`
` 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
`
`
`
`
`------------------------------RECENT MAJOR CHANGES ----------------------­
`
`
`
`Indications and Usage (1)
`11/2015
`
`
`Dosage and Administration (2.1)
`11/2015
`
`
`11/2015
`Contraindications (4)
`
`
`
`Warnings and Precautions (5.1)
` 03/2015
`
`
`Warnings and Precautions (5.3)
`11/2015
`
`
`
`-------------------------------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) genotype 1, 4, 5 or 6 infection (1)
`
`
`
`
`
`------------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`• Recommended dosage: One tablet (90 mg of ledipasvir and 400 mg
`
`
`
`of sofosbuvir) taken orally once daily with or without food (2.1)
`
`
`
`
`
`• Recommended treatment duration: (2.1)
`
`
`
`Patient Population
`
`
`
`
`Duration
`
`
`
`
`
`
`Treatment-naïve with or without cirrhosis
`
`
`12 weeks
`
`
`Genotype 1
`
`Treatment-experienced without cirrhosis
`
`
`12 weeks
`
`
`Treatment-experienced with cirrhosis
`
`Treatment-naïve and treatment-
`
` Genotype 4,
`
`
`
` experienced, with or without cirrhosis
` 5, or 6
`• HCV/HIV-1 co-infection: For patients with HCV/HIV-1 co-infection,
`
`
`follow the dosage recommendations in the table above (2.1)
`
`• A dosage recommendation cannot be made for patients with severe
`
`
`renal impairment or end stage renal disease (2.2)
`
`
`
`
`
`24 weeks
`
`
`12 weeks
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1 INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Recommended Dosage in Adults
`
`
`
`2.2 Severe Renal Impairment and End Stage Renal Disease
`
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Serious Symptomatic Bradycardia When Coadministered
`
`
`
`with Amiodarone
`
`5.2 Risk of Reduced Therapeutic Effect Due to Use with P-gp
`
`
`
`Inducers
`
`5.3 Risks Associated with Ribavirin Combination Treatment
`
`
`5.4 Related Products Not Recommended
`
`
`
`
`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
`
`
`
`8.4 Pediatric Use
`
`
`
`
`
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`
`
`
`Reference ID: 3846181
`
`
`
`
`
`-----------------------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---------------------­
`
`
`
`• 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. (5.1, 6.2, 7.2)
`
`• Use with other drugs containing sofosbuvir is not recommended
`
`
`
`
`
`
`(5.4)
`
`
`-------------------------------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 (5.1, 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 (5.2, 7, 12.3)
`
`• Consult the full prescribing information prior to use for potential drug
`
`
`
`
`interactions (5.1, 5.2, 7, 12.3)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`
`FDA-approved patient labeling.
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 11/2015
`
`
`
`
`
`
`
`
`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 Co-infected with HCV and HIV-1
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
` * Sections or subsections omitted from the full prescribing information are not
`
`
`
`listed.
`
`
`
`
`1
`
`

`

`
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`
` DOSAGE AND ADMINISTRATION
`
`
`
` FULL PRESCRIBING INFORMATION
`
` 1
` INDICATIONS AND USAGE
`
`
`
`
`
`
`
`
`HARVONI is indicated for the treatment of patients with chronic hepatitis C virus (HCV)
`genotype 1, 4, 5, or 6 infection [see Dosage and Administration (2) and Clinical Studies
`
`
`
`
`(14)].
`
`
`
` 2
`
`
`
` 2.1 Recommended Dosage
`
`
`
`
`
`
`The recommended dosage of HARVONI is one tablet taken orally once daily with or
`
`without food [see Clinical Pharmacology (12.3)].
`
`
`Duration of Treatment
`Relapse rates are affected by baseline host and viral factors and differ between
`
`
`
`
`treatment durations for certain subgroups [see Clinical Studies (14)].
`
`
`
`
`Table 1 shows the recommended HARVONI treatment duration based on patient
`
`
`
`
`population.
`
`
`
`For patients with HCV/HIV-1 co-infection, 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 Duration for HARVONI in Patients with
`
`
`
`
`
`
`
`Genotype 1, 4, 5 or 6 HCV
` Patient Population
`
`
`Treatment-naïve with or
`
`without cirrhosis
`Treatment-experienced**
`
`
`without cirrhosis
` Treatment-experienced** with
`
` cirrhosis
`Treatment-naïve and
`treatment-experienced**, with
`
` or without cirrhosis
`
` * HARVONI for 8 weeks can be considered in treatment-naïve genotype 1 patients without cirrhosis who
`
`
`
`
`
`
`
`have pre-treatment HCV RNA less than 6 million IU/mL [see Clinical Studies (14.2)].
`
`
`
`
`
`**Treatment-experienced patients include those who 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)]. 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. Refer to the ribavirin prescribing information.
`
`
`
`
`
`
`
`
`
` Genotype 1
`
`
`
` Genotype 4, 5 or 6
`
`
`
`
`
` Recommended Treatment Duration
`
`12 weeks*
`
`
`
`12 weeks
`
`24 weeks†
`
`
`
`
` 12 weeks
`
`
`
`
`
`
`
`
`
`Reference ID: 3846181
`
`
`
`
`
`

`

`
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`
`
`
`
`WARNINGS AND PRECAUTIONS
`
`
`
` 2.2 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)].
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`
`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.
`
`
`
`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 (2.1)].
`
`
`
`5
`
`
`5.1 Serious Symptomatic Bradycardia When Coadministered with Amiodarone
`
`
`
`
`
`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
`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.
`
`
`
`
`
`
`Reference ID: 3846181
`
`
`
`
`
`

`

`
`
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`
`
` 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)].
`
`
` 5.2 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)].
`
`
` 5.3 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 (2.1)].
`
`
`
`5.4 Related Products Not Recommended
`
`
`The use of HARVONI with other products containing sofosbuvir is not recommended.
`
`
`
`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 (5.1)].
`
`
`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, refer to the prescribing information for
`
`
`ribavirin for a description of ribavirin-associated adverse reactions.
`
`
`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,
`
`
`
`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.
`
`
`
`
`
`
`Reference ID: 3846181
`
`
`
`
`
`

`

`
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`
`
` The most common adverse reactions (at least 10%) were fatigue and headache in
` subjects treated with 8, 12, or 24 weeks of HARVONI.
`
`
`
`
`
`
`
`
`Table 2 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 2 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 2
`
`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 3 presents the adverse
`
`
`
`
`
`
`
`reactions, as defined above, that occurred with at least 5% greater frequency in
`
`
`
`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 3 were Grade 1 or 2 in severity.
`
`
`
`
`Reference ID: 3846181
`
`
`
`
`
`

`

`
`
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`
`
` Table 3
`
`
`
`
`Asthenia
`
`Headache
`
`Fatigue
`
`Cough
`Myalgia
`
`Dyspnea
`
`Irritability
`
`Dizziness
`
`
`
`
`
`
` 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
`
`
`
`Adverse Reactions in Subjects Co-infected 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
`
`
`
`co-infected 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%).
`
`
`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.
`
`
`
`
`
`Reference ID: 3846181
`
`
`
`
`
`

`

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`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.
`
`
`
` 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.
`
`
`
`
`
`6.2 Postmarketing Experience
`
`
`
`The following adverse reactions have been identified during post approval use of
`
`
`
`HARVONI. Because postmarketing reactions are reported voluntarily from a population
`
`
`of uncertain size, it is not always possible to reliably estimate their frequency or
`
`establish a causal relationship to drug exposure.
`
`
`Cardiac Disorders
`Serious symptomatic bradycardia has been reported in patients taking amiodarone who
`
`initiate treatment with HARVONI [see Warnings and Precautions (5.1), Drug Interactions
`
`
`(7.2)].
`
`
`Skin and Subcutaneous Tissue Disorders
`
`Skin rashes, sometimes with blisters or angioedema-like swelling
`
`
`7
`
`
`7.1 Potential for Drug Interaction
`
`
`As HARVONI contains ledipasvir and sofosbuvir, any interactions that have been
`
`identified with these agents individually may occur with HARVONI.
`
`
`After oral administration of HARVONI, sofosbuvir is rapidly absorbed and subject to
`
`
`
`extensive first-pass hepatic extraction. In clinical pharmacology studies, both sofosbuvir
`
`
`and the inactive metabolite GS-331007 were monitored for purposes of pharmacokinetic
`
`
`analyses.
`
`
`Ledipasvir is an inhibitor of the drug transporters P-gp and breast cancer resistance
`
`
`protein (BCRP) and may increase intestinal absorption of coadministered substrates for
`
`
`
`
`these transporters.
`
`
`
`DRUG INTERACTIONS
`
`
`
`
`Reference ID: 3846181
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
` Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while
`
` GS-331007 is not. P-gp inducers (e.g., rifampin or St. John’s wort) may decrease
`
`
`
` ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect
`
`
`
` of HARVONI, and the use with P-gp inducers is not recommended with HARVONI [see
`
`
`
`
`
`
`
`
`
` Warnings and Precautions (5.2)].
`
`
`
`
`7.2 Established and Potentially Significant Drug Interactions
`
`
`
`
`Table 4 provides a listing of established or potentially clinically significant drug
`
`
`
`interactions. The drug interactions described are based on studies conducted with either
`
`
`
`HARVONI, the components of HARVONI (ledipasvir and sofosbuvir) as individual
`
`
`
`agents, or are predicted drug interactions that may occur with HARVONI [see Warnings
`
`
`and Precautions (5.1, 5.2) and Clinical Pharmacology (12.3)].
`
`
`
`Table 4
`
`
`
`
`Potentially Significant Drug Interactions: Alteration in Dose or
`
`Regimen May Be Recommended Based on Drug Interaction Studies
`or Predicted Interactiona
`
`
` Concomitant Drug
`
` Effect on
`
` Concentrationb
`
` Class: Drug Name
`Acid Reducing Agents:
`
`
`↓ ledipasvir
`
`
`
`Antacids (e.g., aluminum
`
`
`and magnesium
`
`
`hydroxide)
`H2-receptor antagonistsc
`
`(e.g., famotidine)
`
`
`
`
`
` Proton-pump inhibitorsc
`
`
` (e.g., omeprazole)
`
`
`Antiarrhythmics:
`
`amiodarone
`
`
`digoxin
`
`Effect on
`
`amiodarone,
`
`ledipasvir, and
`
`sofosbuvir
`
`concentrations
`
`unknown
`
`
`
`↑ digoxin
`
`
` Anticonvulsants:
`carbamazepine
`
`
` phenytoin
`
` phenobarbital
`
` oxcarbazepine
`Antimycobacterials:
`
`rifabutin
`
`
`↓ ledipasvir
`
`
`↓ sofosbuvir
`
`
`
`
`↓ ledipasvir
`
`
`↓ sofosbuvir
`
`
`
`Clinical Comment
`
`
`Ledipasvir solubility decreases as pH increases. Drugs
`
`
`that increase gastric pH are expected to decrease
`
`concentration of ledipasvir.
`
`It is recommended to separate antacid and HARVONI
`
`administration by 4 hours.
`
`
`H2-receptor antagonists may be administered
`
`simultaneously with or 12 hours apart from HARVONI at a
`
`
`
`
`
`dose that does not exceed doses comparable to
`
`famotidine 40 mg twice daily.
`
` Proton-pump inhibitor doses comparable to omeprazole
`
`
` 20 mg or lower can be administered simultaneously with
`
`
` HARVONI under fasted conditions.
`
`
`
`Coadministration of amiodarone with HARVONI may
`result in serious symptomatic bradycardia. The
`
`mechanism of this effect is unknown. Coadministration of
`
`amiodarone with HARVONI is not recommended; if
`
`coadministration is required, cardiac monitoring is
`recommended [see Warnings and Precautions (5.1),
`
`Adverse Reactions (6.2)].
`
`Coadministration of HARVONI with digoxin may increase
`
`the concentration of digoxin. Therapeutic concentration
`monitoring of digoxin is recommended when
`
`
`coadministered with HARVONI.
`Coadministration of HARVONI with carbamazepine,
`
`
`
`phenytoin, phenobarbital, or oxcarbazepine is expected to
`
`decrease the concentration of ledipasvir and sofosbuvir,
`
`leading to reduced therapeutic effect of HARVONI.
`
`Coadministration is not recommended.
`
`Coadministration of HARVONI with rifabutin or rifapentine
`
`
`
`
`is expected to decrease the concentration of ledipasvir
`
`
`
`
`Reference ID: 3846181
`
`
`
`
`
`

`

`
`
`
` rifampinc
`
`
` rifapentine
`
`
`
`
`
`
`
` and sofosbuvir, leading to reduced therapeutic effect of
`
`
` HARVONI. Coadministration is not recommended.
` Coadministration of HARVONI with rifampin, a P-gp
`
`
`
` inducer, is not recommended [see Warnings and
` Precautions (5.2)].
`
`
`
`
`Monitor for tenofovir-associated adverse reactions in
`
`patients receiving HARVONI concomitantly with a regimen
`
`
`containing tenofovir DF without a HIV protease
`
`
`
`inhibitor/ritonavir or cobicistat. Refer to VIREAD or
`
`
`TRUVADA prescribing information for recommendations
`
`
`on renal monitoring.
`
`
`
`The safety of increased tenofovir concentrations in the
`
`
`setting of HARVONI and a HIV protease inhibitor/ritonavir
`
`
`
`or cobicistat has not been established.
`
`Consider alternative HCV or antiretroviral therapy to avoid
`
`increases in tenofovir exposures. If coadministration is
`necessary, monitor for tenofovir-associated adverse
`
`
`reactions. Refer to VIREAD or TRUVADA prescribing
`
`information for recommendations on renal monitoring.
`
`↑ tenofovir
`
`
`
`
`
`↑ tenofovir
`
`HIV Antiretrovirals:
`
`Regimens containing
`tenofovir DF without a
`
`HIV protease
`
`inhibitor/ritonavir or
`
`cobicistat
`
`
`Regimens containing
`tenofovir DF and a HIV
`
`protease inhibitor/ritonavir
`
`or cobicistat
`
`• atazanavir/ritonavir or
`
`
`
`cobicistat +
`
`emtricitabine/tenofovir
`
`DFc
`
`
`
`
`• darunavir/ritonavir or
`
`cobicistat +
`
`emtricitabine/tenofovir
`DFc
`
`
`
`• lopinavir/ritonavir +
`
`emtricitabine/tenofovir
`
`DF
`
`elvitegravir, cobicistat,
`
`
`emtricitabine, tenofovir
`
`DF
`
`
`tipranavir/ritonavir
`
`HCV Products:
`
`
`simeprevirc
`
`
`
`Herbal Supplements:
`
`
`St. John’s wort
`
`(Hypericum perforatum)
`HMG-CoA Reductase
`
`Inhibitors:
`
`rosuvastatin
`
`
`
`↑ tenofovir
`
`
`
`↓ ledipasvir
`
`
`↓ sofosbuvir
`
`
`↑ ledipasvir
`
`
`
`
`↑ simeprevir
`
`
`
`
`↓ ledipasvir
`
`
`↓ sofosbuvir
`
`
`
`↑ rosuvastatin
`
`
`
`
`The safety of increased tenofovir concentrations in the
`
`
`setting of HARVONI and the combination of elvitegravir,
`cobicistat, emtricitabine and tenofovir DF has not been
`
`
`established. Coadministration is not recommended.
`
`
`Coadministration of HARVONI with tipranavir/ritonavir is
`expected to decrease the concentration of ledipasvir and
`
`
`sofosbuvir, leading to reduced therapeutic effect of
`
`HARVONI. Coadministration is not recommended.
`Concentrations of ledipasvir and simeprevir are increased
`
`
`when simeprevir is coadministered with ledipasvir.
`
`
`
`Coadministration of HARVONI with simeprevir is not
`
`recommended.
`
`
`Coadministration of HARVONI with St. John’s wort, a P-gp
`inducer is not recommended [see Warnings and
`
`
`Precautions (5.2)].
`
`Coadministration of HARVONI with rosuvastatin may
`
`
`
`significantly increase the concentration of rosuvastatin
`
`which is associated with increased risk of myopathy,
`
`
`including rhabdomyolysis. Coadministration of HARVONI
`
`
`with rosuvastatin is not recommended.
`
`
`
`
`
`
` tenofovir DF = tenofovir disoproxil fumarate
` a. This table is not all inclusive.
`
`
`
` b. ↓ = decrease, ↑ = increase
`
`
`
`
` c. These interactions have been studied in healthy adults.
`
`
`
`
`
`
`
`
`
`Reference ID: 3846181
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 7.3 Drugs without Clinically Significant Interactions with HARVONI
` Based on drug interaction studies conducted with the components of HARVONI
`
`
`
`
`
`
` (ledipasvir or sofosbuvir) or HARVONI, no clinically significant drug interactions have
` been either observed or are expected when HARVONI is used with the following drugs
`
`
`
`
`
` [see Clinical Pharmacology (12.3)]: abacavir, atazanavir/ritonavir, cyclosporine,
` darunavir/ritonavir, dolutegravir, efavirenz, elvitegravir/cobicistat/emtricitabine/tenofovir
`
`
`
` alafenamide, emtricitabine, lamivudine, methadone, oral contraceptives, pravastatin,
`
`
`
`
` raltegravir, rilpivirine, tacrolimus, or verapamil. See Table 4 for use of HARVONI with
`
`
`
`
`
`
` certain HIV antiretroviral regimens [see Drug Interactions (7.2)].
`
`
`
`
`
`
`
`
`8
`
`
`
`8.1 Pregnancy
`
`Risk Summary
`There are no adequate and well-controlled studies with HARVONI in pregnant women.
`
`
`
`In animal reproduction studies, no evidence of adverse developmental outcomes was
`
`
`
`
`observed with the administration of ledipasvir or sofosbuvir [see Data]. Consider the
`
`benefits and risks of HARVONI when prescribing HARVONI to a pregnant woman.
`
`
`During organogenesis in the rat or rabbit, AUC exposure to ledipasvir was
`
`
`
`approximately 4- and 2-fold, respectively and the predominant circulating metabolite of
`
`
`sofosbuvir (GS-331007) increased during gestation from approximately 3- to 6-fold and
`
`
`7- to 17-fold the exposure in humans at the recommended clinical dose, respectively.
`
`
`
`
`
`In a pre/postnatal development study with ledipasvir or sofosbuvir, plasma exposure in
`
`neonate rats was approximately 4-fold lower than the maternal plasma for ledipasvir
`
`(post-parturition day 10), and the ratio of neonatal to maternal plasma exposure was
`
`
`
`less than 0.1 for the metabolite of sofosbuvir, GS-331007.
`
`
`If HARVONI is administered with ribavirin, the combination regimen is contraindicated in
`
`
`pregnant women and in men whose female partners are pregnant. Refer to the ribavirin
`
`prescribing information for more information on use in pregnancy.
`
`
`The background risk of major birth defects and miscarriage for the indicated population
`
`
`is unknown; however, the estimated background risk in the U.S. general population of
`
`major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized
`
`pregnancies.
`
`
`Data
`
`Animal Data
`
`Ledipasvir: Ledipasvir was administered orally to pregnant rats (up to 100 mg/kg/day)
`
`
`and rabbits (up to 180 mg/kg/day) on gestation days 6 to 18 and 7 to 20, respectively.
`
`No effects on fetal development have been observed in rats and rabbits at the highest
`
`
`
`
`doses tested. In a pre/postnatal development study with ledipasvir, where rats were
`
`
`exposed up to 100 mg/kg/day, no significant adverse effects directly related to drug
`
`
`were noted in the offspring.
`
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`
`Reference ID: 3846181
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`Sofosbuvir: Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day)
`
`
`and rabbits (up to 300 mg/kg/day) on gestation days 6 to 18 and 6 to 19, respectively.
`
`No effects on fetal development have been observed in rats and rabbits at the highest
`
`
`
`
`doses tested. In a pre/postnatal development study with sofosbuvir, where rats were
`
`
`exposed up to 500 mg/kg/day, no significant adverse effects directly related to drug
`
`
`
`
`were noted in the offspring.
`
`
` Lactation
`
` 8.2
`
`
` Risk Summary
`It is not known whether HARVONI and its metabolites are present in human breast milk.
`
`
`
`
`
`
`When administered to lactating rats, ledipasvir was detected in the plasma of suckling
`
`
`rats likely due to the presence of ledipasvir in milk, without clear effects on nursing
`
`
`
`
`
`
`
`
`pups. The predominant circulating metabolite of sofosbuvir (GS-331007) was the
`
`primary component observed in the milk of lactating rats, without effect on nursing pups.
`
`
`The development and health benefits of breastfeeding should be considered along with
`
`
`the mother’s clinical need for HARVONI and any potential adverse effects on the
`breastfed infant from HARVONI or from the underlying maternal condition.