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Glecaprevir And Pibrentasvir

FDA Drug Information • Also known as: Mavyret

Brand Names
Mavyret
Drug Class
Hepatitis C Virus NS3/4A Protease Inhibitor [EPC], Hepatitis C Virus NS5A Inhibitor [EPC]
Route
ORAL
Dosage Form
PELLET
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

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 MAVYRET. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals 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 )] . 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 )

Description

11 DESCRIPTION MAVYRET contains glecaprevir, a HCV NS3/4A PI, and pibrentasvir a HCV NS5A inhibitor. MAVYRET is available as a fixed dose combination tablet or coated pellets in unit-dose packets for oral administration. Glecaprevir/Pibrentasvir Film-Coated Immediate Release Tablets Each tablet contains 100 mg of glecaprevir and 40 mg of pibrentasvir. Glecaprevir and pibrentasvir are presented as a co-formulated, fixed-dose combination, immediate release bilayer tablet. The tablet contains the following inactive ingredients: colloidal silicon dioxide, copovidone (type K 28), croscarmellose sodium, hypromellose 2910, iron oxide red, lactose monohydrate, polyethylene glycol 3350, propylene glycol monocaprylate (type II), sodium stearyl fumarate, titanium dioxide, and vitamin E (tocopherol) polyethylene glycol succinate. The tablets do not contain gluten. Glecaprevir/Pibrentasvir Coated Oral Pellets MAVYRET oral pellets are small, pink and yellow and supplied in unit-dose packets for oral administration. Each unit-dose of MAVYRET oral pellets in packets contains 50 mg glecaprevir and 20 mg pibrentasvir and the following inactive ingredients: colloidal silicon dioxide, copovidone (type K 28), croscarmellose sodium, hypromellose 2910, iron oxide red, iron oxide yellow, lactose monohydrate, polyethylene glycol/macrogol 3350, propylene glycol monocaprylate (type II), sodium stearyl fumarate, titanium dioxide, vitamin E (tocopherol) polyethylene glycol succinate. The oral pellets do not contain gluten. Glecaprevir drug substance: The chemical name of glecaprevir is (3a R ,7 S ,10 S ,12 R ,21 E ,24a R )-7- tert -butyl- N -{(1 R ,2 R )-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl}-20,20-difluoro-5,8-dioxo-2,3,3a,5,6,7,8,11,12,20,23,24a-dodecahydro-1 H ,10 H -9,12-methanocyclopenta[18,19][1,10,17,3,6]trioxadiazacyclononadecino[11,12- b ]quinoxaline-10-carboxamide hydrate. The molecular formula is C 38 H 46 F 4 N 6 O 9 S (anhydrate) and the...

What Is Glecaprevir And Pibrentasvir Used For?

1 INDICATIONS AND USAGE MAVYRET is indicated for the treatment of adult and pediatric patients 3 years and older with acute or chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis (Child-Pugh A). MAVYRET is indicated for the treatment of adult and pediatric patients 3 years and older with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor (PI), but not both [see Dosage and Administration ( 2.2 ) and Clinical Studies ( 14 )]. MAVYRET is a fixed-dose combination of glecaprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, and pibrentasvir, an HCV NS5A inhibitor, and is indicated for the treatment of adult and pediatric patients 3 years and older with acute or chronic HCV genotype (GT) 1, 2, 3, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis (Child-Pugh A). MAVYRET is indicated for the treatment of adult and pediatric patients 3 years and older with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor, but not both. ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Testing Prior to the Initiation of Therapy: Test all patients for HBV infection by measuring HBsAg and anti-HBc. ( 2.1 ) See recommended treatment duration for patients 3 years and older in tables below. ( 2.2 ) Treatment-Naïve Patients 1 HCV Genotype Treatment Duration No Cirrhosis Compensated Cirrhosis (Child-Pugh A) 1, 2, 3, 4, 5, or 6 8 weeks 8 weeks Treatment-naïve patients are those who have not received treatment for the current infection. Treatment-Experienced Patients 1 Treatment Duration HCV Genotype Patients Previously Treated With a Regimen Containing: No Cirrhosis Compensated Cirrhosis (Child-Pugh A) 1 An NS5A inhibitor 2 without prior treatment with an NS3/4A protease inhibitor (PI) 16 weeks 16 weeks An NS3/4A PI 3 without prior treatment with an NS5A inhibitor 12 weeks 12 weeks 1, 2, 4, 5, or 6 PRS 4 8 weeks 12 weeks 3 PRS 4 16 weeks 16 weeks Treatment-experienced patients are those who previously received treatment for the current infection. Treated with prior regimens containing ledipasvir and sofosbuvir or daclatasvir with (peg) interferon and ribavirin. Treated with prior regimens containing simeprevir and sofosbuvir, or simeprevir, boceprevir, or telaprevir with (peg) interferon and ribavirin. PRS=Prior treatment experience with regimens containing (peg) interferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor. Recommended dosage in adults: Three tablets taken at the same time orally once daily (total daily dose: glecaprevir 300 mg and pibrentasvir 120 mg) with food. ( 2.3 ) Recommended dosage in pediatric patients 3 years and older: Pediatric Patients 3 Years to Less than 12 Years Old: Dosing is based on weight. Refer to Table 3 of the full prescribing information for specific dosing guidelines based on body weight. ( 2.4 ) Instructions for Use should be followed for preparation and administration of MAVYRET oral pellets. ( 2.5 ) Pediatric Patients 12 Years of Age and Older, or Pediatric Patients Weighing at Least 45 kg: three tablets taken at the same time orally once daily (total daily dose: glecaprevir 300 mg and pibrentasvir 120 mg) with food. ( 2.4 ) HCV/HIV-1 co-infection and patients with any degree of renal impairment: Follow the dosage recommendations in the tables above. ( 2.2 ) 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 PI or in genotype 3-infected patients who are PRS treatment-experienced. ( 2.6 ) 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 (...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS In subjects receiving MAVYRET, the most commonly reported adverse reactions (greater than 10%) are headache and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of MAVYRET cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Overall Adverse Reactions in Subjects with Chronic HCV Infection without Cirrhosis or with Compensated Cirrhosis (Child-Pugh A) The adverse reactions data for MAVYRET in subjects without cirrhosis or with compensated cirrhosis (Child-Pugh A) were derived from nine registrational Phase 2 and 3 trials which evaluated approximately 2,300 adults infected with genotype 1, 2, 3, 4, 5, or 6 HCV who received MAVYRET for 8, 12 or 16 weeks [see Clinical Studies ( 14 ) ] . The overall proportion of subjects who permanently discontinued treatment due to adverse reactions was 0.1% for subjects who received MAVYRET for 8, 12 or 16 weeks. The most common adverse reactions, all grades, observed in greater than or equal to 5% of subjects receiving 8, 12, or 16 weeks of treatment with MAVYRET were headache (13%), fatigue (11%), and nausea (8%). In subjects receiving MAVYRET who experienced adverse reactions, 80% had an adverse reaction of mild severity (Grade 1). One subject experienced a serious adverse reaction. Adverse reactions (type and severity) were similar for subjects receiving MAVYRET for 8, 12 or 16 weeks. The type and severity of adverse reactions in subjects with compensated cirrhosis (Child-Pugh A) were similar to those seen in subjects without cirrhosis. Adverse Reactions in Subjects with Chronic HCV Infection without Cirrhosis ENDURANCE-2 Among 302 treatment-naïve or PRS treatment-experienced, HCV genotype 2-infected adults without cirrhosis enrolled in ENDURANCE-2, adverse reactions (all intensity) occurring in at least 5% of subjects treated with MAVYRET for 12 weeks are presented in Table 4 . In subjects treated with MAVYRET for 12 weeks, 32% reported an adverse reaction, of which 98% had adverse reactions of mild or moderate severity. No subjects treated with MAVYRET or placebo in ENDURANCE-2 permanently discontinued treatment due to an adverse drug reaction. Table 4. Adverse Reactions Reported in ≥5% of Treatment-Naïve and PRS-Experienced Adults without Cirrhosis Receiving MAVYRET for 12 Weeks in ENDURANCE-2 Adverse Reaction MAVYRET 12 Weeks (N = 202) % Placebo 12 Weeks (N = 100) % Headache 9 6 Nausea 6 2 Diarrhea 5 2 ENDURANCE-3 Among 505 treatment-naïve, HCV genotype 3-infected adults without cirrhosis enrolled in ENDURANCE-3, adverse reactions (all intensity) occurring in at least 5% of subjects treated with MAVYRET for 8 or 12 weeks are presented in Table 5 . In subjects treated with MAVYRET, 45% reported an adverse reaction, of which 99% had adverse reactions of mild or moderate severity. The proportion of subjects who permanently discontinued treatment due to adverse reactions was 0%, < 1% and 1% for the MAVYRET 8-week arm, MAVYRET 12 week arm and DCV + SOF arm, respectively. Table 5. Adverse Reactions Reported in ≥5% of Treatment-Naïve Adults without Cirrhosis Receiving MAVYRET for 8 Weeks or 12 Weeks in ENDURANCE-3 Adverse Reaction MAVYRET* 8 Weeks (N = 157) % MAVYRET 12 Weeks (N = 233) % DCV 1 + SOF 2 12 Weeks (N = 115) % Headache 16 17 15 Fatigue 11 14 12 Nausea 9 12 12 Diarrhea 7 3 3 1 DCV=daclatasvir 2 SOF=sofosbuvir * The 8-week arm was a non-randomized treatment arm. Adverse Reactions in Subjects with Chronic HCV Infection with Compensated Cirrhosis (Child-Pugh A) The safety of MAVYRET in HCV GT 1, 2, 3, 4, 5, or 6 subjects with compensated cirrhosis is based on data from 288 adults from the Phase 2/3 registrational trials treated with MAVYRET for 12...

Drug Interactions

7 DRUG INTERACTIONS Carbamazepine, efavirenz, and St. John’s wort may decrease concentrations of glecaprevir and pibrentasvir. Coadministration of carbamazepine, efavirenz containing regimens, and St. John’s wort with MAVYRET is not recommended. ( 5.3 ) 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 ) Medication- Assisted Treatment (MAT) for Opioid Use Disorder. ( 7.4 ) Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 4 , 7 , 12.3 ) 7.1 Mechanisms for the Potential Effect of MAVYRET on Other Drugs Glecaprevir and pibrentasvir are inhibitors of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide (OATP) 1B1/3. Coadministration with MAVYRET may increase plasma concentration of drugs that are substrates of P-gp, BCRP, OATP1B1 or OATP1B3. Glecaprevir and pibrentasvir are weak inhibitors of cytochrome P450 (CYP) 3A, CYP1A2, and uridine glucuronosyltransferase (UGT) 1A1. 7.2 Mechanisms for the Potential Effect of Other Drugs on MAVYRET Glecaprevir and pibrentasvir are substrates of P-gp and/or BCRP. Glecaprevir is a substrate of OATP1B1/3. Coadministration of MAVYRET with drugs that inhibit hepatic P-gp, BCRP, or OATP1B1/3 may increase the plasma concentrations of glecaprevir and/or pibrentasvir. Coadministration of MAVYRET with drugs that induce P-gp/CYP3A may decrease glecaprevir and pibrentasvir plasma concentrations. Carbamazepine, phenytoin, efavirenz, and St. John’s wort may significantly decrease plasma concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect of MAVYRET. The use of these agents with MAVYRET is not recommended [see Warnings and Precautions ( 5.3 ) and Clinical Pharmacology ( 12.3 )] . 7.3 Established and Other Potential 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 CYP P450 substrates with a narrow therapeutic index (e.g. certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of...

Contraindications

4 CONTRAINDICATIONS 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 Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )] . MAVYRET is contraindicated with atazanavir or rifampin [see Drug Interaction ( 7.3 ) and Clinical Pharmacology ( 12.3 )] . Patients with moderate or severe hepatic impairment (Child-Pugh B or C) or those with any history of prior hepatic decompensation. ( 4 , 5.2 ) Coadministration with atazanavir or rifampin. ( 4 )

Pregnancy and Breastfeeding

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...

Overdosage

10 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING MAVYRET Tablets Configuration Content Package Size NDC Monthly carton (blister pack) 4 weekly cartons 7 daily blisters/carton 3 tablets/blister 84 tablets 0074-2625-04 Monthly carton (wallet) 4 weekly cartons 7 daily wallets/carton 3 tablets/wallet 84 tablets 0074-2625-28 8-Week Carton 2 monthly cartons 4 weekly cartons/monthly carton 7 daily wallets/carton 3 tablets/wallet 168 tablets 0074-2625-56 Bottle 84 tablets 0074-2625-84 MAVYRET tablets are pink-colored, film-coated, oblong biconvex shaped, debossed with “NXT” on one side. Store at or below 30°C (86°F). MAVYRET Oral Pellets MAVYRET oral pellets are dispensed in child-resistant unit-dose packets in cartons. Each carton contains 28 packets. Each packet contains 50 mg glecaprevir/20 mg pibrentasvir pink and yellow oral pellets. The NDC number is 0074-2600-28. Store at or below 30°C (86°F).

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.