Ledipasvir And Sofosbuvir

1 INDICATIONS AND USAGE Ledipasvir and sofosbuvir is indicated for the treatment of adults and pediatric patients 3 years of age and older with chronic hepatitis C virus (HCV) [see Dosage and Administration (2.2 and 2.3) and Clinical Studies (14) ]: genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis genotype 1 infection with decompensated cirrhosis, for use in combination with ribavirin genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, for use in combination with ribavirin Ledipasvir and sofosbuvir is a fixed-dose combination of ledipasvir, a hepatitis C virus (HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor, and is indicated for the treatment of chronic hepatitis C virus (HCV) in adults and pediatric patients 3 years of age and older: Genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis Genotype 1 infection with decompensated cirrhosis, in combination with ribavirin Genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, in combination with ribavirin. ( 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 ) Recommended treatment regimen and duration in patients 3 years of age and older: ( 2.2 ) HCV Genotype Patient Population Regimen and Duration Genotype 1 Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 12 weeks Treatment-experienced without cirrhosis Ledipasvir and sofosbuvir 12 weeks Treatment-experienced with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 24 weeks Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C) Ledipasvir and sofosbuvir + ribavirin 12 weeks Genotype 1 or 4 Treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis, or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir + ribavirin 12 weeks Genotype 4, 5, or 6 Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 12 weeks Recommended dosage in adults: One tablet (90 mg of ledipasvir and 400 mg of sofosbuvir) taken orally once daily with or without food. ( 2.3 ) Recommended dosage in pediatric patients 3 years and older: Recommended dosage of ledipasvir and sofosbuvir in pediatric patients 3 years of age and older is based on weight. Refer to Table 2 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 ledipasvir and sofosbuvir (HARVONI) oral pellets. ( 2.5 ) HCV/HIV-1 coinfection: For adult and pediatric patients with HCV/HIV-1 coinfection, follow the dosage recommendations in the tables in the full prescribing information. ( 2.3 , 2.4 ) If used in combination with ribavirin, follow the recommendations for ribavirin dosing and dosage modifications. ( 2.3 , 2.4 ) For patients with any degree of renal impairment, including end stage renal disease on dialysis, no ledipasvir and sofosbuvir dosage adjustment is recommended. ( 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 ledipasvir and sofosbuvir [see Warnings and Precautions (5.1) ] . 2.2 Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older with Genotype 1, 4, 5, or 6 HCV Table 1 shows the recommended ledipasvir and sofosbuvir treatment regimen and duration based on patient population . Relapse rates are affected by baseline host and viral factors and differ between treatment durations for certain subgroups [see Clinical Studies (14) ]. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1 [see Clinical Studies (14) ]. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs. Table 1 Recommended Treatment Regimen and Duration for Ledipasvir and Sofosbuvir in Patients 3 Years of Age and Older with Genotype 1, 4, 5, or 6 HCV HCV Genotype Patient Population Treatment Regimen and Duration Genotype 1 Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 12 weeks Ledipasvir and sofosbuvir for 8 weeks can be considered in treatment-naïve genotype 1 patients without cirrhosis who have pretreatment HCV RNA less than 6 million IU/mL [see Clinical Studies (14.2) ] . Treatment-experienced Treatment-experienced adult and pediatric subjects have failed a peginterferon alfa +/- ribavirin based regimen with or without an HCV protease inhibitor. without cirrhosis Ledipasvir and sofosbuvir 12 weeks Treatment-experienced with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 24 weeks Ledipasvir and sofosbuvir + ribavirin for 12 weeks can be considered in treatment-experienced genotype 1 patients with cirrhosis who are eligible for ribavirin [see Dosage and Administration (2.3 and 2.4) and Clinical Studies (14.2) ] . Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C) Ledipasvir and sofosbuvir + ribavirin See Dosage and Administration 2.3 and 2.4 for ribavirin dosage recommendations. 12 weeks Genotype 1 or 4 Treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis, or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir + ribavirin 12 weeks Genotype 4, 5, or 6 Treatment-naïve and treatment-experienced , without cirrhosis or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 12 weeks 2.3 Recommended Dosage in Adults The recommended dosage of ledipasvir and sofosbuvir in adults with genotype 1, 4, 5 or 6 HCV is one tablet (90 mg ledipasvir and 400 mg sofosbuvir) taken orally once daily with or without food [see Clinical Pharmacology (12.3) ] . The daily dosage of ribavirin is weight-based (1000 mg for patients <75 kg and 1200 mg for those ≥75 kg) administered orally in two divided doses with food. In patients with decompensated cirrhosis, the starting dosage of ribavirin is 600 mg and can be titrated up to 1000 mg for patients <75 kg and 1200 mg for those ≥75 kg in two divided doses with food. If the starting dosage of ribavirin is not well tolerated, the dosage should be reduced as clinically indicated based on hemoglobin levels. For further information on ribavirin dosing and dosage modifications, refer to the ribavirin prescribing information [see Dosage and Administration (2.4) , Use in Specific Populations (8.6) , and Clinical Studies (14.5) ] . 2.4 Recommended Dosage in Pediatric Patients 3 Years of Age and Older The recommended dosage of ledipasvir and sofosbuvir in pediatric patients 3 years of age and older with genotype 1, 4, 5, or 6 HCV is based on weight (Table 2). Table 3 provides the weight-based dosage of ribavirin when used in combination with ledipasvir and sofosbuvir for pediatric patients. Take ledipasvir and sofosbuvir (with or without food) once daily [see Dosage and Administration (2.5) , Clinical Pharmacology (12.3) , and Clinical Studies (14.7) ] . Ledipasvir and sofosbuvir (HARVONI) oral pellets can be taken in pediatric patients who cannot swallow the tablet formulation. Table 2 Dosing for Pediatric Patients 3 Years and Older Body Weight (kg) Dosing of Ledipasvir and Sofosbuvir Ledipasvir and Sofosbuvir Daily Dose at least 35 one Ledipasvir and Sofosbuvir 90 mg/400 mg tablet once daily or two Ledipasvir and Sofosbuvir (HARVONI) 45 mg/200 mg tablets once daily or two 45 mg/200 mg packets of Ledipasvir and Sofosbuvir (HARVONI) oral pellets once daily 90 mg/400 mg per day 17 to less than 35 one Ledipasvir and Sofosbuvir (HARVONI) 45 mg/200 mg tablet once daily or one 45 mg/200 mg packet of Ledipasvir and Sofosbuvir (HARVONI) oral pellets once daily 45 mg/200 mg per day less than 17 one 33.75 mg/150 mg packet of Ledipasvir and Sofosbuvir (HARVONI) oral pellets once daily 33.75 mg/150 mg per day Table 3 Recommended Dosing for Ribavirin in Combination Therapy with Ledipasvir and Sofosbuvir for Pediatric Patients 3 Years and Older Body Weight (kg) Oral Ribavirin Daily Dosage The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food. less than 47 15 mg per kg per day (divided dose AM and PM) 47–49 600 mg per day (1 × 200 mg AM, 2 × 200 mg PM) 50–65 800 mg per day (2 × 200 mg AM, 2 × 200 mg PM) 66–80 1000 mg per day (2 × 200 mg AM, 3 × 200 mg PM) greater than 80 1200 mg per day (3 × 200 mg AM, 3 × 200 mg PM) 2.5 Preparation and Administration of Ledipasvir and Sofosbuvir (HARVONI) Oral Pellets See the ledipasvir and sofosbuvir (HARVONI) oral pellets full Instructions for Use for details on the preparation and administration of ledipasvir and sofosbuvir (HARVONI) pellets. Do not chew ledipasvir and sofosbuvir (HARVONI) oral pellets. If ledipasvir and sofosbuvir (HARVONI) oral pellets are administered with food, sprinkle the pellets on one or more spoonfuls of non-acidic soft food at or below room temperature. Examples of non-acidic foods include pudding, chocolate syrup, mashed potato, and ice cream. Take ledipasvir and sofosbuvir (HARVONI) oral pellets within 30 minutes of gently mixing with food and swallow the entire contents without chewing to avoid a bitter aftertaste. 2.6 Renal Impairment No dosage adjustment of ledipasvir and sofosbuvir tablets (90 mg/400 mg) is recommended in patients with any degree of renal impairment, including end stage renal disease (ESRD) on dialysis [see Dosage and Administration (2.3) ]. Take ledipasvir and sofosbuvir tablets (90 mg/400 mg) with or without ribavirin according to the recommendations in Table 1 [see Adverse Reactions (6.1) , Use in Specific Populations (8.6) and Clinical Studies (14.6) ] . Refer to ribavirin tablet prescribing information for ribavirin dosage modification for patients with CrCl less than or equal to 50 mL per minute.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see Warnings and Precautions (5.2) ]. The most common adverse reactions (incidence greater than or equal to 10%, all grades) observed with treatment with ledipasvir and sofosbuvir were fatigue, headache, and asthenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Asegua Therapeutics at 1-800-445-3235 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 the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. If ledipasvir and sofosbuvir is administered with ribavirin to adults, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions. Clinical Trials in Adult Subjects The safety assessment of ledipasvir and sofosbuvir was based on pooled data from three randomized, open-label Phase 3 clinical trials (ION-3, ION-1, and ION-2) of subjects with genotype 1 HCV with compensated liver disease (with and without cirrhosis) including 215, 539, and 326 subjects who received ledipasvir and sofosbuvir tablets (90 mg/400 mg) once daily by mouth for 8, 12, and 24 weeks, respectively [see Clinical Studies (14) ]. The proportion of subjects who permanently discontinued treatment due to adverse events was 0%, less than 1%, and 1% for subjects receiving ledipasvir and sofosbuvir for 8, 12, and 24 weeks, respectively. The most common adverse reactions (at least 10%) were fatigue and headache in subjects treated with 8, 12, or 24 weeks of ledipasvir and sofosbuvir. Table 4 lists adverse reactions (adverse events assessed as causally related by the investigator, all grades) observed in at least 5% of subjects receiving 8, 12, or 24 weeks of treatment with ledipasvir and sofosbuvir in clinical trials. The majority of adverse reactions presented in Table 4 occurred at severity of grade 1. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs. Table 4 Adverse Reactions (All Grades) Reported in ≥5% of Subjects Receiving 8, 12, or 24 Weeks of Treatment with Ledipasvir and Sofosbuvir Ledipasvir and Sofosbuvir 8 weeks (N=215) Ledipasvir and Sofosbuvir 12 weeks (N=539) Ledipasvir and Sofosbuvir 24 weeks (N=326) Fatigue 16% 13% 18% Headache 11% 14% 17% Nausea 6% 7% 9% Diarrhea 4% 3% 7% Insomnia 3% 5% 6% The safety assessment of ledipasvir and sofosbuvir was also based on pooled data from three open-label trials (Study 1119, ION-4, and ELECTRON-2) in 118 subjects with chronic HCV genotype 4, 5, or 6 infection with compensated liver disease (with or without cirrhosis) [see Clinical Studies (14.3) ] . The subjects received ledipasvir and sofosbuvir tablets (90 mg/400 mg) once daily by mouth for 12 weeks. The safety profile in subjects with chronic HCV genotype 4, 5, or 6 infection with compensated liver disease was similar to that observed in subjects with chronic HCV genotype 1 infection with compensated liver disease. The most common adverse reactions occurring in at least 10% of subjects were asthenia (18%), headache (14%), and fatigue (10%). Adverse Reactions in Subjects with Cirrhosis The safety assessment of ledipasvir and sofosbuvir with or without ribavirin was based on a randomized, double-blind and placebo-controlled trial in treatment-experienced genotype 1 subjects with compensated cirrhosis and was compared to placebo in the SIRIUS trial . Subjects were randomized to receive 24 weeks of ledipasvir and sofosbuvir tablets (90 mg/400 mg) once daily by mouth without ribavirin or 12 weeks of placebo followed by 12 weeks of ledipasvir and sofosbuvir tablets (90 mg/400 mg) once daily by mouth + ribavirin [see Clinical Studies (14.2) ] . Table 5 presents the adverse reactions, as defined above, that occurred with at least 5% greater frequency in subjects treated with 24 weeks of ledipasvir and sofosbuvir or 12 weeks of ledipasvir and sofosbuvir + ribavirin, compared to those reported for 12 weeks of placebo. The majority of the adverse reactions presented in Table 5 were Grade 1 or 2 in severity. Table 5 Adverse Reactions with ≥5% Greater Frequency Reported in Treatment-Experienced Subjects with Cirrhosis Receiving Ledipasvir and Sofosbuvir for 24 Weeks or Ledipasvir and Sofosbuvir + Ribavirin for 12 Weeks Compared to Placebo for 12 weeks Ledipasvir and Sofosbuvir 24 weeks (N=78) Ledipasvir and Sofosbuvir + RBV 12 weeks (N=76) Placebo 12 weeks (N=77) RBV=ribavirin Asthenia 31% 36% 23% Headache 29% 13% 16% Fatigue 18% 4% 1% Cough 5% 11% 1% Myalgia 9% 4% 0 Dyspnea 3% 9% 1% Irritability 8% 7% 1% Dizziness 5% 1% 0 Adverse Reactions in Subjects Coinfected with HIV-1 The safety assessment of ledipasvir and sofosbuvir was based on an open-label clinical trial in 335 genotype 1 or 4 subjects with HCV/HIV-1 coinfection who were on stable antiretroviral therapy in Study ION-4 [see Clinical Studies (14.4) ] . The safety profile in HCV/HIV-1 coinfected subjects was similar to that observed in HCV mono-infected subjects. The most common adverse reactions occurring in at least 10% of subjects were headache (20%) and fatigue (17%). Adverse Reactions in Liver Transplant Recipients and/or Subjects with Decompensated Cirrhosis The safety assessment of ledipasvir and sofosbuvir with ribavirin in liver transplant recipients and/or those who had decompensated liver disease was based on pooled data from two Phase 2 open-label clinical trials including 336 subjects who received ledipasvir and sofosbuvir tablets (90 mg/400 mg) plus ribavirin for 12 weeks. Subjects with Child-Pugh-Turcotte (CPT) scores greater than 12 were excluded from the trials [see Clinical Studies (14.5) ] . The adverse events observed were consistent with the expected clinical sequelae of liver transplantation and/or decompensated liver disease, or the known safety profile of ledipasvir and sofosbuvir and/or ribavirin. Decreases in hemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were observed in 38% and 13% of subjects treated with ledipasvir and sofosbuvir plus ribavirin for 12 weeks, respectively. Ribavirin was permanently discontinued in 11% of subjects treated with ledipasvir and sofosbuvir plus ribavirin for 12 weeks. Liver Transplant Recipients with Compensated Liver Disease: Among the 174 liver transplant recipients with compensated liver disease who received ledipasvir and sofosbuvir tablets (90 mg/400 mg) with ribavirin for 12 weeks, 2 (1%) subjects permanently discontinued ledipasvir and sofosbuvir due to an adverse event. Subjects with Decompensated Liver Disease: Among the 162 subjects with decompensated liver disease (pre- or post-transplant) who received ledipasvir and sofosbuvir tablets (90 mg/400 mg) with ribavirin for 12 weeks, 7 (4%) subjects died, 4 (2%) subjects underwent liver transplantation, and 1 subject (<1%) underwent liver transplantation and died during treatment or within 30 days after discontinuation of treatment. Because these events occurred in patients with advanced liver disease who are at risk of progression of liver disease including liver failure and death, it is not possible to reliably assess the contribution of drug effect to outcomes. A total of 4 (2%) subjects permanently discontinued ledipasvir and sofosbuvir due to an adverse event. Less Common Adverse Reactions Reported in Clinical Trials (less than 5%): The following adverse reactions occurred in less than 5% of subjects receiving ledipasvir and sofosbuvir tablets (90 mg/400 mg) in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship. Psychiatric disorders: depression (including in subjects with pre-existing history of psychiatric illness). Depression (particularly in subjects with pre-existing history of psychiatric illness) occurred in subjects receiving sofosbuvir containing regimens. Suicidal ideation and suicide have occurred in less than 1% of subjects treated with sofosbuvir in combination with ribavirin or pegylated interferon/ribavirin in other clinical trials. Laboratory Abnormalities Bilirubin Elevations: Bilirubin elevations of greater than 1.5×ULN were observed in 3%, less than 1%, and 2% of subjects treated with ledipasvir and sofosbuvir tablets (90 mg/400 mg) for 8, 12, and 24 weeks, respectively. Bilirubin elevations of greater than 1.5×ULN were observed in 3%, 11%, and 3% of subjects with compensated cirrhosis treated with placebo, ledipasvir and sofosbuvir + ribavirin for 12 weeks, and ledipasvir and sofosbuvir for 24 weeks, respectively, in the SIRIUS trial. Lipase Elevations: Transient, asymptomatic lipase elevations of greater than 3×ULN were observed in less than 1%, 2%, and 3% of subjects treated with ledipasvir and sofosbuvir tablets (90 mg/400 mg) for 8, 12, and 24 weeks, respectively. Transient, asymptomatic lipase elevations of greater than 3×ULN were observed in 1%, 3%, and 9% of subjects with compensated cirrhosis treated with placebo, ledipasvir and sofosbuvir + ribavirin for 12 weeks, and ledipasvir and sofosbuvir for 24 weeks, respectively, in the SIRIUS trial. Creatine Kinase: Creatine kinase was not assessed in Phase 3 trials ION-3, ION-1, or ION-2 of ledipasvir and sofosbuvir. Creatine kinase was assessed in the ION-4 trial. Isolated, asymptomatic creatine kinase elevations of greater than or equal to 10×ULN was observed in 1% of subjects treated with ledipasvir and sofosbuvir tablets (90 mg/400 mg) for 12 weeks in the ION-4 trial and has also been previously reported in subjects treated with sofosbuvir in combination with ribavirin or peginterferon/ribavirin in other clinical trials. Adverse Reactions in Adults with Severe Renal Impairment, Including those on Dialysis In an open-label trial (Trial 0154) in which adults with HCV with compensated liver disease (with or without cirrhosis) and severe renal impairment received ledipasvir and sofosbuvir tablets (90 mg/400 mg) for 12 weeks (N=18), the most common adverse reaction was fatigue (17%) [see Clinical Studies (14.6) ]. In an open-label clinical trial, Trial 4063, a total of 95 adults with HCV with compensated liver disease (with or without cirrhosis) and ESRD requiring dialysis received ledipasvir and sofosbuvir tablets (90 mg/400 mg) for 8 (n=45), 12 (n=31), or 24 (n=19) weeks. The most common adverse reactions were insomnia and headache (each reported in 4% of subjects overall) [see Clinical Studies (14.6) ]. Adverse Reactions in Pediatric Subjects 3 Years of Age and Older The safety assessment of ledipasvir and sofosbuvir tablets (90 mg/400 mg), ledipasvir and sofosbuvir (HARVONI) tablets (45 mg/200 mg), or ledipasvir and sofosbuvir (HARVONI) oral pellets in pediatric subjects 3 years of age and older is based on data from a Phase 2, open-label clinical trial (Study 1116). In total, 226 subjects were enrolled, which included 223 subjects without cirrhosis or with compensated cirrhosis who were treated with ledipasvir and sofosbuvir for 12 weeks; one genotype 1 treatment-experienced subject with cirrhosis who was treated with ledipasvir and sofosbuvir for 24 weeks; and two genotype 3 subjects who were treated with ledipasvir and sofosbuvir + ribavirin for 24 weeks. The adverse reactions observed were consistent with those observed in clinical studies of ledipasvir and sofosbuvir tablets (90 mg/400 mg) in adults. Limited safety data are available in pediatric subjects receiving ledipasvir and sofosbuvir for 24 weeks. No Grade 3 or 4 adverse reactions or discontinuation due to an adverse reaction was observed in those pediatric subjects receiving ledipasvir and sofosbuvir for 24 weeks [see Clinical Studies (14.7) ] . In a 5-year follow-up study, 178 of the 226 subjects from the Phase 2 open-label clinical trial (Study 1116) were followed for a median (Q1, Q3) duration of 239 (143, 244) weeks. No notable effects on growth as assessed by changes from baseline through end of study were observed for height, weight, BMI percentiles, and Z-scores for any age group. No notable effects were observed on the development of secondary sexual characteristics of subjects as assessed by changes from baseline through end of study in Tanner pubertal stages [see Use in Specific Populations (8.4) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ledipasvir and sofosbuvir. Because postmarketing 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. Cardiac Disorders Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with ledipasvir and sofosbuvir [see Warnings and Precautions (5.2) , Drug Interactions (7.2) ]. Skin and Subcutaneous Tissue Disorders Skin rashes, sometimes with blisters or angioedema-like swelling Angioedema

12.3 Pharmacokinetics Absorption The pharmacokinetic properties of ledipasvir, sofosbuvir, and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of ledipasvir and sofosbuvir tablets (90 mg/400 mg), ledipasvir median peak concentrations were observed 4 to 4.5 hours post-dose. Sofosbuvir was absorbed quickly and the peak median plasma concentration was observed ~0.8 to 1 hour post-dose. Median peak plasma concentration of GS-331007 was observed between 3.5 to 4 hours post-dose. Based on the population pharmacokinetic analysis in HCV-infected subjects, geometric mean steady-state AUC 0–24 for ledipasvir (N=2113), sofosbuvir (N=1542), and GS-331007 (N=2113) were 7290, 1320, and 12,000 ng∙hr/mL, respectively. Steady-state C max for ledipasvir, sofosbuvir, and GS-331007 were 323, 618, and 707 ng/mL, respectively. Sofosbuvir and GS-331007 AUC 0–24 and C max were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=191), ledipasvir AUC 0–24 and C max were 24% lower and 32% lower, respectively, in HCV-infected subjects. Effect of Food Relative to fasting conditions, the administration of a single dose of ledipasvir and sofosbuvir tablets (90 mg/400 mg) with a moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal increased sofosbuvir AUC 0–inf by approximately 2-fold, but did not significantly affect sofosbuvir C max . The exposures of GS-331007 and ledipasvir were not altered in the presence of either meal type. The response rates in Phase 3 trials were similar in HCV-infected subjects who received ledipasvir and sofosbuvir tablets (90 mg/400 mg) with food or without food. Ledipasvir and sofosbuvir can be administered without regard to food. Distribution Ledipasvir is greater than 99.8% bound to human plasma proteins. After a single 90 mg dose of [ 14 C]-ledipasvir in healthy subjects, the blood to plasma ratio of 14 C-radioactivity ranged between 0.51 and 0.66. Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 microgram/mL to 20 microgram/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [ 14 C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14 C-radioactivity was approximately 0.7. Metabolism In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Evidence of slow oxidative metabolism via an unknown mechanism has been observed. Following a single dose of 90 mg [ 14 C]-ledipasvir, systemic exposure was almost exclusively to the parent drug (greater than 98%). Unchanged ledipasvir is the major species present in feces. Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. After a single 400 mg oral dose of [ 14 C]-sofosbuvir, GS-331007 accounted for approximately greater than 90% of total systemic exposure. Elimination Following a single 90 mg oral dose of [ 14 C]-ledipasvir, mean total recovery of the [ 14 C]-radioactivity in feces and urine was approximately 87%, with most of the radioactive dose recovered from feces (approximately 86%). Unchanged ledipasvir excreted in feces accounted for a mean of 70% of the administered dose and the oxidative metabolite M19 accounted for 2.2% of the dose. These data indicate that biliary excretion of unchanged ledipasvir is a major route of elimination, with renal excretion being a minor pathway (approximately 1%). The median terminal half-life of ledipasvir following administration of ledipasvir and sofosbuvir tablets (90 mg/400 mg) was 47 hours. Following a single 400 mg oral dose of [ 14 C]-sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, feces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following administration of ledipasvir and sofosbuvir tablets (90 mg/400 mg) were 0.5 and 27 hours, respectively. Specific Populations Race: Population pharmacokinetics analysis in HCV-infected subjects indicated that race had no clinically relevant effect on the exposure of ledipasvir, sofosbuvir, and GS-331007. Gender: Population pharmacokinetics analysis in HCV-infected subjects indicated that gender had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. AUC and C max of ledipasvir were 77% and 58% higher, respectively, in females than males; however, the relationship between gender and ledipasvir exposures was not considered clinically relevant, as high response rates (SVR12 >90%) were achieved in male and female subjects across the Phase 3 studies and the safety profiles are similar in females and males. Pediatric Patients: The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were determined in HCV genotype 1, 3, or 4 infected pediatric subjects 3 years of age and older receiving a daily dose of ledipasvir and sofosbuvir as described below in Table 7. Exposures in pediatric subjects were similar to those observed in adults. Table 7 Pharmacokinetic Properties of Ledipasvir, Sofosbuvir, and GS-331007 in Pediatric Subjects 3 Years of Age and Older Population PK derived parameters Weight Group Dose PK Parameter Geometric Mean (%CV) Ledipasvir Sofosbuvir GS-331007 90/400 mg AUC tau (ng∙hr/mL) 11200 (45.7) 1350 (45.2) 13600 (18.9) ≥35 kg Ledipasvir N=100; Sofosbuvir N=72; GS-331007 N=100 C max (ng/mL) 550 (44.2) 660 (51.1) 921 (17.8) 45/200 mg AUC tau (ng∙hr/mL) 8750 (46.6) 1420 (34.2) 10700 (30.9) 17 to <35 kg Ledipasvir N=86; Sofosbuvir N=66; GS-331007 N=86 C max (ng/mL) 440 (42.7) 690 (24.8) 958 (26.1) 33.75/150 mg AUC tau (ng∙hr/mL) 7460 (31.0) 1720 (23.2) 12200 (15.2) <17 kg Ledipasvir N=9; Sofosbuvir N=9; GS-331007 N=9 C max (ng/mL) 405 (25.7) 791 (16.6) 1070 (13.0) The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 have not been established in pediatric subjects less than 3 years of age [see Use in Specific Populations (8.4) and Clinical Studies (14.7) ] . Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 80 years) analyzed, age did not have a clinically relevant effect on the exposure to ledipasvir, sofosbuvir, and GS-331007 [see Use in Specific Populations (8.5) ] . Patients with Renal Impairment: The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative subjects with severe renal impairment (eGFR less than 30 mL/min by Cockcroft-Gault). No clinically relevant differences in ledipasvir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment. The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild (eGFR between 50 to less than 80 mL/min/1.73 m 2 ), moderate (eGFR between 30 to less than 50 mL/min/1.73 m 2 ), severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ), and subjects with ESRD requiring hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR greater than 80 mL/min/1.73 m 2 ), the sofosbuvir AUC 0–inf was 61%, 107%, and 171% higher in mild, moderate, and severe renal impairment, while the GS-331007 AUC 0–inf was 55%, 88%, and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC 0–inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4-hour hemodialysis session removed approximately 18% of administered dose [see Dosage and Administration (2.6) and Use in Specific Populations (8.6) ]. The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were studied in HCV-infected subjects with severe renal impairment or ESRD requiring dialysis treated with ledipasvir and sofosbuvir tablets (90 mg/400 mg) for 8, 12, or 24 weeks. The results were generally consistent with those observed in HCV-negative subjects with ESRD requiring dialysis. Patients with Hepatic Impairment: The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative subjects with severe hepatic impairment (Child-Pugh Class C). Ledipasvir plasma exposure (AUC 0–inf ) was similar in subjects with severe hepatic impairment and control subjects with normal hepatic function. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of ledipasvir [see Use in Specific Populations (8.7) ] . The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC 0–24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC 0–24 were 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of sofosbuvir and GS-331007 [see Use in Specific Populations (8.7) and Clinical Studies (14.5) ] . Drug Interaction Studies Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. P-gp inducers (e.g., rifampin or St. John's wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of ledipasvir and sofosbuvir, and the use with P-gp inducers is not recommended with ledipasvir and sofosbuvir [see Warnings and Precautions (5.3) ] . Coadministration with drugs that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; ledipasvir and sofosbuvir may be coadministered with P-gp and/or BCRP inhibitors. Neither ledipasvir nor sofosbuvir is a substrate for hepatic uptake transporters OCT1, OATP1B1, or OATP1B3. GS-331007 is not a substrate for renal transporters, including organic anion transporter OAT1 or OAT3, or organic cation transporter OCT2. Ledipasvir is subject to slow oxidative metabolism via an unknown mechanism. In vitro, no detectable metabolism of ledipasvir by CYP enzymes has been observed. Biliary excretion of unchanged ledipasvir is a major route of elimination. Sofosbuvir is not a substrate for CYP and UGT1A1 enzymes. Clinically significant drug interactions with ledipasvir and sofosbuvir mediated by CYP or UGT1A1 enzymes are not expected. The effects of coadministered drugs on the exposure of ledipasvir, sofosbuvir, and GS-331007 are shown in Table 8 [see Drug Interactions (7) ]. Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Ledipasvir, Sofosbuvir, and the Predominant Circulating Metabolite GS-331007 in the Presence of the Coadministered Drug All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) Ledipasvir Dose (mg) Sofosbuvir Dose (mg) N Mean Ratio (90% CI) of Ledipasvir, Sofosbuvir, and GS-331007 PK With/Without Coadministered Drug No Effect=1.00 C max AUC C min NA = not available/not applicable, ND = not dosed. tenofovir DF = tenofovir disoproxil fumarate Atazanavir/ ritonavir + emtricitabine/ tenofovir DF Data generated from simultaneous dosing with ledipasvir and sofosbuvir. Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir DF or darunavir/ritonavir + emtricitabine/tenofovir DF and ledipasvir and sofosbuvir provided similar results. , The effects of atazanavir/ritonavir on ledipasvir and sofosbuvir are similar with or without the presence of emtricitabine/tenofovir DF. 300/100 + 200/300 once daily 90 once daily 400 once daily 24 ledipasvir 1.68 (1.54, 1.84) 1.96 (1.74, 2.21) 2.18 (1.91, 2.50) sofosbuvir 1.01 (0.88, 1.15) 1.11 (1.02, 1.21) NA GS-331007 1.17 (1.12, 1.23) 1.31 (1.25, 1.36) 1.42 (1.34, 1.49) Carbamazepine 300 twice daily ND 400 single dose 24 sofosbuvir 0.52 (0.43, 0.62) 0.52 (0.46, 0.59) NA GS-331007 1.04 (0.97, 1.11) 0.99 (0.94, 1.04) NA Cyclosporine 600 single dose ND 400 single dose 19 sofosbuvir 2.54 (1.87, 3.45) 4.53 (3.26, 6.30) NA GS-331007 0.60 (0.53, 0.69) 1.04 (0.90, 1.20) NA Darunavir/ ritonavir 800/100 once daily 90 once daily ND 23 ledipasvir 1.45 (1.34, 1.56) 1.39 (1.28, 1.49) 1.39 (1.29, 1.51) ND 400 single dose 18 sofosbuvir 1.45 (1.10, 1.92) 1.34 (1.12, 1.59) NA GS-331007 0.97 (0.90, 1.05) 1.24 (1.18, 1.30) NA Darunavir/ ritonavir + emtricitabine/ tenofovir DF 800/100 + 200/300 once daily 90 once daily 400 once daily 23 ledipasvir 1.11 (0.99, 1.24) 1.12 (1.00, 1.25) 1.17 (1.04, 1.31) sofosbuvir 0.63 (0.52, 0.75) 0.73 (0.65, 0.82) NA GS-331007 1.10 (1.04, 1.16) 1.20 (1.16, 1.24) 1.26 (1.20, 1.32) Efavirenz/ emtricitabine/ tenofovir DF Administered as Atripla ® (efavirenz, emtricitabine, tenofovir DF). 600/200/300 once daily 90 once daily 400 once daily 14 ledipasvir 0.66 (0.59, 0.75) 0.66 (0.59, 0.75) 0.66 (0.57, 0.76) sofosbuvir 1.03 (0.87, 1.23) 0.94 (0.81, 1.10) NA GS-331007 0.86 (0.76, 0.96) 0.90 (0.83, 0.97) 1.07 (1.02, 1.13) Elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide 150/150/200/10 once daily 90 once daily 400 once daily 30 ledipasvir 1.65 (1.53, 1.78) 1.79 (1.64, 1.96) 1.93 (1.74, 2.15) sofosbuvir 1.28 (1.13, 1.47) 1.47 (1.35, 1.59) NA GS-331007 1.29 (1.24, 1.35) 1.48 (1.44, 1.53) 1.66 (1.60, 1.73) Famotidine 40 single dose simultaneously with ledipasvir and sofosbuvir tablets 90 single dose 400 single dose 12 ledipasvir 0.80 (0.69, 0.93) 0.89 (0.76, 1.06) NA sofosbuvir 1.15 (0.88, 1.50) 1.11 (1.00, 1.24) NA GS-331007 1.06 (0.97, 1.14) 1.06 (1.02, 1.11) NA 40 single dose 12 hours prior to ledipasvir and sofosbuvir tablets 12 ledipasvir 0.83 (0.69, 1.00) 0.98 (0.80, 1.20) NA sofosbuvir 1.00 (0.76, 1.32) 0.95 (0.82, 1.10) NA GS-331007 1.13 (1.07, 1.20) 1.06 (1.01, 1.12) NA Methadone 30 to 130 daily ND 400 once daily 14 sofosbuvir 0.95 (0.68, 1.33) 1.30 (1.00, 1.69) NA GS-331007 0.73 (0.65, 0.83) 1.04 (0.89, 1.22) NA Omeprazole 20 once daily simultaneously with ledipasvir and sofosbuvir tablets 90 single dose 400 single dose 16 ledipasvir 0.89 (0.61, 1.30) 0.96 (0.66, 1.39) NA sofosbuvir 1.12 (0.88, 1.42) 1.00 (0.80, 1.25) NA GS-331007 1.14 (1.01, 1.29) 1.03 (0.96, 1.12) NA 20 once daily 2 hours prior to ledipasvir 30 single dose ND 17 ledipasvir 0.52 (0.41, 0.66) 0.58 (0.48, 0.71) NA Rifabutin 300 once daily ND 400 single dose 20 sofosbuvir 0.64 (0.53, 0.77) 0.76 (0.63, 0.91) NA GS-331007 1.15 (1.03, 1.27) 1.03 (0.95, 1.12) NA Rifampin 600 once daily 90 single dose This study was conducted in the presence of two other investigational HCV direct-acting agents. ND 31 ledipasvir 0.65 (0.56, 0.76) 0.41 (0.36, 0.48) NA ND 400 single dose 17 sofosbuvir 0.23 (0.19, 0.29) 0.28 (0.24, 0.32) NA GS-331007 1.23 (1.14, 1.34) 0.95 (0.88, 1.03) NA Simeprevir 150 once daily 30 once daily ND 22 ledipasvir 1.81 (1.69, 2.94) 1.92 (1.77, 2.07) NA Tacrolimus 5 single dose ND 400 single dose 16 sofosbuvir 0.97 (0.65, 1.43) 1.13 (0.81, 1.57) NA GS-331007 0.97 (0.83, 1.14) 1.00 (0.87, 1.13) NA No effect on the pharmacokinetic parameters of ledipasvir, sofosbuvir, and GS-331007 was observed with raltegravir and the combination of abacavir and lamivudine; emtricitabine, rilpivirine, and tenofovir disoproxil fumarate; or dolutegravir, emtricitabine, and tenofovir disoproxil fumarate. Ledipasvir is an inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters. Ledipasvir is an inhibitor of transporters OATP1B1, OATP1B3, and BSEP only at concentrations exceeding those achieved in clinic. Ledipasvir is not an inhibitor of transporters MRP2, MRP4, OCT2, OAT1, OAT3, MATE1, and OCT1. The drug-drug interaction potential of ledipasvir is primarily limited to the intestinal inhibition of P-gp and BCRP. Clinically relevant transporter inhibition by ledipasvir in the systemic circulation is not expected due to its high protein binding. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, and OCT1, and GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1. Ledipasvir, sofosbuvir, and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes. The effects of ledipasvir or sofosbuvir on the exposure of coadministered drugs are shown in Table 9 [see Drug Interactions (7) ]. Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Ledipasvir, Sofosbuvir, or Ledipasvir and Sofosbuvir All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) Ledipasvir Dose (mg) Sofosbuvir Dose (mg) N Mean Ratio (90% CI) of Coadministered Drug PK With/Without Ledipasvir, Sofosbuvir, or Ledipasvir and Sofosbuvir No Effect=1.00 C max AUC C min NA = not available/not applicable, ND = not dosed. tenofovir DF = tenofovir disoproxil fumarate Atazanavir/ ritonavir + emtricitabine /tenofovir DF Data generated from simultaneous dosing with ledipasvir and sofosbuvir. Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir DF or darunavir/ritonavir + emtricitabine/tenofovir DF and ledipasvir and sofosbuvir provided similar results. , The effects of ledipasvir and sofosbuvir on atazanavir and ritonavir are similar with or without the presence of emtricitabine/tenofovir DF. , This magnitude of change in tenofovir exposure does not reflect the approximately 60–80% increase caused by the effects of an HIV PI/ritonavir and the effect of food. Therefore, tenofovir exposure is approximately 130% higher when administered as tenofovir DF + atazanavir/ritonavir + ledipasvir and sofosbuvir or tenofovir DF + darunavir/ritonavir + ledipasvir and sofosbuvir and with food as compared to the tenofovir exposure observed following fasted administration of tenofovir DF-based regimens that do not contain an HIV PI/ritonavir and ledipasvir and sofosbuvir. atazanavir 300 once daily 90 once daily 400 once daily 24 1.07 (0.99, 1.14) 1.27 (1.18, 1.37) 1.63 (1.45, 1.84) ritonavir 100 once daily 0.86 (0.79, 0.93) 0.97 (0.89, 1.05) 1.45 (1.27, 1.64) tenofovir DF 300 once daily 1.47 (1.37, 1.58) 1.35 (1.29, 1.42) 1.47 (1.38, 1.57) Darunavir/ ritonavir + emtricitabine/ tenofovir DF , darunavir 800 once daily 90 once daily 400 once daily 23 1.01 (0.96, 1.06) 1.04 (0.99, 1.08) 1.08 (0.98, 1.20) ritonavir 100 once daily 1.17 (1.01, 1.35) 1.25 (1.15, 1.36) 1.48 (1.34, 1.63) tenofovir DF 300 once daily 1.64 (1.54, 1.74) 1.50 (1.42, 1.59) 1.59 (1.49, 1.70) Elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide elvitegravir 150 once daily 90 once daily 400 once daily 30 0.98 (0.90, 1.07) 1.11 (1.02, 1.20) 1.46 (1.28, 1.66) cobicistat 150 once daily 1.23 (1.15, 1.32) 1.53 (1.45, 1.62) 3.25 (2.88, 3.67) tenofovir alafenamide 10 once daily 0.90 (0.73, 1.11) 0.86 (0.78, 0.95) NA Norelgestromin norgestimate 0.180/0.215/0.25/ethinyl estradiol 0.025 once daily 90 once daily ND 15 1.02 (0.89, 1.16) 1.03 (0.90, 1.18) 1.09 (0.91, 1.31) ND 400 once daily 1.07 (0.94, 1.22) 1.06 (0.92, 1.21) 1.07 (0.89, 1.28) Norgestrel 90 once daily ND 1.03 (0.87, 1.23) 0.99 (0.82, 1.20) 1.00 (0.81, 1.23) ND 400 once daily 1.18 (0.99, 1.41) 1.19 (0.98, 1.45) 1.23 (1.00, 1.51) Ethinyl estradiol 90 once daily ND 1.40 (1.18, 1.66) 1.20 (1.04, 1.39) 0.98 (0.79, 1.22) ND 400 once daily 1.15 (0.97, 1.36) 1.09 (0.94, 1.26) 0.99 (0.80, 1.23) Midazolam 2.5 single dose 90 single dose ND 30 1.07 (1.00, 1.14) 0.99 (0.95, 1.04) NA 0.95 (0.87, 1.04) 0.89 (0.84, 0.95) NA Raltegravir 400 twice daily 90 once daily ND 28 0.82 (0.66, 1.02) 0.85 (0.70, 1.02) 1.15 (0.90, 1.46) ND 400 single dose 19 0.57 (0.44, 0.75) 0.73 (0.59, 0.91) 0.95 (0.81, 1.12) Simeprevir 150 once daily 30 once daily ND 22 2.61 (2.39, 2.86) 2.69 (2.44, 2.96) NA Tacrolimus 5 single dose ND 400 single dose 16 0.73 (0.59, 0.90) 1.09 (0.84, 1.40) NA Tenofovir DF 300 once daily Administered as Atripla (efavirenz, emtricitabine, tenofovir DF). The effects of ledipasvir and sofosbuvir on tenofovir exposures are similar when tenofovir is administered as Atripla, Complera ® , or Truvada + dolutegravir. 90 once daily 400 once daily 15 1.79 (1.56, 2.04) 1.98 (1.77, 2.23) 2.63 (2.32, 2.97) No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with ledipasvir or sofosbuvir: abacavir, cyclosporine, darunavir/ritonavir, dolutegravir, efavirenz, emtricitabine, lamivudine, methadone, or rilpivirine.