Vosevi

1 INDICATIONS AND USAGE 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, a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor, velpatasvir, an HCV NS5A inhibitor, and voxilaprevir, an HCV NS3/4A protease inhibitor, and is indicated for the treatment of adult patients with chronic HCV infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have ( 1 , 2.2 , 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.

2 DOSAGE AND ADMINISTRATION 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 ): Genotype Patients Previously Treated with an HCV Regimen Containing: VOSEVI Duration 1, 2, 3, 4, 5, or 6 An NS5A inhibitor In clinical trials, prior NS5A inhibitor experience included daclatasvir, elbasvir, ledipasvir, ombitasvir, or velpatasvir. 12 weeks 1a or 3 Sofosbuvir without an NS5A inhibitor In clinical trials, prior treatment experience included sofosbuvir with or without any of the following: peginterferon alfa/ribavirin, ribavirin, HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir). 12 weeks 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 ) 2.1 Testing Prior to the Initiation of Therapy 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) ]. 2.2 Recommended Dosage 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. Table 1 Recommended Treatment Regimen and Duration in Adults Without Cirrhosis or With Compensated Cirrhosis (Child-Pugh A) Genotype Patients Previously Treated with an HCV Regimen Containing: VOSEVI Duration 1, 2, 3, 4, 5, or 6 An NS5A inhibitor In clinical trials, prior NS5A inhibitor experience included daclatasvir, elbasvir, ledipasvir, ombitasvir, or velpatasvir. 12 weeks 1a or 3 Sofosbuvir without an NS5A inhibitor In clinical trials, prior treatment experience included sofosbuvir with or without any of the following: peginterferon alfa/ribavirin, ribavirin, HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir). 12 weeks 2.3 Renal Impairment 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) ]. 2.4 Moderate or Severe Hepatic Impairment 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) ].

5 WARNINGS AND PRECAUTIONS 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 ) 5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV 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. 5.2 Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease 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…

4 CONTRAINDICATIONS VOSEVI is contraindicated with rifampin [see Drug Interactions (7.3) , and Clinical Pharmacology (12.3) ]. Coadministration with rifampin. ( 4 )

7 DRUG INTERACTIONS 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 ) 7.1 Potential for Other Drugs to Affect VOSEVI 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) ]. 7.2 Potential for VOSEVI to Affect Other Drugs 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) ]. 7.3 Established and Potentially Significant Drug Interactions 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) ]. Table 3 Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction This table is not all inclusive. Concomitant Drug Class: Drug Name Effect on Concentra…

8.1 Pregnancy Risk Summary No adequate human data are available to establish whether or not VOSEVI poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of VOSEVI (sofosbuvir, velpatasvir, or voxilaprevir) at exposures greater than those in humans at the recommended human dose (RHD) [see Data ] . 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 VOSEVI 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 2–4% and 15–20%, 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.

6 ADVERSE REACTIONS 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) ]. The most common adverse reactions (incidence greater than or equal to 10%, all grades) observed with treatment with VOSEVI for 12 weeks were headache, fatigue, diarrhea, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 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. Table 2 Adverse Reactions (All Grades) Reported in ≥5% of Subjects With HCV Without Cirrhosis or With Compensated Cirrhosis Receiving VOSEVI in POLARIS-1 and POLARIS-4 POLARIS-1 POLARIS-4 VOSEVI 12 weeks (N=263) Placebo 12 weeks (N=152) VOSEVI 12 weeks (N=182) SOF/VEL 12 weeks (N=151) Headache 21% 14% 23% 23% Fatigue 17% 15% 19% 23% Diarrhea 13% 9% 14% 3% Nausea 13% 7% 10% 3% Asthenia 6% 4% 4% 6% Insomnia 6% 3% 3% 1% 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. 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 VOSEVI 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 VOSEVI, 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 VOSEVI, 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 3×ULN were observed in POLARIS-1 in 2% of subjects treate…