DRUG INTERACTIONS

P-gp inducers and/or moderate to potent CYP inducers (e.g., St. John’s wort, carbamazepine):

May decrease concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir.                     Use of VOSEVI with Pgp inducers and/or moderate to potent CYP inducers is not recommended.

Consult the full prescribing information prior to use for potential drug interactions.

U.S. FDA APPROVED  DRUGS DURING 2017

ADVERSE REACTIONS

 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. 

CONTRAINDICATIONS

 Coadministration with rifampin. 

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 followup. Initiate appropriate patient management for HBV infection as clinically indicated.

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. 

DOSAGE FORMS AND STRENGTHS

 Tablets: 400 mg sofosbuvir, 100 mg velpatasvir, and 100 mg voxilaprevir 

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 followup. Initiate appropriate patient management for HBV infection as clinically indicated. (5.1) ? 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. (5.2, 7.3)

-------------------------------ADVERSE REACTIONS----------------------------- ? 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 potent CYP inducers (e.g., St. John’s wort, carbamazepine): May decrease concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir. Use of VOSEVI with Pgp inducers and/or moderate to potent CYP inducers is not recommended (5.3, 7) ? Consult the full prescribing information prior to use for potential drug interactions (4, 5.2, 5.3, 7) See 17 for

PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 07/2017 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Testing Prior to Initiation of Therapy 2.2 Recommended Dosage 2.3 No Dosage Recommendations in Severe Renal Impairment and End Stage Renal Disease 2.4 Moderate or Severe Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV 5.2 Serious Symptomatic Bradycardia When Coadministered with Amiodarone 5.3 Risk of Reduced Therapeutic Effect Due to Concomitant Use of VOSEVI with Inducers of P-gp and/or Moderate to Potent Inducers of CYP 6

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information). 

Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV      Inform patients that HBV reactivation can occur in patients coinfected with HBV during or after treatment of HCV virus infection.

Advise patients to tell their healthcare provider if they have a history of hepatitis B infection

Serious Symptomatic Bradycardia-                                                                                When Coadministered with Amiodarone Advise patients to seek medical evaluation immediately for symptoms of bradycardia such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems.

Adverse Reactions, and Drug Interactions.

Drug Interactions -                                                                                                     Inform patients that VOSEVI may interact with other drugs.                                            Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products including St. John’s wort..

Administration                                                                                                               Advise patients to take VOSEVI once daily on a regular dosing schedule with food. Inform patients that it is important not to miss or skip doses and to take VOSEVI for the duration that is recommended by the physician.

Manufactured and distributed by:Gilead Sciences, Inc. Foster City, CA 94404 VOSEVI, GENVOYA, HARVONI, and ODEFSEY are trademarks of Gilead Science

CLINICAL PHARMACOLOGY

1. Mechanism of Action                                                                                              VOSEVI is a fixed-dose combination of sofosbuvir, velpatasvir, and voxilaprevir which are DAA agents against the hepatitis C.

2.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. 

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. Table 4 Pharmacokinetic Properties of the Components of VOSEVI Sofosbuvir Velpatasvir Voxilaprevir 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

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary

No adequate human data are available to establish whether or not VOSEVI poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of VOSEVI (sofosbuvir, velpatasvir, or voxilaprevir) at exposures greater than those in humans at the recommended human dose (RHD) 

The background risk of major birth defects and miscarriage for the indicated population is unknown.                                                                                                                            In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively..

2. Lactation Risk Summary

It is not known whether the components of VOSEVI and its metabolites are present in human breast milk, affect human milk production, or have effects on the breastfed infant. When the components of VOSEVI were administered to lactating rats, GS331007 (the predominant circulating metabolite of sofosbuvir) and velpatasvir were detected in milk, while voxilaprevir was detected in the plasma of nursing pups likely due to the presence of voxilaprevir in milk.

3. Pediatric Use-                                                                                                        Safety and effectiveness of VOSEVI have not been established in pediatric patients.

4.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.

5. Renal Impairment-                                                                                                         No dosage adjustment of VOSEVI is required for patients with mild or moderate renal impairment.                                                                                                                      The safety and efficacy of VOSEVI have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2 ) or ESRD requiring hemodialysis. 

6.Hepatic Impairment-                                                                                                    No dosage adjustment of VOSEVI is required 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

7.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