U.S. FDA APPROVED  DRUGS DURING 2017

 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 infection.

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

Drug Interactions

Inform patients that MAVYRET may interact with some drugs; therefore, patients should be advised to report to their healthcare provider the use of any prescription, non-prescription medication or herbal products .

Administration

Advise patients to take MAVYRET recommended dosage (three tablets) once daily with food as directed.

Inform patients that it is important not to miss or skip doses and to take MAVYRET for the duration that is recommended by the physician [see Dosage and Administration 

If a dose is missed and it is:

• Less than 18 hours from the usual time that MAVYRET should have been taken – advise the patient to take the dose as soon as possible and then to take the next dose at the usual time.

• More than 18 hours from the usual time that MAVYRET should have been taken – advise the patient not to take the missed dose and to take the next dose at the usual time.

Manufactured by AbbVie Inc., North Chicago, IL 60064                                           MAVYRET is a trademark of AbbVie Inc. © 2017 AbbVie Inc. All rights reserved

 CLINICAL PHARMACOLOGY

1.Mechanism of Action Mechanism of Action

MAVYRET is a fixed-dose combination of glecaprevir and pibrentasvir, which are direct-acting antiviral agents against the hepatitis C virus.

2.Pharmacodynamics Cardiac Electrophysiology

The effect of doses up to glecaprevir 600 mg (2 times the recommended dosage) with doses up to pibrentasvir 240 mg (2 times the recommended dosage) on QTc interval was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT study.

At 20-fold of glecaprevir and 5­ fold of pibrentasvir therapeutic concentrations, the glecaprevir and pibrentasvir combination does not prolong the QTc interval to any clinically relevant extent.

3.Pharmacokinetics

The pharmacokinetic properties of the components of MAVYRET in healthy subjects are provided in the published tables.

Specific Populations

Pediatric Patients

The pharmacokinetics of MAVYRET in pediatric patients has not been established.

Subjects with Renal Impairment

Glecaprevir and pibrentasvir AUC were increased = 56% in non-HCV infected subjects with mild, moderate, severe, or end-stage renal impairment (GFR estimated using Modification of Diet in Renal Disease) not on dialysis compared to subjects with normal renal function. Glecaprevir and pibrentasvir AUC were similar with and without dialysis (= 18% difference) in dialysis-dependent non-HCV infected subjects.

In HCV-infected subjects, 86% higher glecaprevir and 54% higher pibrentasvir AUC were observed for subjects with end stage renal disease, with or without dialysis, compared to subjects with normal renal function.

Subjects with Hepatic Impairment -                                                                           Following administration of MAVYRET in HCV infected subjects with compensated cirrhosis (Child-Pugh A), exposure of glecaprevir was approximately 2-fold and pibrentasvir exposure was similar to non-cirrhotic HCV infected subjects.                       

At the clinical dose, compared to non-HCV infected subjects with normal hepatic function, glecaprevir AUC 100% higher in Child-Pugh B subjects, and increased to 11-fold in Child-Pugh C subjects. 

Pibrentasvir AUC was 26% higher in Child-Pugh B subjects, and 114% higher in Child-Pugh C subjects. Age/Gender/Race/Body Weight No clinically significant differences in the pharmacokinetics of glecaprevir or pibrentasvir were observed based on age [18-88 years], sex, race/ethnicity or body weight.

Drug Interaction Studies

Drug interaction studies were performed with glecaprevir/pibrentasvir and other drugs that are likely to be coadministered and with drugs commonly used as probes for pharmacokinetic interactions.

The pharmacokinetic effects when glecaprevir/pibrentasvir was coadministered with other drugs which showed potentially clinically relevant changes. Significant interactions are not expected when MAVYRET is coadministered with substrates of CYP3A, CYP1A2, CYP2C9, CYP2C19, CYP2D6, UGT1A1, or UGT1A4.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary

No adequate human data are available to establish whether or not MAVYRET poses a risk to pregnancy outcomes.

In animal reproduction studies, no adverse developmental effects were observed when the components of MAVYRET were administered separately during organogenesis at exposures up to 53 times (rats; glecaprevir) or 51 and 1.5 times (mice and rabbits, respectively; pibrentasvir) the human exposures at the recommended dose of MAVYRET 

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% to 4% and 15% to 20%, respectively.

2.Lactation Risk Summary

It is not known whether the components of MAVYRET are excreted in human breast milk, affect human milk production, or have effects on the breastfed infant. When administered to lactating rodents, the components of MAVYRET were present in milk, without effect on growth and development observed in the nursing pups 

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MAVYRET and any potential adverse effects on the breastfed child from MAVYRET or from the underlying maternal condition.

3.Pediatric Use

Safety and effectiveness of MAVYRET in children less than 18 years of age have not been established.

4.Geriatric Use

In clinical trials of MAVYRET, 328 subjects were age 65 years and over (14% of the total number of subjects in the Phase 2 and 3 clinical trials) and 47 subjects were age 75 and over (2%).

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 subjects.

No dosage adjustment of MAVYRET is warranted in geriatric patients

5.Renal Impairment

No dosage adjustment of MAVYRET is required in patients with mild, moderate or severe renal impairment, including those on dialysis

6.Hepatic Impairment

No dosage adjustment of MAVYRET is required in patients with mild hepatic impairment (Child-Pugh A). MAVYRET is not recommended in patients with moderate hepatic impairment (Child-Pugh B). Safety and efficacy have not been established in HCV-infected patients with moderate hepatic impairment.

MAVYRET is contraindicated in patients with severe hepatic impairment (Child-Pugh C) due to higher exposures of glecaprevir and pibrentasvir .

 OVERDOSAGE

In case of overdose, the patient should be monitored for any signs and symptoms of toxicities. Appropriate symptomatic treatment should be instituted immediately. Glecaprevir and pibrentasvir are not significantly removed by hemodialysis.