Sovaldi Drug Information

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.

Recommended Dosage in Adults

The recommended dosage of SOVALDI is one 400 mg tablet, taken orally, once daily with or without food. 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 for dosage recommendations for concomitant HIV-1 antiviral drugs. Table 1 Recommended Treatment Regimen and Duration in Adult Patients with Genotype HCV 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.

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.

Table 4 provides the weight-based dosage of ribavirin when used in combination with SOVALDI for pediatric patients. Table 2 Recommended Treatment Regimen and Duration in Pediatric Patients 3 Years and Older with 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. SOVALDI pellets can be taken by pediatric patients who cannot swallow the tablet formulation.

Table 3 Dosing for Pediatric Patients 3 Years and Older Using SOVALDI Tablets or Oral Pellets Table 4 Recommended Dosing for Ribavirin in Combination Therapy with SOVALDI for Pediatric Patients 3 Years and Older

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.

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.

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

Severe Renal Impairment and End Stage Renal Disease

No dosage recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate 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.

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 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. Table 5 Adverse Events (All Grades and without Regard to Causality) Reported in ≥15% of Subjects with HCV in Any Treatment Arm 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. 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. Lipase Elevations Isolated, asymptomatic lipase elevation of greater than 3×ULN was observed in less than 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. The safety profile in HCV/HIV-1 coinfected subjects was similar to that observed in HCV mono-infected subjects. None of the subjects had concomitant transaminase increases.

The adverse reactions observed were consistent with those observed in clinical studies of SOVALDI plus ribavirin in adults. 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.

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.

Skin and Subcutaneous Tissue Disorders Skin rashes, sometimes with blisters or angioedema-like swelling Angioedema

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.

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 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. 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. Coadministration of amiodarone with SOVALDI is not recommended; if coadministration is required, cardiac monitoring is recommended.

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. 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. 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.

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: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, oral contraceptives, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil fumarate.

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). 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 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.

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. The safety, pharmacokinetics, and efficacy were comparable to that observed in adults. 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. All subjects who had achieved SVR12 maintained SVR through end of study.

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.

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.