MAVYRET

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 molecular weight for the drug substance is 838.87 g/mol (anhydrate). The strength of glecaprevir is based on anhydrous glecaprevir. Glecaprevir is a white to off-white crystalline powder with a solubility of less than 0.1 to 0.3 mg/mL across a pH range of 2–7 at 37°C and is practically insoluble in water, but is sparingly soluble in ethanol. Glecaprevir has the following molecular structure: Pibrentasvir drug substance: The chemical name of pibrentasvir is Methyl {(2 S ,3 R )-1-[(2 S )-2-{5-[(2 R ,5 R )-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}-5-(6-fluoro-2-{(2 S )-1-[ N -(methoxycarbonyl)- O -methyl-L-threonyl]pyrrolidin-2-yl}-1 H -benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1 H -benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate. The molecular formula is C 57 H 65 F 5 N 10 O 8 and the molecular weight for the drug substance is 1113.18 g/mol. Pibrentasvir is a white to off-white to light yellow crystalline powder with a solubility of less than 0.1 mg/mL across a pH range of 1–7 at 37°C and is practically insoluble in water, but is freely soluble in ethanol. Pibrentasvir has the following molecular structure: Glecaprevir Pibrentasvir

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 )

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 ( 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. Table 1. Recommended Duration for 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 1. Treatment-naïve patients are those who have not received treatment for the current infection. Table 2. Recommended Duration for 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. In clinical trials, subjects were treated with prior regimens containing ledipasvir and sofosbuvir or daclatasvir with (peg)interferon and ribavirin. In clinical trials, subjects were 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. 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 . Table 3. Recommended Dosage in Pediatric Patients 3 Years of Age and Older Body Weight (kg) or Age (yrs) Daily Dose of glecaprevir/ pibrentasvir Dosing of MAVYRET Less than 20 kg 150 mg/60 mg per day Three 50 mg/20 mg packets of oral pellets once daily 20 kg to less than 30 kg 200 mg/80 mg per day Four 50 mg/20 mg packets of oral pellets once daily 30 kg to less than 45 kg 250 mg/100 mg per day Five 50 mg/20 mg packets of oral pellets once daily 45 kg and greater OR 12 years of age and older 300 mg/120 mg per day Three 100 mg/40 mg tablets once daily 1 (see Recommended Dosage in Adults) 1 Pediatric patients weighing 45 kg and greater who are unable to swallow tablets may take six 50 mg/20 mg packets of oral pellets once daily. Dosing with oral pellets has not been studied for pediatric patients weighing greater than 45 kg [see Clinical Pharmacology ( 12.3 ) ] . 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 )] .

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 )

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 or more weeks and 343 adults from EXPEDITION-8 treated with MAVYRET for 8 weeks. The adverse reactions observed were generally consistent with those observed in clinical studies of MAVYRET in non-cirrhotic subjects [see Clinical Studies ( 14 )] . In the Phase 2/3 registrational trials, the adverse reactions reported in greater than or equal to 5% of compensated cirrhotic subjects (n=288) treated across all durations of MAVYRET were fatigue (15%), headache (14%), nausea (8%), diarrhea (6%), and pruritus (6%). In EXPEDITION-8, the adverse reactions reported in greater than or equal to 5% of compensated cirrhotic subjects (n=343) were fatigue (8%), pruritus (7%), and headache (6%). No subjects with compensated cirrhosis in the Phase 2/3 registrational trials (without severe renal impairment) or in EXPEDITION-8 discontinued treatment with MAVYRET due to an adverse reaction. Adverse Reactions in Subjects with Chronic HCV Infection with Severe Renal Impairment Including Those on Dialysis The safety of MAVYRET in subjects with chronic kidney disease (Stage 4 or Stage 5 including subjects on dialysis) with genotypes 1, 2, 3, 4, 5 or 6 chronic HCV infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) was assessed in 104 adults (EXPEDITION-4) who received MAVYRET for 12 weeks. The most common adverse reactions observed in greater than or equal to 5% of subjects receiving 12 weeks of treatment with MAVYRET were pruritus (17%), fatigue (12%), nausea (9%), asthenia (7%), and headache (6%). In subjects treated with MAVYRET who reported an adverse reaction, 90% had adverse reactions of mild or moderate severity (Grade 1 or 2). The proportion of subjects who permanently discontinued treatment due to adverse reactions was 2%. Adverse Reactions in Subjects with Chronic HCV Infection Co- I nfected with HIV-1 The safety of MAVYRET in subjects with HIV-1 co-infection with genotypes 1, 2, 3, 4 or 6 chronic HCV infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) was assessed in 153 adults (EXPEDITION-2) who received MAVYRET for 8 or 12 weeks. Thirty-three subjects with HIV-1 coinfection also received 8 or 12 weeks of therapy in ENDURANCE-1. The overall safety profile in HCV/HIV-1 co-infected subjects (ENDURANCE-1 and EXPEDITION-2) was similar to that observed in HCV mono-infected subjects. Adverse reactions observed in greater than or equal to 5% of subjects receiving MAVYRET in EXPEDITION-2 for 8 or 12 weeks were fatigue (10%), nausea (8%), and headache (5%). Adverse Reactions in Subjects with Chronic HCV Infection with Liver or Kidney Transplant The safety of MAVYRET was assessed in 100 adult post-liver or -kidney transplant recipients with genotypes 1, 2, 3, 4, or 6 chronic HCV infection without cirrhosis (MAGELLAN-2). The overall safety profile in transplant recipients was similar to that observed in subjects in the Phase 2 and 3 studies, without a history of transplantation. Adverse reactions observed in greater than or equal to 5% of subjects receiving MAVYRET for 12 weeks were headache (17%), fatigue (16%), nausea (8%) and pruritus (7%). In subjects treated with MAVYRET who reported an adverse reaction, 81% had adverse reactions of mild severity. Two percent of subjects experienced a serious adverse reaction, and no subjects permanently discontinued treatment due to adverse reactions. Adverse Reactions in People Who Inject Drugs (PWID) and those on Medication-Assisted Treatment (MAT) for Opioid Use Disorder with Chronic HCV Infection PWID The safety of MAVYRET in PWID with chronic HCV GT 1, 2, 3, 4, 5, or 6 infection is based on data from adults and adolescents in Phase 2 and 3 trials in which 62 subjects identified as current/recent PWID (defined as self-reported injection drug use within the last 12 months prior to starting MAVYRET) and 3,282 subjects reported no injection drug use (non-PWID). Among current/recent PWID, adverse reactions observed in greater than or equal to 5% of subjects were fatigue (16%), headache (13%), diarrhea (6%), and nausea (6%). Among non-PWID subjects, adverse reactions observed in greater than or equal to 5% were headache (7%) and fatigue (6%). Serious adverse reactions and/or adverse reactions leading to treatment discontinuation occurred in one current/recent PWID subject (2%) compared to less than 1% in non-PWID subjects [see Use in Specific Populations ( 8.8 ) and Clinical Studies ( 14.9 ) ]. MAT The safety of MAVYRET in subjects with chronic HCV GT 1, 2, 3, 4, 5, or 6 infection reporting concomitant use of MAT for opioid use disorder is based on data from adults and adolescents in Phase 2 and 3 trials in which 225 subjects reported concomitant use of MAT and 4,098 subjects reported no concomitant use of MAT. Among subjects on MAT, adverse reactions observed in greater than or equal to 5% were headache (15%), fatigue (12%), nausea (11%), and diarrhea (6%). Among subjects who were not on MAT, adverse reactions observed in greater than or equal to 5% were headache (9%), fatigue (8%), and nausea (5%). Serious adverse reactions and/or adverse reactions leading to treatment discontinuation were not observed among subjects on MAT and were experienced by less than 1% of subjects not on MAT [see Use in Specific Populations ( 8.8 ) and Clinical Studies ( 14.9 ) ]. Adverse Reactions in Subjects with Acute HCV Infection The safety of MAVYRET in subjects with acute HCV GT 1, 2, 3, or 4 infection was assessed in 286 adults who received MAVYRET for 8 weeks. Among these subjects, 142 had HIV-1 co-infection, 41 identified as current/recent PWID, and 21 reported concomitant use of MAT. At baseline, 49% of subjects had ALT elevations greater than 3 x upper limit of normal (ULN), 13% had ALT elevations greater than 10 x ULN, and 12% had total bilirubin elevations greater than ULN. The overall safety profile in these subjects was similar to that observed in subjects with chronic HCV infection. Serious adverse reactions and/or adverse reactions leading to treatment discontinuation were not observed among subjects with acute HCV infection. The most commonly reported adverse reactions were fatigue (3%), asthenia (2%), headache (2%) and diarrhea (2%) [see Use in Specific Populations ( 8.4 ), Use in Specific Populations ( 8.5 ) Clinical Studies (14.11)] . Adverse Reactions in Pediatric Subjects 3 Y ears and Older with Chronic HCV Infection The safety of MAVYRET in HCV GT 1, 2, 3, or 4 infected adolescents is based on data from a Phase 2/3 open-label trial in 47 subjects aged 12 years to less than 18 years without cirrhosis treated with MAVYRET for 8 or 16 weeks (DORA-Part 1). The adverse reactions observed in subjects 12 years to less than 18 years of age were consistent with those observed in clinical trials of MAVYRET in adults. The only adverse reaction observed in greater than or equal to 5% of subjects receiving MAVYRET in DORA Part 1 was fatigue (6%). No subjects discontinued or interrupted treatment with MAVYRET due to an adverse reaction. The safety of MAVYRET in HCV GT 1, 2, 3, or 4 infected pediatric subjects aged 3 years to less than 12 years is based on data from a Phase 2/3 open-label trial in 80 subjects aged 3 to less than 12 years without cirrhosis treated with weight-based MAVYRET oral pellets in packets for 8, 12 or 16 weeks (DORA-Part 2). The adverse reactions observed in subjects 3 years to less than 12 years of age were consistent with those observed in clinical trials of MAVYRET in adults with the exception of vomiting (occurring at 8%), rash, and abdominal pain upper (each occurring at 4%) which were observed more frequently in pediatric subjects less than 12 years of age compared to adults. Other adverse reactions observed in greater than or equal to 5% of subjects receiving MAVYRET in DORA-Part 2 include fatigue and headache, each occurring at 8%. One subject discontinued treatment due to an adverse reaction of erythematous rash (Grade 3). All other adverse reactions were Grade 1 or 2 and no subjects interrupted treatment due to an adverse reaction [see Use in Specific Populations ( 8.4 ), Clinical Studies ( 14.10 ) ] . Laboratory Abnormalities Serum bilirubin elevations in su bjects wit h chronic HCV infection Elevations of total bilirubin at least 2 times the ULN occurred in 3.5% of adult subjects treated with MAVYRET versus 0% in placebo; these elevations were observed in 1.2% of adult subjects across the Phase 2 and 3 trials. In adult subjects with compensated cirrhosis (Child-Pugh A), 17% experienced early, transient post-baseline elevations of bilirubin above the ULN. These bilirubin elevations were typically less than 2 × ULN, generally occurred within the first 2 weeks of treatment and resolved with continued treatment. The subjects with compensated cirrhosis and bilirubin elevations did not have concurrent increases in ALT or AST, or signs of liver decompensation or failure, and these laboratory events did not lead to treatment discontinuation. MAVYRET inhibits OATP1B1/3 and is a weak inhibitor of UGT1A1 and may have the potential to impact bilirubin transport and metabolism, including direct and indirect bilirubin. Few subjects experienced jaundice or ocular icterus and total bilirubin levels decreased after completing MAVYRET. Liver tests in subjects with acute HCV infection Elevations of total bilirubin at least 2 times ULN occurred in 2.8% of subjects treated with MAVYRET. Subjects with total bilirubin elevations did not have concurrent increases in ALT or AST, or signs of liver decompensation or failure, and these laboratory events did not lead to treatment discontinuation. All subjects with baseline ALT > 3 × ULN improved from baseline by the final treatment visit. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of MAVYRET. Because these 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. Skin and Subcutaneous Tissue Disorders : Angioedema Hepatobiliary Disorders: Hepatic decompensation, hepatic failure [see Warnings and Precautions ( 5.2 )] .

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 concomitant medications may be necessary. Table 6 provides the effect of MAVYRET on concentrations of coadministered drugs and the effect of coadministered drugs on glecaprevir and pibrentasvir [see Contraindications ( 4 ) , Warnings and Precautions ( 5.3 ) , and Clinical Pharmacology ( 12.3 ) ] . All interaction studies were performed in adults. Table 6. Potentially Significant Drug Interactions Identified in Drug Interaction Studies Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comments Antiarrhythmics: Digoxin ↑ digoxin Measure serum digoxin concentrations before initiating MAVYRET. Reduce digoxin concentrations by decreasing the dose by approximately 50% or by modifying the dosing frequency and continue monitoring. Anticoagulants: Dabigatran etexilate ↑ dabigatran If MAVYRET and dabigatran etexilate are coadministered, refer to the dabigatran etexilate prescribing information for dabigatran etexilate dose modifications in combination with P-gp inhibitors in the setting of renal impairment. Anticonvulsants: Carbamazepine ↓ glecaprevir ↓ pibrentasvir Coadministration may lead to reduced therapeutic effect of MAVYRET and is not recommended. Antimycobacterials: Rifampin ↓ glecaprevir ↓ pibrentasvir Coadministration is contraindicated because of potential loss of therapeutic effect [see Contraindications ( 4 ) ] . Ethinyl Estradiol-Containing Products: Ethinyl estradiol-containing medications such as combined oral contraceptives ↔ glecaprevir ↔ pibrentasvir MAVYRET may be used with products containing 20 mcg or less of ethinyl estradiol. Coadministration of MAVYRET with products containing more than 20 mcg of ethinyl estradiol may increase the risk of ALT elevations and is not recommended. Herbal Products: St. John’s wort ( hypericum perforatum ) ↓ glecaprevir ↓ pibrentasvir Coadministration may lead to reduced therapeutic effect of MAVYRET and is not recommended. HIV-Antiviral Agents: Atazanavir ↑ glecaprevir ↑ pibrentasvir Coadministration is contraindicated due to increased risk of ALT elevations [see Contraindications ( 4 ) ] . Darunavir Lopinavir Ritonavir ↑ glecaprevir ↑ pibrentasvir Coadministration is not recommended. Efavirenz ↓ glecaprevir ↓ pibrentasvir Coadministration may lead to reduced therapeutic effect of MAVYRET and is not recommended. HMG-CoA Reductase Inhibitors: Atorvastatin Lovastatin Simvastatin ↑ atorvastatin ↑ lovastatin ↑ simvastatin Coadministration may increase the concentration of atorvastatin, lovastatin, and simvastatin. Increased statin concentrations may increase the risk of myopathy, including rhabdomyolysis. Coadministration with these statins is not recommended. Pravastatin ↑ pravastatin Coadministration may increase the concentration of pravastatin. Increased statin concentrations may increase the risk of myopathy, including rhabdomyolysis. Reduce pravastatin dose by 50% when coadministered with MAVYRET. Rosuvastatin ↑ rosuvastatin Coadministration may significantly increase the concentration of rosuvastatin. Increased statin concentrations may increase the risk of myopathy, including rhabdomyolysis. Rosuvastatin may be administered with MAVYRET at a dose that does not exceed 10 mg. Fluvastatin Pitavastatin ↑ fluvastatin ↑ pitavastatin Coadministration may increase the concentrations of fluvastatin and pitavastatin. Increased statin concentrations may increase the risk of myopathy, including rhabdomyolysis. Use the lowest approved dose of fluvastatin or pitavastatin. If higher doses are needed, use the lowest necessary statin dose based on a risk/benefit assessment. Immunosuppressants: Cyclosporine ↑ glecaprevir ↑ pibrentasvir MAVYRET is not recommended for use in patients requiring stable cyclosporine doses > 100 mg per day. See Clinical Pharmacology, Tables 10 and 11 . ↑= increase; ↓= decrease; ↔ = no effect 7.4 Medication-Assisted Treatment (MAT) for Opioid Use Disorder No buprenorphine/naloxone or methadone dosage adjustment is required when used concomitantly with MAVYRET. There is insufficient information to make a recommendation regarding the concomitant use of naltrexone with MAVYRET. 7.5 Drugs with No Observed Clinically Significant Interactions with MAVYRET No dose adjustment is required when MAVYRET is coadministered with the following medications: abacavir, amlodipine, caffeine, dextromethorphan, dolutegravir, elvitegravir/ cobicistat, emtricitabine, ethinyl estradiol of 20 mcg or less, felodipine, lamivudine, lamotrigine, losartan, midazolam, norethindrone or other progestin-only contraceptives, omeprazole, raltegravir, rilpivirine, sofosbuvir, tacrolimus, tenofovir alafenamide, tenofovir disoproxil fumarate, tolbutamide, and valsartan.