Sofosbuvir

5 WARNINGS AND PRECAUTIONS Risk of Hepatitis B Virus Reactivation: Test all patients for evidence of current or prior HBV infection before initiation of HCV treatment. Monitor HCV/HBV coinfected patients for HBV reactivation and hepatitis flare during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. ( 5.1 ) Bradycardia with amiodarone coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone with a sofosbuvir-containing regimen, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Coadministration of amiodarone with SOVALDI is not recommended. In patients without alternative, viable treatment options, cardiac monitoring is recommended. ( 5.2 , 6.2 , 7.1 ) 5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients. HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection, reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur. Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with SOVALDI. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with SOVALDI and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. 5.2 Serious Symptomatic Bradycardia When Coadministered with Amiodarone Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with a sofosbuvir-containing regimen. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir-containing regimen (HARVONI [ledipasvir/sofosbuvir]). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown. Coadministration of amiodarone with SOVALDI is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered SOVALDI: Counsel patients about the risk of serious symptomatic bradycardia Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Patients who are taking SOVALDI who need to start amiodarone therapy due to no other alternative, viable treatment options should undergo similar cardiac monitoring as outlined above. Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to starting SOVALDI should also undergo similar cardiac monitoring as outlined above. Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems [see Adverse Reactions (6.2) , Drug Interactions (7.1) ] . 5.3 Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers Drugs that are P-gp inducers in the intestine (e.g., rifampin, St. John’s wort) may significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of SOVALDI. The use of rifampin and St. John’s wort with SOVALDI is not recommended [see Drug Interactions (7.1) ] . 5.4 Risks Associated with Combination Treatment Because SOVALDI is used in combination with other antiviral drugs for treatment of HCV infection, consult the prescribing information for these drugs used in combination with SOVALDI. Warnings and Precautions related to these drugs also apply to their use in SOVALDI combination treatment.

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

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 Warnings and Precautions (5.3) ]. HIV Protease Inhibitors: tipranavir/ritonavir ↓ sofosbuvir ↓ GS-331007 Coadministration of SOVALDI with tipranavir/ritonavir is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Coadministration is not recommended. 7.2 Drugs without Clinically Significant Interactions with SOVALDI Based on drug interaction studies conducted with SOVALDI, no clinically significant drug interactions have been either observed or are expected when SOVALDI is combined with the following drugs [see Clinical Pharmacology (12.3) ]: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, oral contraceptives, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil fumarate.

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 with regard to pregnancy testing, contraception, and infertility also applies to these combination regimens. Refer to ribavirin and/or peginterferon prescribing information for additional information. 8.4 Pediatric Use The safety, pharmacokinetics, and efficacy of SOVALDI in pediatric patients 3 years of age and older with genotype 2 and 3 infection have been established. SOVALDI was evaluated in an open-label clinical trial (Study 1112), which included 106 subjects (31 genotype 2; 75 genotype 3) 3 years of age and older. The safety, pharmacokinetics, and efficacy were comparable to that observed in adults [see Dosage and Administration (2.3) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.5) ] . The safety and efficacy of SOVALDI in pediatric patients 3 years of age and older with compensated cirrhosis is supported by comparable sofosbuvir and GS-331007 exposures between: 1) adults and pediatric patients without cirrhosis and 2) adults without cirrhosis and adults with compensated cirrhosis. Thus, similar efficacy would be expected for pediatric patients with compensated cirrhosis as adults with compensated cirrhosis. The safety and efficacy of SOVALDI have not been established in pediatric patients less than 3 years of age with HCV genotype 2 or 3. The safety and efficacy of SOVALDI have not been established in pediatric patients with HCV genotype 1 or 4. In a 5-year follow-up study, the long-term effects of SOVALDI on pediatric growth were assessed in 88 pediatric subjects 3 years of age and older treated with SOVALDI in Study 1112. No notable effects on growth from baseline through end of study were observed [see Adverse Reactions (6.1) ]. All subjects who had achieved SVR12 maintained SVR through end of study. 8.5 Geriatric Use SOVALDI was administered to 90 subjects aged 65 and over. The response rates observed for subjects over 65 years of age were similar to that of younger subjects across treatment groups . No dosage adjustment of SOVALDI is warranted in geriatric patients [see Clinical Pharmacology (12.3) ] . 8.6 Renal Impairment No dosage adjustment of SOVALDI is required for patients with mild or moderate renal impairment. The safety and efficacy of SOVALDI have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73m 2 ) or ESRD requiring hemodialysis. No dosage recommendation can be given for patients with severe renal impairment or ESRD [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3) ] . Refer also to ribavirin and peginterferon alfa prescribing information for patients with CrCl less than 50 mL/min. 8.7 Hepatic Impairment No dosage adjustment of SOVALDI is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C) [see Clinical Pharmacology (12.3) ] . Safety and efficacy of SOVALDI have not been established in patients with decompensated cirrhosis . See peginterferon alfa prescribing information for contraindication in hepatic decompensation. 8.8 Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation SOVALDI was studied in HCV-infected adult subjects with hepatocellular carcinoma prior to undergoing liver transplantation in an open-label clinical trial evaluating the safety and efficacy of SOVALDI and ribavirin administered pre-transplant to prevent post-transplant HCV reinfection. The primary endpoint of the trial was post-transplant virologic response (pTVR) defined as HCV RNA less than lower limit of quantification (LLOQ) at 12 weeks post-transplant. HCV-infected subjects, regardless of genotype, with hepatocellular carcinoma (HCC) meeting the MILAN criteria (defined as the presence of a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas and no more than three tumor nodules, each 3 cm or less in diameter in patients with multiple tumors and no extrahepatic manifestations of the cancer or evidence of vascular invasion of tumor) received 400 mg SOVALDI and weight-based 1000–1200 mg ribavirin daily for 24–48 weeks or until the time of liver transplantation, whichever occurred first. An interim analysis was conducted on 61 subjects who received SOVALDI and ribavirin; 45 subjects had HCV genotype 1; 44 subjects had a baseline CPT score less than 7 and all subjects had a baseline unadjusted MELD score up to 14. Of these 61 subjects, 41 subjects underwent liver transplantation following up to 48 weeks of treatment with SOVALDI and ribavirin; 37 had HCV RNA less than LLOQ at the time of transplantation. Of the 37 subjects, the post-transplant virologic response (pTVR) rate is 64% (23/36) in the 36 evaluable subjects who have reached the 12 week post-transplant time point. The safety profile of SOVALDI and ribavirin in HCV-infected subjects prior to liver transplantation was comparable to that observed in subjects treated with SOVALDI and ribavirin in Phase 3 clinical trials. 8.9 Post-Liver Transplant Patients The safety and efficacy of SOVALDI have not been established in post-liver transplant patients. 8.10 Patients with Genotype 5 or 6 HCV Infection Available data on subjects with genotype 5 or 6 HCV infection are insufficient for dosing recommendations.

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.