Glecaprevir And Pibrentasvir

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 )

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 ( 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 )] .

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 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 )] .

12.3 Pharmacokinetics The pharmacokinetic properties of the components of MAVYRET in healthy subjects are provided in Table 7 . The steady-state pharmacokinetic parameters of glecaprevir and pibrentasvir in subjects with chronic HCV infection without cirrhosis are provided in Table 8 . For pellets relative to tablets in healthy adult subjects under non-fasting conditions, geometric mean ratios (GMRs) of glecaprevir and pibrentasvir C max were 0.664 and 1.137, AUC inf were 0.795 and 1.219, and C 24 (concentrations at 24 hours post-dose) were 0.917 and 1.174. These differences were not considered clinically significant. Table 7. Pharmacokinetic Properties of the Components of MAVYRET in Healthy Subjects Glecaprevir Pibrentasvir Absorption T max (h) a of tablets 5.0 5.0 T max (h) a of oral pellets 3.0 5.0 Effect of meal (relative to fasting) b on tablets ↑ 83-163% ↑ 40-53% Effect of meal (relative to fasting) b on oral pellets ↑ 131-167% ↑ 56-114% Distribution % Bound to human plasma proteins 97.5 >99.9 Blood-to-plasma ratio 0.57 0.62 Elimination t 1/2 (h) 6 13 Metabolism secondary, None CYP3A Major route of excretion biliary-fecal biliary-fecal % of dose excreted in urine c 0.7 0 % of dose excreted in feces c 92.1 96.6 a. Median T max following single doses of glecaprevir and pibrentasvir in healthy subjects. b. Mean systemic exposures with low/moderate to high fat meals. c. Single dose administration of radiolabeled glecaprevir or pibrentasvir in mass balance studies. Table 8. Steady-State Pharmacokinetic Parameters of Glecaprevir and Pibrentasvir Following Administration of MAVYRET in Subjects with Chronic HCV In f ection without Cirrhosis Pharmacokinetic Parameter Glecaprevir b Pibrentasvir c C max (ng/mL) a 597 (114) 110 (49) AUC 24,ss (ng•h/mL) a 4800 (122) 1430 (57) C trough,ss (ng/mL) a 13.0 (334) 18.9 (92) a Geometric mean (%CV) of individual-estimated C max , AUC 24,ss and C trough,ss values b Relative to healthy subjects, glecaprevir C max was 51% lower, AUC 24,ss was similar (10% difference), and C trough,ss was 157% higher in subjects without cirrhosis with chronic HCV infection c Relative to healthy subjects, pibrentasvir C max was 63% lower, AUC 24,ss was 34% lower, and C trough,ss was 37% lower in subjects without cirrhosis with chronic HCV infection No clinically meaningful differences in glecaprevir and pibrentasvir exposures are expected among adult patients with acute HCV infection and adult patients with chronic HCV infection. Specific Populations Pediatric Patients The pharmacokinetics of glecaprevir and pibrentasvir were determined in pediatric subjects with chronic HCV infection who were 3 years of age and older receiving a daily dose of MAVYRET as described below in Table 9 . GMRs of glecaprevir and pibrentasvir C max and AUC 24 in pediatrics vs. adults with chronic HCV infection ranged from 1.58-2.68 and 0.965-1.64, respectively. GMRs of glecaprevir C trough ranged from 0.292-0.954 and GMRs of pibrentasvir C trough ranged from 0.794-1.93. All pediatric glecaprevir and pibrentasvir PK parameter values fell within the range observed in adult subjects. These differences were not considered clinically significant. No clinically meaningful differences in glecaprevir and pibrentasvir exposures are expected among pediatric patients with acute HCV infection and pediatric patients with chronic HCV infection. The pharmacokinetics of glecaprevir and pibrentasvir have not been established in children less than 3 years of age. Table 9. Pharmacokinetic Parameters of Glecaprevir (GLE) and Pibrentasvir (PIB) in Pediatric Subjects with Chronic HCV Infection Age and Weight (kg) N Total Daily Dose of GLE/PIB (mg) PK Parameter Geometric Mean (%CV) GLE PIB 12 to < 18 years, ≥ 45 kg 14 300/120 AUC 24 (ng•h/mL) 4790 (72) 1380 (40) C max (ng/mL) 1040 (86) 174 (36) C trough (ng/mL) 3.79 (82) 15.0 (61) 9 to < 12 years, 30 to < 45 kg 13 250/100 AUC 24 (ng•h/mL) 7870 (209) 2200 (99) C max (ng/mL) 1370 (169) 225 (72) C trough (ng/mL) 12.4 (856) 36.5 (164) 6 to < 9 years, 20 to < 30 kg 13 200/80 AUC 24 (ng•h/mL) 6860 (142) 1640 (63) C max (ng/mL) 1600 (155) 197 (52) C trough (ng/mL) 7.44 (383) 19.4 (103) 3 to < 6 years, 12 to < 20 kg 12 150/60 AUC 24 (ng•h/mL) 7520 (205) 1790 (58) C max (ng/mL) 1530 (280) 233 (48) C trough (ng/mL) 6.58 (318) 17.9 (119) 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 subjects with chronic HCV infection, 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 subjects with chronic HCV infection and compensated cirrhosis (Child-Pugh A), exposure of glecaprevir was approximately 2-fold and pibrentasvir exposure was similar to non-cirrhotic subjects with chronic HCV infection. At the clinical dose, compared to non-HCV infected subjects with normal hepatic function, glecaprevir AUC was 100% higher in Child-Pugh B subjects, and increased 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 (12-88 years), sex, race/ethnicity or body weight (45 kg or greater). Patients under the age of 12 and weighing less than 45 kg are dosed based on body weight [see Dosage and Administration ( 2.4 ) ] . 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. Tables 10 and 11 summarize 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. Table 10. Drug Interactions: Changes in Pharmacokinetic Parameters of Glecaprevir (GLE) or Pibrentasvir (PIB) in the Presence of Coadministered Drug Co- administered Drug Regimen of Co- administered Drug (mg) Regimen of GLE/PIB (mg) N DAA Central Value Ratio (90% CI) C max AUC C min Atazanavir + ritonavir 300 + 100 once daily 300/120 once daily a 12 GLE ≥4.06 (3.15, 5.23) ≥6.53 (5.24, 8.14) ≥14.3 (9.85, 20.7) PIB ≥1.29 (1.15, 1.45) ≥1.64 (1.48, 1.82) ≥2.29 (1.95, 2.68) Carbamazepine 200 twice daily 300/120 single dose 10 GLE 0.33 (0.27, 0.41) 0.34 (0.28, 0.40) -- PIB 0.50 (0.42, 0.59) 0.49 (0.43, 0.55) -- Cyclosporine 100 single dose 300/120 once daily 12 GLE b 1.30 (0.95, 1.78) 1.37 (1.13, 1.66) 1.34 (1.12, 1.60) PIB ↔ ↔ 1.26 (1.15, 1.37) 400 single dose 300/120 single dose 11 GLE 4.51 (3.63, 6.05) 5.08 (4.11, 6.29) -- PIB ↔ 1.93 (1.78, 2.09) -- Darunavir + ritonavir 800 + 100 once daily 300/120 once daily 8 GLE 3.09 (2.26, 4.20) 4.97 (3.62, 6.84) 8.24 (4.40, 15.4) PIB ↔ ↔ 1.66 (1.25, 2.21) Elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide 150/150/ 200/10 once daily 300/120 once daily 11 GLE 2.50 (2.08, 3.00) 3.05 (2.55, 3.64) 4.58 (3.15,6.65) PIB ↔ 1.57 (1.39, 1.76) 1.89 (1.63, 2.19) Omeprazole 20 once daily 300/120 single dose 9 GLE 0.78 (0.60, 1.00) 0.71 (0.58, 0.86) -- PIB ↔ ↔ -- 40 once daily (1 hour before GLE/PIB) 300/120 single dose 12 GLE 0.36 (0.21, 0.59) 0.49 (0.35, 0.68) -- PIB ↔ ↔ -- Rifampin 600 (first dose) 300/120 single dose 12 GLE 6.52 (5.06, 8.41) 8.55 (7.01, 10.4) -- PIB ↔ ↔ -- 600 once daily 300/120 single dose c 12 GLE 0.14 (0.11, 0.19) 0.12 (0.09, 0.15) -- PIB 0.17 (0.14, 0.20) 0.13 (0.11, 0.15) -- Lopinavir/ ritonavir 400/100 twice daily 300/120 once daily 9 GLE 2.55 (1.84, 3.52) 4.38 (3.02, 6.36) 18.6 (10.4, 33.5) PIB 1.40 (1.17, 1.67) 2.46 (2.07, 2.92) 5.24 (4.18, 6.58) ↔ = No change (central value ratio 0.80 to 1.25) a. Effect of atazanavir and ritonavir on the first dose of glecaprevir and pibrentasvir is reported. b. HCV-infected transplant recipients who received cyclosporine dose of 100 mg or less per day had mean glecaprevir exposures 2.4-fold of those not receiving cyclosporine. c. Effect of rifampin on glecaprevir and pibrentasvir 24 hours after final rifampin dose. Table 11. Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Combination of Glecaprevir/Pibrentasvir (GLE/PIB) Co- administered Drug Regimen of Co- administered Drug (mg) Regimen of GLE/PIB (mg) N Central Value Ratio (90% CI) C max AUC C min Abacavir ABC/DTG/3TC 600/50/300 once daily 300/120 once daily 12 ↔ ↔ 1.31 (1.05, 1.63) Atorvastatin 10 once daily 400/120 once daily 11 22.0 (16.4, 29.6) 8.28 (6.06, 11.3) -- Caffeine 100 single dose 300/120 once daily 12 ↔ 1.35 (1.23, 1.48) -- Dabigatran Dabigatran etexilate 150 single dose 300/120 once daily 11 2.05 (1.72, 2.44) 2.38 (2.11, 2.70) -- Darunavir DRV + RTV 800 + 100 once daily 300/120 once daily 12 1.30 (1.21, 1.40) 1.29 (1.18, 1.42) ↔ Ritonavir 2.03 (1.78, 2.32) 1.87 (1.74, 2.02) ↔ Dextro- methorphan Dextromethorphan hydrobromide 30 single dose 300/120 once daily 12 0.70 (0.61, 0.81) 0.75 (0.66, 0.85) -- Digoxin 0.5 single dose 400/120 once daily 12 1.72 (1.45, 2.04) 1.48 (1.40, 1.57) -- Ethinyl estradiol (EE) EE/ Norgestimate 35 µg/250 µg once daily 300/120 once daily 11 1.31 (1.24, 1.38) 1.28 (1.23, 1.32) 1.38 (1.25, 1.52) Norgestrel 1.54 (1.34, 1.76) 1.63 (1.50, 1.76) 1.75 (1.62, 1.89) Norgestromin ↔ 1.44 (1.34, 1.54) 1.45 (1.33, 1.58) Ethinyl estradiol EE/ Levonorgestrel 20 µg/100 µg once daily 300/120 once daily 12 1.30 (1.18, 1.44) 1.40 (1.33, 1.48) 1.56 (1.41, 1.72) Norgestrel 1.37 (1.23, 1.52) 1.68 (1.57, 1.80) 1.77 (1.58, 1.98) Elvitegravir EVG/COBI/FTC/ TAF 150/ 150/200/10 once daily 300/120 once daily 12 1.36 (1.24, 1.49) 1.47 (1.37, 1.57) 1.71 (1.50, 1.95) Tenofovir ↔ ↔ ↔ Felodipine 2.5 single dose 300/120 once daily 11 1.31 (1.05, 1.62) 1.31 (1.08, 1.58) -- Losartan 50 single dose 300/120 once daily 12 2.51 (2.00, 3.15) 1.56 (1.28, 1.89) -- Losartan carboxylic acid 2.18 (1.88, 2.53) ↔ -- Lovastatin Lovastatin 10 once daily 300/120 once daily 12 ↔ 1.70 (1.40, 2.06) -- Lovastatin acid 5.73 (4.65, 7.07) 4.10 (3.45, 4.87) -- Midazolam 1 single dose 300/120 once daily 12 ↔ 1.27 (1.11, 1.45) -- Omeprazole 20 single dose 300/120 once daily 12 0.57 (0.43, 0.75) 0.79 (0.70, 0.90) -- Pravastatin 10 once daily 400/120 once daily 12 2.23 (1.87, 2.65) 2.30 (1.91, 2.76) -- Raltegravir 400 twice daily 300/120 once daily 12 1.34 (0.89, 1.98) 1.47 (1.15, 1.87) 2.64 (1.42, 4.91) Rilpivirine 25 once daily 300/120 once daily 12 2.05 (1.73, 2.43) 1.84 (1.72, 1.98) 1.77 (1.59, 1.96) Rosuvastatin 5 once daily 400/120 once daily 11 5.62 (4.80, 6.59) 2.15 (1.88, 2.46) -- Simvastatin Simvastatin 5 once daily 300/120 once daily 12 1.99 (1.60, 2.48) 2.32 (1.93, 2.79) -- Simvastatin acid 10.7 (7.88, 14.6) 4.48 (3.11, 6.46) -- Sofosbuvir Sofosbuvir 400 once daily 400/120 once daily 8 1.66 (1.23, 1.22) 2.25 (1.86, 2.72) -- GS-331007 ↔ ↔ 1.85 (1.67, 2.04) Tacrolimus 1 single dose 300/120 once daily 10 1.50 (1.24, 1.82) 1.45 (1.24, 1.70) -- Tenofovir EFV/FTC/TDF 300/200/300 once daily 300/120 once daily 12 ↔ 1.29 (1.23, 1.35) 1.38 (1.31, 1.46) Valsartan 80 single dose 300/120 once daily 12 1.36 (1.17, 1.58) 1.31 (1.16, 1.49) -- ↔ = No change (central value ratio 0.80 to 1.25) 3TC – lamivudine; ABC – abacavir; COBI – cobicistat; DRV – darunavir; DTG – dolutegravir; EFV – efavirenz; EVG – elvitegravir; FTC – emtricitabine; RTV – ritonavir; TAF – tenofovir alafenamide; TDF – tenofovir disoproxil fumarate