Vosevi

You should not use this medicine if you also use rifampin, or if you are allergic to sofosbuvir, velpatasvir, or voxilaprevir.

To make sure this medicine is safe for you, tell your doctor if you have ever had:

• hepatitis B;

• liver problems other than hepatitis;

• kidney disease (or if you are on dialysis); or

• if you have recently used a heart rhythm medicine called amiodarone (Cordarone, Pacerone).

It is not known whether sofosbuvir, velpatasvir, and voxilaprevir will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether sofosbuvir, velpatasvir, and voxilaprevir passes into breast milk or if it could affect the nursing baby. Tell your doctor if you are breast-feeding.

This medicine is usually taken once per day for 12 weeks. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Take this medicine with food, at the same time each day.

You will need frequent blood tests to check your liver function.

Hepatitis C is often treated with a combination of drugs. Use all medications as directed by your doctor. Read all patient information, medication guides, and instruction sheets provided to you. Do not change your doses or medication schedule without your doctor's advice. Every person with chronic hepatitis C should remain under the care of a doctor.

You should not stop using this medicine suddenly. Stopping suddenly could make your condition harder to treat with hepatitis C antiviral medicine.

If you have ever had hepatitis B, this medicine can cause the condition to come back or get worse. You will need liver function tests during treatment and for several months after you stop using sofosbuvir, velpatasvir, and voxilaprevir.

Store this medicine in the original container at room temperature away from moisture and heat.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have new or worsening symptoms such as:

• loss of appetite, upper stomach pain;

• dark urine, clay-colored stools; or

• jaundice (yellowing of the skin or eyes).

If you also take amiodarone: Seek medical help right away if you feel weak, tired, or light-headed, or if you have chest pain, shortness of breath, confusion, or memory problems.

Common side effects may include:

• headache;

• feeling tired; or

• nausea, diarrhea.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In the U.S.

• Vosevi

Available Dosage Forms:

• Tablet

Therapeutic Class: Antiviral

Pharmacologic Class: Hepatitis C Virus NS5A Inhibitor

Sofosbuvir, velpatasvir, and voxilaprevir combination is used to treat chronic hepatitis C infection in adults (with or without cirrhosis) who have been previously treated with other medicines.

This medicine is available only with your doctor's prescription.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Vosevi, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Vosevi. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Vosevi.

Review Date: October 4, 2017

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.

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)].

Risk of Reduced Therapeutic Effect Due to Concomitant Use of Vosevi with Inducers of P-gp and/or Moderate to Potent Inducers of CYP

Drugs that are inducers of P-gp and/or moderate to potent 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)].

The following serious adverse reactions are described below and elsewhere in labeling:

• Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see Warnings and Precautions (5.2)].

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.

In POLARIS-1, of the subjects receiving Vosevi who experienced adverse reactions, 99% were mild or moderate (Grade 1 or 2) in severity. In POLARIS-4, of the subjects receiving Vosevi who experienced adverse reactions, all the reported adverse reactions were mild or moderate (Grade 1 or 2) in severity.

Less Common Adverse Reactions Reported in Clinical Trials

The following adverse reactions occurred in less than 5% of subjects without cirrhosis or with compensated cirrhosis treated with Vosevi for 12 weeks and are included because of a potential causal relationship.

Rash: In the POLARIS-1 and POLARIS-4 trials, rash occurred in less than 1% and 2% of subjects treated with Vosevi, respectively. Rash was reported in 1% of subjects treated with placebo in POLARIS-1, and was not reported by any subject taking sofosbuvir/velpatasvir in POLARIS-4. No serious adverse reactions of rash occurred and all rashes were mild or moderate in severity.

Depression: In the POLARIS-1 and POLARIS-4 trials, depressed mood occurred in less than 1% and 1% of subjects treated with Vosevi, respectively. Depressed mood was not reported by any subject taking placebo in POLARIS-1 and was reported in 1% of subjects treated with sofosbuvir/velpatasvir in POLARIS-4. No serious adverse reactions of depressed mood occurred and all events were mild or moderate in severity.

Laboratory Abnormalities

Lipase Elevations: Isolated, asymptomatic lipase elevations of greater than 3×ULN were observed in POLARIS-1 in 2% of subjects treated with Vosevi and 3% of subjects treated with placebo, and in POLARIS-4 in 2% of subjects treated with Vosevi and less than 1% of subjects treated with sofosbuvir/velpatasvir.

Creatine Kinase: Isolated, asymptomatic creatine kinase elevations greater than or equal to 10×ULN were reported in POLARIS-1 in 1% of subjects treated with Vosevi and 1% of subjects treated with placebo, and in POLARIS-4 in less than 1% of subjects treated with Vosevi and no subjects treated with sofosbuvir/velpatasvir.

Total bilirubin: Increases in total bilirubin less than or equal to 1.5×ULN were observed in subjects treated with Vosevi due to inhibition of OATP1B1 and OATP1B3 by voxilaprevir: 4% and 6% of subjects without cirrhosis in POLARIS-1 and POLARIS-4, respectively; and 7% and 13% of subjects with compensated cirrhosis in POLARIS-1 and POLARIS-4, respectively. No subjects experienced jaundice and total bilirubin levels decreased after completing Vosevi treatment.

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.

Cardiac Disorders

Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiated treatment with a sofosbuvir-containing regimen [see Warnings and Precautions (5.2) and Drug Interactions (7.3)].

Skin and Subcutaneous Tissue Disorders

Skin rashes, sometimes with blisters or angioedema-like swelling

Angioedema

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 potent 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 (5.3) 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)].

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)].

Established and Potentially Significant Drug Interactions

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 (5.2, 5.3), and Clinical Pharmacology (12.3)].

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

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)].

Pharmacodynamics

Cardiac Electrophysiology

The effect of sofosbuvir 400 mg (recommended dosage) and 1200 mg (3 times the recommended dosage) on QTc interval was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT trial. At a dose 3 times the recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent.

The effect of velpatasvir 500 mg (5 times the recommended dosage) was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT trial. At a dose 5 times the recommended dose, velpatasvir does not prolong QTc interval to any clinically relevant extent.

The effect of voxilaprevir 900 mg (9 times the recommended dosage) was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT trial. At a dose 9 times the recommended dose, voxilaprevir does not prolong QTc interval to any clinically relevant extent.

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 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

Pediatric Patients: The pharmacokinetics of Vosevi in pediatric patients has not been established [see Use in Specific Populations (8.4)].

Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 85 years) analyzed, age did not have a clinically relevant effect on the exposure to sofosbuvir, GS-331007, velpatasvir, or voxilaprevir [see Use in Specific Populations (8.5)].

Patients with Renal Impairment:

The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild (eGFR between 50 to less than 80 mL/min/1.73 m2), moderate (eGFR between 30 to less than 50 mL/min/1.73 m2), severe renal impairment (eGFR less than 30 mL/min/1.73 m2), and subjects with ESRD requiring hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR greater than 80 mL/min/1.73 m2), the sofosbuvir AUC0–inf was 61%, 107%, and 171% higher in subjects with mild, moderate, and severe renal impairment, while the GS-331007 AUC0–inf was 55%, 88%, and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC0–inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4-hour hemodialysis session removed approximately 18% of administered dose of sofosbuvir [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].

The pharmacokinetics of velpatasvir were studied with a single dose of 100 mg velpatasvir in HCV negative subjects with severe renal impairment (eGFR less than 30 mL/min by Cockcroft-Gault). No clinically relevant differences in velpatasvir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.

The pharmacokinetics of voxilaprevir were studied with a single dose of 100 mg voxilaprevir in HCV negative subjects with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault). No clinically relevant differences in voxilaprevir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.

Patients with Hepatic Impairment:

The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC0–24 was 126% and 143% higher in subjects with moderate and severe hepatic impairment, respectively, while the GS-331007 AUC0–24 was 18% and 9% higher, respectively. Population pharmacokinetic analysis in HCV-infected subjects indicated that compensated cirrhosis (Child-Pugh A) had no clinically relevant effect on the exposure of sofosbuvir and GS-331007.

The pharmacokinetics of velpatasvir were studied with a single dose of 100 mg velpatasvir in HCV-negative subjects with moderate and severe hepatic impairment (Child-Pugh B and C). Velpatasvir plasma exposure (AUCinf) was similar in subjects with moderate hepatic impairment, severe hepatic impairment, and control subjects with normal hepatic function. Population pharmacokinetic analysis in HCV-infected subjects indicated that compensated cirrhosis (Child-Pugh A) had no clinically relevant effect on the exposure of velpatasvir.

The pharmacokinetics of voxilaprevir were studied with a single dose of 100 mg voxilaprevir in HCV-negative subjects with moderate and severe hepatic impairment (Child-Pugh B and C). Relative to subjects with normal hepatic function, the voxilaprevir AUCinf was 299% and 500% higher in subjects with moderate and severe hepatic impairment, respectively. Population pharmacokinetic analysis in HCV-infected subjects indicated that subjects with compensated cirrhosis (Child-Pugh A) had 73% higher exposure of voxilaprevir than those without cirrhosis [see Dosage and Administration (2.4) and Use in Specific Populations (8.7)].

Race and Gender: Population pharmacokinetics analysis in HCV-infected subjects indicated that race and gender had no clinically relevant effect on the exposure of sofosbuvir, GS-331007, velpatasvir, or voxilaprevir.

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 potent 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 (5.3), 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.

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.

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).

Microbiology

Mechanism of Action

Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a, and 4a with an IC50 value ranging from 0.36 to 3.3 µM. GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.

Velpatasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication. Resistance selection in cell culture and cross-resistance studies indicate velpatasvir targets NS5A as its mode of action.

Voxilaprevir is a noncovalent, reversible inhibitor of the NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical inhibition assay, voxilaprevir inhibited the proteolytic activity of recombinant NS3/4A enzymes from clinical isolates of HCV genotypes 1b and 3a with Ki values of 38 and 66 pM, respectively.

Antiviral Activity

In HCV replicon assays, sofosbuvir had median EC50 values of 15–110 nM against full-length or chimeric laboratory isolates and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 5a, and 6a. Velpatasvir had median EC50 values of 0.002–0.13 nM against full-length or chimeric laboratory isolates and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 4r, 5a, 6a, and 6e. Voxilaprevir had median EC50 values of 0.2–6.6 nM against full-length or chimeric laboratory isolates and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 4r, 5a, 6a, 6e, and 6n.

Evaluation of sofosbuvir in combination with velpatasvir or voxilaprevir, as well as the combination of velpatasvir and voxilaprevir, showed no antagonistic effect in reducing HCV RNA levels in replicon cells.

Resistance

In Cell Culture

HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with the nucleotide analog NS5B polymerase inhibitor resistance substitution, S282T, in all replicon genotypes examined. An M289L substitution emerged along with the S282T substitution in genotypes 2a, 5 and 6 replicons. Site-directed mutagenesis of the S282T substitution in replicons of genotype 1 to 6 conferred 2- to 18-fold reduced susceptibility to sofosbuvir.

HCV genotype 1a, 1b, 2a, 3a, 4a, 5a, and 6a replicon variants with reduced susceptibility to velpatasvir were selected in cell culture. The replicon variants developed amino acid substitutions at NS5A inhibitor resistance-associated positions 24, 28, 30, 31, 32, 58, 92, and 93. Phenotypic analysis of site-directed mutant replicons of the selected NS5A substitutions showed that single Y93H/N and the combination of L31V + Y93H/N in genotype 1a, the combination of L31V + Y93H in genotype 1b, the single substitution Y93H/S in genotype 3a, and single substitutions L31V and P32A/L/Q/R in genotype 6 conferred greater than 100-fold reduction in velpatasvir susceptibility. In the genotype 2a replicon, the single substitutions F28S and Y93H showed 91-fold and 46-fold reduced susceptibility to velpatasvir, respectively. The single substitution Y93H conferred 3-fold reduced susceptibility to velpatasvir in genotype 4a replicons. Combinations of these NS5A substitutions often showed greater reductions in susceptibility to velpatasvir than single substitutions alone.

HCV genotype 1a, 1b, 2a, 3a, 4a, 5a, and 6a replicon variants with reduced susceptibility to voxilaprevir were selected in cell culture. Amino acid substitutions were selected at NS3/4A protease inhibitor resistance-associated positions 41, 156, and 168. Site-directed mutagenesis of NS3 resistance-associated substitutions showed that substitutions conferring a greater than 100-fold reduction in voxilaprevir susceptibility were A156L/T in genotype 1a, A156T/V in genotype 1b, A156L/V in genotype 2a, A156T/V in genotype 3a, and A156L/T/V in genotype 4. Combinations of these NS3 substitutions often showed greater reductions in susceptibility to voxilaprevir than single substitutions alone.

In Clinical Trials

Of the 263 NS5A inhibitor-experienced subjects treated with Vosevi for 12 weeks in POLARIS-1, 7 of 263 (3%) subjects (2 with genotype 1a, 4 with genotype 3a, and 1 with genotype 4d) did not achieve SVR12 and qualified for resistance analysis; 6 relapsed and 1 experienced virologic breakthrough. All the virologic failures had cirrhosis and all had a previous DAA regimen containing sofosbuvir; 3 were previously treated with ledipasvir/sofosbuvir, 2 were previously treated with sofosbuvir/velpatasvir, and 2 were previously treated with daclatasvir and sofosbuvir. Six of the 7 virologic failures had baseline NS5A inhibitor resistance-associated substitutions at position 30 or 93. All 7 virologic failures had NS5A resistance-associated substitutions at failure using a sensitivity threshold of 1% of the viral population.

Of the 2 genotype 1a virologic failure subjects, one subject with virologic breakthrough at Week 12 had virus with the NS5A resistance-associated substitution Q30T at baseline and failure and emergent NS5A resistance-associated substitutions L31M and Y93H at breakthrough; the other subject had virus with the NS5A resistance-associated substitution Y93N at baseline and relapse and emergence of low-level K24R (1.2%) in NS5A and V36A (2%) in NS3 at relapse.

Of the 4 genotype 3a virologic failure subjects, one subject had virus with emergent NS5A resistance-associated substitution E92K. Two subjects had virus with Y93H at relapse that was enriched from baseline. The remaining subject had virus with the NS5A resistance-associated substitution A30K at baseline and relapse and emergence of low-level Q41K (2%), V55A (3%) and R155M (1%) substitutions in NS3 at relapse.

The genotype 4d subject who relapsed had virus with emergent NS5A resistance-associated substitution Y93H.

No NS5B nucleotide analog inhibitor resistance-associated substitutions emerged among the virologic failure subjects from POLARIS-1.

In POLARIS-4, of the 182 DAA-experienced subjects who had not received an NS5A inhibitor treated with Vosevi for 12 weeks, 1 subject (genotype 1a) of 182 (1%) subjects relapsed and qualified for resistance analysis. The NS5A resistance-associated substitution M28T (7.5%) emerged in this subject at relapse. No NS3/4A protease inhibitor or nucleotide analog NS5B inhibitor substitutions were observed in this subject at relapse.

Persistence of Resistance-Associated Substitutions

No data are available on the persistence of sofosbuvir, velpatasvir or voxilaprevir resistance-associated substitutions. NS5A inhibitor resistance-associated substitutions observed with administration of other NS5A inhibitors have been found to persist for longer than 1 year in most patients. The long-term clinical impact of the emergence or persistence of virus containing sofosbuvir, velpatasvir, or voxilaprevir resistance-associated substitutions is unknown.

Effect of Baseline HCV Variants on Treatment Response

Analyses were conducted to explore the association between SVR12 rates and preexisting baseline NS3/4A protease inhibitor and NS5A inhibitor resistance-associated substitutions for subjects in POLARIS-1 and POLARIS-4. Amino acid positions considered in resistance analyses included NS3 positions 36, 41, 43, 54, 55, 56, 155, 156, and 168, and NS5A positions 24, 28, 30, 31, 58, 92, or 93. Baseline resistance-associated amino acid substitutions, which may include natural polymorphisms or prior treatment-emergent substitutions relative to subtype-specific references, were identified by next generation sequencing analysis using a sensitivity threshold of 15% of the viral population.

Overall, the presence of baseline NS3/4A protease inhibitor, NS5A inhibitor, and nucleotide analog NS5B polymerase inhibitor resistance-associated substitutions did not alter the SVR rates for DAA-experienced subjects in the POLARIS-1 and POLARIS-4 trials who received 12 weeks of Vosevi. For subjects treated with Vosevi for 12 weeks, SVR12 rates in subjects with or without baseline NS3 and NS5A resistance-associated substitutions in the POLARIS-1 and POLARIS-4 trials were all greater than or equal to 97%.

In POLARIS 1, which included NS5A inhibitor-experienced subjects, 79% (206/260) of subjects had baseline NS5A resistance-associated substitutions across all genotypes. The most prevalent NS5A resistance-associated substitutions were at primary resistance-associated amino acid positions 30 (97/206; 47%), 31 (58/206; 28%) and 93 (103/206; 50%). Fifty-five percent (n=113/206) of the subjects had a single NS5A resistance-associated substitution, while 2 resistance-associated substitutions were detected in 65/206 subjects (32%) and 3 or more were detected in 28/206 subjects (14%). Overall prevalence of NS3/4A protease inhibitor resistance-associated substitutions across all genotypes was 15% (37/248). The most prevalent NS3 resistance-associated substitutions were at positions 36 (5/17; 29%) and 168 (7/17; 41%) in genotype 1a and position 56 in genotype 1b (8/12; 67%). Substitutions at positions 36, 56, or 168 were detected in 1–2 subjects for each genotype 2, 3 or 4.

In POLARIS-4, which included DAA-experienced subjects who had not received an NS5A inhibitor, 32% (57/177) of subjects who received 12 weeks of Vosevi had baseline NS5A inhibitor resistance-associated substitutions. Most of the subjects had a single NS5A resistance-associated substitution (n=40; 70%). The most prevalent NS5A resistance-associated substitution was at amino acid position 31 (n=27; 47%). Overall prevalence of baseline NS3/4A protease inhibitor resistance-associated substitutions was 12% (21/169). The most prevalent NS3 resistance-associated substitutions were at positions 55 (5/10) and 168 (3/10) in genotype 1a, position 56 in genotype 1b (3/5) and genotype 2 (3/3), and at position 168 in genotype 4 (3/3).

SVR12 was achieved in 18 of 19 (95%) subjects who had baseline nucleotide analog NS5B polymerase inhibitor resistance-associated substitutions in POLARIS-1, including 2 subjects who had virus with the S282T nucleotide analog NS5B polymerase inhibitor resistance-associated substitution in addition to NS5A resistance-associated substitutions at baseline. In POLARIS-4, a total of 14 subjects had virus with nucleotide analog NS5B polymerase inhibitor resistance-associated substitutions at baseline and all achieved SVR12.

Cross Resistance

Cross-resistance is possible between HCV NS3/4A protease inhibitors and between HCV NS5A inhibitors by class. Sofosbuvir, velpatasvir, and voxilaprevir were each active against substitutions associated with resistance to other classes of DAAs with different mechanisms of actions (e.g., voxilaprevir was fully active against virus with NS5A resistance-associated substitutions and nucleotide analog NS5B inhibitor resistance-associated substitutions).

NDC 61958-2401-1
28 tablets

Vosevi™
(sofosbuvir, velpatasvir,
and voxilaprevir) tablets
400 mg / 100 mg / 100 mg

Take 1 tablet once daily

Note to pharmacist:
Do not cover ALERT box with pharmacy label.

ALERT: Find out about medicines that
should NOT be taken with Vosevi

If you have ever had hepatitis B, Vosevi can cause the condition to come back or get worse. You will need frequent blood tests to check your liver function.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Sometimes it is not safe to use certain medications at the same time. Some drugs can affect your blood levels of other drugs you take, which may increase side effects or make the medications less effective.

Other drugs may interact with sofosbuvir, velpatasvir, and voxilaprevir, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all your current medicines and any medicine you start or stop using.