Sovaldi

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- …

3 DOSAGE FORMS AND STRENGTHS SOVALDI is available as tablets or pellets for oral use. Each dosage form is available in two dose strengths. 400 mg Tablets: 400 mg sofosbuvir: yellow, capsule-shaped, film-coated tablet debossed with "GSI" on one side and "7977" on the other side. 200 mg Tablets: 200 mg sofosbuvir: yellow, oval-shaped, film-coated tablet debossed with "GSI" on one side and "200" on the other side. 200 mg Pellets: 200 mg sofosbuvir: white to off-white pellets in unit-dose packets. 150 mg Pellets: 150 mg sofosbuvir: white to off-white pellets in unit-dose packets. Tablets: 400 mg and 200 mg of sofosbuvir. ( 3 ) Oral Pellets: 200 mg and 150 mg of sofosbuvir. ( 3 )

4 CONTRAINDICATIONS When SOVALDI is used in combination with ribavirin or peginterferon alfa/ribavirin, the contraindications applicable to those agents are applicable to combination therapies. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications. When used in combination with peginterferon alfa/ribavirin or ribavirin alone, all contraindications to peginterferon alfa and/or ribavirin also apply to SOVALDI combination therapy. ( 4 )

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 …

7 DRUG INTERACTIONS Coadministration of amiodarone with a sofosbuvir-containing regimen may result in serious symptomatic bradycardia. ( 5.2 , 6.2 , 7.1 ) Drugs that are intestinal P-gp inducers (e.g., rifampin, St. John's wort) may alter the concentrations of sofosbuvir. ( 5.3 , 7 , 12.3 ) Consult the full prescribing information prior to use for potential drug-drug interactions. ( 5.2 , 5.3 , 7 , 12.3 ) Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact safe and effective use of concomitant medications. Frequent monitoring of relevant laboratory parameters (INR or blood glucose) and dose adjustments of certain concomitant medications may be necessary. ( 7.1 ) 7.1 Potentially Significant Drug Interactions Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while the predominant circulating metabolite GS-331007 is not. Drugs that are P-gp inducers in the intestine (e.g., rifampin or St. John's wort) may decrease sofosbuvir plasma concentration, leading to reduced therapeutic effect of SOVALDI, and thus concomitant use with SOVALDI is not recommended [see Warnings and Precautions (5.3) ] . Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment. Frequent monitoring of relevant laboratory parameters (e.g. International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with a narrow therapeutic index (e.g. certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary. Information on potential drug interactions with SOVALDI is summarized in Table 7. The table is not all-inclusive [see Warnings and Precautions (5.2 , 5.3) and Clinical Pharmacology (12.3) ]. Table 7 Potentially Significant Drug Interactions: Alteration in Dosage or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction This table is not all-inclusive. Concomitant Drug Class: Drug Name Effect on Concentration ↓ = decrease. Clinical Comment Antiarrhythmics: amiodarone Effect on amiodarone and sofosbuvir concentrations unknown Coadministration of amiodarone with a sofosbuvir-containing regimen may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with SOVALDI is not recommended; if coadministration is required, cardiac monitoring is recommended [see Warnings and Precautions (5.2) , Adverse Reactions (6.2) ]. Anticonvulsants: Carbamazepine phenytoin phenobarbital oxcarbazepine ↓ sofosbuvir ↓ GS-331007 Coadministration of SOVALDI with carbamazepine, phenytoin, phenobarbital or oxcarbazepine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Coadministration is not recommended. Antimycobacterials: Rifabutin rifampin rifapentine ↓ sofosbuvir ↓ GS-331007 Coadministration of SOVALDI with rifabutin or rifapentine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Coadministration is not recommended. Coadministration of SOVALDI with rifampin, an intestinal P-gp inducer, is not recommended [see Warnings and Precautions (5.3) ]. Herbal Supplements: St. John's wort (Hypericum perforatum) ↓ sofosbuvir ↓ GS-331007 Coadministration of SOVALDI with St. John's wort, an intestinal P-gp inducer, is not recommended [see Warn …

8 USE IN SPECIFIC POPULATIONS Patients with HCV/HIV-1 coinfection: Safety and efficacy have been studied. ( 14.4 ) Patients with hepatocellular carcinoma awaiting liver transplantation: Safety and efficacy have been studied. ( 8.8 ) 8.1 Pregnancy Risk Summary If SOVALDI is administered with ribavirin or peginterferon alfa and ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin and/or peginterferon alfa prescribing information for more information on ribavirin- and peginterferon alfa-associated risks of use during pregnancy. No adequate human data are available to establish whether or not SOVALDI poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with sofosbuvir at exposures greater than those in humans at the recommended human dose (RHD) [see Data ] . During organogenesis in the rat and rabbit, systemic exposures (AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) were ≥5 (rats) and 12 (rabbits) times the exposure in humans at the RHD. In the rat pre/postnatal development study, maternal systemic exposure (AUC) to GS-331007 was ≥6 times the exposure in humans at the RHD. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day) and rabbits (up to 300 mg/kg/day) on gestation days 6 to 18 and 6 to 19, respectively, and also to rats (oral doses up to 500 mg/kg/day) on gestation day 6 to lactation/post-partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. Systemic exposures (AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) were ≥5 (rats) and 12 (rabbits) times the exposure in humans at the RHD, with exposures increasing during gestation from approximately 5 to 10 (rats) and 12 to 28 (rabbits) times the exposure in humans at the RHD. 8.2 Lactation Risk Summary It is not known whether sofosbuvir or its metabolites are present in human breast milk, affect human milk production or have effects on the breastfed infant. The predominant circulating metabolite of sofosbuvir (GS-331007) was the primary component observed in the milk of lactating rats, without effect on nursing pups [see Data ] . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SOVALDI and any potential adverse effects on the breastfed child from SOVALDI or from the underlying maternal condition. If SOVALDI is administered with ribavirin, the nursing mother's information for ribavirin also applies to this combination regimen. Refer to the ribavirin prescribing information for more information on use during lactation. Data Animal Data No effects of sofosbuvir on growth and postnatal development were observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure (AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) was approximately 12 times the exposure in humans at the RHD, with exposure of approximately 2% that of maternal exposure observed in nursing pups on lactation day 10. In a lactation study, sofosbuvir metabolites (primarily GS-331007) were excreted into the milk of lactating rats following administration of a single oral dose of sofosbuvir (20 mg/kg) on lactation day 2, with milk concentrations of approximately 10% that of maternal plasma concentrations observed 1 hour post-dose. 8.3 Females and Males of Reproductive Potential If SOVALDI is administered with ribavirin or peginterferon and ribavirin, the information for ribavirin and peginterferon wit …

12.1 Mechanism of Action Sofosbuvir is a direct-acting antiviral agent against the hepatitis C virus [see Microbiology (12.4) ].

11 DESCRIPTION SOVALDI (sofosbuvir) is a nucleotide analog inhibitor of HCV NS5B polymerase. The IUPAC name for sofosbuvir is ( S )-isopropyl 2-(( S )-(((2 R ,3 R ,4 R ,5 R )-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2 H )-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of C 22 H 29 FN 3 O 9 P and a molecular weight of 529.45. It has the following structural formula: Sofosbuvir is a white to off-white crystalline solid with a solubility of ≥ 2 mg/mL across the pH range of 2–7.7 at 37 °C and is slightly soluble in water. SOVALDI tablets, 200 mg or 400 mg, are for oral administration. Each tablet contains 200 mg or 400 mg of sofosbuvir. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide. SOVALDI pellets, 150 mg or 200 mg, are for oral administration, supplied as white to off-white pellets in unit-dose packets. Each unit-dose packet contains 150 mg or 200 mg of sofosbuvir. The pellets include the following inactive ingredients: amino methacrylate copolymer, colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, silicon dioxide, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, and talc. Chemical Structure

10 OVERDOSAGE The highest documented dosage of sofosbuvir was a single dose of sofosbuvir 1200 mg (three times the recommended dosage) administered to 59 healthy subjects. In that trial, there were no untoward effects observed at this dosage level, and adverse events were similar in frequency and severity to those reported in the placebo and sofosbuvir 400 mg treatment groups. The effects of higher dosages are not known. No specific antidote is available for overdose with SOVALDI. If overdose occurs, the patient must be monitored for evidence of toxicity. Treatment of overdose with SOVALDI consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. A 4-hour hemodialysis session removed 18% of the administered dose.

16 HOW SUPPLIED/STORAGE AND HANDLING Tablets SOVALDI tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets containing 400 mg sofosbuvir debossed with "GSI" on one side and "7977" on the other side. Each bottle contains 28 tablets (NDC 61958-1501-1), a silica gel desiccant and polyester coil with a child-resistant closure. SOVALDI tablets, 200 mg, are yellow, oval-shaped, film-coated tablets containing 200 mg sofosbuvir debossed with "GSI" on one side and "200" on the other side. Each bottle contains 28 tablets (NDC 61958-1503-1) and a polyester coil with a child-resistant closure. Store below 30 °C (86 °F). Dispense only in original container Do not use if seal over bottle opening is broken or missing Oral Pellets SOVALDI pellets, 150 mg, are white to off-white pellets supplied as unit-dose packets in cartons. Each carton contains 28 packets (NDC 61958-1504-1) SOVALDI pellets, 200 mg, are white to off-white pellets supplied as unit-dose packets in cartons. Each carton contains 28 packets (NDC 61958-1505-1) Store below 30 °C (86 °F). Do not use if carton tamper-evident or packet seal is broken or damaged.