Dosage & Administration
| Genotype | Patients Previously Treated with an HCV Regimen Containing: | VOSEVI Duration |
|---|---|---|
| 1, 2, 3, 4, 5, or 6 | An NS5A inhibitorIn clinical trials, prior NS5A inhibitor experience included daclatasvir, elbasvir, ledipasvir, ombitasvir, or velpatasvir. | 12 weeks |
| 1a or 3 | Sofosbuvir without an NS5A inhibitorIn 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 |
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Vosevi Prescribing Information
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.
Dosage and Administration, 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)]. | 11/2019 |
Warnings and Precautions, 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 develop evidence of hepatic decompensation/failure. VOSEVI is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B or C) or those with any history of prior hepatic decompensation [see Dosage and Administration (2.4), Adverse Reactions (6.2), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)] . | 09/2019 |
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
The recommended dosage of VOSEVI is one tablet, taken orally, once daily with food
| Genotype | Patients Previously Treated with an HCV Regimen Containing: | VOSEVI Duration |
|---|---|---|
| 1, 2, 3, 4, 5, or 6 | An NS5A inhibitorIn clinical trials, prior NS5A inhibitor experience included daclatasvir, elbasvir, ledipasvir, ombitasvir, or velpatasvir. | 12 weeks |
| 1a or 3 | Sofosbuvir without an NS5A inhibitorIn 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 |
The efficacy of VOSEVI was evaluated in two Phase 3 trials in DAA-experienced subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection without cirrhosis or with compensated cirrhosis, as summarized in Table 8.
| Trial | Population | Study Arms and Comparator Groups (Number of Subjects Treated) |
|---|---|---|
| DAA: direct-acting antiviral; SOF: sofosbuvir; VEL: velpatasvir | ||
| POLARIS-1Double-blind, placebo-controlled. (NCT02607735) | Genotype 1, 2, 3, 4, 5, or 6 NS5A inhibitor-experiencedIn clinical trials, prior NS5A inhibitor experience included daclatasvir, elbasvir, ledipasvir, ombitasvir, or velpatasvir., without cirrhosis or with compensated cirrhosis | VOSEVI 12 weeks (263) Placebo 12 weeks (152) |
| POLARIS-4Open-label. (NCT02639247) | Genotype 1, 2, 3, or 4 DAA-experiencedIn 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).who have not received an NS5A inhibitor, without cirrhosis or with compensated cirrhosis | VOSEVI 12 weeks (182) SOF/VEL 12 weeks (151) |
Serum HCV RNA values were measured during the clinical trials using the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU/mL. Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in both trials. Relapse is defined as HCV RNA greater than or equal to LLOQ after end-of-treatment response among subjects who completed treatment. On-treatment virologic failure is defined as breakthrough, rebound, or non-response.
POLARIS-1 was a randomized, double-blind, placebo-controlled trial that evaluated 12 weeks of treatment with VOSEVI compared with 12 weeks of placebo in DAA-experienced subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection without cirrhosis or with compensated cirrhosis who previously failed a regimen containing an NS5A inhibitor. Subjects with genotype 1 HCV infection were randomized 1:1 to each group. Subjects with genotype 2, 3, 4, 5, or 6 HCV infection were enrolled to the VOSEVI group. Randomization was stratified by the presence or absence of cirrhosis.
Demographics and baseline characteristics were generally balanced across treatment groups. Of the 415 treated subjects, the median age was 59 years (range: 27 to 84); 77% of the subjects were male; 81% were White; 14% were Black; 6% were Hispanic or Latino; 33% had a baseline body mass index at least 30 kg/m2; the majority of subjects had genotype 1 (72%) or genotype 3 (19%) HCV infection; 82% had a non-CC IL28B genotype (CT or TT); 74% had baseline HCV RNA levels at least 800,000 IU/mL; and 41% had compensated cirrhosis. In the POLARIS-1 trial, prior DAA regimens contained the following NS5A inhibitors: ledipasvir (51%), daclatasvir (27%), ombitasvir (11%), velpatasvir (7%), and elbasvir (3%).
Table 9 presents the SVR12 by HCV genotype for the POLARIS-1 trial. No subjects in the placebo group achieved SVR12.
| VOSEVI 12 Weeks (N=263) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Total (all GTs)One subject with undetermined genotype achieved SVR12. (N=263) | GT-1 | GT-2 (N=5) | GT-3 (N=78) | GT-4 (N=22) | GT-5 (N=1) | GT-6 (N=6) | |||
| GT-1a (N=101) | GT-1b (N=45) | TotalFour subjects had GT-1 subtypes other than GT-1a or GT-1b; all 4 subjects achieved SVR12.(N=150) | |||||||
| GT: genotype | |||||||||
| SVR12 | 96% (253/263) | 96% (97/101) | 100% (45/45) | 97% (146/150) | 100% (5/5) | 95% (74/78) | 91% (20/22) | 100% (1/1) | 100% (6/6) |
| Outcome for Subjects without SVR | |||||||||
| On-Treatment Virologic Failure | <1% (1/263) | 1% (1/101) | 0/45 | 1% (1/150) | 0/5 | 0/78 | 0/22 | 0/1 | 0/6 |
| RelapseThe denominator for relapse is the number of subjects with HCV RNA | 2% (6/261) | 1% (1/100) | 0/45 | 1% (1/149) | 0/5 | 5% (4/78) | 5% (1/21) | 0/1 | 0/6 |
| OtherOther includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal. | 1% (3/263) | 2% (2/101) | 0/45 | 1% (2/150) | 0/5 | 0/78 | 5% (1/22) | 0/1 | 0/6 |
POLARIS-4 was a randomized, open-label trial that evaluated 12 weeks of treatment with VOSEVI and 12 weeks of treatment with SOF/VEL in subjects with genotype 1, 2, 3, or 4 HCV infection without cirrhosis or with compensated cirrhosis who had previously failed a HCV DAA-containing regimen that did not include an NS5A inhibitor. Subjects whose only DAA exposure was an NS3/4A protease inhibitor were excluded. Subjects with genotype 1, 2, or 3 HCV infection were randomized 1:1 to each group. Randomization was stratified by HCV genotype and by the presence or absence of cirrhosis. Subjects with genotype 4 HCV infection were enrolled to the VOSEVI group. No subjects with genotype 5 or 6 were enrolled.
Demographics and baseline characteristics were generally balanced across treatment groups. Of the 333 treated subjects, the median age was 58 years (range: 24 to 85); 77% of the subjects were male; 87% were White, 9% were Black; 8% were Hispanic or Latino; 35% had a baseline body mass index at least 30 kg/m2; 81% had non-CC IL28B genotypes (CT or TT); 75% had baseline HCV RNA levels at least 800,000 IU/mL; and 46% had compensated cirrhosis. In the POLARIS-4 trial, prior DAA regimens contained sofosbuvir (85%) with the following: peginterferon alfa and ribavirin or ribavirin (69%), HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir; 15%), and investigational DAA (<1%). Of the 15% of subjects without prior sofosbuvir exposure, most received investigational HCV DAAs or approved HCV NS3/4A protease inhibitors, with or without peginterferon alfa and ribavirin.
Treatment with VOSEVI for 12 weeks resulted in numerically higher SVR12 rates than treatment with sofosbuvir/velpatasvir for 12 weeks in subjects with HCV genotype 1a and 3 infection. Comparable SVR12 rates were observed in subjects with HCV genotype 1b and 2 infection treated with VOSEVI for 12 weeks or with sofosbuvir/velpatasvir for 12 weeks. No comparison data are available for HCV genotypes 4, 5, and 6. Given these data, the additional benefit of VOSEVI has not been shown over sofosbuvir/velpatasvir for these genotypes and VOSEVI is only indicated for the treatment of HCV genotypes 1a or 3 infection in adults who previously received sofosbuvir without an NS5A inhibitor.
Table 10 presents the comparative virologic outcome data for HCV genotype 1, 2, and 3 subjects with prior exposure to a sofosbuvir-containing regimen.
| *Subjects with prior exposure to a SOF-containing regimen | VOSEVI 12 Weeks (N=139) | SOF/VEL 12 Weeks (N=125) |
|---|---|---|
| Overall (Genotypes 1, 2, and 3) | ||
| SVR12 | 97% (135/139) | 88% (110/125) |
| Not achieving SVR12 | ||
| On-treatment virologic failure | 0% (0/139) | 1% (1/125) |
| RelapseThe denominator for relapse is the number of subjects with HCV RNA | 1% (1/139) | 10% (13/124) |
| OtherOther includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal. | 2% (3/139) | 1% (1/125) |
| Genotype 1 | ||
| SVR12 | 96% (52/54) | 85% (34/40) |
| Not achieving SVR12 | ||
| On-treatment virologic failure | 0% (0/54) | 0% (0/40) |
| Relapse | 2% (1/54) | 13% (5/40) |
| Other | 2% (1/54) | 3% (1/40) |
| Genotype 1a | ||
| SVR12 | 97% (35/36) | 82% (23/28) |
| Not achieving SVR12 | ||
| On-treatment virologic failure | 0% (0/36) | 0% (0/28) |
| Relapse | 3% (1/36) | 18% (5/28) |
| Other | 0% (0/36) | 0% (0/28) |
| Genotype 1b | ||
| SVR12 | 94% (17/18) | 92% (11/12) |
| Not achieving SVR12 | ||
| On-treatment virologic failure | 0% (0/18) | 0% (0/12) |
| Relapse | 0% (0/18) | 0% (0/12) |
| Other | 6% (1/18) | 8% (1/12) |
| Genotype 2 | ||
| SVR12 | 100% (31/31) | 97% (32/33) |
| Not achieving SVR12 | ||
| On-treatment virologic failure | 0% (0/31) | 3% (1/33) |
| Relapse | 0% (0/31) | 0% (0/32) |
| Other | 0% (0/31) | 0% (0/33) |
| Genotype 3 | ||
| SVR12 | 96% (52/54) | 85% (44/52) |
| Not achieving SVR12 | ||
| On-treatment virologic failure | 0% (0/54) | 0% (0/52) |
| Relapse | 0% (0/54) | 15% (8/52) |
| Other | 4% (2/54) | 0% (0/52) |
In POLARIS-4, VOSEVI was administered for 12 weeks to 18 HCV genotype 4 subjects (with or without cirrhosis) who had prior exposure to a SOF-containing regimen without an NS5A inhibitor. All subjects achieved SVR12.
- 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.
- Testing: Prior to initiating VOSEVI, test all patients for HBV infection by measuring HBsAg and anti-HBc. ()
2.1 Testing Prior to the Initiation of TherapyTest 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)]. - 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 Recommended DosageThe 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
Duration1, 2, 3, 4, 5, or 6 An NS5A inhibitorIn clinical trials, prior NS5A inhibitor experience included daclatasvir, elbasvir, ledipasvir, ombitasvir, or velpatasvir. 12 weeks 1a or 3 Sofosbuvir without an NS5A inhibitorIn 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 - See recommended treatment regimen and duration in table below ():
2.2 Recommended DosageThe 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
Duration1, 2, 3, 4, 5, or 6 An NS5A inhibitorIn clinical trials, prior NS5A inhibitor experience included daclatasvir, elbasvir, ledipasvir, ombitasvir, or velpatasvir. 12 weeks 1a or 3 Sofosbuvir without an NS5A inhibitorIn 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
| Genotype | Patients Previously Treated with an HCV Regimen Containing: | VOSEVI Duration |
|---|---|---|
| 1, 2, 3, 4, 5, or 6 | An NS5A inhibitorIn clinical trials, prior NS5A inhibitor experience included daclatasvir, elbasvir, ledipasvir, ombitasvir, or velpatasvir. | 12 weeks |
| 1a or 3 | Sofosbuvir without an NS5A inhibitorIn 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 Renal ImpairmentNo 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)]. - VOSEVI is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C). (,
2.4 Moderate or Severe Hepatic ImpairmentVOSEVI 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)].)5.2 Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver DiseasePostmarketing cases of hepatic decompensation/failure, including those with fatal outcomes, have been reported in patients treated with HCV NS3/4A protease inhibitor-containing regimens, including treatment with VOSEVI. Reported cases occurred in patients with baseline cirrhosis with and without moderate or severe liver impairment (Child-Pugh B or C). Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.In patients with compensated cirrhosis (Child-Pugh A) or evidence of advanced liver disease such as portal hypertension, perform hepatic laboratory testing as clinically indicated; and monitor for signs and symptoms of hepatic decompensation such as the presence of jaundice, ascites, hepatic encephalopathy, and variceal hemorrhage. Discontinue VOSEVI in patients who develop evidence of hepatic decompensation/failure.VOSEVI is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B or C) or those with any history of prior hepatic decompensation[see Dosage and Administration (2.4), Adverse Reactions (6.2), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].
Each VOSEVI tablet contains 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir. The tablets are beige, capsule-shaped, film-coated, and debossed with "GSI" on one side and "
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)
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.