`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
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`
` These highlights do not include all the information needed to use
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` SOVALDI safely and effectively. See full prescribing information
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` for SOVALDI.
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` SOVALDI® (sofosbuvir) tablets, for oral use
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` SOVALDI® (sofosbuvir) oral pellets
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` Initial U.S. Approval: 2013
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`WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
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`PATIENTS COINFECTED WITH HCV AND HBV
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` See full prescribing information for complete boxed warning.
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` Hepatitis B virus (HBV) reactivation has been reported, in some
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` cases resulting in fulminant hepatitis, hepatic failure, and death.
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` (5.1)
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`• Recommended treatment regimen and duration for pediatric patients
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` 3 years of age and older: (2.3, 2.4)
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` Pediatric Patient Population
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` 3 Years of Age and Older
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` Regimen
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` and
` Duration
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` Genotype
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` 2
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` Genotype
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` 3
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` Treatment-naïve and treatment-
` experienced without cirrhosis or
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` with compensated cirrhosis
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` (Child-Pugh A)
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` Treatment-naïve and treatment-
` experienced without cirrhosis or
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` with compensated cirrhosis
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` (Child-Pugh A)
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`• A dosage recommendation cannot be made for patients with severe
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` renal impairment or end stage renal disease. (2.7, 8.6)
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` SOVALDI +
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` ribavirin
` 12 weeks
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` SOVALDI +
`
` ribavirin
` 24 weeks
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`
`
`
`
`
` -----------------------DOSAGE FORMS AND STRENGTHS-------------------
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`
`• Tablets: 400 mg and 200 mg of sofosbuvir. (3)
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`• Oral Pellets: 200 mg and 150 mg of sofosbuvir. (3)
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`
` -----------------------------RECENT MAJOR CHANGES------------------------
`Indications and Usage (1)
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` 08/2019
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` Dosage and Administration
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` Recommended Dosage in Pediatric Patients 3 Years of
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` Age and Older with Genotype 2 or 3 HCV (2.3)
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` Preparation and Administration of Oral Pellets (2.4)
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` 08/2019
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` 08/2019
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`
`
` ------------------------------INDICATIONS AND USAGE-------------------------
`
` SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B
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` polymerase inhibitor indicated for the treatment of:
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`• Adult patients with genotype 1, 2, 3 or 4 chronic HCV infection
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` without cirrhosis or with compensated cirrhosis as a component of a
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` combination antiviral treatment regimen. (1)
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`• Pediatric patients 3 years of age and older with genotype 2 or 3
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` chronic HCV infection without cirrhosis or with compensated
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` cirrhosis in combination with ribavirin. (1)
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` ------------------------DOSAGE AND ADMINISTRATION---------------------
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`• Testing Prior to the Initiation of Therapy: Test all patients for HBV
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` infection by measuring HBsAg and anti-HBc. (2.1)
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`• Recommended dosage in adults: One 400 mg tablet taken once
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` daily with or without food. (2.2)
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`• Recommended dosage in pediatric patients 3 years of age and
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` older: Recommended dosage of SOVALDI in pediatric patients 3
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` years of age and older with genotype 2 or 3 HCV using SOVALDI
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` tablets or oral pellets is based on weight. Refer to Table 3 of the full
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` prescribing information for specific dosing guidelines based on body
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` weight. (2.3)
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`• HCV/HIV-1 coinfection: For adult and pediatric patients with
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` HCV/HIV-1 coinfection, follow the dosage recommendations in the
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` tables below, respectively. (2.2, 2.3)
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`• Recommended adult treatment regimen and duration: (2.2)
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` Regimen
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` and
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` Duration
` SOVALDI +
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` peginterferon
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` alfa + ribavirin
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` 12 weeks
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` Adult Patient Population
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`--------------------------------CONTRAINDICATIONS-----------------------------
`• When used in combination with peginterferon alfa/ribavirin or
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` ribavirin alone, all contraindications to peginterferon alfa and/or
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` ribavirin also apply to SOVALDI combination therapy. (4)
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` -------------------------WARNINGS AND PRECAUTIONS---------------------
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`• Risk of Hepatitis B Virus Reactivation: Test all patients for evidence
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` of current or prior HBV infection before initiation of HCV treatment.
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` Monitor HCV/HBV coinfected patients for HBV reactivation and
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` hepatitis flare during HCV treatment and post-treatment follow-up.
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` Initiate appropriate patient management for HBV infection as
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` clinically indicated. (5.1)
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`• Bradycardia with amiodarone coadministration: Serious symptomatic
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` bradycardia may occur in patients taking amiodarone with a
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` sofosbuvir-containing regimen, particularly in patients also receiving
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` beta blockers, or those with underlying cardiac comorbidities and/or
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` advanced liver disease. Coadministration of amiodarone with
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` SOVALDI is not recommended. In patients without alternative,
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` viable treatment options, cardiac monitoring is recommended. (5.2,
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` 6.2, 7.1)
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` --------------------------------ADVERSE REACTIONS----------------------------
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`• The most common adverse events (incidence greater than or equal
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` to 20%, all grades) observed with SOVALDI in combination with
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` ribavirin were fatigue and headache. The most common adverse
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` events observed with SOVALDI in combination with peginterferon
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` alfa and ribavirin were fatigue, headache, nausea, insomnia and
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` anemia. (6.1). The most common adverse events observed with
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` SOVALDI in combination with ribavirin oral solution in pediatric
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` patients was decreased appetite. (6.1)
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` To report SUSPECTED ADVERSE REACTIONS, contact Gilead
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` Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or
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`
`
`
` www.fda.gov/medwatch.
`
`
`
`
`---------------------------------DRUG INTERACTIONS----------------------------
`• Coadministration of amiodarone with a sofosbuvir-containing
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` regimen may result in serious symptomatic bradycardia. (5.2, 6.2,
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` 7.1)
`• Drugs that are intestinal P-gp inducers (e.g., rifampin, St. John’s
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` wort) may alter the concentrations of sofosbuvir. (5.3, 7, 12.3)
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`• Frequent monitoring of international normalized ratio (INR) values is
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` recommended in patients receiving warfarin. (7.1)
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`• Consult the full prescribing information prior to use for potential
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` drug-drug interactions. (5.2, 5.3, 7, 12.3)
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`
` ---------------------------USE IN SPECIFIC POPULATIONS-------------------
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`• Patients with HCV/HIV-1 coinfection: Safety and efficacy have been
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` studied. (14.4)
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`• Patients with hepatocellular carcinoma awaiting liver transplantation:
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` Safety and efficacy have been studied. (8.8)
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` See 17 for PATIENT COUNSELING INFORMATION and
` FDA-approved patient labeling.
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` Revised: 08/2019
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` Genotype
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` 1 or 4
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` Treatment-naïve without cirrhosis
` or with compensated cirrhosis
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` (Child-Pugh A)
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` Genotype
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` 2
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` Genotype
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` 3
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` Treatment-naïve and treatment-
` experienced without cirrhosis or
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` with compensated cirrhosis
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` (Child-Pugh A)
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` Treatment-naïve and treatment-
` experienced without cirrhosis or
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` with compensated cirrhosis
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` (Child-Pugh A)
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`• SOVALDI in combination with ribavirin for 24 weeks can be
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` considered for adult patients with genotype 1 infection who are
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` interferon ineligible. (2.2)
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`• Should be used in combination with ribavirin for treatment of HCV in
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` adult patients with hepatocellular carcinoma awaiting liver
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` transplantation for up to 48 weeks or until liver transplantation,
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` whichever occurs first. (2.2)
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`
` SOVALDI +
`
` ribavirin
` 12 weeks
`
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`
`
` SOVALDI +
`
` ribavirin
` 24 weeks
`
`
`
`
`Reference ID: 4483740
`
`
`
` 1
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`8.1 Pregnancy
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`8.2 Lactation
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`8.3 Females and Males of Reproductive Potential
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`8.4 Pediatric Use
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`8.5 Geriatric Use
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`8.6 Renal Impairment
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`8.7 Hepatic Impairment
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`8.8 Patients with Hepatocellular Carcinoma Awaiting Liver
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`Transplantation
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`8.9 Post-Liver Transplant Patients
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`8.10 Patients with Genotype 5 or 6 HCV Infection
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` 10 OVERDOSAGE
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` 11 DESCRIPTION
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` 12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
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`12.2 Pharmacodynamics
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`12.3 Pharmacokinetics
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`12.4 Microbiology
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` 13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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` 14 CLINICAL STUDIES
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`14.1 Description of Clinical Trials
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`14.2 Clinical Trials in Subjects with Genotype 1 or 4 HCV
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`14.3 Clinical Trials in Subjects with Genotype 2 or 3 HCV
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`14.4 Clinical Trials in Adult Subjects Coinfected with HCV and
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`HIV-1 – Photon-1 (Study 0123)
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`14.5 Clinical Trial in Pediatrics (Study 1112)
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` 16 HOW SUPPLIED/STORAGE AND HANDLING
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` 17 PATIENT COUNSELING INFORMATION
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` FULL PRESCRIBING INFORMATION: CONTENTS*
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`
`
` WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
`
` PATIENTS COINFECTED WITH HCV AND HBV
`
`
`
`
`
` 1 INDICATIONS AND USAGE
`
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`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`2.1 Testing Prior to the Initiation of Therapy
`
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`2.2 Recommended Dosage in Adults
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`2.3 Recommended Dosage in Pediatric Patients 3 Years of
`
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`
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`Age and Older with Genotype 2 or 3 HCV
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`2.4 Preparation and Administration of Oral Pellets
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`2.5 Dosage Modification
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`2.6 Discontinuation of Dosing
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`2.7 Severe Renal Impairment and End Stage Renal Disease
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` 3 DOSAGE FORMS AND STRENGTHS
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` 4 CONTRAINDICATIONS
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` 5 WARNINGS AND PRECAUTIONS
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`5.1 Risk of Hepatitis B Virus Reactivation in Patients
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`
`Coinfected with HCV and HBV
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`5.2 Serious Symptomatic Bradycardia When Coadministered
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`with Amiodarone
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`5.3 Risk of Reduced Therapeutic Effect Due to Use with P-gp
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`
`Inducers
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`5.4 Risks Associated with Combination Treatment
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` 6 ADVERSE REACTIONS
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`6.1 Clinical Trials Experience
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`6.2 Postmarketing Experience
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` 7 DRUG INTERACTIONS
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`7.1 Potentially Significant Drug Interactions
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`7.2 Drugs without Clinically Significant Interactions with
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`SOVALDI
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` 8 USE IN SPECIFIC POPULATIONS
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` * Sections or subsections omitted from the full prescribing information are not
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` listed.
`
`
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`
`
`
`
`Reference ID: 4483740
`
`
`
` 2
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS
`
`
`COINFECTED WITH HCV AND HBV
`
`
`
`
`Test all patients for evidence of current or prior hepatitis B virus (HBV) infection
`
` before initiating treatment with SOVALDI. HBV reactivation has been reported in
` HCV/HBV coinfected patients who were undergoing or had completed treatment
`
`
` with HCV direct acting antivirals and were not receiving HBV antiviral therapy.
`Some cases have resulted in fulminant hepatitis, hepatic failure, and death.
`Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation
` during HCV treatment and post-treatment follow-up. Initiate appropriate patient
`
`management for HBV infection as clinically indicated [see Warnings and
`
` Precautions (5.1)].
`
`
`
` 1
`
`
`
` INDICATIONS AND USAGE
`
`
`
`
`
` 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
`
`
`
`
`
` 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)].
`
`
`
`
`
`
`
`Reference ID: 4483740
`
`
`
` 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 alfaa
` + ribavirinb 12 weeks
`
`
`
`
`
`
`
`
`
`
`
`
` SOVALDI + ribavirinb 12 weeks
`
`Genotype 2
`
`
`
`Genotype 3
`
`
`
` Treatment-naïve and treatment-experiencedc
`
` without cirrhosis or with compensated cirrhosis
`
`
`
` (Child-Pugh A)
`
` Treatment-naïve and treatment-experiencedc
`
` without cirrhosis or with compensated cirrhosis
`
`
`
` (Child-Pugh A)
`
`
`
` SOVALDI + ribavirinb 24 weeks
`
`
`
`
`
`a. See peginterferon alfa prescribing information for dosage recommendation for patients with genotype 1 or 4 HCV.
`
`
`
`
`
`
`
`b. 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.
`
`
`
`c. Treatment-experienced patients have failed an interferon-based regimen with or without ribavirin.
`
`
`
`
`
` 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
`
`
`
`
`
` 4
`
`
`
`Reference ID: 4483740
`
`
`
`
`
` 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
`
`
`
`
`Genotype 2
`
`
`
`Genotype 3
`
`
`
`
` Recommended Treatment Regimen and Duration in Pediatric
` Patients 3 Years and Older with Genotype 2 or 3 HCV
`
`
`
`
` Treatment Regimen and
`
` Duration
`
`
`
` Patient Population
`
`
`
`
`
`
`
`
`
`
`
`
`
` SOVALDI + ribavirinb 12 weeks
`
`
`
`
`
`
`
` SOVALDI + ribavirinb 24 weeks
`
` Treatment-naïve and treatment-experienceda
`
` without cirrhosis or with compensated cirrhosis
`
`
`
` (Child-Pugh A)
`
` Treatment-naïve and treatment-experienceda
`
` without cirrhosis or with compensated cirrhosis
`
`
`
` (Child-Pugh A)
`
`
`
`
`
`
` a. Treatment-experienced patients have failed an interferon based regimen with or without ribavirin.
`
` b. See Table 4 for weight-based ribavirin dosing recommendations.
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
` 200 mg per day
`
`
`
` one 200 mg tablet once daily
`
` or
` one 200 mg packet of pellets once daily
`
`
`
`
`
`
`
`
`
`
`
` one 150 mg packet of pellets once daily
`
`
`
`
`
` 17 to less than 35
`
`
`
`
`
`
`
` less than 17
`
`
`
`
`
`
`
`Reference ID: 4483740
`
`
`
`
`
` 150 mg per day
`
`
`
`
`
`
`
` 5
`
`
`
`
`
` Table 4
`
`
`
` Recommended Dosing for Ribavirin in Combination Therapy with
`
`SOVALDI for Pediatric Patients 3 Years and Older
`Oral Ribavirin Daily Dosagea
` Body Weight (kg)
`
`
`
`
`
`
`
`
`
`
`
`
`
` 15 mg per kg per day
`
`
`
`
`
` less than 47
`
`47–49
`
`
`
`50–65
`
`
`
`66–80
`
`
`
`
`
` greater than 80
`
`
`
` (divided dose AM and PM)
`
`
`
`
`
`
`
` 600 mg per day
`
`
`
`
`
` (1 x 200 mg AM, 2 x 200 mg PM)
`
` 800 mg per day
`
`
`
`
`
`
`
`
`
` (2 x 200 mg AM, 2 x 200 mg PM)
`
`
`
`
`
` 1000 mg per day
`
`
`
`
`
` (2 x 200 mg AM, 3 x 200 mg PM)
`
`
`
` 1200 mg perday
`
`
`
`
`
` (3 x 200 mg AM, 3 x 200 mg PM)
`
`
`
` a. The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food.
`
`
`
`
`
`
`
` 2.4 Preparation and Administration of Oral 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/1.73m2) 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)].
`
`
`
`Reference ID: 4483740
`
`
`
` 6
`
`
`
`
`
` 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.
`
`
`
`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.
`
`
`
`
`
`
`5
`
` WARNINGS AND PRECAUTIONS
`
`
`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.
`
`
`
`
`
`
` 7
`
`
`
`Reference ID: 4483740
`
`
`
`
`
` 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.
`
`
`
`
`
`Reference ID: 4483740
`
`
`
` 8
`
`
`
`
`
` 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)].
`
`
`
` 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.
`
`
`
` 9
`
`
`
`Reference ID: 4483740
`
`
`
`
`
` Table 5
`
`
`
`
`
`
`
`Adverse Events (All Grades and without Regard to Causality)
`
`
` Reported in ≥15% of Subjects with HCV in Any Treatment Arm
` Interferon-containing Regimens
` Interferon-free Regimens
`
`
`
`
`
` PBO
`
`
`
` 12 weeks
`
` SOVALDI
`
` + RBVa
`
`
`
`
` 12 weeks
`
`
`
` SOVALDI
`
` + RBVa
`
`
`
` 24 weeks
`
` Peg-IFN alfa +
`
`
`RBVb
`
`
`
` 24 weeks
`
`
`
` SOVALDI
`
`
` + Peg-IFN alfa
`
` + RBVa
`
`
`
`
` 12 weeks
`
`
`
` Fatigue
`
`
`
` Headache
`
`
`
` N=71
`
`
`
` 24%
`
`
`
` 20%
`
`
`
` N=650
`
`
`
` N=250
`
`
`
` N=243
`
`
`
` N=327
`
`
`
` 38%
`
`
`
` 24%
`
`
`
` 30%
`
`
`
` 30%
`
`
`
` 55%
`
`
`
` 44%
`
`
`
` 59%
`
`
`
` 36%
`
` 34%
`
`
`
` Nausea
`
`
`
` 18%
`
`
`
` Insomnia
`
`
`
` Pruritus
`
`
`
` Anemia
`
`
`
` Asthenia
`
`
`
` 4%
`
`
`
` 8%
`
`
`
` 0%
`
`
`
` 3%
`
`
`
` 22%
`
`
`
` 15%
`
`
`
` 11%
`
`
`
` 10%
`
`
`
` 6%
`
`
`
` 13%
`
`
`
` 16%
`
`
`
` 27%
`
`
`
` 6%
`
`
`
` 21%
`
`
`
` 29%
`
`
`
` 29%
`
`
`
` 17%
`
`
`
` 12%
`
`
`
` 3%
`
`
`
`
`
` 25%
`
`
`
` 17%
`
`
`
` 21%
`
`
`
` 5%
`
` 18%
`
`
`
` Rash
`
`
` Decreased
`
` Appetite
`
`
`
` Chills
`
`Influenza
` Like Illness
`
`
`
`
` Pyrexia
`
`
`
` 8%
`
`
`
` 10%
`
`
`
` 1%
`
`
`
` 3%
`
`
`
` 0%
`
`
`
` 8%
`
`
`
` 6%
`
`
`
` 2%
`
`
`
` 3%
`
`
`
` 4%
`
`
`
` 9%
`
`
`
` 6%
`
`
`
` 2%
`
`
`
` 6%
`
`
`
` 4%
`
` 12%
`
`
`
` 18%
`
`
`
` 18%
`
`
`
` 18%
`
`
`
` 18%
`
`
`
` 14%
`
` 17%
`
`
`
`
`
` 18%
`
`
`
` 17%
`
`
`
` 16%
`
`
`
` 18%
`
` 12%
`
`
`
` Diarrhea
`
`
`
` Neutropenia
`
`
`
` Myalgia
`
`
`
` Irritability
`
`
`
` 6%
`
`
`
` 0%
`
`
`
` 0%
`
`
`
` 1%
`
`
`
` 9%
`
`
`
` <1%
`
`
`
` 6%
`
`
`
` 10%
`
`
`
`
`
` <1%
`
`
`
` 9%
`
`
`
` 10%
`
`
`
`
`
` 12%
`
`
`
` 16%
`
`
`
` 16%
`
`
`
`
`
` 17%
`
`
`
` 14%
`
`
`
` 13%
`
`
`
`
`
`
`
`
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` a. Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing
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` ≥75 kg).
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` b. Subjects received 800 mg ribavirin per day regardless of weight.
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` 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.
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` Less Common Adverse Reactions Reported in Clinical Trials (less than 1%): The
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` following adverse reactions occurred in less than 1% of subjects receiving SOVALDI in
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`a combination regimen in any one trial. These events have been included because of
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` their seriousness or assessment of potential causal relationship.
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` Hematologic Effects: pancytopenia (particularly in subjects receiving concomitant
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` pegylated interferon).
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`Reference ID: 4483740
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` 10
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` Psychiatric Disorders: severe depression (particula