AHFS Class:

• HCV Polymerase Inhibitors 8:18.40.16

Generic Name(s):

• Sofosbuvir

• Velpatasvir

• Voxilaprevir

Chemical Name:

• N -[[ P ( S ),2' R ]-2'-Deoxy-2'-fluoro-2'-methyl- P -phenyl-5'-uridylyl]-l-alanine, 1-methylethyl ester

• N -[(1 R )-2-[(2 S ,4 S )-2-[5-[1,11-Dihydro-2-[(2 S ,5 S )-1-[(2 S )-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-5-methyl-2-pyrrolidinyl][2]benzopyrano[4',3':6,7]naphth[1,2- d ]imidazol-9-yl]-1 H -imidazol-2-yl]-4-(methoxymethyl)-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-carbamic acid, methyl ester

• N -[(1 R ,2 R )-2-(difluoromethyl)-1-[[[(1-methylcyclopropyl)sulfonyl]amino]carbonyl]cyclopropyl]-5-(1,1-dimethylethyl)-9-ethyl-18,18-difluoro-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-14-methoxy-3,6-dioxo-, (1a R ,5 S ,8 S ,9 S ,10 R ,22a R )

Molecular Formula:

• C₂₂H₂₉FN₃O₉P

• C₄₉H₅₄N₈O₈

• C₄₀H₅₂F₄N₆O₉S

Sofosbuvir, velpatasvir, and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir) is a fixed combination containing 3 hepatitis C virus (HCV) antivirals;1 sofosbuvir is a nucleotide analog HCV nonstructural 5B (NS5B) polymerase inhibitor,1 velpatasvir is an HCV nonstructural 5A (NS5A) replication complex inhibitor (NS5A inhibitor),1 and voxilaprevir is an HCV nonstructural 3/4A (NS3/4A) protease inhibitor.1

Chronic Hepatitis C Virus Infection

The fixed combination of sofosbuvir, velpatasvir, and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir) is used for the treatment of chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection in adults previously treated with an HCV regimen containing an HCV nonstructural 5A (NS5A) replication complex inhibitor (NS5A inhibitor), including those without cirrhosis or with compensated cirrhosis (Child-Pugh class A).1,2,119

Sofosbuvir/velpatasvir/voxilaprevir also is used for the treatment of HCV genotype 1a or 3 infection in adults previously treated with an HCV regimen containing sofosbuvir without an HCV NS5A inhibitor, including those without cirrhosis or with compensated cirrhosis (Child-Pugh class A).1,2,119 Clinical trial data to date indicate that sofosbuvir/velpatasvir/voxilaprevir does not provide any additional benefit over the fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir) for the treatment of HCV genotype 1b, 2, 4, 5, or 6 infection in adults previously treated with sofosbuvir without an HCV NS5A inhibitor.1

Although sofosbuvir/velpatasvir/voxilaprevir has been used for treatment of chronic HCV infection caused by HCV genotypes 1, 2, 3, 4, 5, or 6 in some treatment-naive† (previously untreated) adults,3,119 the drug is not labeled by FDA for use in such patients.1

Because the treatment of chronic HCV infection is complex and rapidly evolving, it is recommended that treatment be directed by clinicians who are familiar with the disease and that a specialist be consulted to obtain the most up-to-date information.119 Information from the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at [Web].119

HCV Genotype 1 Infection

Efficacy and safety of sofosbuvir/velpatasvir/voxilaprevir for the treatment of chronic HCV genotype 1 infection in adults have been evaluated in 3 randomized, phase 3 trials (POLARIS-1, POLARIS-2, and POLARIS-4).1,2,3 The primary end point in each study was sustained virologic response at 12 weeks after the end of treatment (SVR12; defined as plasma HCV RNA level less than 15 IU/mL [the lower limit of quantification] at 12 weeks after end of treatment).1,2,3

POLARIS-1, a double-blind, placebo-controlled trial, included 415 adults with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection who were noncirrhotic or had compensated cirrhosis and had previously failed treatment with an HCV regimen containing an HCV NS5A inhibitor (median age 59 years, 77% male, 74% with baseline HCV RNA levels 800,000 IU/mL or greater, 41% with compensated cirrhosis).1,2 Patients were previously treated with HCV treatment regimens containing ledipasvir (51%), daclatasvir (27%), ombitasvir (11%), velpatasvir (7%), or elbasvir (3%).1 Those with HCV genotype 1 infection were randomized in a 1:1 ratio to receive a 12-week regimen of sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) or placebo once daily.1,2 Of the 101 patients with HCV genotype 1a infection treated with sofosbuvir/velpatasvir/voxilaprevir, 96% achieved SVR12;1 of the 45 patients with HCV genotype 1b infection treated with sofosbuvir/velpatasvir/voxilaprevir, 100% achieved SVR12.1,2 No patients treated with placebo achieved SVR12.1,2

POLARIS-4, a randomized, open-label trial, included 333 previously treated adults with chronic HCV genotype 1, 2, 3, or 4 infection who were noncirrhotic or had compensated cirrhosis and had previously failed treatment with an HCV regimen that included a direct acting antiviral (DAA), but did not include an HCV NS5A inhibitor (median age 58 years, 77% male, 75% with baseline HCV RNA levels 800,000 IU/mL or greater, 81% with non-CC IL28B alleles [CT or TT], 46% with compensated cirrhosis).1,2 Patients whose only DAA exposure was an HCV NS3/4A protease inhibitor were excluded.1,2 Those with HCV genotype 1 infection were randomized in a 1:1 ratio to receive sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) or sofosbuvir/velpatasvir (a fixed-combination tablet containing 400 mg of sofosbuvir and 100 mg of velpatasvir) once daily for 12 weeks.1,2 Of the 54 patients with HCV genotype 1 infection treated with a regimen of sofosbuvir/velpatasvir/voxilaprevir, 96% achieved SVR12 (97 or 94% of those with HCV genotype 1a or 1b, respectively).1 Of the 40 patients with HCV genotype 1 infection treated with a regimen of sofosbuvir/velpatasvir, 85% achieved SVR12 (82 or 92% of those with HCV genotype 1a or 1b, respectively).1

POLARIS-2, a randomized, open-label trial, evaluated sofosbuvir/velpatasvir/voxilaprevir in adults with any genotype of HCV infection who were treatment naive or previously failed treatment with an HCV regimen that did not include a DAA.3 Enrolled patients were noncirrhotic or had compensated cirrhosis, although those with HCV genotype 3 infection were excluded if they had cirrhosis.3 Patients were randomized in a 1:1 ratio to receive sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) once daily for 8 weeks or sofosbuvir/velpatasvir (a fixed-combination tablet containing 400 mg of sofosbuvir and 100 mg of velpatasvir) once daily for 12 weeks.3 Results showed that the 8-week regimen of sofosbuvir/velpatasvir/voxilaprevir in these patients did not meet noninferiority criteria when compared with the 12-week regimen of sofosbuvir/velpatasvir (overall SVR12 achieved by 95 or 98% of patients, respectively).3

HCV Genotype 2 Infection

Efficacy and safety of sofosbuvir/velpatasvir/voxilaprevir for the treatment of chronic HCV genotype 2 infection in adults have been evaluated in 3 randomized, phase 3 trials (POLARIS-1, POLARIS-2, and POLARIS-4).1,2,3 The primary end point in each study was sustained virologic response at 12 weeks after the end of treatment (SVR12; defined as plasma HCV RNA level less than 15 IU/mL [the lower limit of quantification] at 12 weeks after end of treatment).1,2,3

POLARIS-1, a double-blind, placebo-controlled trial, included 415 adults with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection who were noncirrhotic or had compensated cirrhosis and had previously failed treatment with an HCV regimen containing an HCV NS5A inhibitor (median age 59 years, 77% male, 74% with baseline HCV RNA levels 800,000 IU/mL or greater, 41% with compensated cirrhosis).1,2 Patients were previously treated with HCV treatment regimens containing ledipasvir (51%), daclatasvir (27%), ombitasvir (11%), velpatasvir (7%), or elbasvir (3%).1,2 All enrolled patients with HCV genotype 2 infection received a 12-week regimen of sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) once daily.1,2 Of the 5 patients with HCV genotype 2 infection treated with sofosbuvir/velpatasvir/voxilaprevir, 100% achieved SVR12.1,2

POLARIS-4, a randomized, open-label trial, included 333 previously treated adults with chronic HCV genotype 1, 2, 3, or 4 infection who were noncirrhotic or had compensated cirrhosis and had previously failed treatment with an HCV regimen that included a DAA, but did not include an HCV NS5A inhibitor (median age 58 years, 77% male, 75% with baseline HCV RNA levels 800,000 IU/mL or greater, 81% with non-CC IL28B alleles [CT or TT], 46% with compensated cirrhosis).1,2 Patients whose only DAA exposure was an HCV NS3/4A protease inhibitor were excluded.1,2 Those with HCV genotype 2 infection were randomized in a 1:1 ratio to receive sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) or sofosbuvir/velpatasvir (a fixed-combination tablet containing 400 mg of sofosbuvir and 100 mg of velpatasvir) once daily for 12 weeks.1,2 Of the 31 patients with HCV genotype 2 infection treated with a regimen of sofosbuvir/velpatasvir/voxilaprevir, 100% achieved SVR12.1,2 Of the 33 patients with HCV genotype 2 infection treated with a regimen of sofosbuvir/velpatasvir, 97% achieved SVR12.1,2

POLARIS-2, a randomized, open-label trial, evaluated sofosbuvir/velpatasvir/voxilaprevir in adults with any genotype of HCV infection who were treatment naive or previously failed treatment with an HCV regimen that did not include a DAA.3 Enrolled patients were noncirrhotic or had compensated cirrhosis, although those with HCV genotype 3 infection were excluded if they had cirrhosis.3 Patients were randomized in a 1:1 ratio to receive sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) once daily for 8 weeks or sofosbuvir/velpatasvir (a fixed-combination tablet containing 400 mg of sofosbuvir and 100 mg of velpatasvir) once daily for 12 weeks.3 Results showed that the 8-week regimen of sofosbuvir/velpatasvir/voxilaprevir did not meet noninferiority criteria in these patients when compared with the 12-week regimen of sofosbuvir/velpatasvir (overall SVR12 achieved by 95 or 98% of patients, respectively).3

HCV Genotype 3 Infection

Efficacy and safety of sofosbuvir/velpatasvir/voxilaprevir for the treatment of chronic HCV genotype 3 infection in adults have been evaluated in 4 randomized, phase 3 trials (POLARIS-1, POLARIS-2, POLARIS-3, and POLARIS-4).1,2,3 The primary end point in each study was sustained virologic response at 12 weeks after the end of treatment (SVR12; defined as plasma HCV RNA level less than 15 IU/mL [the lower limit of quantification] at 12 weeks after end of treatment).1,2,3

POLARIS-1, a double-blind, placebo-controlled trial, included 415 adults with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection who were noncirrhotic or had compensated cirrhosis and had previously failed treatment with an HCV regimen containing an HCV NS5A inhibitor (median age 59 years, 77% male, 74% with baseline HCV RNA levels 800,000 IU/mL or greater, 41% with compensated cirrhosis).1,2 Patients were previously treated with HCV treatment regimens containing ledipasvir (51%), daclatasvir (27%), ombitasvir (11%), velpatasvir (7%), or elbasvir (3%).1,2 All patients with HCV genotype 3 infection received a 12-week regimen of sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) once daily.1,2 Of the 78 patients with HCV genotype 3 infection treated with sofosbuvir/velpatasvir/voxilaprevir, 95% achieved SVR12.1,2

POLARIS-4, a randomized, open-label trial, included 333 previously treated adults with chronic HCV genotype 1, 2, 3, or 4 infection who were noncirrhotic or had compensated cirrhosis and had previously failed treatment with an HCV regimen that included a DAA, but did not include an HCV NS5A inhibitor (median age 58 years, 77% male, 75% with baseline HCV RNA levels 800,000 IU/mL or greater, 81% with non-CC IL28B alleles [CT or TT], 46% with compensated cirrhosis).1,2 Patients whose only DAA exposure was an HCV NS3/4A protease inhibitor were excluded.1,2 Those with HCV genotype 3 infection were randomized in a 1:1 ratio to receive sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) or sofosbuvir/velpatasvir (a fixed-combination tablet containing 400 mg of sofosbuvir and 100 mg of velpatasvir) once daily for 12 weeks.1,2 Of the 54 patients with HCV genotype 3 infection treated with a regimen of sofosbuvir/velpatasvir/voxilaprevir, 96% achieved SVR12.1,2 Of the 52 patients with HCV genotype 3 infection treated with a regimen of sofosbuvir/velpatasvir, 85% achieved SVR12.1,2

POLARIS-2, a randomized, open-label trial, evaluated sofosbuvir/velpatasvir/voxilaprevir in adults with any genotype of HCV infection who were treatment naive or previously failed treatment with an HCV regimen that did not include a DAA.3 Enrolled patients were noncirrhotic or had compensated cirrhosis, although those with HCV genotype 3 infection were excluded if they had cirrhosis.3 Patients were randomized in a 1:1 ratio to receive sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) once daily for 8 weeks or sofosbuvir/velpatasvir (a fixed-combination tablet containing 400 mg of sofosbuvir and 100 mg of velpatasvir) once daily for 12 weeks.3 Results showed that the 8-week regimen of sofosbuvir/velpatasvir/voxilaprevir did not meet noninferiority criteria in these patients when compared with the 12-week regimen of sofosbuvir/velpatasvir (overall SVR12 achieved by 95 or 98% of patients, respectively).3

POLARIS-3, a randomized, open-label trial, evaluated sofosbuvir/velpatasvir/voxilaprevir in treatment-naive patients with HCV genotype 3 infection who also had compensated cirrhosis.3 Patients were randomized in a 1:1 ratio to receive sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) once daily for 8 weeks or a fixed combination of sofosbuvir and velpatasvir (a fixed-combination tablet containing 400 mg of sofosbuvir and 100 mg of velpatasvir) once daily for 12 weeks.3 SVR12 was achieved by 96% of patients in each group.3 Both groups exceeded the performance goal of 83%, but the two groups were not statistically compared with each other.3,5

HCV Genotype 4 Infection

Efficacy and safety of sofosbuvir/velpatasvir/voxilaprevir for the treatment of chronic HCV genotype 4 infection in adults have been evaluated in 3 randomized, phase 3 trials (POLARIS-1, POLARIS-2, and POLARIS-4).1,2,3 The primary end point in each study was sustained virologic response at 12 weeks after the end of treatment (SVR12; defined as plasma HCV RNA level less than 15 IU/mL [the lower limit of quantification] at 12 weeks after end of treatment).1,2,3

POLARIS-1, a double-blind, placebo-controlled trial, included 415 adults with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection who were noncirrhotic or had compensated cirrhosis and had previously failed treatment with an HCV regimen containing an HCV NS5A inhibitor (median age 59 years, 77% male, 74% with baseline HCV RNA levels 800,000 IU/mL or greater, 41% with compensated cirrhosis).1,2 Patients were previously treated with HCV treatment regimens containing ledipasvir (51%), daclatasvir (27%), ombitasvir (11%), velpatasvir (7%), or elbasvir (3%).1,2 All patients with HCV genotype 4 infection received a 12-week regimen of sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) once daily.1,2 Of the 22 patients with HCV genotype 4 infection treated with sofosbuvir/velpatasvir/voxilaprevir, 91% achieved SVR12.1,2

POLARIS-4, a randomized, open-label trial, included 333 previously treated adults with chronic HCV genotype 1, 2, 3, or 4 infection who were noncirrhotic or had compensated cirrhosis and had previously failed treatment with an HCV regimen that included a DAA, but did not include an HCV NS5A inhibitor (median age 58 years, 77% male, 75% with baseline HCV RNA levels 800,000 IU/mL or greater, 81% with non-CC IL28B alleles [CT or TT], 46% with compensated cirrhosis).1,2 Patients whose only DAA exposure was an HCV NS3/4A protease inhibitor were excluded.1,2 All patients with HCV genotype 4 infection received sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) once daily for 12 weeks.1,2 Of the 18 patients with HCV genotype 4 infection treated with a regimen of sofosbuvir/velpatasvir/voxilaprevir, 100% achieved SVR12.1

POLARIS-2, a randomized, open-label trial, evaluated sofosbuvir/velpatasvir/voxilaprevir in adults with any genotype of HCV infection who were treatment naive or previously failed treatment with an HCV regimen that did not include a DAA.3 Enrolled patients were noncirrhotic or had compensated cirrhosis, although those with HCV genotype 3 infection were excluded if they had cirrhosis.3 Patients were randomized in a 1:1 ratio to receive sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) once daily for 8 weeks or sofosbuvir/velpatasvir (a fixed-combination tablet containing 400 mg of sofosbuvir and 100 mg of velpatasvir) once daily for 12 weeks.3 Results showed that the 8-week regimen of sofosbuvir/velpatasvir/voxilaprevir did not meet noninferiority criteria in these patients when compared with the 12-week regimen of sofosbuvir/velpatasvir (overall SVR12 achieved by 95 or 98% of patients, respectively).3

HCV Genotype 5 Infection

Efficacy and safety of sofosbuvir/velpatasvir/voxilaprevir for the treatment of chronic HCV genotype 5 infection in adults have been evaluated in 2 randomized, phase 3 trials (POLARIS-1 and POLARIS-2).1,2,3 The primary end point in both studies was sustained virologic response at 12 weeks after the end of treatment (SVR12; defined as plasma HCV RNA level less than 15 IU/mL [the lower limit of quantification] at 12 weeks after end of treatment).1,2,3

POLARIS-1, a double-blind, placebo-controlled trial, included 415 adults with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection who were noncirrhotic or had compensated cirrhosis and had previously failed treatment with an HCV regimen containing an HCV NS5A inhibitor (median age 59 years, 77% male, 74% with baseline HCV RNA levels 800,000 IU/mL or greater, 41% with compensated cirrhosis).1,2 Patients were previously treated with HCV treatment regimens containing ledipasvir (51%), daclatasvir (27%), ombitasvir (11%), velpatasvir (7%), or elbasvir (3%).1,2 The single patient with HCV genotype 5 infection enrolled in the study received a 12-week regimen of sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) once daily and achieved SVR12.1,2

POLARIS-2, a randomized, open-label trial, evaluated sofosbuvir/velpatasvir/voxilaprevir in adults with any genotype of HCV infection who were treatment naive or previously failed treatment with an HCV regimen that did not include a DAA.3 Enrolled patients were noncirrhotic or had compensated cirrhosis, although those with HCV genotype 3 infection were excluded if they had cirrhosis.3 Patients were randomized in a 1:1 ratio to receive sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) once daily for 8 weeks or sofosbuvir/velpatasvir (a fixed-combination tablet containing 400 mg of sofosbuvir and 100 mg of velpatasvir) once daily for 12 weeks.3 Results showed that the 8-week regimen of sofosbuvir/velpatasvir/voxilaprevir did not meet noninferiority criteria in these patients when compared with the 12-week regimen of sofosbuvir/velpatasvir (overall SVR12 achieved by 95 or 98% of patients, respectively).3

HCV Genotype 6 Infection

Efficacy and safety of sofosbuvir/velpatasvir/voxilaprevir for the treatment of chronic HCV genotype 6 infection in adults have been evaluated in 2 randomized, phase 3 trials (POLARIS-1 and POLARIS-2).1,2,3 The primary end point in both studies was sustained virologic response at 12 weeks after the end of treatment (SVR12; defined as plasma HCV RNA level less than 15 IU/mL [the lower limit of quantification] at 12 weeks after end of treatment).1,2,3

POLARIS-1, a double-blind, placebo-controlled trial, included 415 adults with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection who were noncirrhotic or had compensated cirrhosis and had previously failed treatment with an HCV regimen containing an HCV NS5A inhibitor (median age 59 years, 77% male, 74% with baseline HCV RNA levels 800,000 IU/mL or greater, 41% with compensated cirrhosis).1,2 Patients were previously treated with HCV treatment regimens containing ledipasvir (51%), daclatasvir (27%), ombitasvir (11%), velpatasvir (7%), or elbasvir (3%).1,2 All patients with HCV genotype 6 infection received a 12-week regimen of sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) once daily.1 Of the 6 patients with HCV genotype 6 infection treated with sofosbuvir/velpatasvir/voxilaprevir, 100% achieved SVR12.1

POLARIS-2, a randomized, open-label trial, evaluated sofosbuvir/velpatasvir/voxilaprevir in adults with any genotype of HCV infection who were treatment naive or previously failed treatment with an HCV regimen that did not include a DAA.3 Enrolled patients were noncirrhotic or had compensated cirrhosis, although those with HCV genotype 3 infection were excluded if they had cirrhosis.3 Patients were randomized in a 1:1 ratio to receive sofosbuvir/velpatasvir/voxilaprevir (a fixed-combination tablet containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) once daily for 8 weeks or sofosbuvir/velpatasvir (a fixed-combination tablet containing 400 mg of sofosbuvir and 100 mg of velpatasvir) once daily for 12 weeks.3 Results showed that the 8-week regimen of sofosbuvir/velpatasvir/voxilaprevir did not meet noninferiority criteria in these patients when compared with the 12-week regimen of sofosbuvir/velpatasvir (overall SVR12 achieved by 95 or 98% of patients, respectively).3

General

Pretreatment Screening

• Prior to initiating HCV treatment, test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc).1,25,119
• In patients with serologic evidence of HBV infection, measure baseline HBV DNA level.25,119
• Perform appropriate laboratory tests to evaluate liver function.119

Patient Monitoring

• Perform appropriate laboratory tests to evaluate liver function during therapy.119
• In all patients with evidence of current or prior HBV infection : Monitor for clinical and laboratory signs (i.e., HBsAg, HBV DNA levels, serum aminotransferase and bilirubin concentrations) of hepatitis flare or HBV reactivation during and after treatment with HCV DAAs.1,25,119

Other General Considerations

• If amiodarone is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir, perform cardiac monitoring in an inpatient setting during the first 48 hours of concomitant use;1 perform heart rate monitoring daily (outpatient or self-monitoring) through at least the first 2 weeks of concomitant use.1 Similar cardiac monitoring is recommended in patients who discontinue amiodarone just prior to initiation of sofosbuvir/velpatasvir/voxilaprevir.1

Administration

Sofosbuvir/velpatasvir/voxilaprevir is administered orally once daily with food.1

Dosage

Sofosbuvir/velpatasvir/voxilaprevir is commercially available as fixed-combination tablets containing 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir.1

Chronic Hepatitis C Virus Infection

HCV Genotype 1, 2, 3, 4, 5, or 6 Infection

For the treatment of chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection in adults who previously failed treatment with an HCV regimen containing an HCV NS5A replication complex inhibitor (NS5A inhibitor) and who are noncirrhotic or have compensated cirrhosis (Child-Pugh class A), the recommended dosage of sofosbuvir/velpatasvir/voxilaprevir is 1 tablet (400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) once daily.1 A treatment duration of 12 weeks is recommended.1,119

HCV Genotype 1a or 3 Infection

For the treatment of chronic HCV genotype 1a or 3 infection in adults who previously failed treatment with an HCV regimen containing sofosbuvir without an HCV NS5A inhibitor and who are noncirrhotic or have compensated cirrhosis (Child-Pugh class A), the recommended dosage of sofosbuvir/velpatasvir/voxilaprevir is 1 tablet (400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) once daily.1 A treatment duration of 12 weeks is recommended.1,119

Special Populations

Hepatic Impairment

Dosage adjustments are not necessary if sofosbuvir/velpatasvir/voxilaprevir is used in adults with mild hepatic impairment or compensated cirrhosis (Child-Pugh class A).1 However, such patients should be monitored for signs and symptoms of hepatic decompensation.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Sofosbuvir/velpatasvir/voxilaprevir is not recommended in adults with moderate or severe hepatic impairment (Child-Pugh class B or C) or in those with any history of hepatic decompensation.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Renal Impairment

Dosage adjustments are not necessary if sofosbuvir/velpatasvir/voxilaprevir is used in adults with mild, moderate, or severe renal impairment, including those with end-stage renal disease undergoing dialysis.1

Geriatric Patients

Dosage adjustments are not necessary if sofosbuvir/velpatasvir/voxilaprevir is used in geriatric patients.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Contraindications

Concomitant use of the fixed combination of sofosbuvir, velpatasvir, and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir) and rifampin is contraindicated.1

Warnings/Precautions

Warnings

Risk of HBV Reactivation in Patients Coinfected with HCV and HBV

Reactivation of hepatitis B virus (HBV) infection has been reported during postmarketing experience when direct-acting antivirals (DAAs) were used for the treatment of chronic hepatitis C virus (HCV) infection in patients with HBV coinfection.1,25 In some cases, HBV reactivation resulted in fulminant hepatitis, hepatic failure, and death.1,25

HBV reactivation (defined as an abrupt increase in HBV replication manifested as a rapid increase in serum HBV DNA levels or detection of hepatitis B surface antigen [HBsAg] in an individual who was previously HBsAg negative and hepatitis B core antibody [anti-HBc] positive) has been reported in patients with HCV and HBV coinfection who were receiving HCV treatment with a regimen that included HCV DAAs without interferon alfa.1,25 Reactivation also may be accompanied by hepatitis (i.e., increased aminotransferase concentrations) and, in severe cases, may lead to increased bilirubin concentrations, liver failure, or death.1

Data to date indicate that HBV reactivation usually occurs within 4-8 weeks after initiation of HCV treatment.25 Patients with HBV reactivation have been heterogeneous in terms of HCV genotype and in terms of baseline HBV disease.25 While some patients with HBV reactivation were HBsAg positive, others had serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive).1,25 HBV reactivation also has been reported in patients receiving certain immunosuppressant or chemotherapeutic drugs;1 the risk of reactivation associated with HCV DAAs may be increased in such patients.1

The mechanism for HBV reactivation in patients with HCV and HBV coinfection receiving HCV DAAs is unknown.25 Although HCV DAAs are not known to cause immunosuppression, HBV reactivation in coinfected patients may result from a complex interplay of host immunologic responses in the setting of infection with 2 hepatitis viruses.25

Prior to initiating treatment with an HCV DAA, including sofosbuvir/velpatasvir/voxilaprevir, all patients should be screened for evidence of current or prior HBV infection by measuring HBsAg, hepatitis B surface antibody (anti-HBs), and anti-HBc.1,25,119 If there is serologic evidence of HBV infection, baseline HBV DNA levels should be measured.25,119

Patients with evidence of current or prior HBV infection should be monitored for clinical and laboratory signs (i.e., HBsAg, HBV DNA levels, serum aminotransferase concentrations, bilirubin concentrations) of hepatitis flare or HBV reactivation during and after treatment with HCV DAAs, including sofosbuvir/velpatasvir/voxilaprevir.1,25,119 Appropriate management for HBV infection should be initiated as clinically indicated.1,119

Patients with HCV and HBV coinfection receiving sofosbuvir/velpatasvir/voxilaprevir should be advised to immediately contact a clinician if they develop any signs or symptoms of serious liver injury.25 (See Advice to Patients.)

When making decisions regarding HBV monitoring or HBV treatment in coinfected patients, consultation with a clinician who has expertise in managing HBV infection is recommended.25,119

Other Warnings and Precautions

Risk of Hepatic Decompensation or Failure in Patients with Evidence of Advanced Liver Disease

Hepatic decompensation or failure, including some fatalities, have been reported during postmarketing experience in patients receiving HCV treatment regimens containing an HCV nonstructural 3/4A (NS3/4A) protease inhibitor, including sofosbuvir/velpatasvir/voxilaprevir.1,26 Data are insufficient to estimate the frequency of such events and a causal relationship has not been established.1 Hepatic decompensation or failure usually occurred within the first 4 weeks of HCV treatment.26

Many of the reported cases of hepatic decompensation or failure occurred in patients with evidence of advanced liver disease with moderate or severe hepatic impairment (Child-Pugh class B or C) prior to initiation of HCV treatment.1,26 Some cases occurred in patients who were reported as noncirrhotic or as having compensated cirrhosis with mild liver impairment (Child-Pugh class A) at baseline,1,26 but had a history of a decompensation event or had evidence of portal hypertension or decreased platelet counts at baseline.26 Some cases also were reported in patients who had confounding factors (e.g., serious liver-related comorbidities).26

If sofosbuvir/velpatasvir/voxilaprevir is used in patients with compensated cirrhosis (Child-Pugh class A) or evidence of advanced liver disease (e.g., portal hypertension), hepatic function tests should be performed as clinically indicated and patients should be monitored for signs and symptoms of hepatic decompensation (e.g., jaundice, ascites, hepatic encephalopathy, variceal hemorrhage).1

Sofosbuvir/velpatasvir/voxilaprevir is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B or C) or any history of hepatic decompensation.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

The drug should be discontinued in patients who develop evidence of hepatic decompensation or failure.1

Patients should be advised to contact a clinician if they develop any signs or symptoms of worsening liver disease.1 (See Advice to Patients.)

Cardiovascular Effects

Symptomatic bradycardia, sometimes requiring pacemaker intervention, has been reported during postmarketing experience in patients receiving amiodarone concomitantly with an HCV treatment regimen containing sofosbuvir in conjunction with daclatasvir or simeprevir (drugs no longer commercially available).1,23 Symptomatic bradycardia, including a fatal cardiac arrest, has been reported in patients receiving amiodarone concomitantly with the fixed combination containing ledipasvir and sofosbuvir (ledipasvir/sofosbuvir).1,23

In most reported cases, bradycardia occurred within hours to days after HCV treatment was initiated in patients receiving amiodarone, but has been observed up to 2 weeks after initiation of HCV treatment.1 Bradycardia generally resolved after HCV treatment was discontinued.1 The mechanism for this adverse cardiovascular effect is unknown.1

Patients who may be at increased risk for symptomatic bradycardia if amiodarone is used concomitantly with an HCV treatment regimen containing sofosbuvir and another HCV DAA include those also receiving a β-adrenergic blocking agent, those with underlying cardiac comorbidities, and/or those with advanced liver disease.1

Concomitant use of amiodarone with sofosbuvir/velpatasvir/voxilaprevir is not recommended.1 If there are no alternative HCV treatment options and sofosbuvir/velpatasvir/voxilaprevir must be used in a patient receiving amiodarone, the patient should be advised about the risk of serious symptomatic bradycardia before sofosbuvir/velpatasvir/voxilaprevir is initiated.1 Cardiac monitoring should be performed in an inpatient setting during the first 48 hours of concomitant use of amiodarone and sofosbuvir/velpatasvir/voxilaprevir;1 heart rate monitoring should then be performed daily (outpatient or self-monitoring) through at least the first 2 weeks of concomitant use.1 Similar cardiac monitoring is recommended in patients who discontinued amiodarone just prior to initiation of sofosbuvir/velpatasvir/voxilaprevir or if there are no other treatment options and amiodarone must be initiated in a patient already receiving sofosbuvir/velpatasvir/voxilaprevir.1

Patients receiving amiodarone concomitantly with sofosbuvir/velpatasvir/voxilaprevir should be advised to immediately contact a clinician if they develop signs or symptoms of bradycardia (e.g., near-fainting or fainting, dizziness, lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, memory problems).1

Interactions

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and inducers of the P-glycoprotein (P-gp) transport system and/or moderate or potent inducers of cytochrome P-450 (CYP) isoenzyme 2B6, 2C8, or 3A4 (e.g., carbamazepine and other anticonvulsants, St. John's wort [ Hypericum perforatum ]) may result in clinically important decreases in plasma concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir and may lead to reduced therapeutic effect of sofosbuvir/velpatasvir/voxilaprevir.1 Concomitant use of such drugs with sofosbuvir/velpatasvir/voxilaprevir is not recommended.1 (See Drug Interactions.)

Precautions Related to Fixed Combinations

When sofosbuvir/velpatasvir/voxilaprevir is used, the cautions, precautions, contraindications, and drug interactions associated with each drug in the fixed combination must be considered.1 Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug.1

Specific Populations

Pregnancy

Adequate data are not available regarding use of sofosbuvir/velpatasvir/voxilaprevir in pregnant women.1 In animal studies, there was no evidence that sofosbuvir, velpatasvir, or voxilaprevir affected fetal development at exposures greater than those in humans receiving the recommended human dosage.1

Lactation

It is not known whether sofosbuvir/velpatasvir/voxilaprevir or their metabolites are distributed into human milk, affect milk production, or have effects on the breast-fed infant.1

The predominant metabolite of sofosbuvir (GS-331007) is distributed into milk in rats;1 velpatasvir is distributed into milk in rats and has been detected in plasma of suckling rat pups;1 and voxilaprevir has been detected in plasma of suckling rat pups.1 GS-331007, velpatasvir, and voxilaprevir had no apparent effects on nursing pups.1

The benefits of breast-feeding and the importance of sofosbuvir/velpatasvir/voxilaprevir to the woman should be considered along with the potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.1

Pediatric Use

Safety and efficacy of sofosbuvir/velpatasvir/voxilaprevir have not been established in pediatric patients younger than 18 years of age.1

Geriatric Use

No overall differences in safety and efficacy of sofosbuvir/velpatasvir/voxilaprevir have been observed between patients 65 years of age and older and younger adults.1 However, greater sensitivity in some older individuals cannot be ruled out.1

Population pharmacokinetic analysis in HCV-infected adults up to 85 years of age indicates that age does not have a clinically important effect on sofosbuvir, GS-331007, velpatasvir, or voxilaprevir exposures.1

Hepatic Impairment

Patients with mild hepatic impairment or compensated cirrhosis (Child-Pugh class A) should be monitored for signs and symptoms of hepatic decompensation (e.g., jaundice, ascites, hepatic encephalopathy, variceal hemorrhage) during sofosbuvir/velpatasvir/voxilaprevir treatment.1

Sofosbuvir/velpatasvir/voxilaprevir is not recommended in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh class B or C) or with any history of hepatic decompensation.1 There have been postmarketing reports of hepatic decompensation or failure in such patients.1 (See Risk of Hepatic Decompensation or Failure in Patients with Evidence of Advanced Liver Disease under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

In HCV-infected individuals with moderate or severe hepatic impairment (Child-Pugh class B or C), sofosbuvir (400 mg daily for 7 days) results in sofosbuvir and GS-331007 plasma exposures higher than those reported in individuals with normal hepatic function.1

In individuals with moderate or severe hepatic impairment (Child-Pugh class B or C) without HCV infection, a single 100-mg dose of velpatasvir results in plasma exposures similar to those reported when the same dose is given to individuals with normal hepatic function.1

In individuals with moderate or severe hepatic impairment (Child-Pugh class B or C) without HCV infection, a single 100-mg dose of voxilaprevir results in plasma exposures substantially higher than those reported in individuals with normal hepatic function (area under the plasma concentration-time curve [AUC] 299 or 500% higher, respectively).1

Renal Impairment

Dosage adjustments are not necessary if sofosbuvir/velpatasvir/voxilaprevir is used in adults with any degree of renal impairment, including those with end-stage renal disease (ESRD) undergoing dialysis.1

In individuals with mild, moderate, or severe renal impairment without HCV infection, sofosbuvir and GS-331007 plasma exposures are higher than those reported in individuals with normal renal function.1 In those with ESRD, sofosbuvir and GS-331007 exposures were higher when the drug was administered 1 hour before or 1 hour after hemodialysis compared with exposures in those with normal renal function;1 a 4-hour hemodialysis session removed approximately 18% of the dose.1

In individuals with severe renal impairment (estimated glomerular filtration rate [eGFR] less than 30 mL/minute per 1.73 m²) without HCV infection, velpatasvir pharmacokinetics following a single 100-mg dose of the drug are similar to pharmacokinetics reported in healthy individuals.1 Velpatasvir is not expected to be removed to any clinically important extent by hemodialysis.1

In individuals with severe renal impairment without HCV infection, voxilaprevir pharmacokinetics following a single 100-mg dose of the drug are similar to pharmacokinetics reported in healthy individuals.1 Voxilaprevir is not expected to be removed to any clinically important extent by hemodialysis.1

In HCV-infected individuals with ESRD requiring dialysis who were receiving the fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir), the pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were similar to the pharmacokinetics reported in those without HCV infection who had ESRD requiring dialysis.1 The pharmacokinetics of voxilaprevir have not been studied in individuals with ESRD;1 however, voxilaprevir exposures in HCV-infected individuals with ESRD requiring dialysis who are receiving sofosbuvir/velpatasvir/voxilaprevir are not expected to be affected to any clinically important extent compared with exposures in those with normal renal function.1

Common Adverse Effects

Adverse effects reported in 5% or more of patients receiving sofosbuvir/velpatasvir/voxilaprevir include headache,1,2 fatigue,1,2 diarrhea,1,2 nausea,1,2 asthenia,1,2 and insomnia.1,2

The following drug interactions are based on studies using the fixed combination containing sofosbuvir, velpatasvir, voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir), the fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir), sofosbuvir alone, velpatasvir alone, or voxilaprevir alone, or are predicted to occur.1 When sofosbuvir/velpatasvir/voxilaprevir is used, interactions associated with each drug in the fixed combination should be considered.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

In vitro studies indicate slow metabolic turnover of velpatasvir by cytochrome P-450 (CYP) isoenzymes 2B6, 2C8, and 3A4 and slow metabolic turnover of voxilaprevir by CYP3A4 and, to a lesser extent, 1A2 and 2C8.1 Sofosbuvir and the predominant metabolite of sofosbuvir (GS-331007) do not inhibit or induce CYP isoenzymes;1 velpatasvir and voxilaprevir do not inhibit CYP isoenzymes at clinically important concentrations.1

Pharmacokinetic interactions are possible with moderate or potent inducers of CYP2B6, 2C8, or 3A4, which may decrease sofosbuvir, velpatasvir, and/or voxilaprevir plasma concentrations potentially leading to reduced therapeutic effect of sofosbuvir/velpatasvir/voxilaprevir.1 Concomitant use of sofosbuvir/velpatasvir/voxilaprevir with moderate or potent inducers of CYP2B6, 2C8, or 3A4 is not recommended.1

Although inhibitors of CYP2B6, 2C8, or 3A4 may increase velpatasvir and/or voxilaprevir plasma concentrations,1 sofosbuvir/velpatasvir/voxilaprevir may be used concomitantly with inhibitors of CYP2B6, 2C8, or 3A4.1

Drugs Affecting or Affected by P-glycoprotein Transport System

Velpatasvir and voxilaprevir are inhibitors of the P-glycoprotein (P-gp) transport system;1 sofosbuvir and GS-331007 are not inhibitors of P-gp.1 Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and P-gp substrates may alter the exposure of such drugs.1

Sofosbuvir, velpatasvir, and voxilaprevir are substrates of P-gp;1 GS-331007 is not a P-gp substrate.1 Pharmacokinetic interactions are possible with P-gp inducers, which may decrease sofosbuvir, velpatasvir, and/or voxilaprevir plasma concentrations potentially leading to reduced therapeutic effect of sofosbuvir/velpatasvir/voxilaprevir.1 Concomitant use of sofosbuvir/velpatasvir/voxilaprevir with P-gp inducers is not recommended.1

Inhibitors of P-gp may increase plasma concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir without increasing plasma concentrations of GS-331007.1 Sofosbuvir/velpatasvir/voxilaprevir may be used concomitantly with P-gp inhibitors.1

Drugs Affecting or Affected by Breast Cancer Resistance Protein

Velpatasvir and voxilaprevir are inhibitors of breast cancer resistance protein (BCRP);1 sofosbuvir and GS-331007 are not BCRP inhibitors.1 Pharmacokinetic interactions are possible if sofosbuvir/velpatasvir/voxilaprevir and BCRP substrates are used concomitantly;1 altered exposure of such drugs may occur.1 Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and BCRP substrates is not recommended.1

Sofosbuvir, velpatasvir, and voxilaprevir are substrates of BCRP;1 GS-331007 is not a BCRP substrate.1 Inhibitors of BCRP may increase plasma concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir without increasing plasma concentrations of GS-331007.1 Sofosbuvir/velpatasvir/voxilaprevir may be used concomitantly with BCRP inhibitors.1

Drugs Affecting or Affected by Organic Anion Transporting Polypeptides

Velpatasvir and voxilaprevir inhibit organic anion transporting polypeptide (OATP) 1B1 and 1B3;1 velpatasvir also inhibits OATP2B1, but does not inhibit OATP1A2 at clinically relevant concentrations.1 Sofosbuvir and GS-331007 do not inhibit OATP1B1 or 1B3.1 Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and OATP1B1, 1B3, or 2B1 substrates may alter exposures of such drugs.1

Voxilaprevir and, to a lesser extent, velpatasvir are substrates of OATP1B1 and 1B3.1 Inhibitors of OATP may substantially increase plasma concentrations of voxilaprevir.1 Therefore, concomitant use of sofosbuvir/velpatasvir/voxilaprevir and OATP inhibitors is not recommended.1

Drugs Affecting or Affected by Other Membrane Transporters

Sofosbuvir and GS-331007 do not inhibit organic cation transporter (OCT) 1; GS-331007 does not inhibit organic anion transporter (OAT) 1, OAT3, OCT2, or multidrug and toxin extrusion protein (MATE) 1.1 Sofosbuvir and GS-331007 do not inhibit or induce uridine diphosphate-glucuronosyl transferase (UGT) 1A1.1

Velpatasvir and voxilaprevir do not inhibit OAT1, OAT3, OCT1, OCT2, MATE1, or UGT1A1 at clinically relevant concentrations.1

Drugs Affecting Gastric pH

The solubility of velpatasvir decreases as pH increases.1 Therefore, drugs that increase gastric pH are expected to decrease velpatasvir plasma concentrations.1

Antacids

Administration of sofosbuvir/velpatasvir/voxilaprevir and antacids (e.g., aluminum and magnesium hydroxide) should be separated by 4 hours.1

Histamine H2-Receptor Antagonists

H₂-receptor antagonists may be administered concurrently with or staggered from sofosbuvir/velpatasvir/voxilaprevir;1 dosage of the H₂-receptor antagonist should not exceed dosages comparable to famotidine 40 mg twice daily.1

Proton-pump Inhibitors

Administration of omeprazole 20 mg 2 hours before or 4 hours after sofosbuvir/velpatasvir/voxilaprevir results in decreased velpatasvir plasma concentrations and area under the plasma concentration-time curve (AUC).1

Sofosbuvir/velpatasvir/voxilaprevir may be administered with omeprazole 20 mg.1 Use of sofosbuvir/velpatasvir/voxilaprevir with other proton-pump inhibitors has not been studied.1

Antiarrhythmic Agents

Amiodarone

Concomitant use of amiodarone and sofosbuvir/velpatasvir/voxilaprevir may result in serious symptomatic bradycardia and is not recommended.1,23 If there are no alternative hepatitis C virus (HCV) treatment options and a regimen of sofosbuvir/velpatasvir/voxilaprevir must be used in a patient receiving amiodarone, the patient should be advised about the risk of serious symptomatic bradycardia and cardiac monitoring should be performed in an inpatient setting during the first 48 hours of concomitant use and then heart rate monitoring (outpatient or self-monitoring) should be performed daily through at least the first 2 weeks of concomitant use.1 Similar cardiac monitoring is recommended in patients who discontinued amiodarone just prior to initiation of sofosbuvir/velpatasvir/voxilaprevir or if there are no other treatment options and amiodarone must be initiated in a patient already receiving sofosbuvir/velpatasvir/voxilaprevir.1 (See Cardiovascular Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

The effect of concomitant use of amiodarone and sofosbuvir/velpatasvir/voxilaprevir on plasma concentrations of amiodarone, sofosbuvir, velpatasvir, and voxilaprevir is unknown.1

Anticoagulants

Dabigatran

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir once daily and a single 75-mg dose of dabigatran etexilate results in 2.9- and 2.6-fold increased dabigatran peak plasma concentrations and AUC, respectively.1

If sofosbuvir/velpatasvir/voxilaprevir and dabigatran are used concomitantly, clinical effects of the anticoagulant should be monitored; recommendations from the manufacturer of dabigatran etexilate should be consulted regarding dosage modifications.1

Warfarin

In patients receiving warfarin, subtherapeutic international normalized ratios (INRs) have been reported after initiation of sofosbuvir-containing HCV treatment regimens.27,28,29 INR fluctuations have been reported in patients receiving warfarin and sofosbuvir/velpatasvir/voxilaprevir concomitantly.1

If a sofosbuvir-containing regimen (e.g., sofosbuvir/velpatasvir/voxilaprevir) is used in patients receiving warfarin, INR should be frequently monitored at the time of initiation, during treatment, and after discontinuance of the sofosbuvir-containing regimen.1,27,28,29 Adjustment of warfarin dosage may be needed.1

Anticonvulsants

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and certain anticonvulsants (i.e., carbamazepine, oxcarbazepine, phenobarbital, phenytoin) is expected to decrease sofosbuvir, velpatasvir, and voxilaprevir plasma concentrations.1

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and carbamazepine, oxcarbazepine, phenobarbital, or phenytoin is not recommended.1

Antifungal Agents

Ketoconazole

No clinically important pharmacokinetic interactions were observed when sofosbuvir/velpatasvir was used concomitantly with ketoconazole.1

No clinically important pharmacokinetic interactions were observed when a single 100-mg dose of velpatasvir was used concomitantly with ketoconazole (200 mg twice daily).1

Voriconazole

No clinically important pharmacokinetic interactions were observed when sofosbuvir/velpatasvir/voxilaprevir was used concomitantly with voriconazole.1

No clinically important pharmacokinetic interactions were observed when a single 100-mg dose of voxilaprevir was used concomitantly with voriconazole (200 mg twice daily).1

Antimycobacterial Agents

Rifabutin

Rifabutin is expected to decrease plasma concentrations of sofosbuvir, velpatasvir, and voxilaprevir.1

Concomitant use of rifabutin and sofosbuvir/velpatasvir/voxilaprevir is not recommended.1

Rifampin

Concomitant use of rifampin (600 mg once daily) and sofosbuvir (single 400-mg dose), velpatasvir (single 100-mg dose), or voxilaprevir (single 100-mg dose) results in decreased plasma concentrations and AUCs of sofosbuvir, velpatasvir, and voxilaprevir.1 Concomitant use of rifampin (single 600-mg dose) and velpatasvir (single 100-mg dose) or voxilaprevir (single 100-mg dose) results in increased velpatasvir or voxilaprevir plasma concentrations and AUC.1

Concomitant use of rifampin and sofosbuvir/velpatasvir/voxilaprevir is contraindicated.1

Rifapentine

Rifapentine is expected to decrease plasma concentrations of sofosbuvir, velpatasvir, and voxilaprevir.1

Concomitant use of rifapentine and sofosbuvir/velpatasvir/voxilaprevir is not recommended.1

Antineoplastic Agents

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, or topotecan is not recommended.1

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Maraviroc

Concomitant use of maraviroc and sofosbuvir/velpatasvir/voxilaprevir is not expected to affect maraviroc pharmacokinetics.200

Dosage adjustments are not necessary if maraviroc is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir.200

HIV Integrase Inhibitors (INSTIs)

Bictegravir

Pharmacokinetic interactions are not expected if bictegravir is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir.200

Dosage adjustments are not necessary if bictegravir is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir.200

Dolutegravir

No clinically important pharmacokinetic interactions were observed when dolutegravir was used concomitantly with sofosbuvir/velpatasvir.1

Dosage adjustments are not necessary if dolutegravir is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir.200

Elvitegravir

Concomitant use of cobicistat-boosted elvitegravir results in increased AUCs of sofosbuvir and voxilaprevir, but does not affect velpatasvir concentrations.200 Dosage adjustments are not necessary if cobicistat-boosted elvitegravir is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir.200

No clinically important pharmacokinetic interactions were observed when the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate (EVG/c/FTC/TAF) was used concomitantly with sofosbuvir/velpatasvir/voxilaprevir.1

If sofosbuvir/velpatasvir/voxilaprevir is used concomitantly with the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/c/FTC/TDF), increased tenofovir concentrations may occur.1 Patients should be monitored for tenofovir-associated adverse effects if sofosbuvir/velpatasvir/voxilaprevir is used concomitantly with EVG/c/FTC/TDF.1 (See Tenofovir under Antiretroviral Agents: HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors [NRTIs], in Drug Interactions.)

Raltegravir

No clinically important pharmacokinetic interactions were observed when raltegravir was used concomitantly with sofosbuvir/velpatasvir.1

Concomitant use of sofosbuvir/velpatasvir and an HIV antiretroviral regimen of raltegravir in conjunction with the fixed combination of emtricitabine and TDF (emtricitabine/TDF) did not have a clinically important effect on the pharmacokinetics of raltegravir or emtricitabine, but tenofovir plasma concentrations and AUC were increased.1

Dosage adjustments are not necessary if raltegravir is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir.200

If sofosbuvir/velpatasvir/voxilaprevir is used concomitantly with an HIV antiretroviral regimen that includes raltegravir and TDF, patients should be monitored for tenofovir-associated adverse effects.1 (See Tenofovir under Antiretroviral Agents: HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors [NRTIs], in Drug Interactions.)

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Doravirine

Clinically important pharmacokinetic interactions are not expected if doravirine is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir.200

Dosage adjustments are not necessary if doravirine is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir.200

Efavirenz

Decreased velpatasvir and voxilaprevir concentrations are expected if efavirenz is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir.1,200

Concomitant use of the fixed combination of efavirenz, emtricitabine, and TDF (efavirenz/emtricitabine/TDF) and sofosbuvir/velpatasvir did not have a clinically important effect on the pharmacokinetics of sofosbuvir,1 but velpatasvir plasma concentrations and AUC were decreased and tenofovir plasma concentrations and AUC were increased.1

Concomitant use of efavirenz and sofosbuvir/velpatasvir/voxilaprevir is not recommended.1,200

Etravirine

Concomitant use of the etravirine and sofosbuvir/velpatasvir/voxilaprevir is expected to result in decreased velpatasvir and voxilaprevir plasma concentrations.200

Concomitant use of etravirine and sofosbuvir/velpatasvir/voxilaprevir is not recommended.200

Nevirapine

Concomitant use of nevirapine and sofosbuvir/velpatasvir/voxilaprevir is expected to result in decreased velpatasvir and voxilaprevir plasma concentrations.200

Concomitant use of nevirapine and sofosbuvir/velpatasvir/voxilaprevir is not recommended.200

Rilpivirine

No clinically important pharmacokinetic interactions when rilpivirine is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir.1

Concomitant use of the fixed combination of emtricitabine, rilpivirine, and TAF and sofosbuvir/velpatasvir/voxilaprevir did not have a clinically important effect on the pharmacokinetics of sofosbuvir, velpatasvir, or voxilaprevir.1

Concomitant use of the fixed combination of emtricitabine, rilpivirine, and TDF (emtricitabine/rilpivirine/TDF) and sofosbuvir/velpatasvir/voxilaprevir did not have a clinically important effect on the pharmacokinetics of emtricitabine or rilpivirine,1 but tenofovir plasma concentrations and AUC were increased.1

Dosage adjustments are not necessary if rilpivirine is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir.200

If sofosbuvir/velpatasvir/voxilaprevir is used concomitantly with an HIV antiretroviral regimen that contains rilpivirine and TDF, patients should be monitored for tenofovir-associated adverse effects.1 (See Tenofovir under Antiretroviral Agents: HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors [NRTIs], in Drug Interactions.)

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Emtricitabine

No clinically important pharmacokinetic interactions were observed when sofosbuvir/velpatasvir/voxilaprevir was used concomitantly with emtricitabine.1

Tenofovir

No clinically important pharmacokinetic interactions were observed when tenofovir alafenamide fumarate (TAF) was used concomitantly with sofosbuvir/velpatasvir/voxilaprevir.1,200 Dosage adjustments are not necessary if TAF is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir.200

Concomitant use of tenofovir disoproxil fumarate (TDF; tenofovir DF) or HIV antiretroviral regimens that include TDF and certain other antiretroviral agents (e.g., EVG/c/FTC/TDF, emtricitabine/rilpivirine/TDF, raltegravir in conjunction with emtricitabine/TDF, ritonavir-boosted darunavir in conjunction with emtricitabine/TDF) may result in increased tenofovir peak plasma concentrations and AUC.1,200 Patients should be monitored for tenofovir-associated adverse effects if sofosbuvir/velpatasvir/voxilaprevir is used concomitantly with any HIV antiretroviral regimen containing TDF.1,200 Some experts recommend that TAF should be considered instead of TDF in patients who are receiving sofosbuvir/velpatasvir/voxilaprevir and are at risk of TDF-associated adverse effects.200

HIV Protease Inhibitors (PIs)

Atazanavir

Concomitant use of ritonavir-boosted atazanavir and sofosbuvir/velpatasvir/voxilaprevir results in substantially increased voxilaprevir peak plasma concentrations and AUC.1

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and ritonavir-boosted , cobicistat-boosted , or unboosted atazanavir is not recommended.1,200

Darunavir

No clinically important pharmacokinetic interactions were observed when sofosbuvir/velpatasvir/voxilaprevir was used concomitantly with ritonavir-boosted darunavir in conjunction with emtricitabine/TDF,1 but tenofovir plasma concentrations and AUC were increased.1

Dosage adjustments are not necessary if ritonavir-boosted or cobicistat-boosted darunavir is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir.200

Lopinavir

Pharmacokinetic interactions are expected if the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir (increased voxilaprevir concentrations).1,200

Concomitant use of lopinavir/ritonavir and sofosbuvir/velpatasvir/voxilaprevir is not recommended.1,200

Tipranavir

Pharmacokinetic interactions are expected if ritonavir-boosted tipranavir is used concomitantly with sofosbuvir/velpatasvir/voxilaprevir (decreased sofosbuvir and velpatasvir plasma concentrations);1 the effect of ritonavir-boosted tipranavir on voxilaprevir concentrations is not known.1

Concomitant use of ritonavir-boosted tipranavir and sofosbuvir/velpatasvir/voxilaprevir is not recommended.1,200

Digoxin

Concomitant use of velpatasvir 100 mg once daily and a single 0.25-mg dose of digoxin results in increased digoxin concentrations and AUC.1

If sofosbuvir/velpatasvir/voxilaprevir and digoxin are used concomitantly, therapeutic concentration monitoring of digoxin is recommended.1

Estrogens and Progestins

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and an oral contraceptive containing ethinyl estradiol and norgestimate does not have a clinically important effect on the pharmacokinetics of ethinyl estradiol or norgestimate.1

Gemfibrozil

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and gemfibrozil does not result in clinically important pharmacokinetic interactions.1

HCV Antivirals

In vitro in replicon studies, there was no evidence of antagonistic anti-HCV effects between sofosbuvir and velpatasvir or voxilaprevir.1

In vitro in replicon studies, there was no evidence of antagonistic anti-HCV effects between velpatasvir and voxilaprevir.1

HMG-CoA Reductase Inhibitors

Atorvastatin

Concomitant use of sofosbuvir/velpatasvir once daily and a single 40-mg dose of atorvastatin results in increased atorvastatin peak plasma concentrations and AUC, which is associated with increased risk of myopathy and rhabdomyolysis.1

If sofosbuvir/velpatasvir/voxilaprevir and atorvastatin are used concomitantly, the lowest atorvastatin dosage should be used.1 If higher atorvastatin dosages are required, the lowest necessary dosage should be used taking into account the risks and benefits.1

Fluvastatin, Lovastatin, and Simvastatin

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir with fluvastatin, lovastatin, or simvastatin may increase concentrations of the statin, which is associated with increased risk of myopathy and rhabdomyolysis.1

If sofosbuvir/velpatasvir/voxilaprevir is used concomitantly with fluvastatin, lovastatin, or simvastatin, the lowest statin dosage should be used.1 If higher statin dosages are required, the lowest necessary dosage should be used taking into account the risks and benefits.1

Pitavastatin

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and pitavastatin may increase pitavastatin concentrations, which is associated with increased risk of myopathy and rhabdomyolysis.1

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and pitavastatin is not recommended.1

Pravastatin

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir once daily and a single 40-mg dose of pravastatin results in increased pravastatin peak plasma concentrations and AUC, which is associated with increased risk of myopathy and rhabdomyolysis.1

If sofosbuvir/velpatasvir/voxilaprevir and pravastatin are used concomitantly, the pravastatin dose should not exceed 40 mg.1

Rosuvastatin

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and rosuvastatin (single 10-mg dose) results in substantially increased rosuvastatin plasma concentrations and AUC, which is associated with increased risk of myopathy and rhabdomyolysis.1

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and rosuvastatin is not recommended.1

Immunosuppressive Agents

Cyclosporine

Concomitant use of cyclosporine (single 600-mg dose) and voxilaprevir (single100-mg dose) results in substantially increased voxilaprevir peak plasma concentrations and AUC.1 Increased sofosbuvir or velpatasvir exposures are observed when cyclosporine (single 600-mg dose) is used concomitantly with sofosbuvir (single 400-mg dose) or velpatasvir (single 100-mg dose).1

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and cyclosporine is not recommended.1

Tacrolimus

No clinically important pharmacokinetic interactions were observed when tacrolimus (single 5-mg dose) was used concomitantly with sofosbuvir (single 400-mg dose).1

Methadone

No clinically important pharmacokinetic interactions were observed when sofosbuvir (400 mg once daily) was used concomitantly with methadone hydrochloride (30-130 mg daily).1

St. John's Wort

Concomitant use of St. John's wort ( Hypericum perforatum ) and sofosbuvir/velpatasvir/voxilaprevir may result in clinically important decreases in sofosbuvir, velpatasvir, and voxilaprevir plasma concentrations.1

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and St. John's wort is not recommended.1

Sulfasalazine

Concomitant use of sulfasalazine and sofosbuvir/velpatasvir/voxilaprevir is not recommended.1

Description

Sofosbuvir, velpatasvir, and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir) is a fixed combination containing 3 hepatitis C virus (HCV) antivirals.1 Sofosbuvir is a nucleotide analog HCV nonstructural 5B (NS5B) polymerase inhibitor.1 Velpatasvir is an HCV nonstructural 5A (NS5A) replication complex inhibitor (NS5A inhibitor).1 Voxilaprevir is an HCV nonstructural 3/4A (NS3/4A) protease inhibitor.1 All three drugs are direct-acting antivirals (DAAs) with activity against HCV.1 There is no in vitro evidence of antagonistic anti-HCV effects between sofosbuvir and velpatasvir or voxilaprevir and no in vitro evidence of antagonistic anti-HCV effects between velpatasvir and voxilaprevir.1

Sofosbuvir is a prodrug that is converted in the liver to a pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by NS5B polymerase and acts as an RNA chain terminator.1,7 In vitro studies using biochemical assays indicate that GS-461203 has activity against HCV genotypes 1b, 2a, 3a, and 4a.1 Sofosbuvir has shown in vitro activity against full-length or chimeric replicons of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 5a, and 6a (median concentration of the drug required to inhibit viral replication by 50% [EC₅₀] has ranged from 15-110 nM).1

Velpatasvir inhibits the HCV NS5A protein, which is required for viral replication.1,7 Velpatasvir has shown in vitro activity against full-length or chimeric replicons of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 4r, 5a, 6a, and 6e (median EC₅₀ has ranged from 0.002-0.13 nM).1

Voxilaprevir reversibly binds to the active site of HCV NS3/4A protease, thereby blocking enzyme activity essential for viral replication (i.e., blocking cleavage of the HCV-encoded polyproteins into mature forms of NS3, NS4A, NS4B, NS5A, and NS5B).1,4,5,7 In vitro studies using biochemical assays indicate that voxilaprevir has activity against HCV genotypes 1b and 3a.1 Voxilaprevir has shown in vitro activity against full-length or chimeric replicons of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 4r, 5a, 6a, 6e, and 6n (median EC₅₀ has ranged from 0.2-6.6 nM).1,4

Certain amino acid substitutions in NS5B polymerase of HCV genotypes 1b, 2a, 2b, 3a, 4a, 5a, and 6a have been selected in cell culture and have been associated with reduced susceptibility to sofosbuvir in vitro in replicon studies.1 In all replicon genotypes tested, the S282T substitution was associated with reduced susceptibility to sofosbuvir;1 in genotypes 2a, 5, and 6 replicons, an M289L substitution developed along with the S282T substitution.1 Treatment-emergent NS5B resistance-associated substitutions were not detected in patients who experienced virologic failure or relapsed with sofosbuvir/velpatasvir/voxilaprevir in phase 3 clinical trials (POLARIS-1, POLARIS-4).1

Certain amino acid substitutions in NS5A of HCV genotype 1a (e.g., L31V, Y93H/N), genotype 1b (e.g., L31V, Y93H), genotype 2a (e.g., F28S, Y93H), genotype 3a (e.g., Y93H/S), genotype 4a (e.g., Y93H), and genotype 6 (e.g., L31V, P32A/L/Q/R) have been selected in cell culture and have been associated with reduced susceptibility to velpatasvir in vitro in replicon studies.1 Combinations of these NS5A substitutions often resulted in greater reductions in susceptibility to velpatasvir compared with a single NS5A substitution.1 Treatment-emergent NS5A resistance-associated substitutions were detected in phase 3 clinical trials evaluating sofosbuvir/velpatasvir/voxilaprevir in patients with HCV genotype 1a (e.g., L31M, Y93H, K24R), genotype 3a (e.g., E92K), or genotype 4 (e.g., Y93H) infection who relapsed or experienced virologic failure.1 Some of these patients also had baseline NS5A polymorphisms at resistance-associated amino acid positions.1

Certain amino acid substitutions in NS3/4A protease inhibitor resistance-associated positions of HCV genotypes 1a (e.g., A156 L/T), 1b (e.g., A156T/V), 2a (e.g., A156L/V), 3a (e.g., A156T/V), 4a (e.g., A156L/T/V), 5a, and 6a have been selected in cell culture and have been associated with reduced susceptibility to voxilaprevir in vitro in replicon studies.1 Combinations of these NS3 substitutions often resulted in greater reductions in susceptibility to voxilaprevir compared with a single NS3 substitution.1 Treatment-emergent NS3 resistance-associated substitutions were detected in phase 3 clinical trials evaluating sofosbuvir/velpatasvir/voxilaprevir in patients with HCV genotype 1a (e.g., V36A) or genotype 3a (e.g., Q41K, V55A, R155M) infection who relapsed.1

Sofosbuvir, velpatasvir, and voxilaprevir are each active against HCV with substitutions associated with resistance to other HCV DAAs that have different mechanisms of action.1 Cross-resistance is possible among the HCV NS5A inhibitors and among the HCV NS3/4A protease inhibitors.1

Following oral administration of sofosbuvir/velpatasvir/voxilaprevir, peak plasma concentrations of sofosbuvir occur 2 hours after the dose and peak plasma concentrations of velpatasvir and voxilaprevir both occur 4 hours after the dose.1 Administration of sofosbuvir/velpatasvir/voxilaprevir with food increases sofosbuvir exposures by 64-144%, increases velpatasvir exposures by 40-166%, and increases voxilaprevir exposures by 112-435%.1

Sofosbuvir is a prodrug that undergoes intracellular metabolic activation in the liver (hydrolysis by human cathepsin A [CatA] or carboxylesterase 1 [CES1], phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 [HINT1], and phosphorylation by pyrimidine nucleotide biosynthesis pathway).1,181 This results in formation of the pharmacologically active metabolite, GS-461203;1,181 desphosphorylation subsequently occurs leading to formation of GS-331007 (the predominant circulating metabolite), which has no anti-HCV activity.1,181 Sofosbuvir is approximately 61-65% bound to plasma proteins.1 The major route of elimination is renal clearance (glomerular filtration and active tubular secretion).1 Following a single oral dose of sofosbuvir, 80% is eliminated in urine (mainly as GS-331007) and 14% is excreted in feces.1 The median terminal plasma half-lives of sofosbuvir and GS-331007 are 0.5 and 29 hours, respectively.1

Velpatasvir is metabolized by cytochrome P-450 (CYP) isoenzymes 2B6, 2C8, and 3A4.1 The drug is greater than 99% bound to plasma proteins.1 The major route of elimination of velpatasvir is biliary excretion (approximately 77% excreted as the parent drug).1 Following a single oral dose of velpatasvir, 94% is excreted in feces and 0.4% is eliminated in urine.1 The median terminal plasma half-life of velpatasvir is 17 hours.1

Voxilaprevir is metabolized by CYP3A4.1 The drug is greater than 99% bound to plasma proteins.1 The major route of elimination of velpatasvir is biliary excretion (approximately 40% excreted as the parent drug).1 Following a single oral dose of voxilaprevir, 94% is excreted in feces and no drug is eliminated in urine.1 The median terminal plasma half-life of velpatasvir is 33 hours.1

Advice to Patients

Importance of reading patient information provided by the manufacturer.1

Advise patients that the fixed-combination preparation of sofosbuvir, velpatasvir, and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir) should be taken once daily with food on a regular dosing schedule.1

Importance of taking the recommended dosage of sofosbuvir/velpatasvir/voxilaprevir for the recommended duration of treatment;1 importance of not missing doses.1

Inform patients that reactivation of hepatitis B virus (HBV) infection has occurred in patients being treated for hepatitis C virus (HCV) infection who were coinfected with HBV.1,25 Importance of informing clinician of any history of HBV infection or other liver problems (e.g., cirrhosis).1,25 Importance of immediately contacting a clinician if any signs or symptoms of serious liver injury (e.g., fatigue, weakness, loss of appetite, nausea and vomiting, yellowing of the eyes or skin, light-colored bowel movements) occur.25 (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Warnings/Precautions: Warnings, in Cautions.)

Advise patients to immediately contact a clinician if they have symptoms of worsening liver problems (e.g., nausea, tiredness, yellowing of skin or white part of the eyes, bleeding or bruising more easily than normal, confusion, loss of appetite, diarrhea, dark or brown urine, dark or bloody stool, abdominal swelling, pain in upper right side of stomach area, sleepiness, vomiting of blood).1 (See Risk of Hepatic Decompensation or Failure in Patients with Evidence of Advanced Liver Disease under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

If sofosbuvir/velpatasvir/voxilaprevir is used in a patient receiving amiodarone, advise the patient about the risk of serious symptomatic bradycardia and the importance of immediately contacting a clinician if signs or symptoms of bradycardia (e.g., near-fainting or fainting, dizziness, lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, memory problems) occur.1 (See Cardiovascular Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Gilead Sciences, Inc. Vosevi^® (sofosbuvir, velpatasvir, and voxilaprevir) tablets prescribing information. Foster City, CA; 2019 Nov.

2. Bourlière M, Gordon SC, Flamm SL et al. Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. N Engl J Med . 2017; 376:2134-2146. [PubMed 28564569]

3. Jacobson IM, Lawitz E, Gane EJ et al. Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials. Gastroenterology . 2017; 153:113-122. [PubMed 28390869]

4. Lawitz E, Yang JC, Stamm LM et al. Characterization of HCV resistance from a 3-day monotherapy study of voxilaprevir, a novel pangenotypic NS3/4A protease inhibitor. Antivir Ther . 2017; [PubMed 29063860]

5. Chahine EB, Kelley D, Childs-Kean LM. Sofosbuvir/Velpatasvir/Voxilaprevir: A Pan-Genotypic Direct-Acting Antiviral Combination for Hepatitis C. Ann Pharmacother . 2017; :1060028017741508. [PubMed 29115151]

6. Mogalian E, German P, Kearney BP et al. Use of Multiple Probes to Assess Transporter- and Cytochrome P450-Mediated Drug-Drug Interaction Potential of the Pangenotypic HCV NS5A Inhibitor Velpatasvir. Clin Pharmacokinet . 2016; 55:605-13. [PubMed 26519191]

7. Soriano V, Benítez-Gutiérrez L, Arias A et al. Evaluation of sofosbuvir, velpatasvir plus voxilaprevir as fixed-dose co-formulation for treating hepatitis C. Expert Opin Drug Metab Toxicol . 2017; 13:1015-1022. [PubMed 28753040]

23. US Food and Drug Administration. FDA drug safety communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir (Harvoni) or Sovaldi in combination with another direct acting antiviral. 2015 Mar 24. From FDA website. [Web]

25. US Food and Drug Administration. FDA drug safety communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C. 2016 Oct 4. From FDA website. [Web]

26. US Food and Drug Administration. FDA drug safety communication: FDA warns about rare occurrence of serious liver injury with use of hepatitis C medicines Mavyret, Zepatier, and Vosevi in some patients with advanced liver disease. 2019 Aug 28. From FDA website. [Web]

27. DeCarolis DD, Westanmo AD, Chen YC et al. Evaluation of a Potential Interaction Between New Regimens to Treat Hepatitis C and Warfarin. Ann Pharmacother . 2016; 50:909-917. [PubMed 27465881]

28. Peterson D, Van Ermen A. Increased warfarin requirements in a patient with chronic hepatitis C infection receiving sofosbuvir and ribavirin. Am J Health Syst Pharm . 2017; 74:888-892. [PubMed 28596225]

29. Britnell SR, Willets AE, Vanderman AJ et al. Influence of Successful Chronic Hepatitis C Virus Treatment with Ledipasvir/Sofosbuvir on Warfarin Dosing Requirements in Four Veterans. Pharmacotherapy . 2016; 36:1173-1179. [PubMed 27716978]

119. American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America. HCV guidance: Recommendations for testing, managing, and treating hepatitis C. From the AASLD website. Accessed 2019 November 8. [Web]

181. Gilead Sciences, Inc. Harvoni^® (ledipasvir and sofosbuvir) tablets prescribing information. Foster City, CA; 2017 Apr.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Accessed January 2, 2010. Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]