Drug Detail:Vosevi (Sofosbuvir, velpatasvir, and voxilaprevir [ soe-fos-bue-vir, vel-pat-as-vir, and-vox-i-la-pre-vir ])
Drug Class: Antiviral combinations
Highlights of Prescribing Information
VOSEVI® (sofosbuvir, velpatasvir, and voxilaprevir) tablets, for oral use
Initial U.S. Approval: 2017
WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV
See full prescribing information for complete boxed warning.
Hepatitis B virus (HBV) reactivation has been reported, in some cases resulting in fulminant hepatitis, hepatic failure, and death. (5.1)
Recent Major Changes
| Dosage and Administration, Renal Impairment (2.3) | 11/2019 |
| Warnings and Precautions, Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease (5.2) | 09/2019 |
Indications and Usage for Vosevi
VOSEVI is a fixed-dose combination of sofosbuvir, a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor, velpatasvir, an HCV NS5A inhibitor, and voxilaprevir, an HCV NS3/4A protease inhibitor, and is indicated for the treatment of adult patients with chronic HCV infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have (1, 2.2, 14):
- genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen containing an NS5A inhibitor.
- genotype 1a or 3 infection and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor.
- Additional benefit of VOSEVI over sofosbuvir/velpatasvir was not shown in adults with genotype 1b, 2, 4, 5, or 6 infection previously treated with sofosbuvir without an NS5A inhibitor.
Vosevi Dosage and Administration
- Testing: Prior to initiating VOSEVI, test all patients for HBV infection by measuring HBsAg and anti-HBc. (2.1)
- Recommended dosage: One tablet (400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) taken orally once daily with food. (2.2)
- See recommended treatment regimen and duration in table below (2.2):
| Genotype | Patients Previously Treated with an HCV Regimen Containing: | VOSEVI Duration |
|---|---|---|
|
||
| 1, 2, 3, 4, 5, or 6 | An NS5A inhibitor* | 12 weeks |
| 1a or 3 | Sofosbuvir without an NS5A inhibitor† | 12 weeks |
- For patients with renal impairment including end stage renal disease on dialysis, follow the dosage recommendations in the table above. (2.3)
- VOSEVI is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C). (2.4, 5.2)
Dosage Forms and Strengths
Tablets: 400 mg sofosbuvir, 100 mg velpatasvir, and 100 mg voxilaprevir (3)
Contraindications
Coadministration with rifampin. (4)
Warnings and Precautions
- Risk of Hepatitis B Virus Reactivation: Test all patients for evidence of current or prior HBV infection before initiation of HCV treatment. Monitor HCV/HBV coinfected patients for HBV reactivation and hepatitis flare during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. (5.1)
- Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease: Hepatic decompensation/failure, including fatal outcomes, have been reported mostly in patients with cirrhosis and baseline moderate or severe liver impairment (Child-Pugh B or C) treated with HCV NS3/4A protease inhibitor-containing regimens. Monitor for clinical and laboratory evidence of hepatic decompensation. Discontinue VOSEVI in patients who develop evidence of hepatic decompensation/failure. (5.2)
- Bradycardia with Amiodarone Coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone with VOSEVI, a sofosbuvir-containing regimen, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Coadministration of amiodarone with VOSEVI is not recommended. In patients without alternative viable treatment options, cardiac monitoring is recommended. (5.3, 7.3)
Adverse Reactions/Side Effects
- The most common adverse reactions (incidence greater than or equal to 10%, all grades) observed with treatment with VOSEVI for 12 weeks were headache, fatigue, diarrhea, and nausea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions
- P-gp inducers and/or moderate to strong CYP inducers (e.g., St. John's wort, carbamazepine): May decrease concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir. Use of VOSEVI with P-gp inducers and/or moderate to strong CYP inducers is not recommended. (5.4, 7)
- Consult the full prescribing information prior to use for potential drug interactions. (4, 5.3, 5.4, 7)
- Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact safe and effective use of concomitant medications. Frequent monitoring of relevant laboratory parameters (INR or blood glucose) and dose adjustments of certain concomitant medications may be necessary. (7.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 11/2019
Full Prescribing Information
WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV
Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with VOSEVI. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals (DAA) and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated [see Warnings and Precautions (5.1)].
1. Indications and Usage for Vosevi
VOSEVI is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have [see Dosage and Administration (2.2) and Clinical Studies (14)]:
- genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen containing an NS5A inhibitor.
- genotype 1a or 3 infection and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor.
- Additional benefit of VOSEVI over sofosbuvir/velpatasvir was not shown in adults with genotype 1b, 2, 4, 5, or 6 infection previously treated with sofosbuvir without an NS5A inhibitor.
2. Vosevi Dosage and Administration
2.1 Testing Prior to the Initiation of Therapy
Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with VOSEVI [see Warnings and Precautions (5.1)].
2.2 Recommended Dosage
The recommended dosage of VOSEVI is one tablet, taken orally, once daily with food [see Clinical Pharmacology (12.3)]. One tablet of VOSEVI contains 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir. Table 1 shows the recommended treatment regimen and duration based on patient population.
| Genotype | Patients Previously Treated with an HCV Regimen Containing: | VOSEVI Duration |
|---|---|---|
|
||
| 1, 2, 3, 4, 5, or 6 | An NS5A inhibitor* | 12 weeks |
| 1a or 3 | Sofosbuvir without an NS5A inhibitor† | 12 weeks |
2.3 Renal Impairment
No dosage adjustment of VOSEVI is recommended in patients with any degree of renal impairment including patients on dialysis [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
2.4 Moderate or Severe Hepatic Impairment
VOSEVI is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C) due to higher exposures of voxilaprevir in these patients [see Warnings and Precautions (5.2), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].
3. Dosage Forms and Strengths
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 "
" on the other side.
4. Contraindications
VOSEVI is contraindicated with rifampin [see Drug Interactions (7.3), and Clinical Pharmacology (12.3)].
5. Warnings and Precautions
5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV
Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.
HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.
Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with VOSEVI. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with VOSEVI and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.
5.2 Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease
Postmarketing cases of hepatic decompensation/failure, including those with fatal outcomes, have been reported in patients treated with HCV NS3/4A protease inhibitor-containing regimens, including treatment with VOSEVI. Reported cases occurred in patients with baseline cirrhosis with and without moderate or severe liver impairment (Child-Pugh B or C). Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
In patients with compensated cirrhosis (Child-Pugh A) or evidence of advanced liver disease such as portal hypertension, perform hepatic laboratory testing as clinically indicated; and monitor for signs and symptoms of hepatic decompensation such as the presence of jaundice, ascites, hepatic encephalopathy, and variceal hemorrhage. Discontinue VOSEVI in patients who 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)].
5.3 Serious Symptomatic Bradycardia When Coadministered with Amiodarone
Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with a sofosbuvir-containing regimen. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir-containing regimen (HARVONI® (ledipasvir/sofosbuvir)). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown.
Coadministration of amiodarone with VOSEVI is not recommended. For patients taking amiodarone who have no other alternative viable treatment options and who will be coadministered VOSEVI:
- Counsel patients about the risk of symptomatic bradycardia.
- Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.
Patients who are taking VOSEVI who need to start amiodarone therapy due to no other alternative viable treatment options should undergo similar cardiac monitoring as outlined above.
Due to amiodarone's long half-life, patients discontinuing amiodarone just prior to starting VOSEVI should also undergo similar cardiac monitoring as outlined above.
Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion, or memory problems [see Adverse Reactions (6.2) and Drug Interactions (7.3)].
5.4 Risk of Reduced Therapeutic Effect Due to Concomitant Use of VOSEVI with Inducers of P-gp and/or Moderate to Strong Inducers of CYP
Drugs that are inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., St. John's wort, carbamazepine) may significantly decrease plasma concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir, leading to potentially reduced therapeutic effect of VOSEVI. The use of these agents with VOSEVI is not recommended [see Drug Interactions (7.3)].
6. Adverse Reactions/Side Effects
The following serious adverse reactions are described below and elsewhere in labeling:
- Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see Warnings and Precautions (5.3)].
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse Reactions in HCV-Infected Subjects without Cirrhosis or with Compensated Cirrhosis
The adverse reactions data for VOSEVI were derived from two Phase 3 clinical trials (POLARIS-1 and POLARIS-4) that evaluated a total of 445 subjects infected with genotype 1, 2, 3, 4, 5, or 6 HCV, without cirrhosis or with compensated cirrhosis (Child-Pugh A), who received VOSEVI for 12 weeks. VOSEVI was studied in placebo- and active-controlled (sofosbuvir/velpatasvir) trials [see Clinical Studies (14.1 and 14.2)].
The proportion of subjects who permanently discontinued treatment due to adverse events was 0.2% for subjects who received VOSEVI for 12 weeks.
The most common adverse reactions (adverse events assessed as causally related by the investigator and at least 10%) were headache, fatigue, diarrhea, and nausea in subjects treated with VOSEVI for 12 weeks.
Table 2 lists adverse reactions (adverse events assessed as causally related by the investigator, all grades) observed in at least 5% of subjects receiving 12 weeks of treatment with VOSEVI in the Phase 3 clinical trials. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.
| POLARIS-1 | POLARIS-4 | |||
|---|---|---|---|---|
| VOSEVI 12 weeks (N=263) | Placebo 12 weeks (N=152) | VOSEVI 12 weeks (N=182) | SOF/VEL 12 weeks (N=151) |
|
| Headache | 21% | 14% | 23% | 23% |
| Fatigue | 17% | 15% | 19% | 23% |
| Diarrhea | 13% | 9% | 14% | 3% |
| Nausea | 13% | 7% | 10% | 3% |
| Asthenia | 6% | 4% | 4% | 6% |
| Insomnia | 6% | 3% | 3% | 1% |
In POLARIS-1, of the subjects receiving VOSEVI who experienced adverse reactions, 99% were mild or moderate (Grade 1 or 2) in severity. In POLARIS-4, of the subjects receiving VOSEVI who experienced adverse reactions, all the reported adverse reactions were mild or moderate (Grade 1 or 2) in severity.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of sofosbuvir-containing regimens. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
7. Drug Interactions
7.1 Potential for Other Drugs to Affect VOSEVI
Sofosbuvir, velpatasvir, and voxilaprevir are substrates of drug transporters P-gp and BCRP while GS-331007 (predominant circulating metabolite of sofosbuvir) is not. Voxilaprevir is also a substrate of OATP1B1 and OATP1B3. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 and of voxilaprevir by CYP1A2, CYP2C8, and primarily CYP3A4 was observed.
Drugs that are inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., St. John's wort, carbamazepine) may significantly decrease plasma concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir leading to reduced therapeutic effect of VOSEVI. The use of these agents with VOSEVI is not recommended [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. VOSEVI may be coadministered with P-gp, BCRP, and CYP inhibitors. The use of OATP inhibitors which may substantially increase exposure of voxilaprevir (e.g., cyclosporine) with VOSEVI is not recommended [see Clinical Pharmacology (12.3)].
7.2 Potential for VOSEVI to Affect Other Drugs
Velpatasvir and voxilaprevir are inhibitors of drug transporters P-gp, BCRP, OATP1B1, and OATP1B3. Velpatasvir is also an inhibitor of OATP2B1. Coadministration of VOSEVI with drugs that are substrates of these transporters may alter the exposure of such drugs. Coadministration of VOSEVI with BCRP substrates (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) is not recommended [see Clinical Pharmacology (12.3)].
7.3 Established and Potentially Significant Drug Interactions
Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment.
Frequent monitoring of relevant laboratory parameters (e.g., International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with a narrow therapeutic index (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary.
Table 3 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either VOSEVI, the components of VOSEVI (sofosbuvir, velpatasvir, and/or voxilaprevir), or are predicted drug interactions that may occur with VOSEVI [see Contraindications (4), Warnings and Precautions (5.3, 5.4), and Clinical Pharmacology (12.3)].
| Concomitant Drug Class: Drug Name | Effect on Concentration† | Clinical Effect/Recommendation |
|---|---|---|
|
||
| Acid Reducing Agents: | ↓ velpatasvir | Velpatasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease concentration of velpatasvir. |
| Antacids (e.g., aluminum and magnesium hydroxide) | Separate antacid and VOSEVI administration by 4 hours. | |
| H2-receptor antagonists (e.g., famotidine)‡ | H2-receptor antagonists may be administered simultaneously with or staggered from VOSEVI at a dose that does not exceed doses comparable with famotidine 40 mg twice daily. | |
| Proton-pump inhibitors (e.g., omeprazole)‡ | Omeprazole 20 mg can be administered with VOSEVI. Use with other proton pump-inhibitors has not been studied. | |
| Antiarrhythmics: | ||
| amiodarone | Effect on amiodarone, sofosbuvir, velpatasvir, and voxilaprevir concentrations unknown | Coadministration of amiodarone with VOSEVI may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with VOSEVI is not recommended; if coadministration is required, cardiac monitoring is recommended [see Warnings and Precautions (5.3)]. |
| digoxin‡ | ↑ digoxin | Therapeutic concentration monitoring of digoxin is recommended when coadministered with VOSEVI. Refer to digoxin prescribing information for monitoring and dose modification recommendations for concentration increases with unclear magnitude. |
| Anticoagulants: | ||
| dabigatran etexilate‡ | ↑ dabigatran | Clinical monitoring of dabigatran is recommended when coadministered with VOSEVI. Refer to dabigatran etexilate prescribing information for dose modification recommendations in the setting of moderate renal impairment. |
| Anticonvulsants: | ||
| carbamazepine‡
phenytoin phenobarbital | ↓ sofosbuvir ↓ velpatasvir ↓ voxilaprevir | Coadministration is not recommended. |
| Antimycobacterials: | ||
| rifampin‡ | ↓ sofosbuvir ↓ velpatasvir ↑ voxilaprevir (single dose) ↓ voxilaprevir (multiple dose) | Coadministration with rifampin is contraindicated [see Contraindications (4)]. |
| rifabutin‡
rifapentine | ↓ sofosbuvir ↓ velpatasvir ↓ voxilaprevir | Coadministration is not recommended. |
| Antiretrovirals: | ||
| atazanavir‡
lopinavir | ↑ voxilaprevir | Coadministration of VOSEVI with atazanavir- or lopinavir-containing regimens is not recommended. |
| tipranavir/ritonavir | ↓ sofosbuvir ↓ velpatasvir | Coadministration is not recommended. The effect on voxilaprevir is unknown. |
| efavirenz‡ | ↓ velpatasvir ↓ voxilaprevir | Coadministration of VOSEVI with efavirenz-containing regimens is not recommended. |
| tenofovir disoproxil fumarate (tenofovir DF)‡ | ↑ tenofovir | Monitor for tenofovir-associated adverse reactions in patients receiving VOSEVI concomitantly with a regimen containing tenofovir DF. Refer to the prescribing information of the tenofovir DF-containing product for recommendations on renal monitoring. |
| Herbal Supplements: | ||
| St. John's wort | ↓ sofosbuvir ↓ velpatasvir ↓ voxilaprevir | Coadministration is not recommended. |
| HMG-CoA Reductase Inhibitors: | ||
| pravastatin‡ | ↑ pravastatin | Coadministration of VOSEVI with pravastatin has been shown to increase the concentration of pravastatin, which is associated with increased risk of myopathy, including rhabdomyolysis. Pravastatin may be administered with VOSEVI at a dose that does not exceed pravastatin 40 mg. |
| rosuvastatin‡ | ↑ rosuvastatin | Coadministration of VOSEVI with rosuvastatin may significantly increase the concentration of rosuvastatin which is associated with increased risk of myopathy, including rhabdomyolysis. Coadministration of VOSEVI with rosuvastatin is not recommended. |
| pitavastatin | ↑ pitavastatin | Coadministration with VOSEVI may increase the concentration of pitavastatin and is not recommended, due to an increased risk of myopathy, including rhabdomyolysis. |
| atorvastatin‡
fluvastatin lovastatin simvastatin | ↑ atorvastatin ↑ fluvastatin ↑ lovastatin ↑ simvastatin | Coadministration with VOSEVI may increase the concentrations of atorvastatin, fluvastatin, lovastatin, and simvastatin. Increased statin concentrations may increase the risk of myopathy, including rhabdomyolysis. Use the lowest approved statin dose. If higher doses are needed, use the lowest necessary statin dose based on a risk/benefit assessment. |
| Immunosuppressants: | ||
| cyclosporine‡ | ↑ voxilaprevir | Coadministration of voxilaprevir with cyclosporine has been shown to substantially increase the plasma concentration of voxilaprevir, the safety of which has not been established. Coadministration of VOSEVI with cyclosporine is not recommended. |
7.4 Drugs without Clinically Significant Interactions with VOSEVI
Based on drug interaction studies conducted with the components of VOSEVI (sofosbuvir, velpatasvir, and/or voxilaprevir) or VOSEVI, no clinically significant drug interactions have been observed with the following drugs [see Clinical Pharmacology (12.3)]:
- VOSEVI: cobicistat, darunavir, elvitegravir, emtricitabine, ethinyl estradiol/norgestimate, gemfibrozil, rilpivirine, ritonavir, tenofovir alafenamide, voriconazole
- Sofosbuvir/velpatasvir: dolutegravir, ketoconazole, raltegravir
- Sofosbuvir: methadone, tacrolimus
8. Use In Specific Populations
8.4 Pediatric Use
Safety and effectiveness of VOSEVI have not been established in pediatric patients.
8.5 Geriatric Use
Clinical trials of VOSEVI included 74 subjects aged 65 and over (17% of total number of subjects in the POLARIS-1 and POLARIS-4 Phase 3 clinical trials). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment of VOSEVI is warranted in geriatric patients [see Clinical Pharmacology (12.3)].
8.6 Renal Impairment
No dosage adjustment of VOSEVI is recommended for patients with mild, moderate, or severe renal impairment, including ESRD requiring dialysis [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
No dosage adjustment of VOSEVI is recommended for patients with mild hepatic impairment (Child-Pugh A). VOSEVI is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C) due to the higher exposures of voxilaprevir (up to 6-fold in non-HCV infected subjects); the safety and efficacy have not been established in HCV-infected patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. Postmarketing cases of hepatic decompensation/failure have been reported in these patients [see Warnings and Precautions (5.2)].
10. Overdosage
No specific antidote is available for overdose with VOSEVI. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with VOSEVI consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Hemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%. Hemodialysis is unlikely to result in significant removal of velpatasvir or voxilaprevir since velpatasvir and voxilaprevir are highly bound to plasma protein.
11. Vosevi Description
VOSEVI is a fixed-dose combination tablet containing sofosbuvir, velpatasvir, and voxilaprevir for oral administration. Sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor, velpatasvir is an NS5A inhibitor, and voxilaprevir is an NS3/4A protease inhibitor.
Each tablet contains 400 mg sofosbuvir, 100 mg velpatasvir, and 100 mg of voxilaprevir. The tablets include the following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: ferrosoferric oxide, iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
12. Vosevi - Clinical Pharmacology
12.1 Mechanism of Action
VOSEVI is a fixed-dose combination of sofosbuvir, velpatasvir, and voxilaprevir which are DAA agents against the hepatitis C virus [see Microbiology (12.4)].
12.3 Pharmacokinetics
The pharmacokinetic properties of the components of VOSEVI are provided in Table 4. The multiple dose pharmacokinetic parameters of sofosbuvir and its metabolite GS-331007, velpatasvir, and voxilaprevir are provided in Table 5.
| Sofosbuvir | Velpatasvir | Voxilaprevir | |
|---|---|---|---|
| CES1 = carboxylesterase 1; HINT1 = histidine triad nucleotide-binding protein 1. | |||
|
|||
| Absorption | |||
| Tmax (h) | 2 | 4 | 4 |
| Effect of food (relative to fasting)* | ↑ 64% to 144% | ↑ 40% to 166% | ↑ 112% to 435% |
| Distribution | |||
| % Bound to human plasma proteins | 61–65 | >99 | >99 |
| Blood-to-plasma ratio | 0.7 | 0.5–0.7 | 0.5–0.8 |
| Metabolism | |||
| Metabolism | Cathepsin A CES1 HINT1 | CYP2B6 CYP2C8 CYP3A4 | CYP3A4 |
| Elimination | |||
| Major route of elimination | SOF: metabolism GS-331007†: glomerular filtration and active tubular secretion | Biliary excretion | Biliary excretion |
| t1/2 (h)‡ | SOF: 0.5 GS-331007†: 29 | 17 | 33 |
| % Of dose excreted in urine§ | 80¶ | 0.4 | 0 |
| % Of dose excreted in feces§ | 14 | 94 (77%# as parent) | 94 (40%# as parent) |
| Parameter Mean (%CV) | Sofosbuvir* | GS-331007† | Velpatasvir‡ | Voxilaprevir§ |
|---|---|---|---|---|
| CV = coefficient of variation; NA = not applicable. | ||||
|
||||
| Cmax
(nanogram per mL) | 678 (35.4) | 744 (28.3) | 311 (56.1) | 192 (85.8) |
| AUCtau
(nanogram∙hr per mL) | 1665 (30.1) | 12834 (29.0) | 4041 (48.6) | 2577 (73.7) |
| Ctrough
(nanogram per mL) | NA | NA | 51 (64.7) | 47 (82.0) |
Sofosbuvir and GS-331007 AUC0–24 and Cmax were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=137), velpatasvir AUC0–24 and Cmax were 41% lower and 39% lower, respectively, in HCV-infected subjects. Relative to healthy subjects (N=63), voxilaprevir AUC0–24 and Cmax were both 260% higher in HCV-infected subjects.
Sofosbuvir and GS-331007 AUCs are near dose-proportional over the dose range of 200 mg to 1200 mg. Velpatasvir AUC increases in a greater than proportional manner from 5 to 50 mg and in a less than proportional manner from 50 to 450 mg in healthy volunteers. However, velpatasvir exhibited near dose-proportional increase in exposures 25 mg to 150 mg in HCV-infected patients. Voxilaprevir AUC increases in a greater than proportional manner over the dose range of 100 to 900 mg when administered with food.
Specific Populations
Drug Interaction Studies
After oral administration of VOSEVI, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic extraction (hydrolysis followed by sequential phosphorylation) to form the pharmacologically active triphosphate. In clinical pharmacology studies, both sofosbuvir and the primary circulating metabolite GS-331007 (dephosphorylated nucleotide metabolite) were monitored for purposes of pharmacokinetic analyses.
Sofosbuvir, velpatasvir, and voxilaprevir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. Voxilaprevir, and to a lesser extent velpatasvir, are also substrates of OATP1B1 and OATP1B3. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 and of voxilaprevir by CYP1A2, CYP2C8, and primarily CYP3A4 was observed. Inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., St. John's wort, carbamazepine) may significantly decrease plasma concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir leading to reduced therapeutic effect of VOSEVI [see Contraindications (4), Warnings and Precautions (5.4), and Drug Interactions (7.3)]. Coadministration with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir, velpatasvir, and/or voxilaprevir plasma concentrations without increasing GS-331007 plasma concentration. Coadministration with drugs that inhibit OATP may increase voxilaprevir plasma concentrations. Drugs that inhibit CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir and/or voxilaprevir.
Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, OATP1B1, OATP1B3, or OCT1 and GS-331007 is not an inhibitor of OAT1, OAT3, OCT2, or MATE1. Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes.
Velpatasvir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1, OATP1B3, and OATP2B1, and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. At clinically relevant concentrations, velpatasvir is not an inhibitor of hepatic transporters OATP1A2 or OCT1, renal transporters OCT2, OAT1, OAT3 or MATE1, or CYP or UGT1A1 enzymes.
Voxilaprevir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1, and OATP1B3, and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. At clinically relevant concentrations, voxilaprevir is not an inhibitor of hepatic transporters OCT1, renal transporters OCT2, OAT1, OAT3, or MATE1, or CYP or UGT1A1 enzymes.
The effects of coadministered drugs on the exposure of sofosbuvir, GS-331007, velpatasvir, and voxilaprevir are shown in Table 6. The effects of sofosbuvir, velpatasvir, voxilaprevir, sofosbuvir/velpatasvir, or VOSEVI on the exposure of coadministered drugs are shown in Table 7 [see Drug Interactions (7)].
| Coadministered Drug | Sofosbuvir (SOF)/ Velpatasvir (VEL)/Voxilaprevir (VOX) | N | Geometric Mean Ratio (90% CI) of Sofosbuvir, GS-331007, Velpatasvir, and Voxilaprevir PK With/Without Coadministered Drug No Effect=1.00 |
|||||
|---|---|---|---|---|---|---|---|---|
| Drug | Dosage (mg) | Active Component | Dosage (mg) |
|||||
| Component | Cmax | AUC | Cmin | |||||
| NA = not available/not applicable, ND = not dosed. | ||||||||
|
||||||||
| Atazanavir + ritonavir | 300 + 100 single dose | SOF/VEL/VOX | 400/100/100 single dose | 15 | sofosbuvir | 1.29 (1.09, 1.52) | 1.40 (1.25, 1.57) | NA |
| GS-331007 | 1.05 (0.99, 1.12) | 1.25 (1.16, 1.36) | NA | |||||
| velpatasvir | 1.29 (1.07, 1.56) | 1.93 (1.58, 2.36) | NA | |||||
| voxilaprevir | 4.42 (3.65, 5.35) | 4.31 (3.76, 4.93) | NA | |||||
| Carbamazepine | 300 twice daily | SOF | 400 single dose | 24 | sofosbuvir | 0.52 (0.43, 0.62) | 0.52 (0.46, 0.59) | NA |
| GS-331007 | 1.04 (0.97, 1.11) | 0.99 (0.94, 1.04) | NA | |||||
| Cyclosporine | 600 single dose | SOF | 400 single dose | 19 | sofosbuvir | 2.54 (1.87, 3.45) | 4.53 (3.26, 6.30) | NA |
| GS-331007 | 0.60 (0.53, 0.69) | 1.04 (0.90, 1.20) | NA | |||||
| VEL | 100 single dose | 12 | velpatasvir | 1.56 (1.22, 2.01) | 2.03 (1.51, 2.71) | NA | ||
| VOX | 100 single dose | 25 | voxilaprevir | 19.02 (14.12, 25.62) | 9.39 (7.37, 11.96) | NA | ||
| Darunavir + ritonavir + emtricitabine/ tenofovir DF | 800 + 100 + 200/300 once daily | SOF/VEL/VOX + VOX | 400/100/100 + 100 once daily | 29 | sofosbuvir | 0.70 (0.62, 0.78) | 0.78 (0.73, 0.83) | NA |
| GS-331007 | 1.06 (1.01, 1.10) | 1.15 (1.12, 1.19) | NA | |||||
| velpatasvir | 0.78 (0.73, 0.84) | 0.95 (0.88, 1.02) | 1.16 (1.07, 1.26) |
|||||
| voxilaprevir | 1.72 (1.51, 1.97) | 2.43 (2.15, 2.75) | 4.00 (3.44, 4.65) |
|||||
| Dolutegravir | 50 once daily | SOF/VEL | 400/100 once daily | 24 | sofosbuvir | 0.88 (0.80, 0.98) | 0.92 (0.85, 0.99) | NA |
| GS-331007 | 1.01 (0.93, 1.10) | 0.99 (0.97, 1.01) | 0.99 (0.97, 1.01) |
|||||
| velpatasvir | 0.94 (0.86, 1.02) | 0.91 (0.84, 0.98) | 0.88 (0.82, 0.94) |
|||||
| Efavirenz/emtricitabine/tenofovir DF† | 600/200/300 once daily | SOF/VEL | 400/100 once daily | 14 | sofosbuvir | 1.38 (1.14, 1.67) | 0.97 (0.83, 1.14) | NA |
| GS-331007 | 0.86 (0.80, 0.93) | 0.90 (0.85, 0.96) | 1.01 (0.95, 1.07) |
|||||
| velpatasvir | 0.53 (0.43, 0.64) | 0.47 (0.39, 0.57) | 0.43 (0.36, 0.52) |
|||||
| Elvitegravir/cobicistat/ emtricitabine/tenofovir alafenamide‡ | 150/150/200/ 10 once daily | SOF/VEL/VOX + VOX | 400/100/100 + 100 once daily | 29 | sofosbuvir | 1.27 (1.09, 1.48) | 1.22 (1.12, 1.32) | NA |
| GS-331007 | 1.28 (1.25, 1.32) | 1.43 (1.39, 1.47) | NA | |||||
| velpatasvir | 0.96 (0.89, 1.04) | 1.16 (1.06, 1.27) | 1.46 (1.30, 1.64) |
|||||
| voxilaprevir | 1.92 (1.63, 2.26) | 2.71 (2.30, 3.19) | 4.50 (3.68, 5.50) |
|||||
| Ketoconazole | 200 twice daily | VEL | 100 single dose | 12 | velpatasvir | 1.29 (1.02, 1.64) | 1.71 (1.35, 2.18) | NA |
| Methadone | 30 to 130 daily | SOF | 400 once daily | 14 | sofosbuvir | 0.95 (0.68, 1.33) | 1.30 (1.00, 1.69) | NA |
| GS-331007 | 0.73 (0.65, 0.83) | 1.04 (0.89, 1.22) | NA | |||||
| Omeprazole | 20 once daily 2 hours prior to VOSEVI | SOF/VEL/VOX | 400/100/100 single dose | 34 | sofosbuvir | 0.77 (0.65, 0.91) | 0.73 (0.67, 0.79) | NA |
| GS-331007 | 1.27 (1.20, 1.34) | 0.97 (0.94, 1.01) | NA | |||||
| velpatasvir | 0.43 (0.38, 0.49) | 0.46 (0.41, 0.52) | NA | |||||
| voxilaprevir | 0.76 (0.69, 0.85) | 0.80 (0.74, 0.87) | NA | |||||
| 20 once daily 4 hours after VOSEVI | SOF/VEL/ VOX | 400/100/100 single dose | 34 | sofosbuvir | 0.94 (0.83, 1.06) | 0.82 (0.77, 0.87) | NA | |
| GS-331007 | 1.19 (1.13, 1.26) | 0.99 (0.97, 1.01) | NA | |||||
| velpatasvir | 0.49 (0.43, 0.55) | 0.49 (0.43, 0.55) | NA | |||||
| voxilaprevir | 1.08 (0.96, 1.22) | 0.95 (0.88, 1.03) | NA | |||||
| Rifabutin | 300 once daily | SOF | 400 single dose | 20 | Sofosbuvir | 0.64 (0.53, 0.77) | 0.76 (0.63, 0.91) | NA |
| GS-331007 | 1.15 (1.03, 1.27) | 1.03 (0.95, 1.12) | NA | |||||
| Rifampin | 600 once daily | SOF | 400 single dose | 17 | sofosbuvir | 0.23 (0.19, 0.29) | 0.28 (0.24, 0.32) | NA |
| GS-331007 | 1.23 (1.14, 1.34) | 0.95 (0.88, 1.03) | NA | |||||
| VEL | 100 single dose | 12 | velpatasvir | 0.29 (0.23, 0.37) | 0.18 (0.15, 0.22) | NA | ||
| VOX | 100 single dose | 24 | voxilaprevir | 0.91 (0.76, 1.10) | 0.27 (0.23, 0.31) | NA | ||
| 600 single dose | VEL | 100 single dose | 12 | velpatasvir | 1.28 (1.05, 1.56) | 1.46 (1.17, 1.83) | NA | |
| VOX | 100 single dose | 24 | voxilaprevir | 11.10 (8.23, 14.98) | 7.91 (6.20, 10.09) | NA | ||
| Tacrolimus | 5 single dose | SOF | 400 single dose | 16 | sofosbuvir | 0.97 (0.65, 1.43) | 1.13 (0.81, 1.57) | NA |
| GS-331007 | 0.97 (0.83, 1.14) | 1.00 (0.87, 1.13) | NA | |||||
| Voriconazole | 200 twice daily | VOX | 100 single dose | 24 | voxilaprevir | 1.13 (0.98, 1.31) | 1.84 (1.66, 2.03) | NA |
No effect on the pharmacokinetic parameters of sofosbuvir, GS-331007, velpatasvir, or voxilaprevir was observed with the combination of emtricitabine, rilpivirine, and tenofovir alafenamide; famotidine; gemfibrozil; or the combination of raltegravir, emtricitabine, and tenofovir DF.
| Coadministered Drug | Sofosbuvir (SOF)/ Velpatasvir (VEL)/Voxilaprevir (VOX) | N | Geometric Mean Ratio (90% CI) of Coadministered Drug PK With/Without Sofosbuvir, Velpatasvir, Voxilaprevir, or VOSEVI No Effect=1.00 |
||||
|---|---|---|---|---|---|---|---|
| Drug | Dosage (mg) | Active Component | Dosage (mg) |
||||
| Cmax | AUC | Cmin | |||||
| NA = not available/not applicable. | |||||||
|
|||||||
| Atorvastatin | 40 single dose | SOF/VEL | 400/100 once daily | 26 | 1.68 (1.49, 1.89) | 1.54 (1.45, 1.64) | NA |
| Cyclosporine | 600 single dose | SOF | 400 single dose | 19 | 1.06 (0.94, 1.18) | 0.98 (0.85, 1.14) | NA |
| VEL | 100 single dose | 12 | 0.92 (0.82, 1.02) | 0.88 (0.78, 1.00) | NA | ||
| VOX | 100 single dose | 24 | 0.95 (0.88, 1.03) | 0.94 (0.84, 1.06) | NA | ||
| Dabigatran etexilate | 75 single dose | SOF/VEL/VOX + VOX | 400/100/100 + 100 once daily | 36 | 2.87 (2.61, 3.15) | 2.61 (2.41, 2.82) | NA |
| Darunavir + ritonavir + emtricitabine/tenofovir DF† | darunavir 800 once daily | SOF/VEL/VOX + VOX | 400/100/100 + 100 once daily | 29 | 0.89 (0.85, 0.94) | 0.86 (0.81, 0.91) | 0.66 (0.58, 0.74) |
| ritonavir 100 once daily | 1.60 (1.47, 1.75) | 1.45 (1.35, 1.57) | 0.80 (0.72, 0.89) |
||||
| emtricitabine 200 once daily | 0.88 (0.82, 0.94) | 0.99 (0.96, 1.03) | 1.20 (1.15, 1.26) |
||||
| tenofovir DF 300 once daily | 1.48 (1.36, 1.61) | 1.39 (1.32, 1.46) | 1.47 (1.38, 1.56) |
||||
| Digoxin | 0.25 single dose | VEL | 100 once daily | 21 | 1.88 (1.71, 2.08) | 1.34 (1.13, 1.60) | NA |
| Efavirenz/emtricitabine/tenofovir DF‡ | efavirenz 600 once daily | SOF/VEL | 400/100 once daily | 15 | 0.81 (0.74, 0.89) | 0.85 (0.80, 0.91) | 0.90 (0.85, 0.95) |
| emtricitabine 200 once daily | 1.07 (0.98, 1.18) | 1.07 (1.00, 1.14) | 1.10 (0.97, 1.25) |
||||
| tenofovir DF 300 once daily | 1.77 (1.53, 2.04) | 1.81 (1.68, 1.94) | 2.21 (2.00, 2.43) |
||||
| Elvitegravir/cobicistat/ emtricitabine/tenofovir alafenamide§ | elvitegravir 150 once daily | SOF/VEL/VOX + VOX | 400/100/100 + 100 once daily | 29 | 0.79 (0.75, 0.85) | 0.94 (0.88, 1.00) | 1.32 (1.17, 1.49) |
| cobicistat 150 once daily | 1.23 (1.18, 1.28) | 1.50 (1.44, 1.58) | 3.50 (3.01, 4.07) |
||||
| emtricitabine 200 once daily | 0.87 (0.84, 0.91) | 0.96 (0.94, 0.99) | 1.14 (1.09, 1.20) |
||||
| tenofovir alafenamide 10 once daily | 0.79 (0.68, 0.92) | 0.93 (0.85, 1.01) | NA | ||||
| Emtricitabine/rilpivirine/tenofovir alafenamide¶ | emtricitabine 200 once daily | SOF/VEL/VOX + VOX | 400/100/100 + 100 once daily | 30 | 0.88 (0.83, 0.93) | 0.93 (0.90, 0.96) | 1.07 (1.01, 1.14) |
| rilpivirine 25 once daily | 0.79 (0.74, 0.84) | 0.80 (0.76, 0.85) | 0.82 (0.77, 0.87) |
||||
| tenofovir alafenamide 25 once daily | 1.32 (1.17, 1.48) | 1.52 (1.43, 1.61) | NA | ||||
| Pravastatin | 40 single dose | SOF/VEL/VOX + VOX | 400/100/100 + 100 once daily | 19 | 1.89 (1.53, 2.34) | 2.16 (1.79, 2.60) | NA |
| Rosuvastatin | 10 single dose | SOF/VEL/VOX + VOX | 400/100/100 + 100 once daily | 19 | 18.88 (16.23, 21.96) | 7.39 (6.68, 8.18) | NA |
| Raltegravir + emtricitabine/tenofovir DF | emtricitabine 200 once daily | SOF/VEL | 400/100 once daily | 30 | 1.08 (1.04, 1.12) | 1.05 (1.03, 1.07) | 1.02 (0.97, 1.08) |
| tenofovir DF 300 once daily | 1.46 (1.39, 1.54) | 1.40 (1.34, 1.45) | 1.70 (1.61, 1.79) |
||||
| raltegravir 400 twice daily | 1.03 (0.74, 1.43) | 0.97 (0.73, 1.28) | 0.79 (0.42, 1.48) |
||||
| Tacrolimus | 5 single dose | SOF | 400 once daily | 16 | 0.73 (0.59, 0.90) | 1.09 (0.84, 1.40) | NA |
No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with VOSEVI (ethinyl estradiol/norgestimate) or its components sofosbuvir/velpatasvir (dolutegravir) or sofosbuvir (methadone).
13. Nonclinical Toxicology
14. Clinical Studies
14.1 Description of Clinical Trials
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-1*
(NCT02607735) | Genotype 1, 2, 3, 4, 5, or 6 NS5A inhibitor-experienced†, without cirrhosis or with compensated cirrhosis | VOSEVI 12 weeks (263) Placebo 12 weeks (152) |
| POLARIS-4‡
(NCT02639247) | Genotype 1, 2, 3, or 4 DAA-experienced§ 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.
14.2 Clinical Trials in HCV DAA-Experienced Subjects
NS5A Inhibitor-Experienced Adults Without Cirrhosis or With Compensated Cirrhosis (POLARIS-1)
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)* (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) | Total† (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 |
| Relapse‡ | 2% (6/261) | 1% (1/100) | 0/45 | 1% (1/149) | 0/5 | 5% (4/78) | 5% (1/21) | 0/1 | 0/6 |
| Other§ | 1% (3/263) | 2% (2/101) | 0/45 | 1% (2/150) | 0/5 | 0/78 | 5% (1/22) | 0/1 | 0/6 |
DAA-Experienced Adults Without Cirrhosis or With Compensated Cirrhosis Who Had Not Received An NS5A Inhibitor (POLARIS-4)
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) |
| Relapse* | 1% (1/139) | 10% (13/124) |
| Other† | 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.
16. How is Vosevi supplied
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 "" on the other side. Each bottle contains 28 tablets (NDC 61958-2401-1), polyester coil, silica gel desiccant, and is closed with a child-resistant closure.
17. Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information).
| This Patient Information has been approved by the U.S. Food and Drug Administration. | Revised: 11/2019 | ||
| Patient Information VOSEVI® (voh-SEV-ee) (sofosbuvir, velpatasvir, and voxilaprevir) tablets |
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| What is the most important information I should know about VOSEVI?
VOSEVI can cause serious side effects, including, Hepatitis B virus reactivation: Before starting treatment with VOSEVI, your healthcare provider will do blood tests to check for hepatitis B virus infection. If you have ever had hepatitis B virus infection, the hepatitis B virus could become active again during or after treatment of hepatitis C virus with VOSEVI. Hepatitis B virus becoming active again (called reactivation) may cause serious liver problems including liver failure and death. Your healthcare provider will monitor you if you are at risk for hepatitis B virus reactivation during treatment and after you stop taking VOSEVI. For more information about side effects, see the section "What are the possible side effects of VOSEVI?" |
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| What is VOSEVI?
VOSEVI is a prescription medicine used to treat adults with chronic (lasting a long time) hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis who have:
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| Do not take VOSEVI: if you also take any medicines that contain rifampin (Rifater®, Rifamate®, Rimactane®, Rifadin®) | |||
Before taking VOSEVI, tell your healthcare provider about all your medical conditions, including if you:
Keep a list of your medicines to show your healthcare provider and pharmacist.
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How should I take VOSEVI?
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| What are the possible side effects of VOSEVI? VOSEVI may cause serious side effects, including:
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Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. |
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How should I store VOSEVI?
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| General information about the safe and effective use of VOSEVI
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use VOSEVI for a condition for which it was not prescribed. Do not give VOSEVI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VOSEVI that is written for health professionals. |
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| What are the ingredients in VOSEVI? Active ingredients: sofosbuvir, velpatasvir, and voxilaprevir Inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablet film-coat contains: ferrosoferric oxide, iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Manufactured and distributed by: Gilead Sciences, Inc., Foster City, CA 94404 For more information, call 1-800-445-3235 or go to www.VOSEVI.com. VOSEVI is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners. ©2019 Gilead Sciences, Inc. All rights reserved. 209195-GS-003 |
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| VOSEVI
sofosbuvir, velpatasvir, and voxilaprevir tablet, film coated |
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| Labeler - Gilead Sciences, Inc. (185049848) |
