Sofosbuvir

1 INDICATIONS AND USAGE SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of: Adult patients with genotype 1, 2, 3 or 4 chronic HCV infection without cirrhosis or with compensated cirrhosis as a component of a combination antiviral treatment regimen. ( 1 ) Pediatric patients 3 years of age and older with genotype 2 or 3 chronic HCV infection without cirrhosis or with compensated cirrhosis in combination with ribavirin. ( 1 ) Adult Patients: SOVALDI is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) infection as a component of a combination antiviral treatment regimen [see Dosage and Administration (2.2) , and Clinical Studies (14) ]: genotype 1 or 4 infection without cirrhosis or with compensated cirrhosis for use in combination with pegylated interferon and ribavirin genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis for use in combination with ribavirin. Pediatric Patients: SOVALDI is indicated for the treatment of chronic HCV genotype 2 or 3 infection in pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis for use in combination with ribavirin [see Dosage and Administration (2.3) and Clinical Studies (14.5) ] .

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 dosage in adults: One 400 mg tablet taken once daily with or without food. ( 2.2 ) Recommended dosage in pediatric patients 3 years of age and older: Recommended dosage of SOVALDI in pediatric patients 3 years of age and older with genotype 2 or 3 HCV using SOVALDI tablets or oral pellets is based on weight. Refer to Table 3 of the full prescribing information for specific dosing guidelines based on body weight. ( 2.3 ) HCV/HIV-1 coinfection: For adult and pediatric patients with HCV/HIV-1 coinfection, follow the dosage recommendations in the tables below, respectively. ( 2.2 , 2.3 ) Recommended adult treatment regimen and duration: ( 2.2 ) Adult Patient Population Regimen and Duration Genotype 1 or 4 Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) SOVALDI + peginterferon alfa + ribavirin 12 weeks Genotype 2 Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A) SOVALDI + ribavirin 12 weeks Genotype 3 Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A) SOVALDI + ribavirin 24 weeks SOVALDI in combination with ribavirin for 24 weeks can be considered for adult patients with genotype 1 infection who are interferon ineligible. ( 2.2 ) Should be used in combination with ribavirin for treatment of HCV in adult patients with hepatocellular carcinoma awaiting liver transplantation for up to 48 weeks or until liver transplantation, whichever occurs first. ( 2.2 ) Recommended treatment regimen and duration for pediatric patients 3 years of age and older: ( 2.3 , 2.4 ) Pediatric Patient Population 3 Years of Age and Older Regimen and Duration Genotype 2 Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A) SOVALDI + ribavirin 12 weeks Genotype 3 Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A) SOVALDI + ribavirin 24 weeks A dosage recommendation cannot be made for patients with severe renal impairment or end stage renal disease. ( 2.7 , 8.6 ) Instructions for Use should be followed for preparation and administration of SOVALDI oral pellets. ( 2.4 ) 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 SOVALDI [see Warnings and Precautions (5.1)] . 2.2 Recommended Dosage in Adults The recommended dosage of SOVALDI is one 400 mg tablet, taken orally, once daily with or without food [see Clinical Pharmacology (12.3) ] . Administer SOVALDI in combination with ribavirin or in combination with pegylated interferon and ribavirin for the treatment of HCV. The recommended treatment regimen and duration for SOVALDI combination therapy is provided in Table 1. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs. Table 1 Recommended Treatment Regimen and Duration in Adult Patients with Genotype 1, 2, 3, or 4 HCV Patient Population Treatment Regimen and Duration Genotype 1 or 4 Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) SOVALDI + peginterferon alfa See peginterferon alfa prescribing information for dosage recommendation for patients with genotype 1 or 4 HCV. + ribavirin Dosage of ribavirin is weight-based (<75 kg = 1000 mg and ≥75 kg = 1200 mg). The daily dosage of ribavirin is administered orally in two divided doses with food. Patients with renal impairment (CrCl ≤50 mL/min) require ribavirin dosage reduction; refer to ribavirin tablet prescribing information. 12 weeks Genotype 2 Treatment-naïve and treatment-experienced Treatment-experienced patients have failed an interferon-based regimen with or without ribavirin. without cirrhosis or with compensated cirrhosis (Child-Pugh A) SOVALDI + ribavirin 12 weeks Genotype 3 Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A) SOVALDI + ribavirin 24 weeks Patients with Genotype 1 HCV Who are Ineligible to Receive an Interferon-Based Regimen SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic option for patients with genotype 1 infection who are ineligible to receive an interferon-based regimen [see Clinical Studies (14.4) ] . Treatment decision should be guided by an assessment of the potential benefits and risks for the individual patient. Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation Administer SOVALDI in combination with ribavirin for up to 48 weeks or until the time of liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection [see Use in Specific Populations (8.8) ] . 2.3 Recommended Dosage in Pediatric Patients 3 Years of Age and Older with Genotype 2 or 3 HCV The recommended treatment regimen, duration, and recommended dosage for SOVALDI combination therapy is provided in Table 2 and Table 3. Table 4 provides the weight-based dosage of ribavirin when used in combination with SOVALDI for pediatric patients. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 3 and Table 4. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs. In pediatric patients with hepatocellular carcinoma awaiting liver transplantation, administer SOVALDI in combination with ribavirin for up to 48 weeks or until the time of liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection [see Use in Specific Populations (8.8) ] . Table 2 Recommended Treatment Regimen and Duration in Pediatric Patients 3 Years and Older with Genotype 2 or 3 HCV Patient Population Treatment Regimen and Duration Genotype 2 Treatment-naïve and treatment-experienced Treatment-experienced patients have failed an interferon based regimen with or without ribavirin. without cirrhosis or with compensated cirrhosis (Child-Pugh A) SOVALDI + ribavirin See Table 4 for weight-based ribavirin dosing recommendations. 12 weeks Genotype 3 Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A) SOVALDI + ribavirin 24 weeks The recommended dosage of SOVALDI in pediatric patients 3 years and older with genotype 2 or 3 HCV using SOVALDI tablets or oral pellets (with or without food) is based on weight (Table 3), and is to be taken orally once daily in combination with ribavirin [see Dosage and Administration (2.4) , Use in Specific Populations (8.4) , Clinical Pharmacology (12.3) , and Clinical Studies (14.5) ] . SOVALDI pellets can be taken by pediatric patients who cannot swallow the tablet formulation [see Dosage and Administration (2.4) ] . Table 3 Dosing for Pediatric Patients 3 Years and Older Using SOVALDI Tablets or Oral Pellets Body Weight (kg) Dosing of SOVALDI Tablets or Oral Pellets SOVALDI Daily Dose at least 35 one 400 mg tablet once daily or two 200 mg tablets once daily or two 200 mg packets of pellets once daily 400 mg per day 17 to less than 35 one 200 mg tablet once daily or one 200 mg packet of pellets once daily 200 mg per day less than 17 one 150 mg packet of pellets once daily 150 mg per day Table 4 Recommended Dosing for Ribavirin in Combination Therapy with SOVALDI 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) 2.4 Preparation and Administration of Oral Pellets See the SOVALDI oral pellets full Instructions for Use for details on the preparation and administration of SOVALDI pellets. Do not chew SOVALDI pellets. If SOVALDI 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 SOVALDI pellets within 30 minutes of gently mixing with food and swallow the entire contents without chewing to avoid a bitter aftertaste. 2.5 Dosage Modification Dosage reduction of SOVALDI is not recommended. If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dosage should be reduced or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. Refer to the peginterferon alfa and ribavirin prescribing information for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dosage. 2.6 Discontinuation of Dosing If the other agents used in combination with SOVALDI are permanently discontinued, SOVALDI should also be discontinued. 2.7 Severe Renal Impairment and End Stage Renal Disease No dosage recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate [eGFR] less than 30 mL/min/1.73m 2 ) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] .

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see Warnings and Precautions (5.2) ] . The most common adverse events (incidence greater than or equal to 20%, all grades) observed with SOVALDI in combination with ribavirin were fatigue and headache. The most common adverse events observed with SOVALDI in combination with peginterferon alfa and ribavirin were fatigue, headache, nausea, insomnia and anemia. ( 6.1 ). The most common adverse events observed with SOVALDI in combination with ribavirin oral solution in pediatric patients was decreased appetite. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 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. When SOVALDI is administered with ribavirin or peginterferon alfa/ribavirin, refer to the respective prescribing information for a description of adverse reactions associated with their use. Adverse Reactions in Adult Subjects The safety assessment of SOVALDI was based on pooled Phase 3 clinical trial data (both controlled and uncontrolled) including: 650 subjects who received SOVALDI + ribavirin (RBV) combination therapy for 12 weeks, 98 subjects who received SOVALDI + ribavirin combination therapy for 16 weeks, 250 subjects who received SOVALDI + ribavirin combination therapy for 24 weeks, 327 subjects who received SOVALDI + peginterferon (Peg-IFN) alfa + ribavirin combination therapy for 12 weeks, 243 subjects who received peginterferon alfa + ribavirin for 24 weeks, and 71 subjects who received placebo (PBO) for 12 weeks [see Clinical Studies (14) ] . The proportion of subjects who permanently discontinued treatment due to adverse events was 4% for subjects receiving placebo, 1% for subjects receiving SOVALDI + ribavirin for 12 weeks, less than 1% for subjects receiving SOVALDI + ribavirin for 24 weeks, 11% for subjects receiving peginterferon alfa + ribavirin for 24 weeks and 2% for subjects receiving SOVALDI + peginterferon alfa + ribavirin for 12 weeks. Adverse events observed in at least 15% of subjects in the Phase 3 clinical trials outlined above are provided in Table 5. A side-by-side tabulation is displayed to simplify presentation; direct comparison across trials should not be made due to differing trial designs. The most common adverse events (at least 20%) for SOVALDI + ribavirin combination therapy were fatigue and headache. The most common adverse events (at least 20%) for SOVALDI + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia. Table 5 Adverse Events (All Grades and without Regard to Causality) Reported in ≥15% of Subjects with HCV in Any Treatment Arm Interferon-free Regimens Interferon-containing Regimens PBO 12 weeks SOVALDI + RBV Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing ≥75 kg). 12 weeks SOVALDI + RBV 24 weeks Peg-IFN alfa + RBV Subjects received 800 mg ribavirin per day regardless of weight. 24 weeks SOVALDI + Peg-IFN alfa + RBV 12 weeks N=71 N=650 N=250 N=243 N=327 Fatigue 24% 38% 30% 55% 59% Headache 20% 24% 30% 44% 36% Nausea 18% 22% 13% 29% 34% Insomnia 4% 15% 16% 29% 25% Pruritus 8% 11% 27% 17% 17% Anemia 0% 10% 6% 12% 21% Asthenia 3% 6% 21% 3% 5% Rash 8% 8% 9% 18% 18% Decreased Appetite 10% 6% 6% 18% 18% Chills 1% 2% 2% 18% 17% Influenza Like Illness 3% 3% 6% 18% 16% Pyrexia 0% 4% 4% 14% 18% Diarrhea 6% 9% 12% 17% 12% Neutropenia 0% <1% <1% 12% 17% Myalgia 0% 6% 9% 16% 14% Irritability 1% 10% 10% 16% 13% With the exception of anemia and neutropenia, the majority of events presented in Table 5 occurred at severity of grade 1 in SOVALDI-containing regimens. Less Common Adverse Reactions Reported in Clinical Trials (less than 1%): The following adverse reactions occurred in less than 1% of subjects receiving SOVALDI in a combination regimen in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship. Hematologic Effects: pancytopenia (particularly in subjects receiving concomitant pegylated interferon). Psychiatric Disorders: severe depression (particularly in subjects with pre-existing history of psychiatric illness), including suicidal ideation and suicide. Laboratory Abnormalities: Changes in selected hematological parameters are described in Table 6. A side-by-side tabulation is displayed to simplify presentation; direct comparison across trials should not be made due to differing trial designs. Table 6 Percentage of Subjects Reporting Selected Hematological Parameters Hematological Parameters Interferon-free Regimens Interferon-containing Regimens PBO 12 weeks SOVALDI + RBV Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing ≥75 kg). 12 weeks SOVALDI + RBV 24 weeks Peg-IFN + RBV Subjects received 800 mg ribavirin per day regardless of weight. 24 weeks SOVALDI + Peg-IFN + RBV 12 weeks N=71 N=647 N=250 N=242 N=327 Hemoglobin (g/dL) <10 0 8% 6% 14% 23% <8.5 0 1% <1% 2% 2% Neutrophils (×10 9 /L) ≥0.5 – <0.75 1% <1% 0 12% 15% <0.5 0 <1% 0 2% 5% Platelets (×10 9 /L) ≥25 – <50 3% <1% 1% 7% <1% <25 0 0 0 0 0 Bilirubin Elevations Total bilirubin elevation of more than 2.5×ULN was observed in none of the subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + ribavirin 12 weeks and SOVALDI + ribavirin 24 weeks groups, respectively. Bilirubin levels peaked during the first 1 to 2 weeks of treatment and subsequently decreased and returned to baseline levels by post-treatment Week 4. These bilirubin elevations were not associated with transaminase elevations. Creatine Kinase Elevations Creatine kinase was assessed in the FISSION and NEUTRINO trials. Isolated, asymptomatic creatine kinase elevation of greater than or equal to 10×ULN was observed in less than 1%, 1% and 2% of subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + peginterferon alfa + ribavirin 12 weeks and SOVALDI + ribavirin 12 weeks groups, respectively. Lipase Elevations Isolated, asymptomatic lipase elevation of greater than 3×ULN was observed in less than 1%, 2%, 2%, and 2% of subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks, SOVALDI + ribavirin 12 weeks, SOVALDI + ribavirin 24 weeks and peginterferon alfa + ribavirin 24 weeks groups, respectively. Patients with HCV/HIV-1 Coinfection SOVALDI used in combination with ribavirin was assessed in 223 HCV/HIV-1 coinfected subjects [see Clinical Studies (14.4) ] . The safety profile in HCV/HIV-1 coinfected subjects was similar to that observed in HCV mono-infected subjects. Elevated total bilirubin (grade 3 or 4) was observed in 30/32 (94%) subjects receiving atazanavir as part of the antiretroviral regimen. None of the subjects had concomitant transaminase increases. Among subjects not taking atazanavir, grade 3 or 4 elevated total bilirubin was observed in 2 (1.5%) subjects, similar to the rate observed with HCV mono-infected subjects receiving SOVALDI + ribavirin in Phase 3 trials. Adverse Reactions in Pediatric Subjects 3 Years of Age and Older The safety assessment of SOVALDI in pediatric subjects 3 years of age and older is based on data from 106 subjects who were treated with SOVALDI plus ribavirin for 12 weeks (genotype 2 subjects) or 24 weeks (genotype 3 subjects) in a Phase 2, open-label clinical trial. The adverse reactions observed were consistent with those observed in clinical studies of SOVALDI plus ribavirin in adults. Among pediatric subjects 3 years to < 12 years of age taking SOVALDI in combination with ribavirin oral solution, decreased appetite was observed in 13% (7/54) of subjects [see Clinical Studies 14.5) ] . In a 5-year follow-up study, 88 of the 106 subjects from the Phase 2 open-label clinical trial (Study 1112) were followed for a median (Q1, Q3) duration of 239 (179, 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 SOVALDI. 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 a sofosbuvir-containing regimen [see Warnings and Precautions (5.2) , Drug Interactions (7.1) ]. Skin and Subcutaneous Tissue Disorders Skin rashes, sometimes with blisters or angioedema-like swelling Angioedema