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 12 years of age and older or weighing at least 35 kg without cirrhosis or with compensated cirrhosis for use in combination with ribavirin [see Dosage and Administration (2.3) and Clinical Studies (14.5)] .

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.

2.3 Recommended Dosage in Pediatric Patients 12 Years of Age and Older or Weighing at Least 35 kg

The recommended dosage of SOVALDI in pediatric patients 12 years of age and older or weighing at least 35 kg is one 400 mg tablet taken orally once daily with or without food in combination with ribavirin [see Clinical Pharmacology (12.3) and Clinical Studies (14.5)] .

The recommended treatment regimen and duration for SOVALDI combination therapy is provided in Table 2. Table 3 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 2 and Table 3. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs.

2.4 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.

2.5 Discontinuation of Dosing

If the other agents used in combination with SOVALDI are permanently discontinued, SOVALDI should also be discontinued.

2.6 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)] .

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.

6.1 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.

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.

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 6. The table is not all-inclusive [see Warnings and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3)].

7.2 Drugs without Clinically Significant Interactions with SOVALDI

In addition to the drugs included in Table 6, the interaction between SOVALDI and the following drugs was evaluated in clinical trials and no dose adjustment is needed for either drug [See Clinical Pharmacology (12.3)]: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, oral contraceptives, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil fumarate.

8.1 Pregnancy

8.2 Lactation

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 12 years of age and older or weighing at least 35 kg with genotype 2 and 3 infection have been established. SOVALDI was evaluated in an open-label clinical trial (Study 1112), which included 50 subjects (13 genotype 2; 37 genotype 3) 12 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 12 years of age and older or weighing at least 35 kg with compensated cirrhosis is supported by comparable sofosbuvir and GS-331007 exposures between: 1) adults and adolescents without cirrhosis and 2) adults without cirrhosis and adults with compensated cirrhosis. Thus, similar efficacy would be expected for adolescent patients with compensated cirrhosis as adults with compensated cirrhosis.

The safety and efficacy of SOVALDI have not been established in pediatric patients less than 12 years of age and weighing less than 35 kg 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.

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 (2.6) 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.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Description of Clinical Trials

The safety and efficacy of SOVALDI was evaluated in five Phase 3 trials in a total of 1724 HCV mono-infected subjects with genotypes 1 to 6 chronic hepatitis C virus, one Phase 3 trial in 223 HCV/HIV-1 coinfected subjects with genotype 1, 2 or 3 HCV, and one trial in 50 pediatric subjects 12 years of age and older with genotype 2 or 3 HCV, as summarized in Table 10 [see Clinical Studies (14.2, 14.3, 14.4, and 14.5)] .

Subjects in the adult trials did not have cirrhosis or had compensated cirrhosis. SOVALDI was administered at a dose of 400 mg once daily. The ribavirin (RBV) dosage for adult subjects was weight-based at 1000–1200 mg daily administered in two divided doses when used in combination with SOVALDI, and the peginterferon alfa 2a dosage, where applicable, was 180 micrograms per week. Treatment duration was fixed in each trial and was not guided by subjects' HCV RNA levels (no response guided algorithm). Plasma HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU per mL. Sustained virologic response (SVR12) was the primary endpoint which was defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment.

14.2 Clinical Trials in Subjects with Genotype 1 or 4 HCV

14.3 Clinical Trials in Subjects with Genotype 2 or 3 HCV

14.4 Clinical Trials in Adult Subjects Coinfected with HCV and HIV-1

SOVALDI was studied in an open-label clinical trial (Study PHOTON-1) evaluating the safety and efficacy of 12 or 24 weeks of treatment with SOVALDI and ribavirin in adult subjects with genotype 1, 2 or 3 chronic hepatitis C coinfected with HIV-1. Genotype 2 and 3 subjects were either HCV treatment-naïve or experienced, whereas genotype 1 subjects were all treatment-naïve. Subjects received 400 mg SOVALDI and weight-based ribavirin (1000 mg for subjects weighing less than 75 kg or 1200 mg for subjects weighing at least 75 kg) daily for 12 or 24 weeks based on genotype and prior treatment history. Subjects were either not on antiretroviral therapy with a CD4+ cell count greater than 500 cells/mm 3 or had virologically suppressed HIV-1 with a CD4+ cell count greater than 200 cells/mm 3. Efficacy data 12 weeks post treatment are available for 210 subjects (see Table 21).

In subjects with HCV genotype 1 infection, the SVR12 rate was 82% (74/90) in subjects with genotype 1a infection and 54% (13/24) in subjects with genotype 1b infection, with relapse accounting for the majority of treatment failures. SVR12 rates in subjects with HCV genotype 1 infection were 80% (24/30) in subjects with baseline IL28B C/C allele and 75% (62/83) in subjects with baseline IL28B non-C/C alleles.

In the 223 HCV subjects with HIV-1 coinfection, the percentage of CD4+ cells did not change during treatment. Median CD4+ cell count decreases of 85 cells/mm 3 and 84 cells/mm 3 were observed at the end of treatment with SOVALDI + ribavirin for 12 or 24 weeks, respectively. HIV-1 rebound during SOVALDI + ribavirin treatment occurred in 2 subjects (0.9%) on antiretroviral therapy.

14.5 Clinical Trial in Pediatrics

The efficacy of SOVALDI in HCV-infected pediatric subjects 12 years of age and older was evaluated in 50 subjects with HCV genotype 2 (N = 13) or genotype 3 (N = 37) in a Phase 2, open label clinical trial. Subjects with HCV genotype 2 or 3 infection in the trial were treated with SOVALDI and weight-based ribavirin for 12 or 24 weeks, respectively [see Dosage and Administration (2.3)] .

Of the 50 treated subjects, the median age was 15 years (range: 12 to 17); 42% of the subjects were female; 90% were White, 4% were Black, and 2% were Asian; 4% were Hispanic/Latino; mean weight was 61 kg (range: 30 to 101 kg); 18% were treatment experienced; 66% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 74% of subjects had non-CC IL28B alleles (CT or TT); and no subjects had known cirrhosis. The majority of subjects (69%) had been infected through vertical transmission.

The SVR12 rate was 100% (13/13) in genotype 2 subjects and 97% (36/37) in genotype 3 subjects. No subject experienced on-treatment virologic failure or relapse.

Store below 30°C (86°F).

• Dispense only in original container
• Do not use if seal over bottle opening is broken or missing

Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV

Inform patients that HBV reactivation can occur in patients coinfected with HBV during or after treatment of HCV infection. Advise patients to tell their healthcare provider if they have a history of HBV infection [see Warnings and Precautions (5.1)] .

Serious Symptomatic Bradycardia When Coadministered with Amiodarone

Advise patients to seek medical evaluation immediately for symptoms of bradycardia such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems [see Warnings and Precautions (5.2), Adverse Reactions (6.2), and Drug Interactions (7.1)] .

Pregnancy

Advise patients to avoid pregnancy during combination treatment with SOVALDI and ribavirin or SOVALDI and peginterferon and ribavirin. Inform patients to notify their health care provider immediately in the event of a pregnancy [see Use in Specific Populations (8.1)] .

Drug Interactions

Advise patients that SOVALDI may interact with some drugs; therefore, patients should be advised to report the use of any prescription, non-prescription medication or herbal products to their healthcare provider [see Warnings and Precautions (5.3) and Drug Interactions (7.1)] .

Hepatitis C Virus Transmission

Inform patients that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus during treatment or in the event of treatment failure should be taken.

Important Information on Coadministration with Ribavirin or Peginterferon and Ribavirin

Advise patients that the recommended regimen for patients with genotype 1 or 4 HCV infection is SOVALDI administered in combination with peginterferon alfa and ribavirin and the recommended regimen for patients with genotype 2 or 3 HCV infection is SOVALDI administered in combination with ribavirin. If peginterferon and/or ribavirin are permanently discontinued, SOVALDI should also be discontinued.