` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`212480Orig1s000
`
`
`LABELING
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`SOVALDI safely and effectively. See full prescribing information
`for SOVALDI.
`
`SOVALDI® (sofosbuvir) tablets, for oral use
`SOVALDI® (sofosbuvir) oral pellets
`Initial U.S. Approval: 2013
`
`
`WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
`PATIENTS COINFECTED WITH HCV AND HBV
`See full prescribing information for complete boxed warning.
`
`Hepatitis B virus (HBV) reactivation has been reported, in some
`cases resulting in fulminant hepatitis, hepatic failure, and death.
`(5.1)
`
`-----------------------------RECENT MAJOR CHANGES-------------------------
`Indications and Usage (1)
`
`
`
`08/2019
`Dosage and Administration
` Recommended Dosage in Pediatric Patients 3 Years of
` Age and Older with Genotype 2 or 3 HCV (2.3)
`
` Preparation and Administration of Oral Pellets (2.4)
`
`08/2019
`08/2019
`
`------------------------------INDICATIONS AND USAGE--------------------------
`SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B
`polymerase inhibitor indicated for the treatment of:
`• Adult patients with genotype 1, 2, 3 or 4 chronic HCV infection
`without cirrhosis or with compensated cirrhosis as a component of a
`combination antiviral treatment regimen. (1)
`• Pediatric patients 3 years of age and older with genotype 2 or 3
`chronic HCV infection without cirrhosis or with compensated
`cirrhosis in combination with ribavirin. (1)
`
`------------------------DOSAGE AND ADMINISTRATION----------------------
`• Testing Prior to the Initiation of Therapy: Test all patients for HBV
`infection by measuring HBsAg and anti-HBc. (2.1)
`• Recommended dosage in adults: One 400 mg tablet taken once
`daily with or without food. (2.2)
`• Recommended dosage in pediatric patients 3 years of age and
`older: Recommended dosage of SOVALDI in pediatric patients 3
`years of age and older with genotype 2 or 3 HCV using SOVALDI
`tablets or oral pellets is based on weight. Refer to Table 3 of the full
`prescr bing information for specific dosing guidelines based on body
`weight. (2.3)
`• HCV/HIV-1 coinfection: For adult and pediatric patients with
`HCV/HIV-1 coinfection, follow the dosage recommendations in the
`tables below, respectively. (2.2, 2.3)
`• Recommended adult treatment regimen and duration: (2.2)
`Regimen
`and
`Duration
`SOVALDI +
`peginterferon
`alfa + ribavirin
`12 weeks
`
`Genotype
`1 or 4
`
`Treatment-naïve without cirrhosis
`or with compensated cirrhosis
`(Child-Pugh A)
`
`
`
`Adult Patient Population
`
`Genotype
`2
`
`Genotype
`3
`
`Treatment-naïve and treatment-
`experienced without cirrhosis or
`with compensated cirrhosis
`(Child-Pugh A)
`Treatment-naïve and treatment-
`experienced without cirrhosis or
`with compensated cirrhosis
`(Child-Pugh A)
`• SOVALDI in combination with ribavirin for 24 weeks can be
`considered for adult patients with genotype 1 infection who are
`interferon ineligible. (2.2)
`• Should be used in combination with r bavirin for treatment of HCV in
`adult patients with hepatocellular carcinoma awaiting liver
`transplantation for up to 48 weeks or until liver transplantation,
`whichever occurs first. (2.2)
`
`SOVALDI +
`ribavirin
`12 weeks
`
`SOVALDI +
`ribavirin
`24 weeks
`
`
`Reference ID: 4483740
`
`• Recommended treatment regimen and duration for pediatric patients
`3 years of age and older: (2.3, 2.4)
`
`
`
`Pediatric Patient Population
`3 Years of Age and Older
`
`Regimen
`and
`Duration
`
`Genotype
`2
`
`Genotype
`3
`
`Treatment-naïve and treatment-
`experienced without cirrhosis or
`with compensated cirrhosis
`(Child-Pugh A)
`Treatment-naïve and treatment-
`experienced without cirrhosis or
`with compensated cirrhosis
`(Child-Pugh A)
`• A dosage recommendation cannot be made for patients with severe
`renal impairment or end stage renal disease. (2.7, 8.6)
`
`SOVALDI +
`ribavirin
`12 weeks
`
`SOVALDI +
`ribavirin
`24 weeks
`
`-----------------------DOSAGE FORMS AND STRENGTHS--------------------
`• Tablets: 400 mg and 200 mg of sofosbuvir. (3)
`• Oral Pellets: 200 mg and 150 mg of sofosbuvir. (3)
`
`--------------------------------CONTRAINDICATIONS------------------------------
`• When used in combination with peginterferon alfa/ribavirin or
`ribavirin alone, all contraindications to peginterferon alfa and/or
`ribavirin also apply to SOVALDI combination therapy. (4)
`
`-------------------------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)
`
`--------------------------------ADVERSE REACTIONS-----------------------------
`• 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.
`
`---------------------------------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)
`• Frequent monitoring of international normalized ratio (INR) values is
`recommended in patients receiving warfarin. (7.1)
`• Consult the full prescr bing information prior to use for potential
`drug-drug interactions. (5.2, 5.3, 7, 12.3)
`
`---------------------------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)
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling.
`
`
`
`
`
`
`
`
`
`
`
`Revised: 08/2019
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
`PATIENTS COINFECTED WITH HCV AND HBV
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Testing Prior to the Initiation of Therapy
`
`2.2 Recommended Dosage in Adults
`
`2.3 Recommended Dosage in Pediatric Patients 3 Years of
`Age and Older with Genotype 2 or 3 HCV
`2.4 Preparation and Administration of Oral Pellets
`
`2.5 Dosage Modification
`
`2.6 Discontinuation of Dosing
`
`2.7 Severe Renal Impairment and End Stage Renal Disease
`
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Risk of Hepatitis B Virus Reactivation in Patients
`Coinfected with HCV and HBV
`5.2 Serious Symptomatic Bradycardia When Coadministered
`with Amiodarone
`5.3 Risk of Reduced Therapeutic Effect Due to Use with P-gp
`Inducers
`5.4 Risks Associated with Combination Treatment
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`
`7.1 Potentially Significant Drug Interactions
`
`7.2 Drugs without Clinically Significant Interactions with
`SOVALDI
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`
`
`
`
`
`
`Reference ID: 4483740
`
`
`
`
`
`
`
`
`
`
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`8.8 Patients with Hepatocellular Carcinoma Awaiting Liver
`Transplantation
`8.9 Post-Liver Transplant Patients
`
`8.10 Patients with Genotype 5 or 6 HCV Infection
`
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`12.4 Microbiology
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`
`14.1 Description of Clinical Trials
`
`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 – Photon-1 (Study 0123)
`14.5 Clinical Trial in Pediatrics (Study 1112)
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the full prescribing information are not
`listed.
`
`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
`
`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 12 weeks
`
`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
`
`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)
`
`SOVALDI + ribavirinb 12 weeks
`
`SOVALDI + ribavirinb 24 weeks
`
`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
`
`17 to less than 35
`
`one 400 mg tablet once daily
`or
`two 200 mg tablets once daily
`or
`two 200 mg packets of pellets once daily
`
`one 200 mg tablet once daily
`or
`one 200 mg packet of pellets once daily
`
`400 mg per day
`
`200 mg per day
`
`less than 17
`
`one 150 mg packet of pellets once daily
`
`150 mg per day
`
`
`
`
`
`
`
`
`
`Reference ID: 4483740
`
`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)
`
`less than 47
`
`47–49
`
`50–65
`
`66–80
`
`greater than 80
`
`15 mg per kg per day
`
`(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-free Regimens
`Interferon-containing 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
`
`N=71
`
`N=650
`
`N=250
`
`N=243
`
`N=327
`
`Fatigue
`
`Headache
`
`Nausea
`
`Insomnia
`
`Pruritus
`
`Anemia
`
`24%
`
`20%
`
`18%
`
`4%
`
`8%
`
`0%
`
`3%
`
`38%
`
`24%
`
`22%
`
`15%
`
`11%
`
`10%
`
`6%
`
`30%
`
`30%
`
`13%
`
`16%
`
`27%
`
`6%
`
`21%
`
`55%
`
`44%
`
`29%
`
`29%
`
`17%
`
`12%
`
`3%
`
`59%
`
`36%
`
`34%
`
`25%
`
`17%
`
`21%
`
`5%
`
`Asthenia
`
`Rash
`
`Decreased
`Appetite
`
`Chills
`
`Influenza
`Like Illness
`
`Pyrexia
`
`Diarrhea
`
`Neutropenia
`
`Myalgia
`
`Irritability
`
`8%
`
`10%
`
`1%
`
`3%
`
`0%
`
`6%
`
`0%
`
`0%
`
`1%
`
`8%
`
`6%
`
`2%
`
`3%
`
`4%
`
`9%
`
`<1%
`
`6%
`
`10%
`
`9%
`
`6%
`
`2%
`
`6%
`
`4%
`
`12%
`
`<1%
`
`9%
`
`10%
`
`18%
`
`18%
`
`18%
`
`18%
`
`14%
`
`17%
`
`12%
`
`16%
`
`16%
`
`18%
`
`18%
`
`17%
`
`16%
`
`18%
`
`12%
`
`17%
`
`14%
`
`13%
`
`a. Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing
`≥75 kg).
`b. Subjects received 800 mg ribavirin per day regardless of weight.
`
`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).
`
`
`
`Reference ID: 4483740
`
`10
`
`

`

`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
`Interferon-free Regimens
`
`Interferon-containing Regimens
`
`Hematological
`Parameters
`
`PBO
`
`12 weeks
`
`SOVALDI +
`RBVa
`
`SOVALDI +
`RBVa
`
`12 weeks
`
`24 weeks
`
`Peg-IFN
`+ RBVb
`
`24 weeks
`
`SOVALDI
`+ Peg-IFN + RBVa
`12 weeks
`
`
`
`N=71
`
`N=647
`
`N=250
`
`N=242
`
`N=327
`
`Hemoglobin (g/dL)
`
`
`
`
`
` <10
`
`<8.5
`
`Neutrophils (x109/L)
`
`≥0.5 – <0.75
`
`<0.5
`
`Platelets (x109/L)
`
` ≥25 – <50
`
` <25
`
`0
`
`0
`
`1%
`
`0
`
`3%
`
`0
`
`8%
`
`1%
`
`
`
`<1%
`
`<1%
`
`
`
`<1%
`
`0
`
`6%
`
`<1%
`
`0
`
`0
`
`1%
`
`0
`
`14%
`
`2%
`
`12%
`
`2%
`
`7%
`
`0
`
`
`
`
`
`23%
`
`2%
`
`15%
`
`5%
`
`<1%
`
`0
`
`a. Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing
`≥75 kg).
`b. Subjects received 800 mg ribavirin per day regardless of weight.
`
`Bilirubin Elevations
`
`Total bilirubin elevation of more than 2.5xULN 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 10xULN 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.
`
`11
`
`
`
`Reference ID: 4483740
`
`

`

`Lipase Elevations
`
`Isolated, asymptomatic lipase elevation of greater than 3xULN 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) subjects [see Clinical Studies 14.5)].
`
`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 r