`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
`These highlights do not include all the information needed to use
`HARVONI® safely and effectively. See full prescribing information
`
`
`
`for HARVONI.
`
`
`
`HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use
`
`
`
`Initial U.S. Approval: 2014
`
`
`
`
`
`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 ----------------------­
`
`
`
`Boxed Warning
`02/2017
`
`
`Indications and Usage (1)
`04/2017
`
`
`Dosage and Administration (2.1)
` 02/2017
`
`
`Dosage and Administration (2.3)
`04/2017
`
`
` 02/2017
`Warnings and Precautions (5.1)
`
`
`
`-------------------------------INDICATIONS AND USAGE------------------------­
`
`HARVONI is a fixed-dose combination of ledipasvir, a hepatitis C virus
`
`
`
`
`(HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog
`NS5B polymerase inhibitor, and is indicated for the treatment of
`
`
`
`
`
`
`chronic hepatitis C virus (HCV) in:
`
`
`• Adults with genotype 1, 4, 5, or 6 infection without cirrhosis or with
`
`
`
`compensated cirrhosis
`
`• Adults with genotype 1 infection with decompensated cirrhosis, in
`
`
`
`
`combination with ribavirin
`
`• Adults with genotype 1 or 4 infection who are liver transplant
`
`
`
`
`recipients without cirrhosis or with compensated cirrhosis, in
`
`
`
`combination with ribavirin
`
`• Pediatric patients 12 years of age and older or weighing at least 35
`
`
`
`kg with genotype 1, 4, 5, or 6 without cirrhosis or with compensated
`
`
`
`cirrhosis. (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 adult and pediatric dosage: One tablet (90 mg of
`
`
`
`
`
`
`ledipasvir and 400 mg of sofosbuvir) taken orally once daily with or
`
`
`
`
`
`without food. (2.2, 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)
`
`
`
`• If used in combination with ribavirin, follow the recommendations for
`
`
`
`
`ribavirin dosing and dosage modifications. (2.2)
`
`
`• Recommended adult treatment regimen and duration: (2.2)
`
`
`
`
`
`
` Regimen
`
`and
`
` Duration
`HARVONI
`
`12 weeks
`
`
` HARVONI
`
` 12 weeks
`
` HARVONI
`
` 24 weeks
`
` HARVONI
`
` + ribavirin
`
` 12 weeks
`
` HARVONI
`
`
` + ribavirin
`
` 12 weeks
`
`
`
`Genotype
`1
`
`
`Genotype
`1 or 4
`
`
`Genotype
`
`Adult Patient Population
`
`
`
`Treatment-naïve without cirrhosis or with
`
`compensated cirrhosis (Child-Pugh A)
`
`
`
`
`
`Treatment-experienced without cirrhosis
`
`Treatment-experienced with
`
` compensated cirrhosis (Child-Pugh A)
`Treatment-naïve and treatment-
`experienced with decompensated
`
`
`
` cirrhosis (Child-Pugh B or C)
`Treatment-naïve and treatment-
`experienced liver transplant recipients
`
`
`
`without cirrhosis, or with compensated
`
` cirrhosis (Child-Pugh A)
`
`
`Treatment-naïve and treatment-
`
`HARVONI
`
`
`
`
`Reference ID: 4179390
`
`
`
` 4, 5, or 6
`
`
`
` 12 weeks
`
`
` experienced without cirrhosis or with
`
` compensated cirrhosis (Child-Pugh A)
`
`• Recommended treatment duration for pediatric patients 12 years of
`
`
`
`age and older or weighing at least 35 kg. (2.3)
`
`
`
`
` Pediatric Patient Population 12
`
` Years of Age and Older or
`
`
` Weighing at Least 35 Kg
`
` Treatment-naïve without cirrhosis
`
` or with compensated cirrhosis
`
` (Child-Pugh A)
` Treatment-experienced without
`
` cirrhosis
`
` Treatment-experienced 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. (2.4)
`
`
`
`
`
`
`
`Genotype
`1
`
`
`
`
`Genotype
`
`4, 5, or 6
`
` Regimen
`
`and
`Duration
`
`HARVONI
`
`12 weeks
`
`
` HARVONI
`
` 12 weeks
`HARVONI
`
`24 weeks
`
`
`HARVONI
`
`12 weeks
`
`
`
`
`
`
`
`
`-----------------------DOSAGE FORMS AND STRENGTHS-------------------­
`
`
`Tablets: 90 mg ledipasvir and 400 mg sofosbuvir. (3)
`
`
`
`
`
`
`
`--------------------------------CONTRAINDICATIONS-----------------------------­
`If used in combination with ribavirin, all contraindications to ribavirin
`
`also apply to HARVONI 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, particularly in
`
`
`patients also receiving beta blockers, or those with underlying
`cardiac comorbidities and/or advanced liver disease.
`
`Coadministration of amiodarone with HARVONI is not
`
`
`recommended. In patients without alternative, viable treatment
`
`
`options, cardiac monitoring is recommended. (5.2, 6.2, 7.2)
`
`
`
`
`-------------------------------ADVERSE REACTIONS----------------------------­
`
`The most common adverse reactions (incidence greater than or equal
`
`
`
`to 10%, all grades) observed with treatment with HARVONI were
`
`
`
`fatigue, headache and asthenia. (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 with amiodarone may result in serious
`
`
`symptomatic bradycardia. Use of HARVONI with amiodarone is not
`
`
`
`recommended. (5.2, 6.2, 7.2)
`
`
`
`• P-gp inducers (e.g., rifampin, St. John’s wort): May alter
`
`
`
`
`
`concentrations of ledipasvir and sofosbuvir. Use of HARVONI with
`
`
`P-gp inducers is not recommended. (5.3, 7, 12.3)
`
`
`
`• Frequent monitoring of international normalized ratio (INR) values is
`
`
`
`
`recommended in patients receiving warfarin. (7.1)
`
`
`
`• Consult the full prescribing information prior to use for potential drug
`
`
`
`interactions. (5.2, 5.3, 7, 12.3)
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`FDA-approved patient labeling.
`
`
`
`
`
`
`Revised: 11/2017
`
`
`
` 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 12 Years of
`
`
`
`
`
`
`Age and Older or Weighing at Least 35 kg
`
`
`
`
`2.4 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 Ribavirin Combination Treatment
`
`
`
`
`6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trials Experience
`
`
`
`
`
`6.2 Postmarketing Experience
`
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Potential for Drug Interaction
`
`
`
`
`7.2 Established and Potentially Significant Drug Interactions
`
`
`
`
`
`7.3 Drugs without Clinically Significant Interactions with
`
`
`
`
`HARVONI
`
`
`
`
`
`
`
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`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
`
`
`
`
`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 HCV
`
`
`
`
`
`14.3 Clinical Trials in Subjects with Genotype 4, 5, or 6 HCV
`
`
`
`
`
`
`14.4 Clinical Trials in Subjects Coinfected with HCV and HIV-1
`
`
`
`
`
`
`
`14.5 Clinical Trials in Liver Transplant Recipients and/or Subjects with
`
`
`
`
`
`
`
`Decompensated Cirrhosis
`
`
`14.6 Clinical Trial in Pediatric Subjects
`
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
` * Sections or subsections omitted from the full prescribing information are not
`
`
`
`listed.
`
`
`
`
`
`Reference ID: 4179390
`
`
`
`
`
` 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 HARVONI. 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)].
`
`
`INDICATIONS AND USAGE
`
`1
`
`
`
`Adult Patients:
`
`
`
`
`
`
`
`
`
`
`HARVONI is indicated for the treatment of adult patients with chronic hepatitis C virus
`
`(HCV) [see Dosage and Administration (2.2) and Clinical Studies (14)]:
`
`
`
`
`
`• genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis
`
`
`
`
`
`
`• genotype 1 infection with decompensated cirrhosis, for use in combination with
`
`
`
`ribavirin
`
`• genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or
`
`
`
`
`
`with compensated cirrhosis, for use in combination with ribavirin
`
`
`Pediatric Patients:
`
`HARVONI is indicated for the treatment of pediatric patients 12 years of age and older
`
`
`
`
`or weighing at least 35 kg with HCV genotype 1, 4, 5, or 6 infection without cirrhosis or
`
`with compensated cirrhosis [see Dosage and Administration (2.3) and Clinical Studies
`
`
`
`(14.6)].
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`
`Testing Prior to the Initiation of Therapy
`2.1
`
`
`
`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 HARVONI [see Warnings and Precautions (5.1)].
`
`
`
`2.2 Recommended Dosage in Adults
`
`
`The recommended dosage of HARVONI is one tablet (90 mg ledipasvir and 400 mg
`
`
`
`
`sofosbuvir) taken orally once daily with or without food [see Clinical Pharmacology
`
`
`
`(12.3)].
`
`
`Relapse rates are affected by baseline host and viral factors and differ between
`
`
`
`
`treatment durations for certain subgroups [see Clinical Studies (14)].
`
`
`
`
`
`
`Reference ID: 4179390
`
`
`3
`
`

`

`
`
`
`
`Table 1 shows the recommended HARVONI treatment regimen and duration based on
`
`patient population.
`
`
`
`For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1
`
`
`
`[see Clinical Studies (14)]. Refer to Drug Interactions (7) for dosage recommendations
`
`
`
`for concomitant HIV-1 antiviral drugs.
`
`
`Table 1
`
`
`
`Recommended Treatment Regimen and Duration for HARVONI in
`
`
`
`
`
`Adult Patients with Genotype 1, 4, 5, or 6 HCV
`
`Treatment Regimen
`
`Patient Population
`
`and Duration
`
`
`
`
`
`
`HARVONI 12 weeks*
`
`
`
`
` HARVONI 12 weeks
`
`HARVONI 24 weeks†
`
`
`
`
` HARVONI + ribavirin‡ 12 weeks
`
`
`
`
`
`
`
`Genotype 1
`
`
`
`
`
`
`
`Genotype 1 or 4
`
`
`
`Genotype 4, 5, or
`
`6
`
`
`
`Treatment-naïve without cirrhosis or
`
`
`with compensated cirrhosis (Child-
`Pugh A)
`
` Treatment-experienced** without
`
` cirrhosis
` Treatment-experienced** with
`
`
` compensated cirrhosis (Child-Pugh A)
`Treatment-naïve and treatment-
`
` experienced** with decompensated
` cirrhosis (Child-Pugh B or C)
`
`Treatment-naïve and treatment-
`experienced** liver transplant recipients
`
`
`without cirrhosis, or with compensated
`cirrhosis (Child-Pugh A)
`
`Treatment-naïve and treatment-
`
`
`experienced**, without cirrhosis or with
`
`compensated cirrhosis (Child-Pugh A)
`
`
`
`
` * HARVONI for 8 weeks can be considered in treatment-naïve genotype 1 patients without cirrhosis who
` have pretreatment HCV RNA less than 6 million IU/mL [see Clinical Studies (14.2)].
`
`
`
`
`
`
`
`
`
` **Treatment-experienced patients have failed a peginterferon alfa + ribavirin based regimen with or
` without an HCV protease inhibitor.
`
`
`† HARVONI + ribavirin for 12 weeks can be considered in treatment-experienced genotype 1 patients with
`
`
`
`
`
`
`
`
`
`cirrhosis who are eligible for ribavirin [see Clinical Studies (14.2)]. See footnote § for ribavirin dosage
`
`
`
`
`recommendations.
`‡ In patients with decompensated cirrhosis, the starting dosage of ribavirin is 600 mg and can be titrated
`
`
`
`
`
`
`
`
`
`
` up to 1000 mg for patients <75 kg and 1200 mg for those ≥75 kg in two divided doses with food. If the
` starting dosage of ribavirin is not well tolerated, the dosage should be reduced as clinically indicated
`
`
`
`
` based on hemoglobin levels.
`§ The daily dosage of ribavirin is weight-based (1000 mg for patients <75 kg and 1200 mg for those ≥75 kg)
`
`
`
`
`
`
`administered orally in two divided doses with food.
`
`
`HARVONI + ribavirin§ 12 weeks
`
`
`
`
`
`HARVONI 12 weeks
`
`
`
`
`
`
`
`
` For further information on ribavirin dosing and dosage modifications, refer to the
`
`
` ribavirin prescribing information [see Clinical Studies (14.5)].
`
`
`
`
`Reference ID: 4179390
`
`
`4
`
`

`

`
`
`
`
`
`
` 2.3 Recommended Dosage in Pediatric Patients 12 Years of Age and Older or
`Weighing at Least 35 kg
`
`
`
`The recommended dosage of HARVONI in pediatric patients 12 years of age and older
`
`or weighing at least 35 kg is one tablet (90 mg ledipasvir and 400 mg sofosbuvir) taken
`orally once daily with or without food for 12 weeks [see Clinical Pharmacology (12.3)
`
`
`
`
`and Clinical Studies (14.6)].
`
`
`
`Table 2 shows the recommended HARVONI duration based on pediatric patient
`
`
`population.
`
`
` For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 2
`
`
`[see Use in Specific Populations (8.4)]. Refer to Drug Interactions (7) for dosage
`
`
`recommendations for concomitant HIV-1 antiviral drugs.
`
`
`
`Table 2
`
`
`
`
`Recommended Regimen and Duration for HARVONI in Pediatric
`
`Patients 12 Years of Age or Older or Weighing at Least 35 kg with
`
`
`
`Genotype 1, 4, 5, or 6 HCV without Cirrhosis or with Compensated
`
`
`Cirrhosis
`
`
`
`
`
`Patient Population
`
`Treatment-naïve without cirrhosis or with
`
`compensated cirrhosis (Child-Pugh A)
`
`
`
`Treatment Regimen
`
`and Duration
`
`HARVONI 12 weeks
`
`
`Genotype
`
`1
`
`
`
`
`
`
`HARVONI 24 weeks
`
`
`
`HARVONI 12 weeks
`
` Treatment-experienceda without cirrhosis HARVONI 12 weeks
`
`Treatment-experienceda with
`
`
` compensated cirrhosis (Child-Pugh A)
`
`Treatment-naïve and treatment­
`Genotype
`
`experienceda without cirrhosis or with
`
`4, 5, or 6
`
`
`compensated cirrhosis (Child-Pugh A)
`
`
` a. Treatment-experienced patients have failed an interferon based regimen with or without ribavirin.
`
` Severe Renal Impairment and End Stage Renal Disease
` 2.4
`
`
` No dosage recommendation can be given for patients with severe renal impairment
`
`
` (estimated Glomerular Filtration Rate [eGFR] less than 30 mL/min/1.73 m2) 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)].
`
` 3
` DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`
`
` HARVONI is available as an orange colored, diamond shaped, film-coated tablet
` debossed with “GSI” on one side and “7985” on the other side of the tablet. Each tablet
`
`
` contains 90 mg ledipasvir and 400 mg sofosbuvir.
`
`
`
`
`
`
`Reference ID: 4179390
`
`
`5
`
`

`

` CONTRAINDICATIONS
` 4
`
`
`
` If HARVONI is administered with ribavirin, the contraindications to ribavirin also apply to
` this combination regimen. Refer to the ribavirin prescribing information for a list of
`
`
`
` contraindications for ribavirin [see Dosage and Administration (2.2)].
`
`
`
`
`
` WARNINGS AND PRECAUTIONS
` 5
`
`
`
`
` 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 immunosuppressants 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 HARVONI. In patients with serologic
`
`evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or
`
`
`
`
`
`HBV reactivation during HCV treatment with HARVONI and during post-treatment
`
`
`
`
`follow-up. Initiate appropriate patient management for HBV infection as clinically
`indicated.
`
`Serious Symptomatic Bradycardia When Coadministered with Amiodarone
`5.2
`
`
`
`Postmarketing cases of symptomatic bradycardia, as well as fatal cardiac arrest and
`
`
`
`cases requiring pacemaker intervention, have been reported when amiodarone is
`
`coadministered with HARVONI. 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 HARVONI is not recommended. For patients
`
`
`taking amiodarone who have no other alternative, viable treatment options and who will
`
`
`
`be coadministered HARVONI:
`
`• 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
`
`
`
`Reference ID: 4179390
`
`
`6
`
`

`

`
`
` heart rate should occur on a daily basis through at least the first 2 weeks of
`treatment.
`
`
`
`Patients who are taking HARVONI 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 HARVONI 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
`
`
`(7.2)].
`
`
`
`
`5.3 Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers
`
`
`The concomitant use of HARVONI and P-gp inducers (e.g., rifampin, St. John’s wort)
`
`may significantly decrease ledipasvir and sofosbuvir plasma concentrations and may
`
`
`
`
`
`lead to a reduced therapeutic effect of HARVONI. Therefore, the use of HARVONI with
`
`
`
`
`P-gp inducers (e.g., rifampin or St. John’s wort) is not recommended [see Drug
`
`Interactions (7.2)].
`
`
`
`5.4 Risks Associated with Ribavirin Combination Treatment
`
`
`If HARVONI is administered with ribavirin, the warnings and precautions for ribavirin, in
`
`
`particular the pregnancy avoidance warning, apply to this combination regimen. Refer to
`
`
`the ribavirin prescribing information for a full list of the warnings and precautions for
`
`
`ribavirin [see Dosage and Administration (2.2)].
`
`
`
`ADVERSE REACTIONS
`6
`
`
`The following serious adverse reactions are described below and elsewhere in 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.
`
`
`
`If HARVONI is administered with ribavirin to adults, refer to the prescribing information
`
`for ribavirin for a description of ribavirin-associated adverse reactions.
`
`
`
`Clinical Trials in Adult Subjects
`
`The safety assessment of HARVONI was based on pooled data from three randomized,
`
`
`
`open-label Phase 3 clinical trials (ION-3, ION-1, and ION-2) of subjects with genotype 1
`
`
`
`HCV with compensated liver disease (with and without cirrhosis) including 215, 539,
`
`
`
`
`
`
`Reference ID: 4179390
`
`
`7
`
`

`

`
`
`
`
`
`
` and 326 subjects who received HARVONI once daily by mouth for 8, 12 and 24 weeks,
` respectively [see Clinical Studies (14)].
`
`
`
`The proportion of subjects who permanently discontinued treatment due to adverse
`
`
`
`
`
`
`
` events was 0%, less than 1%, and 1% for subjects receiving HARVONI for 8, 12, and
` 24 weeks, respectively.
`
`
`
`
`
`
`The most common adverse reactions (at least 10%) were fatigue and headache in
`
`
`
`
`
`subjects treated with 8, 12, or 24 weeks of HARVONI.
`
`
`
`Table 3 lists adverse reactions (adverse events assessed as causally related by the
`
`
`
`investigator, all grades) observed in at least 5% of subjects receiving 8, 12, or 24 weeks
`
`
`
`
`treatment with HARVONI in clinical trials. The majority of adverse reactions presented in
`
`
`
`
`Table 3 occurred at severity of grade 1. The side-by-side tabulation is to simplify
`
`
`presentation; direct comparison across trials should not be made due to differing trial
`
`designs.
`
`
`Table 3
`
`Adverse Reactions (All Grades) Reported in ≥5% of Subjects
`
`
`
`
`
`Receiving 8, 12, or 24 Weeks of Treatment with HARVONI
`
`
` HARVONI
`
` HARVONI
`
`
`
` HARVONI
`8 weeks
`12 weeks
`24 weeks
`
`
`
`
`
`
`N=215
`N=539
`N=326
`16%
`13%
`18%
`
`
`
`11%
`14%
`17%
`
`
`
`6%
`7%
`9%
`
`
`
`4%
`3%
`7%
`
`
`
`3%
`5%
`6%
`
`
`
`
`
`
`Fatigue
`
`Headache
`
`Nausea
`
`Diarrhea
`
`Insomnia
`
`
`
`
`
` The safety assessment of HARVONI was also based on pooled data from three open-
` label trials (Study 1119, ION-4, and ELECTRON-2) in 118 subjects with chronic HCV
`
`
`
`
`
`
` genotype 4, 5, or 6 infection with compensated liver disease (with or without cirrhosis)
`
` [see Clinical Studies (14.3)]. The subjects received HARVONI once daily by mouth for
`
`
`
` 12 weeks. The safety profile in subjects with chronic HCV genotype 4, 5, or 6 infection
`
`
` with compensated liver disease was similar to that observed in subjects with chronic
`
` HCV genotype 1 infection with compensated liver disease. The most common adverse
`
` reactions occurring in at least 10% of subjects were asthenia (18%), headache (14%),
`
`
` and fatigue (10%).
`
`
`Adverse Reactions in Subjects with Cirrhosis
`
`
`
`
`
`The safety assessment of HARVONI with or without ribavirin was based on a
`
`randomized, double-blind and placebo-controlled trial in treatment-experienced
`
`
`genotype 1 subjects with compensated cirrhosis and was compared to placebo in the
`
`
`
`
`SIRIUS trial. Subjects were randomized to receive 24 weeks of HARVONI once daily by
`
`
`
`
`mouth without ribavirin or 12 weeks of placebo followed by 12 weeks of HARVONI once
`
`
`
`
`daily by mouth + ribavirin [see Clinical Studies (14.2)]. Table 4 presents the adverse
`
`
`
`
`
`
`
`reactions, as defined above, that occurred with at least 5% greater frequency in
`
`
`
`Reference ID: 4179390
`
`
`8
`
`

`

`
`
` subjects treated with 24 weeks of HARVONI or 12 weeks of HARVONI + ribavirin,
`
` compared to those reported for 12 weeks of placebo. The majority of the adverse
`
`
`
`
`
` reactions presented in Table 4 were Grade 1 or 2 in severity.
`
`
`
`
`Table 4
`
`
`
`
`
`Adverse Reactions with ≥5% Greater Frequency Reported in
`
`Treatment-Experienced Subjects with Cirrhosis Receiving HARVONI
`
`
`
`
`
`for 24 Weeks or HARVONI + RBV for 12 Weeks Compared to Placebo
`
`
`for 12 weeks
`
` HARVONI
`
`
`HARVONI + RBV
`
`24 weeks
`
`12 weeks
`
`(N=78)
`
`(N=76)
`
`
`31%
`36%
`
`
`29%
`13%
`
`
`18%
`4%
`
`
`11%
`5%
`9%
`4%
`
`
`3%
`9%
`
`
`8%
`7%
`
`
`5%
`1%
`
`
`
`
`Placebo
`
`12 weeks
`
`(N=77)
`
`23%
`
`16%
`
`1%
`
`1%
`0
`
`1%
`
`1%
`
`0
`
`
`
`
`
`Asthenia
`
`Headache
`
`Fatigue
`
`Cough
`Myalgia
`
`Dyspnea
`
`Irritability
`
`Dizziness
`
`
`
` Adverse Reactions in Subjects Coinfected with HIV-1
`
`
`
`
`
`
`
`The safety assessment of HARVONI was based on an open-label clinical trial in
`
`
`335 genotype 1 or 4 subjects with HCV/HIV-1 coinfection who were on stable
`
`antiretroviral therapy in Study ION-4 [see Clinical Studies (14.4)]. The safety profile in
`
`HCV/HIV-1 coinfected subjects was similar to that observed in HCV mono-infected
`
`
`
`
`subjects. The most common adverse reactions occurring in at least 10% of subjects
`
`
`were headache (20%) and fatigue (17%).
`
`
`
`
`Adverse Reactions in Liver Transplant Recipients and/or Subjects with Decompensated
`
`Cirrhosis
`
`The safety assessment of HARVONI with ribavirin (RBV) in liver transplant recipients
`
`and/or those who had decompensated liver disease was based on pooled data from two
`
`
`
`Phase 2 open-label clinical trials including 336 subjects who received HARVONI plus
`
`
`
`
`RBV for 12 weeks. Subjects with Child-Pugh-Turcotte (CPT) scores greater than 12
`
`
`were excluded from the trials [see Clinical Studies (14.5)].
`
`
`The adverse events observed were consistent with the expected clinical sequelae of
`
`
`
`liver transplantation and/or decompensated liver disease, or the known safety profile of
`
`
`HARVONI and/or ribavirin.
`
`Decreases in hemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were
`
`
`
`
`
`
`
`observed in 38% and 13% of subjects treated with HARVONI plus RBV for 12 weeks,
`
`
`
`
`respectively. Ribavirin was permanently discontinued in 11% of subjects treated with
`
`
`
`
`HARVONI plus RBV for 12 weeks.
`
`
`
`
`Reference ID: 4179390
`
`
`9
`
`

`

`Liver Transplant Recipients with Compensated Liver Disease:
`
`
`Among the 174 liver transplant recipients with compensated liver disease who received
`HARVONI with RBV for 12 weeks, 2 (1%) subjects permanently discontinued HARVONI
`
`
`due to an adverse event.
`
`
`Subjects with Decompensated Liver Disease:
`
`Among the 162 subjects with decompensated liver disease (pre- or post-transplant) who
`
`received HARVONI with RBV for 12 weeks, 7 (4%) subjects died, 4 (2%) subjects
`
`
`
`
`underwent liver transplantation, and 1 subject (<1%) underwent liver transplantation and
`died during treatment or within 30 days after discontinuation of treatment. Because
`
`
`these events occurred in patients with advanced liver disease who are at risk of
`
`
`progression of liver disease including liver failure and death, it is not possible to reliably
`
`
`
`assess the contribution of drug effect to outcomes. A total of 4 (2%) subjects
`
`
`
`
`permanently discontinued HARVONI due to an adverse event.
`
`
`
`Less Common Adverse Reactions Reported in Clinical Trials (less than 5%): The
`
`
`
`following adverse reactions occurred in less than 5% of subjects receiving HARVONI in
`
`any one trial. These events have been included because of their seriousness or
`
`
`
`assessment of potential causal relationship.
`
`
`
`
`Psychiatric disorders: depression (including in subjects with pre-existing history of
`
`
`
`psychiatric illness).
`
`
`Depression (particularly in subjects with pre-existing history of psychiatric illness)
`
`
`
`occurred in subjects receiving sofosbuvir containing regimens. Suicidal ideation and
`
`
`suicide have occurred in less than 1% of subjects treated with sofosbuvir in
`
`
`
`combination with ribavirin or pegylated interferon/ribavirin in other clinical trials.
`
`
`
`Laboratory Abnormalities
`
`
`Bilirubin Elevations: Bilirubin elevations of greater than 1.5xULN were observed in
`
`
`
`
`
`3%, less than 1%, and 2% of subjects treated with HARVONI for 8, 12, and
`
`24 weeks, respectively. Bilirubin elevations of greater than 1.5xULN were observed
`
`
`
`
`
`in 3%, 11%, and 3% of subjects with compensated cirrhosis treated with placebo,
`
`
`
`
`HARVONI + ribavirin for 12 weeks and HARVONI for 24 weeks, respectively, in the
`
`SIRIUS trial.
`
`
`
`Lipase Elevations: Transient, asymptomatic lipase elevations of greater than 3xULN
`
`
`
`
`
`
`were observed in less than 1%, 2%, and 3% of subjects treated with HARVONI for 8,
`
`
`
`12, and 24 weeks, respectively. Transient, asymptomatic lipase elevations of greater
`
`
`
`than 3x ULN were observed in 1%, 3%, and 9% of subjects with compensated
`
`
`
`
`cirrhosis treated with placebo, HARVONI + ribavirin for 12 weeks, and HARVONI for
`
`24 weeks, respectively, in the SIRIUS trial.
`
`
`
`Reference ID: 4179390
`
`
`
`10
`
`

`

`Creatine Kinase: Creatine kinase was not assessed in Phase 3 trials ION-3, ION-1,
`
`
`or ION-2 of HARVONI. Creatine kinase was assessed in the ION-4 trial. Isolated,
`
`
`asymptomatic creatine kinase elevations of greater than or equal to 10xULN was
`
`
`
`observed in 1% of subjects treated with HARVONI for 12 weeks in the ION-4 trial
`
`
`
`
`
`
`and has also been previously reported in subjects treated with sofosbuvir in
`combination with ribavirin or peginterferon/ribavirin in other clinical trials.
`
`
`Adverse Reactions in Pediatric Subjects 12 Years of Age and Older
`
`
`The safety assessment of HARVONI in pediatric subjects 12 years of age and older is
`
`
`
`based on data from a Phase 2, open-label clinical trial (Study 1116) that enrolled
`
`
`
`
`100 subjects without cirrhosis or with compensated cirrhosis who were treated with
`
`HARVONI for 12 weeks. The adverse reactions observed were consistent with those
`
`observed in clinical studies of HARVONI in adults. Limited safety data are available in
`pediatric subjects receiving HARVONI for 24 weeks. No Grade 3 or 4 advers