-negative subjects with moderate and severe hepatic impairment (Child-Pugh B and C). Relative to subjects with normal hepatic function, the Voxilaprevir AUCinf was 299% and 500% higher in subjects with moderate and severe hepatic impairment, respectively. Population pharmacokinetic analysis in HCV-infected subjects indicated that subjects with compensated cirrhosis (Child-Pugh A) had 73% higher exposure of Voxilaprevir than those without cirrhosis.
- Race and Gender: Population pharmacokinetics analysis in HCV-infected subjects indicated that race and gender had no clinically relevant effect on the exposure of Sofosbuvir, GS-331007, Velpatasvir, or Voxilaprevir.
Drug Interaction Studies
- After oral administration of Sofosbuvir/Velpatasvir/Voxilaprevir, Sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic extraction (hydrolysis followed by sequential phosphorylation) to form the pharmacologically active triphosphate. In clinical pharmacology studies, both Sofosbuvir and the primary circulating metabolite GS-331007 (dephosphorylated nucleotide metabolite) were monitored for purposes of pharmacokinetic analyses.
- Sofosbuvir, Velpatasvir, and Voxilaprevir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. Voxilaprevir, and to a lesser extent Velpatasvir, are also substrates of OATP1B1 and OATP1B3. In vitro, slow metabolic turnover of Velpatasvir by CYP2B6, CYP2C8, and CYP3A4 and of Voxilaprevir by CYP1A2, CYP2C8, and primarily CYP3A4 was observed. Inducers of P-gp and/or moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., St. John's wort, carbamazepine) may significantly decrease plasma concentrations of Sofosbuvir, Velpatasvir, and/or Voxilaprevir leading to reduced therapeutic effect of Sofosbuvir/Velpatasvir/Voxilaprevir. Coadministration with drugs that inhibit P-gp and/or BCRP may increase Sofosbuvir, Velpatasvir, and/or Voxilaprevir plasma concentrations without increasing GS-331007 plasma concentration. Coadministration with drugs that inhibit OATP may increase Voxilaprevir plasma concentrations. Drugs that inhibit CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of Velpatasvir and/or Voxilaprevir.
- Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, OATP1B1, OATP1B3, or OCT1 and GS-331007 is not an inhibitor of OAT1, OAT3, OCT2, or MATE1. Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes.
- Velpatasvir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1, OATP1B3, and OATP2B1, and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. At clinically relevant concentrations, Velpatasvir is not an inhibitor of hepatic transporters OATP1A2 or OCT1, renal transporters OCT2, OAT1, OAT3 or MATE1, or CYP or UGT1A1 enzymes.
- Voxilaprevir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1 and OATP1B3, and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. At clinically relevant concentrations, Voxilaprevir is not an inhibitor of hepatic transporters OCT1, renal transporters OCT2, OAT1, OAT3 or MATE1, or CYP or UGT1A1 enzymes.
- The effects of coadministered drugs on the exposure of Sofosbuvir, GS-331007, Velpatasvir, and Voxilaprevir are shown in Table 6. The effects of Sofosbuvir, Velpatasvir, Voxilaprevir, Sofosbuvir/Velpatasvir, or Sofosbuvir/Velpatasvir/Voxilaprevir on the exposure of coadministered drugs are shown in Table 7.
- No effect on the pharmacokinetic parameters of Sofosbuvir, GS-331007, Velpatasvir, or Voxilaprevir was observed with the combination of emtricitabine, rilpivirine, and tenofovir alafenamide; famotidine; gemfibrozil; or the combination of raltegravir, emtricitabine, and tenofovir DF.
- No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with Sofosbuvir/Velpatasvir/Voxilaprevir (ethinyl estradiol/norgestimate) or its components Sofosbuvir/Velpatasvir (dolutegravir) or Sofosbuvir (methadone).

## Nonclinical Toxicology
Carcinogenesis and Mutagenesis
- Sofosbuvir: Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays.
- Sofosbuvir was not carcinogenic in a 2-year mouse study (up to 200 mg/kg/day in males and 600 mg/kg/day in females) and in a 2-year rat study (up to 750 mg/kg/day), resulting in exposures of the predominant circulating metabolite GS-331007 of approximately 4 and 17 times (in male and female mice, respectively) and 9 times (in rats) the exposure in humans at the recommended human dose (RHD).
- Velpatasvir: Velpatasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays.
- Velpatasvir was not carcinogenic in a 26-week transgenic mouse study (up to 1000 mg/kg/day). A carcinogenicity study in rats is ongoing.
- Voxilaprevir: Voxilaprevir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat micronucleus assays.
- Carcinogenicity studies for Voxilaprevir have not been conducted.
Impairment of Fertility
- Sofosbuvir: Sofosbuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats. At the highest dose tested, AUC exposure to the predominant circulating metabolite GS-331007 was approximately 4 times the exposure in humans at the RHD.
- Velpatasvir: Velpatasvir had no effects on embryo-fetal viability or on fertility when evaluated in rats. At the highest dose tested, Velpatasvir exposure was approximately 4 times the exposure in humans at the RHD.
- Voxilaprevir: Voxilaprevir had no effects on embryo-fetal viability or on fertility when evaluated in rats. At the highest dose tested, Voxilaprevir exposure was approximately 149 times the exposure in humans at the RHD.

# Clinical Studies
- The efficacy of Sofosbuvir/Velpatasvir/Voxilaprevir was evaluated in two Phase 3 trials in DAA-experienced subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection without cirrhosis or with compensated cirrhosis, as summarized in Table 8.
- Serum HCV RNA values were measured during the clinical trials using the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU/mL. Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in both trials. Relapse is defined as HCV RNA greater than or equal to LLOQ after end-of-treatment response among subjects who completed treatment. On-treatment virologic failure is defined as breakthrough, rebound, or non-response.
NS5A Inhibitor-Experienced Adults Without Cirrhosis or With Compensated Cirrhosis (POLARIS-1)
- POLARIS-1 was a randomized, double-blind, placebo-controlled trial that evaluated 12 weeks of treatment with Sofosbuvir/Velpatasvir/Voxilaprevir compared with 12 weeks of placebo in DAA-experienced subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection without cirrhosis or with compensated cirrhosis who previously failed a regimen containing an NS5A inhibitor. Subjects with genotype 1 HCV infection were randomized 1:1 to each group. Subjects with genotype 2, 3, 4, 5, or 6 HCV infection were enrolled to the Sofosbuvir/Velpatasvir/Voxilaprevir group. Randomization was stratified by the presence or absence of cirrhosis.
- Demographics and baseline characteristics were generally balanced across treatment groups. Of the 415 treated subjects, the median age was 59 years (range: 27 to 84); 77% of the subjects were male; 81% were White; 14% were Black; 6% were Hispanic or Latino; 33% had a baseline body mass index at least 30 kg/m2; the majority of subjects had genotype 1 (72%) or genotype 3 (19%) HCV infection; 82% had a non-CC IL28B genotype (CT or TT); 74% had baseline HCV RNA levels at least 800,000 IU/mL; and 41% had compensated cirrhosis. In the POLARIS-1 trial, prior DAA regimens contained the following NS5A inhibitors: ledipasvir (51%), daclatasvir (27%), ombitasvir (11%), Velpatasvir (7%), and elbasvir (3%).
- Table 9 presents the SVR12 by HCV genotype for the POLARIS-1 trial. No subjects in the placebo group achieved SVR12.
DAA-Experienced Adults Without Cirrhosis or With Compensated Cirrhosis Who Had Not Received An NS5A Inhibitor (POLARIS-4)
- POLARIS-4 was a randomized, open-label trial that evaluated 12 weeks of treatment with Sofosbuvir/Velpatasvir/Voxilaprevir and 12 weeks of treatment with SOF/VEL in subjects with genotype 1, 2, 3, or 4 HCV infection without cirrhosis or with compensated cirrhosis who had previously failed a HCV DAA-containing regimen that did not include an NS5A inhibitor. Subjects whose only DAA exposure was an NS3/4A protease inhibitor were excluded. Subjects with genotype 1, 2, or 3 HCV infection were randomized 1:1 to each group. Randomization was stratified by HCV genotype and by the presence or absence of cirrhosis. Subjects with genotype 4 HCV infection were enrolled to the Sofosbuvir/Velpatasvir/Voxilaprevir group. No subjects with genotype 5 or 6 were enrolled.
- Demographics and baseline characteristics were generally balanced across treatment groups. Of the 333 treated subjects, the median age was 58 years (range: 24 to 85); 77% of the subjects were male; 87% were White, 9% were Black; 8% were Hispanic or Latino; 35% had a baseline body mass index at least 30 kg/m2; 81% had non-CC IL28B genotypes (CT or TT); 75% had baseline HCV RNA levels at least 800,000 IU/mL; and 46% had compensated cirrhosis. In the POLARIS-4 trial, prior DAA regimens contained Sofosbuvir (85%) with the following: peginterferon alfa and ribavirin or ribavirin (69%), HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir; 15%) and investigational DAA (<1%). Of the 15% of subjects without prior Sofosbuvir exposure, most received investigational HCV DAAs or approved HCV NS3/4A protease inhibitors, with or without peginterferon alfa and ribavirin.
- Treatment with Sofosbuvir/Velpatasvir/Voxilaprevir for 12 weeks resulted in numerically higher SVR12 rates than treatment with Sofosbuvir/Velpatasvir for 12 weeks in subjects with HCV genotype 1a and 3 infection. Comparable SVR12 rates were observed in subjects with HCV genotype 1b and 2 infection treated with Sofosbuvir/Velpatasvir/Voxilaprevir for 12 weeks or with Sofosbuvir/Velpatasvir for 12 weeks. No comparison data are available for HCV genotypes 4, 5, and 6. Given these data, the additional benefit of Sofosbuvir/Velpatasvir/Voxilaprevir has not been shown over Sofosbuvir/Velpatasvir for these genotypes and Sofosbuvir/Velpatasvir/Voxilaprevir is only indicated for the treatment of HCV genotypes 1a or 3 infection in adults who previously received Sofosbuvir without an NS5A inhibitor.
- Table 10 presents the comparative virologic outcome data for HCV genotype 1, 2, and 3 subjects with prior exposure to a Sofosbuvir-containing regimen.
- In POLARIS-4, Sofosbuvir/Velpatasvir/Voxilaprevir was administered for 12 weeks to 18 HCV genotype 4 subjects (with or without cirrhosis) who had prior exposure to a SOF-containing regimen without an NS5A inhibitor. All subjects achieved SVR12.

# How Supplied
- Each Sofosbuvir/Velpatasvir/Voxilaprevir tablet contains 400 mg of Sofosbuvir, 100 mg of Velpatasvir, and 100 mg of Voxilaprevir. The tablets are beige, capsule-shaped, film-coated, and debossed with "GSI" on one side and "Figure" on the other side. Each bottle contains 28 tablets (NDC 61958-2401-1), polyester coil, silica gel desiccant, and is closed with a child-resistant closure.

## Storage
- Store below 30 C (86 F). Dispense only in original container.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
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.
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.
Drug Interactions
- Inform patients that Sofosbuvir/Velpatasvir/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.
Administration
- Advise patients to take Sofosbuvir/Velpatasvir/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 Sofosbuvir/Velpatasvir/Voxilaprevir for the duration that is recommended by the physician.

# Precautions with Alcohol
Alcohol-Sofosbuvir / velpatasvir / voxilaprevir interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
- Vosevi

# Look-Alike Drug Names
There is limited information regarding Sofosbuvir / velpatasvir / voxilaprevir Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price