Mavyret

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 MAVYRET [see Warnings and Precautions ( 5.1)].

2.2  Recommended Treatment Duration in Patients 3 Years and Older

Tables 1 and 2 provide the recommended MAVYRET treatment duration based on the patient population in HCV mono-infected and HCV/HIV-1 co-infected patients with compensated liver disease (with or without cirrhosis) and with or without renal impairment including patients receiving dialysis [see Contraindications ( 4) and Clinical Studies ( 14)]. Refer to Drug Interactions ( 7) for dosage recommendations for concomitant HIV-1 antiviral drugs.

2.3  Recommended Dosage in Adults

MAVYRET tablets are a fixed combination drug product containing glecaprevir 100 mg and pibrentasvir 40 mg in each tablet.

The recommended oral dosage of MAVYRET in adults is 3 tablets taken at the same time once daily with food (total daily dose: glecaprevir 300 mg and pibrentasvir 120 mg) [see Clinical Pharmacology ( 12.3)]. 

2.4  Recommended Dosage in Pediatric Patients 3 Years of Age and Older

The recommended dosage of MAVYRET in pediatric patients 3 to less than 12 years of age is based on weight. MAVYRET oral pellets are recommended for pediatric patients 3 to less than 12 years old weighing less than 45 kg. MAVYRET oral pellets in packets are a fixed combination drug product containing glecaprevir 50 mg and pibrentasvir 20 mg in each packet.

The recommended dosage of MAVYRET in pediatric patients 12 years of age and older, or in pediatric patients weighing at least 45 kg, is three tablets taken at the same time once daily with food (total daily dose: glecaprevir 300 mg and pibrentasvir 120 mg).

The dosages for pediatric patients are shown in Table 3.

2.5  Preparation and Administration of Oral Pellets

See the MAVYRET oral pellets full Instructions for Use for details on the preparation and administration.

• The oral pellets should be taken together, with food, once daily. In addition, the oral pellets for the total daily dose should be sprinkled on a small amount of soft food with a low water content that will stick to a spoon and should be swallowed without chewing (e.g., peanut butter, chocolate hazelnut spread, cream cheese, thick jam, or Greek yogurt).
  
• The entire mixture of food and oral pellets should be swallowed within 15 minutes of preparation; the oral pellets should not be crushed or chewed.
  
• Liquids or foods that would drip or slide off the spoon are not recommended as the drug may dissolve quickly and become less effective.

2.6  Liver or Kidney Transplant Recipients

MAVYRET is recommended for 12 weeks in patients 3 years and older who are liver or kidney transplant recipients. A 16-week treatment duration is recommended in genotype 1-infected patients who are NS5A inhibitor-experienced without prior treatment with an NS3/4A protease inhibitor or in genotype 3-infected patients who are PRS treatment-experienced [see Clinical Studies ( 14.8)]. 

2.7  Hepatic Impairment

MAVYRET is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C) or those with any history of prior hepatic decompensation [see Contraindications ( 4), Warnings and Precautions ( 5.2), Use in Specific Populations ( 8.7) and Clinical Pharmacology ( 12.3)]. 

8.1  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 (see Data). No definitive conclusions regarding potential developmental effects of glecaprevir could be made in rabbits, since the highest achieved glecaprevir exposure in this species was only 7% (0.07 times) of the human exposure at the recommended dose. There were no effects with either compound in rodent pre/post-natal developmental studies in which maternal systemic exposures (AUC) to glecaprevir and pibrentasvir were approximately 47 and 74 times, respectively, the exposure in humans at the recommended dose (see Data).

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.

Data

Glecaprevir

Glecaprevir was administered orally to pregnant rats (up to 120 mg/kg/day) and rabbits (up to 60 mg/kg/day) during the period of organogenesis (gestation days (GD) 6 to 18, and GD 7 to 19, respectively). No adverse embryo-fetal effects were observed in rats at dose levels up to 120 mg/kg/day (53 times the exposures in humans at the recommended human dose (RHD)).  In rabbits, the highest glecaprevir exposure achieved was 7% (0.07 times) of the exposure in humans at RHD. As such, data in rabbits during organogenesis are not available for glecaprevir systemic exposures at or above the exposures in humans at the RHD.

In the pre/post-natal developmental study in rats, glecaprevir was administered orally (up to 120 mg/kg/day) from GD 6 to lactation day 20. No effects were observed at maternal exposures 47 times the exposures in humans at the RHD.

Pibrentasvir

Pibrentasvir was administered orally to pregnant mice and rabbits (up to 100 mg/kg/day) during the period of organogenesis (GD 6 to 15, and GD 7 to 19, respectively). No adverse embryo-fetal effects were observed at any studied dose level in either species. The systemic exposures at the highest doses were 51 times (mice) and 1.5 times (rabbits) the exposures in humans at the RHD.

In the pre/post-natal developmental study in mice, pibrentasvir was administered orally (up to 100 mg/kg/day) from GD 6 to lactation day 20. No effects were observed at maternal exposures approximately 74 times the exposures in humans at the RHD.

8.2  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 (see Data).

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.

Data

No significant effects of glecaprevir or pibrentasvir on growth and post-natal development were observed in nursing pups at the highest doses tested (120 mg/kg/day for glecaprevir and 100 mg/kg/day for pibrentasvir). Maternal systemic exposure (AUC) to glecaprevir and pibrentasvir was approximately 47 or 74 times the exposure in humans at the RHD. Systemic exposure in nursing pups on post-natal day 14 was approximately 0.6 to 2.2 % of the maternal exposure for glecaprevir and approximately one quarter to one third of the maternal exposure for pibrentasvir.

Glecaprevir or pibrentasvir was administered (single dose; 5 mg/kg oral) to lactating rats, 8 to 12 days post parturition. Glecaprevir in milk was 13 times lower than in plasma and pibrentasvir in milk was 1.5 times higher than in plasma. Parent drug (glecaprevir or pibrentasvir) represented the majority (>96%) of the total drug-related material in milk.

8.4  Pediatric Use

No dosage adjustment of MAVYRET is required in pediatric patients 12 years and older or weighing at least 45 kg. The recommended dosage of MAVYRET in pediatric patients 3 to less than 12 years of age is based on weight [see Dosage and Administration ( 2.2, 2.4), Clinical Pharmacology ( 12.3) and Clinical Studies ( 14.10)].

The safety, efficacy, and pharmacokinetics of MAVYRET in HCV GT1, 2, 3, or 4 infected pediatric patients 3 years and older is based on data from an open-label trial in 127 subjects without cirrhosis aged 3 years to less than 18 years who were either treatment-naïve (n=114) or treatment-experienced (n=13) and received MAVYRET for 8, 12 or 16 weeks (DORA-Part 1 and Part 2). 

The adverse reactions observed in subjects 3 years to less than 18 years of age were consistent with those observed in clinical trials of MAVYRET in adults with the exception of vomiting, rash and abdominal pain upper which were observed more frequently in pediatric subjects less than 12 years of age compared to adults [see Adverse Reactions ( 6.1)].

The efficacy results observed in this trial were consistent with those observed in clinical trials of MAVYRET in adults [see Clinical Studies ( 14.10)].

In pediatric patients with cirrhosis, history of a kidney and/or liver transplant, or HCV GT5 or 6 infection, the safety and efficacy of MAVYRET are supported by the comparable glecaprevir and pibrentasvir exposures observed between pediatric subjects and adults [see Clinical Pharmacology ( 12.3)].

The safety and effectiveness of MAVYRET in children less than 3 years of age have not been studied.

8.5  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 [see Clinical Pharmacology ( 12.3)].

8.6  Renal Impairment

No dosage adjustment of MAVYRET is required in patients with mild, moderate or severe renal impairment, including those on dialysis [see Clinical Pharmacology ( 12.3) and Clinical Studies ( 14.5)].

8.7  Hepatic Impairment

No dosage adjustment of MAVYRET is required in patients with mild hepatic impairment (Child-Pugh A). MAVYRET has not been evaluated and is contraindicated in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh B or Child-Pugh C) or those with any history of prior hepatic decompensation [see Contraindications ( 4)]. Postmarketing cases of hepatic decompensation/failure have been reported in these patients [see Warnings and Precautions ( 5.2)]. Higher exposures of both glecaprevir and pibrentasvir occur in subjects with severe hepatic impairment (Child-Pugh C) [see Clinical Pharmacology ( 12.3)].

8.8  People Who Inject Drugs (PWID) and those on Medication-Assisted Treatment (MAT) for Opioid Use Disorder

No dosage adjustment of MAVYRET is required in PWID or those who are on MAT for opioid use disorder. In clinical trials of MAVYRET, the safety and efficacy were similar between subjects who self-identified as current/recent PWID, those who were former PWID, and those who did not report history of injection drug use. The safety and efficacy of MAVYRET were also similar between subjects who reported concomitant MAT for opioid use disorder and those who did not report concomitant MAT [see Adverse Reactions ( 6.1), Drug Interactions ( 7.4) and Clinical Studies ( 14.9)].