These Highlights Do Not Include All The Information Needed To Use Vosevi Safely And Effectively. See Full Prescribing Information For Vosevi.

Adverse Reactions in HCV-Infected Subjects without Cirrhosis or with Compensated Cirrhosis

The adverse reactions data for VOSEVI 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 VOSEVI for 12 weeks. VOSEVI was studied in placebo- and active-controlled (sofosbuvir/velpatasvir) trials [see Clinical Studies (14.1 and 14.2)].

The proportion of subjects who permanently discontinued treatment due to adverse events was 0.2% for subjects who received VOSEVI 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 VOSEVI 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 VOSEVI 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 VOSEVI who experienced adverse reactions, 99% were mild or moderate (Grade 1 or 2) in severity. In POLARIS-4, of the subjects receiving VOSEVI who experienced adverse reactions, all the reported adverse reactions were mild or moderate (Grade 1 or 2) in severity.

Store below 30 °C (86 °F). Dispense only in original container.

No specific antidote is available for overdose with VOSEVI. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with VOSEVI 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.

VOSEVI is a fixed-dose combination tablet containing sofosbuvir, velpatasvir, and voxilaprevir for oral administration. Sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor, velpatasvir is an NS5A inhibitor, and voxilaprevir is an NS3/4A protease inhibitor.

Each tablet contains 400 mg sofosbuvir, 100 mg velpatasvir, and 100 mg of voxilaprevir. The tablets include the following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: ferrosoferric oxide, iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

Safety and effectiveness of VOSEVI have not been established in pediatric patients.

Clinical trials of VOSEVI 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 VOSEVI is warranted in geriatric patients [see Clinical Pharmacology (12.3)].

VOSEVI is contraindicated with rifampin [see Drug Interactions (7.3), and Clinical Pharmacology (12.3)].

The following serious adverse reactions are described below and elsewhere in labeling:

• Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see Warnings and Precautions (5.3)].

• P-gp inducers and/or moderate to strong CYP inducers (e.g., St. John's wort, carbamazepine): May decrease concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir. Use of VOSEVI with P-gp inducers and/or moderate to strong CYP inducers is not recommended. (5.4, 7)
• Consult the full prescribing information prior to use for potential drug interactions. (4, 5.3, 5.4, 7)
• Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact safe and effective use of concomitant medications. Frequent monitoring of relevant laboratory parameters (INR or blood glucose) and dose adjustments of certain concomitant medications may be necessary. (7.3)

No dosage adjustment of VOSEVI is recommended in patients with any degree of renal impairment including patients on dialysis [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

No dosage adjustment of VOSEVI is recommended for patients with mild, moderate, or severe renal impairment, including ESRD requiring dialysis [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

The pharmacokinetic properties of the components of VOSEVI 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 AUC_0–24 and C_max were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=137), velpatasvir AUC_0–24 and C_max were 41% lower and 39% lower, respectively, in HCV-infected subjects. Relative to healthy subjects (N=63), voxilaprevir AUC_0–24 and C_max 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.

The recommended dosage of VOSEVI is one tablet, taken orally, once daily with food [see Clinical Pharmacology (12.3)]. One tablet of VOSEVI 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 adjustment of VOSEVI is recommended for patients with mild hepatic impairment (Child-Pugh A). VOSEVI 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 [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. Postmarketing cases of hepatic decompensation/failure have been reported in these patients [see Warnings and Precautions (5.2)].

VOSEVI 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 [see Dosage and Administration (2.2) and Clinical Studies (14)]:

• 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 VOSEVI 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.

VOSEVI is a fixed-dose combination of sofosbuvir, velpatasvir, and voxilaprevir which are DAA agents against the hepatitis C virus [see Microbiology (12.4)].

• Risk of Hepatitis B Virus Reactivation: Test all patients for evidence of current or prior HBV infection before initiation of HCV treatment. Monitor HCV/HBV coinfected patients for HBV reactivation and hepatitis flare during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. (5.1)
• Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease: Hepatic decompensation/failure, including fatal outcomes, have been reported mostly in patients with cirrhosis and baseline moderate or severe liver impairment (Child-Pugh B or C) treated with HCV NS3/4A protease inhibitor-containing regimens. Monitor for clinical and laboratory evidence of hepatic decompensation. Discontinue VOSEVI in patients who develop evidence of hepatic decompensation/failure. (5.2)
• Bradycardia with Amiodarone Coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone with VOSEVI, a sofosbuvir-containing regimen, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Coadministration of amiodarone with VOSEVI is not recommended. In patients without alternative viable treatment options, cardiac monitoring is recommended. (5.3, 7.3)

• Testing: Prior to initiating VOSEVI, test all patients for HBV infection by measuring HBsAg and anti-HBc. (2.1)
• Recommended dosage: One tablet (400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) taken orally once daily with food. (2.2)
• See recommended treatment regimen and duration in table below (2.2):

• For patients with renal impairment including end stage renal disease on dialysis, follow the dosage recommendations in the table above. (2.3)
• VOSEVI is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C). (2.4, 5.2)

Each VOSEVI 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 "

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.

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.

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

The efficacy of VOSEVI 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.

Each VOSEVI 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 "

VOSEVI 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 [see Warnings and Precautions (5.2), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with VOSEVI [see Warnings and Precautions (5.1)].

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 strong 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 VOSEVI. The use of these agents with VOSEVI is not recommended [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. VOSEVI 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 VOSEVI is not recommended [see Clinical Pharmacology (12.3)].

Velpatasvir and voxilaprevir are inhibitors of drug transporters P-gp, BCRP, OATP1B1, and OATP1B3. Velpatasvir is also an inhibitor of OATP2B1. Coadministration of VOSEVI with drugs that are substrates of these transporters may alter the exposure of such drugs. Coadministration of VOSEVI with BCRP substrates (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) is not recommended [see Clinical Pharmacology (12.3)].

NDC 61958-2401-1

28 tablets

Vosevi™

(sofosbuvir, velpatasvir,

and voxilaprevir) tablets

400 mg / 100 mg / 100 mg

Take 1 tablet once daily

Note to pharmacist:

Do not cover ALERT box with pharmacy label.

ALERT: Find out about medicines that

should NOT be taken with Vosevi

Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment.

Frequent monitoring of relevant laboratory parameters (e.g., International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with a narrow therapeutic index (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary.

Table 3 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either VOSEVI, the components of VOSEVI (sofosbuvir, velpatasvir, and/or voxilaprevir), or are predicted drug interactions that may occur with VOSEVI [see Contraindications (4), Warnings and Precautions (5.3, 5.4), and Clinical Pharmacology (12.3)].

Based on drug interaction studies conducted with the components of VOSEVI (sofosbuvir, velpatasvir, and/or voxilaprevir) or VOSEVI, no clinically significant drug interactions have been observed with the following drugs [see Clinical Pharmacology (12.3)]:

• VOSEVI: cobicistat, darunavir, elvitegravir, emtricitabine, ethinyl estradiol/norgestimate, gemfibrozil, rilpivirine, ritonavir, tenofovir alafenamide, voriconazole
• Sofosbuvir/velpatasvir: dolutegravir, ketoconazole, raltegravir
• Sofosbuvir: methadone, tacrolimus

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 VOSEVI is not recommended. For patients taking amiodarone who have no other alternative viable treatment options and who will be coadministered VOSEVI:

• 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 VOSEVI 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 VOSEVI 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 [see Adverse Reactions (6.2) and Drug Interactions (7.3)].

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 VOSEVI. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with VOSEVI and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with VOSEVI. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals (DAA) 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 [see Warnings and Precautions (5.1)].

Postmarketing cases of hepatic decompensation/failure, including those with fatal outcomes, have been reported in patients treated with HCV NS3/4A protease inhibitor-containing regimens, including treatment with VOSEVI. Reported cases occurred in patients with baseline cirrhosis with and without moderate or severe liver impairment (Child-Pugh B or C). Because these events 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.

In patients with compensated cirrhosis (Child-Pugh A) or evidence of advanced liver disease such as portal hypertension, perform hepatic laboratory testing as clinically indicated; and monitor for signs and symptoms of hepatic decompensation such as the presence of jaundice, ascites, hepatic encephalopathy, and variceal hemorrhage. Discontinue VOSEVI in patients who develop evidence of hepatic decompensation/failure.

VOSEVI is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B or C) or those with any history of prior hepatic decompensation [see Dosage and Administration (2.4), Adverse Reactions (6.2), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

Drugs that are inducers of P-gp and/or moderate to strong 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 VOSEVI. The use of these agents with VOSEVI is not recommended [see Drug Interactions (7.3)].

Adverse Reactions in HCV-Infected Subjects without Cirrhosis or with Compensated Cirrhosis

The adverse reactions data for VOSEVI 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 VOSEVI for 12 weeks. VOSEVI was studied in placebo- and active-controlled (sofosbuvir/velpatasvir) trials [see Clinical Studies (14.1 and 14.2)].

The proportion of subjects who permanently discontinued treatment due to adverse events was 0.2% for subjects who received VOSEVI 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 VOSEVI 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 VOSEVI 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 VOSEVI who experienced adverse reactions, 99% were mild or moderate (Grade 1 or 2) in severity. In POLARIS-4, of the subjects receiving VOSEVI who experienced adverse reactions, all the reported adverse reactions were mild or moderate (Grade 1 or 2) in severity.

Store below 30 °C (86 °F). Dispense only in original container.

No specific antidote is available for overdose with VOSEVI. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with VOSEVI 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.

VOSEVI is a fixed-dose combination tablet containing sofosbuvir, velpatasvir, and voxilaprevir for oral administration. Sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor, velpatasvir is an NS5A inhibitor, and voxilaprevir is an NS3/4A protease inhibitor.

Each tablet contains 400 mg sofosbuvir, 100 mg velpatasvir, and 100 mg of voxilaprevir. The tablets include the following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: ferrosoferric oxide, iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

Safety and effectiveness of VOSEVI have not been established in pediatric patients.

Clinical trials of VOSEVI 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 VOSEVI is warranted in geriatric patients [see Clinical Pharmacology (12.3)].

VOSEVI is contraindicated with rifampin [see Drug Interactions (7.3), and Clinical Pharmacology (12.3)].

The following serious adverse reactions are described below and elsewhere in labeling:

• Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see Warnings and Precautions (5.3)].

• P-gp inducers and/or moderate to strong CYP inducers (e.g., St. John's wort, carbamazepine): May decrease concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir. Use of VOSEVI with P-gp inducers and/or moderate to strong CYP inducers is not recommended. (5.4, 7)
• Consult the full prescribing information prior to use for potential drug interactions. (4, 5.3, 5.4, 7)
• Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact safe and effective use of concomitant medications. Frequent monitoring of relevant laboratory parameters (INR or blood glucose) and dose adjustments of certain concomitant medications may be necessary. (7.3)

No dosage adjustment of VOSEVI is recommended in patients with any degree of renal impairment including patients on dialysis [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

No dosage adjustment of VOSEVI is recommended for patients with mild, moderate, or severe renal impairment, including ESRD requiring dialysis [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

The pharmacokinetic properties of the components of VOSEVI 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 AUC_0–24 and C_max were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=137), velpatasvir AUC_0–24 and C_max were 41% lower and 39% lower, respectively, in HCV-infected subjects. Relative to healthy subjects (N=63), voxilaprevir AUC_0–24 and C_max 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.

The recommended dosage of VOSEVI is one tablet, taken orally, once daily with food [see Clinical Pharmacology (12.3)]. One tablet of VOSEVI 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 adjustment of VOSEVI is recommended for patients with mild hepatic impairment (Child-Pugh A). VOSEVI 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 [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. Postmarketing cases of hepatic decompensation/failure have been reported in these patients [see Warnings and Precautions (5.2)].

VOSEVI 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 [see Dosage and Administration (2.2) and Clinical Studies (14)]:

• 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 VOSEVI 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.

VOSEVI is a fixed-dose combination of sofosbuvir, velpatasvir, and voxilaprevir which are DAA agents against the hepatitis C virus [see Microbiology (12.4)].

• Risk of Hepatitis B Virus Reactivation: Test all patients for evidence of current or prior HBV infection before initiation of HCV treatment. Monitor HCV/HBV coinfected patients for HBV reactivation and hepatitis flare during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. (5.1)
• Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease: Hepatic decompensation/failure, including fatal outcomes, have been reported mostly in patients with cirrhosis and baseline moderate or severe liver impairment (Child-Pugh B or C) treated with HCV NS3/4A protease inhibitor-containing regimens. Monitor for clinical and laboratory evidence of hepatic decompensation. Discontinue VOSEVI in patients who develop evidence of hepatic decompensation/failure. (5.2)
• Bradycardia with Amiodarone Coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone with VOSEVI, a sofosbuvir-containing regimen, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Coadministration of amiodarone with VOSEVI is not recommended. In patients without alternative viable treatment options, cardiac monitoring is recommended. (5.3, 7.3)

• Testing: Prior to initiating VOSEVI, test all patients for HBV infection by measuring HBsAg and anti-HBc. (2.1)
• Recommended dosage: One tablet (400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) taken orally once daily with food. (2.2)
• See recommended treatment regimen and duration in table below (2.2):

• For patients with renal impairment including end stage renal disease on dialysis, follow the dosage recommendations in the table above. (2.3)
• VOSEVI is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C). (2.4, 5.2)

Each VOSEVI 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 "

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.

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.

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

The efficacy of VOSEVI 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.

Each VOSEVI 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 "

VOSEVI 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 [see Warnings and Precautions (5.2), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with VOSEVI [see Warnings and Precautions (5.1)].

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 strong 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 VOSEVI. The use of these agents with VOSEVI is not recommended [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. VOSEVI 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 VOSEVI is not recommended [see Clinical Pharmacology (12.3)].

Velpatasvir and voxilaprevir are inhibitors of drug transporters P-gp, BCRP, OATP1B1, and OATP1B3. Velpatasvir is also an inhibitor of OATP2B1. Coadministration of VOSEVI with drugs that are substrates of these transporters may alter the exposure of such drugs. Coadministration of VOSEVI with BCRP substrates (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) is not recommended [see Clinical Pharmacology (12.3)].

NDC 61958-2401-1

28 tablets

Vosevi™

(sofosbuvir, velpatasvir,

and voxilaprevir) tablets

400 mg / 100 mg / 100 mg

Take 1 tablet once daily

Note to pharmacist:

Do not cover ALERT box with pharmacy label.

ALERT: Find out about medicines that

should NOT be taken with Vosevi

Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment.

Frequent monitoring of relevant laboratory parameters (e.g., International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with a narrow therapeutic index (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary.

Table 3 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either VOSEVI, the components of VOSEVI (sofosbuvir, velpatasvir, and/or voxilaprevir), or are predicted drug interactions that may occur with VOSEVI [see Contraindications (4), Warnings and Precautions (5.3, 5.4), and Clinical Pharmacology (12.3)].

Based on drug interaction studies conducted with the components of VOSEVI (sofosbuvir, velpatasvir, and/or voxilaprevir) or VOSEVI, no clinically significant drug interactions have been observed with the following drugs [see Clinical Pharmacology (12.3)]:

• VOSEVI: cobicistat, darunavir, elvitegravir, emtricitabine, ethinyl estradiol/norgestimate, gemfibrozil, rilpivirine, ritonavir, tenofovir alafenamide, voriconazole
• Sofosbuvir/velpatasvir: dolutegravir, ketoconazole, raltegravir
• Sofosbuvir: methadone, tacrolimus

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 VOSEVI is not recommended. For patients taking amiodarone who have no other alternative viable treatment options and who will be coadministered VOSEVI:

• 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 VOSEVI 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 VOSEVI 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 [see Adverse Reactions (6.2) and Drug Interactions (7.3)].

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 VOSEVI. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with VOSEVI and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with VOSEVI. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals (DAA) 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 [see Warnings and Precautions (5.1)].

Postmarketing cases of hepatic decompensation/failure, including those with fatal outcomes, have been reported in patients treated with HCV NS3/4A protease inhibitor-containing regimens, including treatment with VOSEVI. Reported cases occurred in patients with baseline cirrhosis with and without moderate or severe liver impairment (Child-Pugh B or C). Because these events 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.

In patients with compensated cirrhosis (Child-Pugh A) or evidence of advanced liver disease such as portal hypertension, perform hepatic laboratory testing as clinically indicated; and monitor for signs and symptoms of hepatic decompensation such as the presence of jaundice, ascites, hepatic encephalopathy, and variceal hemorrhage. Discontinue VOSEVI in patients who develop evidence of hepatic decompensation/failure.

VOSEVI is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B or C) or those with any history of prior hepatic decompensation [see Dosage and Administration (2.4), Adverse Reactions (6.2), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

Drugs that are inducers of P-gp and/or moderate to strong 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 VOSEVI. The use of these agents with VOSEVI is not recommended [see Drug Interactions (7.3)].