Sofosbuvir And Velpatasvir 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 immunosuppressants or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.
HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection, reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.
Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with sofosbuvir and velpatasvir. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with sofosbuvir and velpatasvir and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.
Indications and Usage (Sofosbuvir and velpatasvir is indicated for the treatment of adults and pediatric patients 3 years of age and older with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection [see Dosage and Administration (2.2, 2.3, 2.4) and Clinical Studies (14)] :
Sofosbuvir and velpatasvir is a fixed-dose combination of sofosbuvir, a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor, and velpatasvir, an HCV NS5A inhibitor, and is indicated for the treatment of adults and pediatric patients 3 years of age and older with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection :
| 06/2021 | ||||||||||||||||||||||||||||
| Dosage and Administration | |||||||||||||||||||||||||||||
Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older (Table 1 shows the recommended treatment regimen and duration based on patient population . For patients with HCV/HIV-1 coinfection follow the dosage recommendations in Table 1. For treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A), the recommended regimen is sofosbuvir and velpatasvir once daily for 12 weeks [see Clinical Studies (14.3and 14.5)]. Refer toDrug Interactions (7) for dosage recommendations for concomitant drugs.
| 06/2021 | ||||||||||||||||||||||||||||
Recommended Dosage in Pediatric Patients 3 Years of Age and Older (The recommended dosage of sofosbuvir and velpatasvir in pediatric patients 3 years of age and older is based on weight and provided in Table 2. Table 3 provides the weight-based dosage of ribavirin when used in combination with sofosbuvir and velpatasvir for pediatric patients. Take sofosbuvir and velpatasvir once daily with or without food. In pediatric patients less than 6 years of age, administer the sofosbuvir and velpatasvir (EPCLUSA) oral pellets with food to increase tolerability related to palatability [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14.8)] .
| 06/2021 | ||||||||||||||||||||||||||||
Preparation and Administration of Sofosbuvir and Velpatasvir (EPCLUSA) Oral Pellets (See the sofosbuvir and velpatasvir (EPCLUSA) oral pellets full Instructions for Use for details on the preparation and administration of sofosbuvir and velpatasvir (EPCLUSA) oral pellets. Do not chew sofosbuvir and velpatasvir (EPCLUSA) oral pellets to avoid a bitter aftertaste. Sofosbuvir and velpatasvir (EPCLUSA) oral pellets can be taken directly in the mouth or with food (See Instructions for Use). In pediatric patients less than 6 years of age, administer the oral pellets with food to increase tolerability related to palatability. Sprinkle the oral pellets on one or more spoonfuls of non-acidic soft food at or below room temperature. Examples of non-acidic foods include pudding, chocolate syrup, and ice cream. Take sofosbuvir and velpatasvir (EPCLUSA) oral pellets within 15 minutes of gently mixing with food and swallow the entire contents without chewing. | 06/2021 | ||||||||||||||||||||||||||||
Patient Population | Treatment Regimen and Duration |
|---|---|
| Treatment-naïve and treatment-experiencedIn clinical trials in adults, regimens contained peginterferon alfa/ribavirin with or without an HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir)., without cirrhosis and with compensated cirrhosis (Child-Pugh A) | Sofosbuvir and velpatasvir 12 weeks |
| Treatment-naïve and treatment-experienced, with decompensated cirrhosis (Child-Pugh B or C) | Sofosbuvir and velpatasvir + ribavirinSee Dosage and Administration 2.3and 2.4for ribavirin dosage recommendations. 12 weeks |
The recommended dosage of sofosbuvir and velpatasvir in adults is one tablet (400 mg sofosbuvir and 100 mg velpatasvir) taken orally once daily with or without food
When administered with sofosbuvir and velpatasvir, the recommended dosage of ribavirin is based on weight (administered with food): 1,000 mg per day for patients less than 75 kg and 1,200 mg for those weighing at least 75 kg, divided and administered twice daily. The starting dosage and on-treatment dosage of ribavirin can be decreased based on hemoglobin and creatinine clearance. For ribavirin dosage modifications refer to the ribavirin prescribing information
Body Weight (kg) | Sofosbuvir and Velpatasvir Daily Dose | Dosing of Sofosbuvir and Velpatasvir (EPCLUSA) Oral Pellets | Dosing of Sofosbuvir and Velpatasvir Tablets |
|---|---|---|---|
less than 17 | 150 mg/37.5 mg per day | one 150 mg/37.5 mg packet of Sofosbuvir and Velpatasvir (EPCLUSA) oral pellets once daily | N/A |
17 to less than 30 | 200 mg/50 mg per day | one 200 mg/50 mg packet of Sofosbuvir and Velpatasvir (EPCLUSA) oral pellets once daily | one Sofosbuvir and Velpatasvir (EPCLUSA) 200 mg/50 mg tablet once daily |
at least 30 | 400 mg/100 mg per day | two 200 mg/50 mg packets of Sofosbuvir and Velpatasvir (EPCLUSA) oral pellets once daily | one Sofosbuvir and Velpatasvir 400 mg/100 mg tablet once dailyTwo sofosbuvir and velpatasvir (EPCLUSA) 200 mg/50 mg tablets once daily can be used for patients who cannot swallow the sofosbuvir and velpatasvir 400 mg/100 mg tablet. |
Body Weight (kg) | Oral Ribavirin Daily DosageThe daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food. |
|---|---|
| less than 47 | 15 mg per kg per day (divided dose AM and PM) |
| 47–49 | 600 mg per day (1 × 200 mg AM, 2 × 200 mg PM) |
| 50–65 | 800 mg per day (2 × 200 mg AM, 2 × 200 mg PM) |
| 66–80 | 1,000 mg per day (2 × 200 mg AM, 3 × 200 mg PM) |
| greater than 80 | 1,200 mg per day (3 × 200 mg AM, 3 × 200 mg PM) |
Table 12 presents the clinical trial design including different treatment groups that were conducted with sofosbuvir and velpatasvir with and without ribavirin in subjects with chronic hepatitis C (HCV) genotype 1, 2, 3, 4, 5, and 6 infection. For detailed description of trial design and recommended regimen and duration
| Trial | Population | Sofosbuvir and Velpatasvir and Comparator Groups (Number of Subjects Treated) |
|---|---|---|
| TN = treatment-naïve subjects; SOF = sofosbuvir; RBV = ribavirin; CP = Child-Pugh; ESRD = End Stage Renal Disease; PWID = People Who Inject Drugs; MAT = Medication-Assisted Treatment. | ||
| ASTRAL-1Double-blind, placebo-controlled. (NCT02201940) | Genotype 1, 2, 4, 5, and 6 TN and TETE = treatment-experienced subjects are those who have failed a peginterferon alfa/ribavirin based regimen with or without an HCV protease inhibitor (boceprevir, simeprevir, or telaprevir)., without cirrhosis or with compensated cirrhosis | Sofosbuvir and velpatasvir 12 weeks (624) Placebo 12 weeks (116) |
| ASTRAL-2Open-label. (NCT02220998) | Genotype 2 TN and TE, without cirrhosis or with compensated cirrhosis | Sofosbuvir and velpatasvir 12 weeks (134) SOF + RBV 12 weeks (132) |
| ASTRAL-3(NCT02201953) | Genotype 3 TN and TE, without cirrhosis or with compensated cirrhosis | Sofosbuvir and velpatasvir 12 weeks (277) SOF + RBV 24 weeks (275) |
| ASTRAL-5 (NCT02480712) | Genotype 1, 2, 3, 4, 5, and 6 HCV/HIV-1 coinfected TN and TE, without cirrhosis or with compensated cirrhosis | Sofosbuvir and velpatasvir 12 weeks (106) |
| ASTRAL-4 (NCT02201901) | Genotype 1, 2, 3, 4, 5, and 6 TN and TE, with CP class B decompensated cirrhosis | Sofosbuvir and velpatasvir 12 weeks (90) Sofosbuvir and velpatasvir + RBV 12 weeks (87) Sofosbuvir and velpatasvir 24 weeks (90) |
| 2104 (NCT02781571) | Genotype 1, 2, 3, and 4 TN and TETE = treatment-experienced subjects are those who have failed a peginterferon alfa/ribavirin based regimen or an HCV-specific DAA-based regimen that does not include an NS5A inhibitor.liver transplant recipients, without cirrhosis or with compensated cirrhosis | Sofosbuvir and velpatasvir 12 weeks (79) |
| 4062 (NCT03036852) | Genotype 1, 2, 3, 4, and 6 TN and TETE = treatment-experienced subjects are those who have failed a peginterferon alfa/ribavirin or interferon/ribavirin based regimen.without cirrhosis or with compensated cirrhosis, with ESRD requiring dialysis | Sofosbuvir and velpatasvir 12 weeks (59) |
| SIMPLIFY (NCT02336139) | Genotype 1, 2, 3, and 4 PWID, including those on MAT for opioid use disorder, without cirrhosis or with compensated cirrhosis | Sofosbuvir and velpatasvir 12 weeks (103) |
| 1143 (NCT03022981) | Genotype 1, 2, 3, 4, and 6 TN and TETE = treatment-experienced subjects are those who have failed an interferon-based regimen with or without ribavirin and with or without an HCV protease inhibitor (boceprevir, simeprevir, or telaprevir).pediatric subjects 3 years of age and older | Sofosbuvir and velpatasvir 12 weeks (214) |
The ribavirin dosage was weight-based (1000 mg daily administered in two divided doses for subjects less than 75 kg and 1200 mg for those greater than or equal to 75 kg) and administered in two divided doses when used in combination with sofosbuvir in the ASTRAL-2 and ASTRAL-3 trials or in combination with sofosbuvir and velpatasvir in the ASTRAL-4 trial. Ribavirin dosage adjustments were performed according to the ribavirin prescribing information. 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. SVR12, defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in all the trials. Relapse is defined as HCV RNA greater than or equal to LLOQ during the post-treatment period after having achieved HCV RNA less than LLOQ at the end of treatment. On-treatment virologic failure is defined as breakthrough, rebound, or non-response.
ASTRAL-1 was a randomized, double-blind, placebo-controlled trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) compared with 12 weeks of placebo in subjects with genotype 1, 2, 4, 5, or 6 HCV infection without cirrhosis or with compensated cirrhosis. Subjects with genotype 1, 2, 4, or 6 HCV infection were randomized in a 5:1 ratio to treatment with sofosbuvir and velpatasvir or placebo for 12 weeks. Subjects with genotype 5 HCV infection were enrolled to the sofosbuvir and velpatasvir group. Randomization was stratified by HCV genotype (1, 2, 4, 6, and indeterminate) and the presence or absence of compensated cirrhosis.
Demographics and baseline characteristics were balanced between the sofosbuvir and velpatasvir and placebo group. Of the 740 treated subjects, the median age was 56 years (range: 18 to 82); 60% of the subjects were male; 79% were White, 9% were Black; 21% had a baseline body mass index at least 30 kg/m2; the proportions of subjects with genotype 1, 2, 4, 5, or 6 HCV infection were 53%, 17%, 19%, 5%, and 7%, respectively; 69% had non-CC IL28B alleles (CT or TT); 74% had baseline HCV RNA levels at least 800,000 IU/mL; 19% had compensated cirrhosis; and 32% were treatment-experienced.
Table 13 presents SVR12 and other virologic outcomes in sofosbuvir and velpatasvir-treated subjects in the ASTRAL-1 trial by HCV genotype. No subjects in the placebo group achieved SVR12.
| Sofosbuvir and Velpatasvir 12 Weeks (N=624) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Total (all GTs) (N=624) | GT-1 | GT-2 (N=104) | GT-4 (N=116) | GT-5 (N=35) | GT-6 (N=41) | |||
| GT-1a (N=210) | GT-1b (N=118) | Total (N=328) | ||||||
| GT = genotype; no subjects in the placebo group achieved SVR12. | ||||||||
| SVR12 | 99% (618/624) | 98% (206/210) | 99% (117/118) | 98% (323/328) | 100% (104/104) | 100% (116/116) | 97% (34/35) | 100% (41/41) |
| Outcome for Subjects without SVR | ||||||||
| On-Treatment Virologic Failure | 0/624 | 0/210 | 0/118 | 0/328 | 0/104 | 0/116 | 0/35 | 0/41 |
| RelapseThe denominator for relapse is the number of subjects with HCV RNA | <1% (2/623) | <1% (1/209) | 1% (1/118) | 1% (2/327) | 0/104 | 0/116 | 0/35 | 0/41 |
| OtherOther includes subjects who did not achieve SVR and did not meet virologic failure criteria. | 1% (4/624) | 1% (3/210) | 0/118 | 1% (3/328) | 0/104 | 0/116 | 3% (1/35) | 0/41 |
ASTRAL-2 was a randomized, open-label trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) compared with 12 weeks of treatment with SOF with ribavirin in subjects with genotype 2 HCV infection. Subjects were randomized in a 1:1 ratio to the treatment groups. Randomization was stratified by the presence or absence of compensated cirrhosis and prior treatment experience (treatment-naïve vs treatment-experienced).
Demographics and baseline characteristics were balanced across the two treatment groups. Of the 266 treated subjects, the median age was 58 years (range: 23 to 81); 59% of the subjects were male; 88% were White; 7% were Black; 33% had a baseline body mass index at least 30 kg/m2; 62% had non-CC IL28B alleles (CT or TT); 80% had baseline HCV RNA levels at least 800,000 IU/mL; 14% had compensated cirrhosis; and 15% were treatment-experienced.
Table 14 presents SVR12 and other virologic outcomes from the ASTRAL-2 trial.
| Sofosbuvir and Velpatasvir 12 Weeks (N=134) | SOF + RBV 12 Weeks (N=132) | |
|---|---|---|
| SOF = sofosbuvir; RBV = ribavirin. | ||
| SVR12 | 99% (133/134) | 94% (124/132) |
| Treatment difference +5.2%; 95% confidence interval (+0.2% to +10.3%) | ||
| Outcome for subjects without SVR | ||
| On-Treatment Virologic Failure | 0/134 | 0/132 |
| RelapseThe denominator for relapse is the number of subjects with HCV RNA | 0/133 | 5% (6/132) |
| OtherOther includes subjects who did not achieve SVR12 and did not meet virologic failure criteria. | 1% (1/134) | 2% (2/132) |
ASTRAL-3 was a randomized, open-label trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) compared with 24 weeks of treatment with SOF with ribavirin in subjects with genotype 3 HCV infection. Subjects were randomized in a 1:1 ratio to the treatment groups. Randomization was stratified by the presence or absence of compensated cirrhosis and prior treatment experience (treatment-naïve vs treatment-experienced).
Demographics and baseline characteristics were balanced across the treatment groups. Of the 552 treated subjects, the median age was 52 years (range: 19 to 76); 62% of the subjects were male; 89% were White; 9% were Asian; 20% had a baseline body mass index at least 30 kg/m2; 61% had non-CC IL28B alleles (CT or TT); 70% had baseline HCV RNA levels at least 800,000 IU/mL; 30% had compensated cirrhosis; and 26% were treatment-experienced.
Table 15 presents SVR12 and other virologic outcomes from the ASTRAL-3 trial.
| Sofosbuvir and Velpatasvir 12 Weeks (N=277) | SOF + RBV 24 Weeks (N=275) | |
|---|---|---|
| SOF = sofosbuvir; RBV = ribavirin. | ||
| SVR12 | 95% (264/277) | 80% (221/275) |
| Treatment difference +14.8%; 95% confidence interval (+9.6% to +20.0%) | ||
| Outcome for subjects without SVR | ||
| On-Treatment Virologic Failure | 0/277 | <1% (1/275) |
| RelapseThe denominator for relapse is the number of subjects with HCV RNA | 4% (11/276) | 14% (38/272) |
| OtherOther includes subjects who did not achieve SVR and did not meet virologic failure criteria. | 1% (2/277) | 5% (15/275) |
SVR12 for selected subgroups are presented in Table 16.
| Sofosbuvir and Velpatasvir 12 Weeks | SOF + RBV 24 WeeksFive subjects with missing cirrhosis status in the SOF + RBV 24-week group were excluded from this subgroup analysis. | |||
|---|---|---|---|---|
| Treatment-Naïve (N=206) | Treatment-Experienced (N=71) | Treatment-Naïve (N=201) | Treatment-Experienced (N=69) | |
| SOF = sofosbuvir; RBV = ribavirin. | ||||
| Without cirrhosis | 98% (160/163) | 94% (31/33)One treatment-experienced subject without cirrhosis treated with sofosbuvir and velpatasvir had genotype 1a HCV infection at failure, indicating HCV re-infection, and is therefore excluded from this analysis. | 90% (141/156) | 71% (22/31) |
| With compensated cirrhosis | 93% (40/43) | 89% (33/37) | 73% (33/45) | 58% (22/38) |
ASTRAL-5 was an open-label trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) in subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection who were coinfected with HIV-1. Subjects were on a stable HIV-1 antiretroviral therapy that included emtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine administered with atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, raltegravir or elvitegravir/cobicistat.
Of the 106 treated subjects, the median age was 57 years (range: 25 to 72); 86% of the subjects were male; 51% were White; 45% were Black; 22% had a baseline body mass index at least 30 kg/m2; the proportions of patients with genotype 1, 2, 3, or 4 HCV infection were 74%, 10%, 11%, and 5%, respectively; no subjects with genotype 5 or 6 HCV were treated with sofosbuvir and velpatasvir; 77% had non-CC IL28B alleles (CT or TT); 74% had baseline HCV RNA levels of at least 800,000 IU/mL; 18% had compensated cirrhosis; and 29% were treatment experienced. The overall mean CD4+ count was 598 cells/µL (range: 183−1513 cells/µL) and 57% of subjects had CD4+ counts > 500 cells/μL.
Table 17 presents the SVR12 for the ASTRAL-5 trial by HCV genotype.
| Sofosbuvir and Velpatasvir 12 Weeks (N=106) | |||||||
|---|---|---|---|---|---|---|---|
| Total (all GTs) (N=106) | GT-1 | GT-2 (N=11) | GT-3 (N=12) | GT-4 (N=5) | |||
| GT-1a (N=66) | GT-1b (N=12) | Total (N=78) | |||||
| SVR12 | 95% (101/106) | 95% (63/66) | 92% (11/12) | 95% (74/78) | 100% (11/11) | 92% (11/12) | 100% (5/5) |
| Outcome for Subjects without SVR | |||||||
| On-Treatment Virologic Failure | 0/106 | 0/66 | 0/12 | 0/78 | 0/11 | 0/12 | 0/5 |
| RelapseThe denominator for relapse is the number of subjects with HCV RNA | 2% (2/103) | 3% (2/65) | 0/11 | 3% (2/76) | 0/11 | 0/11 | 0/5 |
| OtherOther includes subjects who did not achieve SVR and did not meet virologic failure criteria. | 3% (3/106) | 2% (1/66) | 8% (1/12) | 3% (2/78) | 0/11 | 8% (1/12) | (0/5) |
No subject had HIV-1 rebound during treatment and CD4+ counts were stable during treatment.
ASTRAL-4 was a randomized, open-label trial in subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection and Child-Pugh B cirrhosis at screening. Subjects were randomized in a 1:1:1 ratio to treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) for 12 weeks (N=90), sofosbuvir and velpatasvir tablets (400 mg/100 mg) with ribavirin for 12 weeks (N=87), or sofosbuvir and velpatasvir tablets (400 mg/100 mg) for 24 weeks (N=90). Randomization was stratified by HCV genotype (1, 2, 3, 4, 5, 6, and indeterminate).
Demographics and baseline characteristics were balanced across the treatment groups. Of the 267 treated subjects, the median age was 59 years (range: 40 to 73); 70% of the subjects were male; 90% were White; 6% were Black; 42% had a baseline body mass index at least 30 kg/m2. The proportions of subjects with genotype 1, 2, 3, 4, or 6 HCV were 78%, 4%, 15%, 3%, and less than 1% (1 subject), respectively. No subjects with genotype 5 HCV infection were enrolled. 76% had non-CC IL28B alleles (CT or TT); 56% had baseline HCV RNA levels at least 800,000 IU/mL; 55% were treatment-experienced; and 95% of subjects had Model for End Stage Liver Disease (MELD) score less than or equal to 15 at baseline. Although all subjects had Child-Pugh B cirrhosis at screening, 6% and 4% of subjects were assessed to have Child-Pugh A and Child-Pugh C cirrhosis, respectively, on the first day of treatment.
Treatment with sofosbuvir and velpatasvir with ribavirin for 12 weeks resulted in numerically higher SVR12 rates than treatment with sofosbuvir and velpatasvir for 12 weeks or 24 weeks. Because sofosbuvir and velpatasvir with ribavirin for 12 weeks is the recommended dosage regimen, the results of the 12- and 24-week sofosbuvir and velpatasvir treatment groups are not presented.
Table 18 presents the SVR12 for subjects treated with sofosbuvir and velpatasvir with ribavirin for 12 weeks in the ASTRAL-4 trial by HCV genotype. No subjects with genotype 5 or 6 HCV were treated with sofosbuvir and velpatasvir with ribavirin for 12 weeks.
| Sofosbuvir and Velpatasvir + RBV 12 Weeks (N=87) | ||
|---|---|---|
| SVR12 | Virologic Failure (relapse and on-treatment failure) | |
| RBV = ribavirin. | ||
| Overall SVR12Includes subjects with baseline CPT C cirrhosis: all 4 subjects achieved SVR12. | 94% (82/87) | 3% (3/87) |
| Genotype 1 | 96% (65/68) | 1% (1/68)This subject with genotype 1a experienced relapse. |
| Genotype 1a | 94% (51/54) | 2% (1/54) |
| Genotype 1b | 100% (14/14) | 0% (0/14) |
| Genotype 3 | 85% (11/13) | 15% (2/13)One subject had on-treatment virologic failure; pharmacokinetic data from this subject was consistent with non- adherence. |
All subjects with genotype 2 (N=4) and genotype 4 (N=2) HCV infection treated with sofosbuvir and velpatasvir and ribavirin achieved SVR12.
Trial 2104 was an open-label clinical trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) in 79 HCV-infected treatment-naïve and previously treated adult subjects who had undergone liver transplantation. The proportions of subjects with genotype 1, 2, 3, or 4 HCV infection were 47%, 4%, 44%, and 5%, respectively. The median age was 62 years (range: 45 to 81); 81% were male; 82% were White; 3% were Black; and 15% were Asian; 28% had a baseline body mass index at least 30 kg/m2. At baseline, 18% had compensated cirrhosis, and 60% were treatment experienced (subjects with prior exposure to any HCV NS5A inhibitor were excluded). Immunosuppressants allowed for coadministration were tacrolimus, mycophenolate mofetil, cyclosporine, and azathioprine. The overall SVR12 rate was 96% (76/79). Of the subjects completing 12 weeks of sofosbuvir and velpatasvir, 2 subjects experienced virologic relapse.
Trial 4062 was an open-label clinical trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) in 59 HCV-infected adults with ESRD requiring dialysis. The proportions of subjects with genotype 1, 2, 3, 4, 6 or indeterminate HCV infection were 42%,12%, 27%, 7%, 3%, and 8%, respectively. At baseline, 29% of subjects had cirrhosis, 22% were treatment-experienced (subjects with prior exposure to any HCV NS5A inhibitor were excluded), 92% were on hemodialysis, and 8% were on peritoneal dialysis; mean duration on dialysis was 7 years (range: 0 to 40 years). The overall SVR rate was 95% (56/59). Of the subjects completing 12 weeks of sofosbuvir and velpatasvir, 1 subject experienced virologic relapse.
SIMPLIFY was an open-label Phase 2 clinical trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) in 103 HCV-infected PWID (defined as self-reported injection drug use within previous 6 months), including 58 subjects on MAT for opioid use disorder. The proportions of subjects with genotype 1, 2, 3, and 4 HCV infection were 35%, 5%, 58%, and 2%, respectively. The median age was 48 years (range: 24 to 67); 71% were male; 89% were White; and 2% were Black. At baseline, 74% and 26% of subjects reported injection drug use or daily injection drug use, respectively, in the past month; 56% had baseline HCV RNA levels at least 800,000 IU/mL; 10% had compensated cirrhosis; and all subjects were naïve to prior exposure with SOF or an HCV NS5A inhibitor. Subjects on MAT for opioid use disorder reported concomitant use of methadone (76%) and buprenorphine naloxone (17%) with sofosbuvir and velpatasvir. The overall SVR rate was 94% (97/103). One subject completed sofosbuvir and velpatasvir treatment and was re-infected with a phylogenetically different virus; the other 5 subjects who did not achieve SVR12 did not meet virologic failure criteria.
The efficacy of sofosbuvir and velpatasvir once daily for 12 weeks was evaluated in an open-label trial (Study 1143) in 214 genotype 1, 2, 3, 4, or 6 HCV treatment-naïve (N=188) or treatment-experienced (N=26) pediatric subjects 3 years of age and older without cirrhosis or with compensated cirrhosis.
The SVR rate was 93% (71/76) in subjects with genotype 1 HCV infection and 100% in subjects with genotype 2 (6/6), genotype 3 (12/12), genotype 4 (2/2), and genotype 6 (6/6) HCV infection. One subject discontinued treatment at Week 4 and subsequently relapsed; the other four subjects who did not achieve SVR12 did not meet virologic failure criteria (lost to follow-up).
The SVR rate was 93% (50/54) in subjects with genotype 1 HCV infection, 91% (10/11) in subjects with genotype 3 HCV infection, and 100% in subjects with genotype 2 (2/2) and genotype 4 (4/4) HCV infection. One subject had on-treatment virologic failure; the other four subjects who did not achieve SVR12 did not meet virologic failure criteria (lost to follow-up).
The SVR12 rate among all subjects was 83% (34/41); with 88% (28/32) in subjects with genotype 1 HCV infection, 50% (3/6) in subjects with genotype 2 HCV infection, and 100% in subjects with genotype 3 (2/2) and genotype 4 (1/1) HCV infection. None of the 34 subjects who completed the treatment had virologic failure. Of the remaining seven subjects who did not achieve SVR12, five discontinued treatment on Day 1, one on Day 7, and one on Day 20
- without cirrhosis or with compensated cirrhosis
- with decompensated cirrhosis for use in combination with ribavirin.
- Testing prior to the initiation of therapy: 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 sofosbuvir and velpatasvir
[see Warnings and Precautions (5.1)]. - See recommended treatment regimen and duration in patients 3 years of age and older with genotypes 1, 2, 3, 4, 5, or 6 HCV in table below: ()
2.2 Recommended Treatment Regimen and Duration in Patients 3 Years of Age and OlderTable 1 shows the recommended treatment regimen and duration based on patient population.For patients with HCV/HIV-1 coinfection follow the dosage recommendations in Table 1. For treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A), the recommended regimen is sofosbuvir and velpatasvir once daily for 12 weeks[see Clinical Studies (14.3and 14.5)].Refer toDrug Interactions (7)for dosage recommendations for concomitant drugs.Table 1 Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older with Genotype 1, 2, 3, 4, 5, or 6 HCV Patient PopulationTreatment Regimen and Duration Treatment-naïve and treatment-experiencedIn clinical trials in adults, regimens contained peginterferon alfa/ribavirin with or without an HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir)., without cirrhosis and with compensated cirrhosis (Child-Pugh A) Sofosbuvir and velpatasvir
12 weeksTreatment-naïve and treatment-experienced, with decompensated cirrhosis (Child-Pugh B or C) Sofosbuvir and velpatasvir + ribavirinSee Dosage and Administration 2.3and 2.4for ribavirin dosage recommendations.
12 weeks
| Patient Population | Regimen and Duration |
|---|---|
| Treatment-naïve and treatment-experiencedIn clinical trials, regimens contained peginterferon alfa/ribavirin with or without an HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir)., without cirrhosis and with compensated cirrhosis (Child-Pugh A) | Sofosbuvir and velpatasvir 12 weeks |
| Treatment-naïve and treatment-experienced, with decompensated cirrhosis (Child-Pugh B and C) | Sofosbuvir and velpatasvir + ribavirin 12 weeks |
- Recommended dosage in adults: One tablet (400 mg of sofosbuvir and 100 mg of velpatasvir) taken orally once daily with or without food. ()
2.3 Recommended Dosage in AdultsThe recommended dosage of sofosbuvir and velpatasvir in adults is one tablet (400 mg sofosbuvir and 100 mg velpatasvir) taken orally once daily with or without food
[see Clinical Pharmacology (12.3)].When administered with sofosbuvir and velpatasvir, the recommended dosage of ribavirin is based on weight (administered with food): 1,000 mg per day for patients less than 75 kg and 1,200 mg for those weighing at least 75 kg, divided and administered twice daily. The starting dosage and on-treatment dosage of ribavirin can be decreased based on hemoglobin and creatinine clearance. For ribavirin dosage modifications refer to the ribavirin prescribing information
[see Use in Specific Populations (8.6)and Clinical Studies (14.4)]. - Recommended dosage in pediatric patients 3 years and older: Recommended dosage is based on weight. Refer to Table 2 of the full prescribing information for specific dosing guidelines based on body weight. ()
2.4 Recommended Dosage in Pediatric Patients 3 Years of Age and OlderThe recommended dosage of sofosbuvir and velpatasvir in pediatric patients 3 years of age and older is based on weight and provided in Table 2. Table 3 provides the weight-based dosage of ribavirin when used in combination with sofosbuvir and velpatasvir for pediatric patients. Take sofosbuvir and velpatasvir once daily with or without food. In pediatric patients less than 6 years of age, administer the sofosbuvir and velpatasvir (EPCLUSA) oral pellets with food to increase tolerability related to palatability[see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14.8)].Table 2 Dosing for Pediatric Patients 3 Years and Older with Genotype 1, 2, 3, 4, 5, or 6 HCV Body Weight (kg)Sofosbuvir and Velpatasvir Daily Dose Dosing of Sofosbuvir and Velpatasvir (EPCLUSA) Oral Pellets Dosing of Sofosbuvir and Velpatasvir Tablets less than 17150 mg/37.5 mg per day one 150 mg/37.5 mg packet of Sofosbuvir and Velpatasvir (EPCLUSA) oral pellets once daily N/A 17 to less than 30200 mg/50 mg per day one 200 mg/50 mg packet of Sofosbuvir and Velpatasvir (EPCLUSA) oral pellets once daily one Sofosbuvir and Velpatasvir (EPCLUSA) 200 mg/50 mg tablet once daily at least 30400 mg/100 mg per day two 200 mg/50 mg packets of Sofosbuvir and Velpatasvir (EPCLUSA) oral pellets once daily one Sofosbuvir and Velpatasvir 400 mg/100 mg tablet once dailyTwo sofosbuvir and velpatasvir (EPCLUSA) 200 mg/50 mg tablets once daily can be used for patients who cannot swallow the sofosbuvir and velpatasvir 400 mg/100 mg tablet. Table 3 Recommended Dosing for Ribavirin in Combination Therapy with Sofosbuvir and Velpatasvir for Pediatric Patients 3 Years and Older Body Weight (kg)Oral Ribavirin Daily DosageThe daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food. less than 47 15 mg per kg per day
(divided dose AM and PM)47–49 600 mg per day
(1 × 200 mg AM, 2 × 200 mg PM)50–65 800 mg per day
(2 × 200 mg AM, 2 × 200 mg PM)66–80 1,000 mg per day
(2 × 200 mg AM, 3 × 200 mg PM)greater than 80 1,200 mg per day
(3 × 200 mg AM, 3 × 200 mg PM) - For pediatric patients less than 6 years of age, administer sofosbuvir and velpatasvir (EPCLUSA) oral pellets with food. ()
2.4 Recommended Dosage in Pediatric Patients 3 Years of Age and OlderThe recommended dosage of sofosbuvir and velpatasvir in pediatric patients 3 years of age and older is based on weight and provided in Table 2. Table 3 provides the weight-based dosage of ribavirin when used in combination with sofosbuvir and velpatasvir for pediatric patients. Take sofosbuvir and velpatasvir once daily with or without food. In pediatric patients less than 6 years of age, administer the sofosbuvir and velpatasvir (EPCLUSA) oral pellets with food to increase tolerability related to palatability[see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14.8)].Table 2 Dosing for Pediatric Patients 3 Years and Older with Genotype 1, 2, 3, 4, 5, or 6 HCV Body Weight (kg)Sofosbuvir and Velpatasvir Daily Dose Dosing of Sofosbuvir and Velpatasvir (EPCLUSA) Oral Pellets Dosing of Sofosbuvir and Velpatasvir Tablets less than 17150 mg/37.5 mg per day one 150 mg/37.5 mg packet of Sofosbuvir and Velpatasvir (EPCLUSA) oral pellets once daily N/A 17 to less than 30200 mg/50 mg per day one 200 mg/50 mg packet of Sofosbuvir and Velpatasvir (EPCLUSA) oral pellets once daily one Sofosbuvir and Velpatasvir (EPCLUSA) 200 mg/50 mg tablet once daily at least 30400 mg/100 mg per day two 200 mg/50 mg packets of Sofosbuvir and Velpatasvir (EPCLUSA) oral pellets once daily one Sofosbuvir and Velpatasvir 400 mg/100 mg tablet once dailyTwo sofosbuvir and velpatasvir (EPCLUSA) 200 mg/50 mg tablets once daily can be used for patients who cannot swallow the sofosbuvir and velpatasvir 400 mg/100 mg tablet. Table 3 Recommended Dosing for Ribavirin in Combination Therapy with Sofosbuvir and Velpatasvir for Pediatric Patients 3 Years and Older Body Weight (kg)Oral Ribavirin Daily DosageThe daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food. less than 47 15 mg per kg per day
(divided dose AM and PM)47–49 600 mg per day
(1 × 200 mg AM, 2 × 200 mg PM)50–65 800 mg per day
(2 × 200 mg AM, 2 × 200 mg PM)66–80 1,000 mg per day
(2 × 200 mg AM, 3 × 200 mg PM)greater than 80 1,200 mg per day
(3 × 200 mg AM, 3 × 200 mg PM) - Instructions for Use should be followed for preparation and administration of sofosbuvir and velpatasvir (EPCLUSA) oral pellets. ()
2.5 Preparation and Administration of Sofosbuvir and Velpatasvir (EPCLUSA) Oral PelletsSee the sofosbuvir and velpatasvir (EPCLUSA) oral pellets full Instructions for Use for details on the preparation and administration of sofosbuvir and velpatasvir (EPCLUSA) oral pellets.Do not chew sofosbuvir and velpatasvir (EPCLUSA) oral pellets to avoid a bitter aftertaste. Sofosbuvir and velpatasvir (EPCLUSA) oral pellets can be taken directly in the mouth or with food (See Instructions for Use). In pediatric patients less than 6 years of age, administer the oral pellets with food to increase tolerability related to palatability. Sprinkle the oral pellets on one or more spoonfuls of non-acidic soft food at or below room temperature. Examples of non-acidic foods include pudding, chocolate syrup, and ice cream. Take sofosbuvir and velpatasvir (EPCLUSA) oral pellets within 15 minutes of gently mixing with food and swallow the entire contents without chewing. - HCV/HIV-1 coinfection: For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in the table above. ()
2.2 Recommended Treatment Regimen and Duration in Patients 3 Years of Age and OlderTable 1 shows the recommended treatment regimen and duration based on patient population.For patients with HCV/HIV-1 coinfection follow the dosage recommendations in Table 1. For treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A), the recommended regimen is sofosbuvir and velpatasvir once daily for 12 weeks[see Clinical Studies (14.3and 14.5)].Refer toDrug Interactions (7)for dosage recommendations for concomitant drugs.Table 1 Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older with Genotype 1, 2, 3, 4, 5, or 6 HCV Patient PopulationTreatment Regimen and Duration Treatment-naïve and treatment-experiencedIn clinical trials in adults, regimens contained peginterferon alfa/ribavirin with or without an HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir)., without cirrhosis and with compensated cirrhosis (Child-Pugh A) Sofosbuvir and velpatasvir
12 weeksTreatment-naïve and treatment-experienced, with decompensated cirrhosis (Child-Pugh B or C) Sofosbuvir and velpatasvir + ribavirinSee Dosage and Administration 2.3and 2.4for ribavirin dosage recommendations.
12 weeks - For treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A), the recommended regimen is sofosbuvir and velpatasvir once daily for 12 weeks. ()
2.2 Recommended Treatment Regimen and Duration in Patients 3 Years of Age and OlderTable 1 shows the recommended treatment regimen and duration based on patient population.For patients with HCV/HIV-1 coinfection follow the dosage recommendations in Table 1. For treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A), the recommended regimen is sofosbuvir and velpatasvir once daily for 12 weeks[see Clinical Studies (14.3and 14.5)].Refer toDrug Interactions (7)for dosage recommendations for concomitant drugs.Table 1 Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older with Genotype 1, 2, 3, 4, 5, or 6 HCV Patient PopulationTreatment Regimen and Duration Treatment-naïve and treatment-experiencedIn clinical trials in adults, regimens contained peginterferon alfa/ribavirin with or without an HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir)., without cirrhosis and with compensated cirrhosis (Child-Pugh A) Sofosbuvir and velpatasvir
12 weeksTreatment-naïve and treatment-experienced, with decompensated cirrhosis (Child-Pugh B or C) Sofosbuvir and velpatasvir + ribavirinSee Dosage and Administration 2.3and 2.4for ribavirin dosage recommendations.
12 weeks - If used in combination with ribavirin, follow the recommendations for ribavirin dosing and dosage modifications. (,
2.3 Recommended Dosage in AdultsThe recommended dosage of sofosbuvir and velpatasvir in adults is one tablet (400 mg sofosbuvir and 100 mg velpatasvir) taken orally once daily with or without food
[see Clinical Pharmacology (12.3)].When administered with sofosbuvir and velpatasvir, the recommended dosage of ribavirin is based on weight (administered with food): 1,000 mg per day for patients less than 75 kg and 1,200 mg for those weighing at least 75 kg, divided and administered twice daily. The starting dosage and on-treatment dosage of ribavirin can be decreased based on hemoglobin and creatinine clearance. For ribavirin dosage modifications refer to the ribavirin prescribing information
[see Use in Specific Populations (8.6)and Clinical Studies (14.4)].)2.4 Recommended Dosage in Pediatric Patients 3 Years of Age and OlderThe recommended dosage of sofosbuvir and velpatasvir in pediatric patients 3 years of age and older is based on weight and provided in Table 2. Table 3 provides the weight-based dosage of ribavirin when used in combination with sofosbuvir and velpatasvir for pediatric patients. Take sofosbuvir and velpatasvir once daily with or without food. In pediatric patients less than 6 years of age, administer the sofosbuvir and velpatasvir (EPCLUSA) oral pellets with food to increase tolerability related to palatability[see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14.8)].Table 2 Dosing for Pediatric Patients 3 Years and Older with Genotype 1, 2, 3, 4, 5, or 6 HCV Body Weight (kg)Sofosbuvir and Velpatasvir Daily Dose Dosing of Sofosbuvir and Velpatasvir (EPCLUSA) Oral Pellets Dosing of Sofosbuvir and Velpatasvir Tablets less than 17150 mg/37.5 mg per day one 150 mg/37.5 mg packet of Sofosbuvir and Velpatasvir (EPCLUSA) oral pellets once daily N/A 17 to less than 30200 mg/50 mg per day one 200 mg/50 mg packet of Sofosbuvir and Velpatasvir (EPCLUSA) oral pellets once daily one Sofosbuvir and Velpatasvir (EPCLUSA) 200 mg/50 mg tablet once daily at least 30400 mg/100 mg per day two 200 mg/50 mg packets of Sofosbuvir and Velpatasvir (EPCLUSA) oral pellets once daily one Sofosbuvir and Velpatasvir 400 mg/100 mg tablet once dailyTwo sofosbuvir and velpatasvir (EPCLUSA) 200 mg/50 mg tablets once daily can be used for patients who cannot swallow the sofosbuvir and velpatasvir 400 mg/100 mg tablet. Table 3 Recommended Dosing for Ribavirin in Combination Therapy with Sofosbuvir and Velpatasvir for Pediatric Patients 3 Years and Older Body Weight (kg)Oral Ribavirin Daily DosageThe daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food. less than 47 15 mg per kg per day
(divided dose AM and PM)47–49 600 mg per day
(1 × 200 mg AM, 2 × 200 mg PM)50–65 800 mg per day
(2 × 200 mg AM, 2 × 200 mg PM)66–80 1,000 mg per day
(2 × 200 mg AM, 3 × 200 mg PM)greater than 80 1,200 mg per day
(3 × 200 mg AM, 3 × 200 mg PM) - For patients with renal impairment including end stage renal disease on dialysis, follow the dosage recommendations in the table above. ()
2.6 Renal ImpairmentNo dosage adjustment of sofosbuvir and velpatasvir tablets (400 mg/100 mg) is recommended in patients with any degree of renal impairment, including patients requiring dialysis. Administer sofosbuvir and velpatasvir tablets (400 mg/100 mg) with or without ribavirin according to the recommendations in Table 1
[see Adverse Reactions (6.1), Use in Specific Populations (8.6), and Clinical Studies (14.6)]. Refer to ribavirin tablet prescribing information for ribavirin dosage modification for patients with CrCl less than or equal to 50 mL per minute.
Each sofosbuvir and velpatasvir tablet contains 400 mg of sofosbuvir and 100 mg of velpatasvir. The tablets are pink, diamond-shaped, film-coated, and debossed with "ASE" on one side and "9761" on the other side.
If sofosbuvir and velpatasvir is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on ribavirin-associated risks of use during pregnancy.
No adequate human data are available to establish whether or not sofosbuvir and velpatasvir pose a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with sofosbuvir or velpatasvir 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.