`
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
`APPLICATION NUMBER:
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`205834Orig1s000
`LABELING
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`HARVONITM safely and effectively. See full prescribing information
`for HARVONI.
`
`HARVONITM (ledipasvir and sofosbuvir) tablets, for oral use
`Initial U.S. Approval: 2014
`
`-------------------------------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 inh bitor, and is indicated for the treatment of
`chronic hepatitis C (CHC) genotype 1 infection in adults (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):
`• Treatment-naïve with or without cirrhosis: 12 weeks
`• Treatment-experienced without cirrhosis: 12 weeks
`• Treatment-experienced with cirrhosis: 24 weeks
`• A dose recommendation cannot be made for patients with severe
`renal impairment or end stage renal disease (2.2)
`
`-----------------------DOSAGE FORMS AND STRENGTHS--------------------
`Tablets: 90 mg ledipasvir and 400 mg sofosbuvir. (3)
`
`--------------------------------CONTRAINDICATIONS------------------------------
`None
`
`-------------------------WARNINGS AND PRECAUTIONS----------------------
`Use with other drugs containing sofosbuvir, including SOVALDI, is not
`recommended (5.2)
`
`-------------------------------ADVERSE REACTIONS----------------------------
`The most common adverse reactions (incidence greater than or equal
`to 10%, all grades) observed with treatment with HARVONI for 8, 12,
`or 24 weeks are fatigue and headache (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---------------------------
`• 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 (5.1, 7, 12.3)
`• Consult the full prescr bing information prior to use for potential drug
`interactions (5.1, 7, 12.3)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling.
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` Revised: 10/2014
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`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 Risk of Reduced Therapeutic Effect Due to P-gp Inducers
`
`5.2 Related Products Not Recommended
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials 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
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Renal Impairment
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`8.7 Hepatic Impairment
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`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
`13.2 Animal Toxicology and/or Pharmacology
`
`14 CLINICAL STUDIES
`
`14.1 Overview of Clinical Trials
`
`14.2 Clinical Trials in Treatment-Naïve
`Subjects
`14.3 Clinical Trials in Subjects Who Failed
`Prior Therapy
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`* Sections or subsections omitted from the full prescribing
`information are not listed.
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`1
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`Reference ID: 3643151
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`FULL PRESCRIBING INFORMATION
`
` 1
`
`INDICATIONS AND USAGE
`
`HARVONI is indicated for the treatment of chronic hepatitis C (CHC) genotype 1
`infection in adults.
`
`Recommended Treatment Duration for HARVONI in Patients with
`CHC Genotype 1
`Patient Population
`Treatment-naïve with or without cirrhosis
`Treatment-experienced** without cirrhosis
`Treatment-experienced** with cirrhosis
`24 weeks
`* HARVONI for 8 weeks can be considered in treatment-naïve patients without cirrhosis who have pre-
`treatment HCV RNA less than 6 million IU/mL [see Clinical Studies (14)].
`**Treatment-experienced patients who have failed treatment with either peginterferon alfa + ribavirin or an
`HCV protease inhibitor + peginterferon alfa + ribavirin.
`
`Recommended Treatment Duration
`12 weeks*
`
`12 weeks
`
`
`2.2 Severe Renal Impairment and End Stage Renal Disease
`No dose recommendation can be given for patients with severe renal impairment
`(estimated Glomerular Filtration Rate [eGFR] <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)].
`
` 3
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`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: 3643151
`
`Gilead Sciences
`
`2
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` 2
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`DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage in Adults
`HARVONI is a two-drug fixed-dose combination product that contains 90 mg of
`ledipasvir and 400 mg of sofosbuvir in a single tablet. 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 below provides the recommended HARVONI treatment durations for
`treatment-naïve and treatment-experienced patients and those with and without
`cirrhosis [see Clinical Studies (14)].
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`Table 1
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`CONTRAINDICATIONS
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`4
`None
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`WARNINGS AND PRECAUTIONS
`
`
`5.1 Risk of Reduced Therapeutic Effect Due to 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)].
`
`5.2 Related Products Not Recommended
`The use of HARVONI with other products containing sofosbuvir (SOVALDI®) is not
`recommended.
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` 5
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` 6
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`ADVERSE REACTIONS
`
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`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.
`
`The safety assessment of HARVONI was based on pooled data from three Phase 3
`clinical trials of subjects with genotype 1 chronic hepatitis C (CHC) with compensated
`liver disease (with and without cirrhosis) including 215, 539, and 326 subjects who
`received HARVONI 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%, <1%, and 1% for subjects receiving HARVONI for 8, 12, and 24 weeks,
`respectively.
`
`The most common adverse reactions (≥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 ≥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.
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`
`
`Reference ID: 3643151
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`Gilead Sciences
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`3
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`Table 2
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`Fatigue
`Headache
`Nausea
`Diarrhea
`Insomnia
`
`
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`
`
`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%
`
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`Laboratory Abnormalities
`
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`Bilirubin Elevations: Bilirubin elevations of greater than 1.5xULN were observed in
`3%, <1%, and 2% of subjects treated with HARVONI for 8, 12, and 24 weeks,
`respectively.
`
`Lipase Elevations: Transient, asymptomatic lipase elevations of greater than 3xULN
`were observed in <1%, 2%, and 3% of subjects treated with HARVONI for 8, 12, and
`24 weeks, respectively.
`
`Creatine Kinase: Creatine kinase was not assessed in Phase 3 trials of HARVONI.
`Isolated, asymptomatic creatine kinase elevations (Grade 3 or 4) have been
`previously reported in subjects treated with sofosbuvir in combination with ribavirin
`or peginterferon/ribavirin in other clinical trials.
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`DRUG INTERACTIONS
`
`
`
` 7
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`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.
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`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.
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`
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`Reference ID: 3643151
`
`Gilead Sciences
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`4
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`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 (5.1)].
`
`7.2 Established and Potentially Significant Drug Interactions
`Table 3 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) and Clinical Pharmacology (12.3)].
`
`Table 3
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`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
`
`Clinical Comment
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`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 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
`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 (5.1)].
`
`Antacids (e.g., aluminum
`and magnesium
`hydroxide)
`H2-receptor antagonistsc
`(e.g., famotidine)
`
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`Proton-pump inhibitorsc
`(e.g., omeprazole)
`
`Antiarrhythmics:
`digoxin
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`↑ digoxin
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`Anticonvulsants:
`carbamazepine
`phenytoin
`phenobarbital
`oxcarbazepine
`Antimycobacterials:
`rifabutin
`rifampinc
`rifapentine
`
`↓ ledipasvir
`↓ sofosbuvir
`↓ GS-331007
`
`↓ ledipasvir
`↓ sofosbuvir
`↓ GS-331007
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`HIV Antiretrovirals:
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`
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`Reference ID: 3643151
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`Gilead Sciences
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`5
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`efavirenz,
`emtricitabine,
`tenofovir disoproxil
`fumarate (DF)
`
`Regimens containing
`tenofovir DF and a HIV
`protease inhibitor/ritonavir
`• atazanavir/ritonavir +
`emtricitabine/tenofovir
`DFc
`• darunavir/ritonavir +
`emtricitabine/tenofovir
`DFc
`• lopinavir/ritonavir +
`emtricitabine/tenofovir
`DF
`elvitegravir, cobicistat,
`emtricitabine, tenofovir
`DF
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`tipranavir/ritonavir
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`HCV Products:
`simeprevirc
`
`Herbal Supplements:
`St. John’s wort
`(Hypericum perforatum)
`HMG-CoA Reductase
`Inhibitors:
`rosuvastatin
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`↑ tenofovir
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`↑ tenofovir
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`Monitor for tenofovir-associated adverse reactions in
`patients receiving HARVONI concomitantly with the
`combination of efavirenz, emtricitabine and tenofovir DF.
`Refer to VIREAD, TRUVADA, or ATRIPLA prescribing
`information for recommendations on renal monitoring.
`The safety of increased tenofovir concentrations in the
`setting of HARVONI and a HIV protease inhibitor/ritonavir
`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
`
`↓ ledipasvir
`↓ sofosbuvir
`↓ GS-331007
`
`↑ ledipasvir
`↑ simeprevir
`
`
`↓ ledipasvir
`↓ sofosbuvir
`↓ GS-331007
`↑ rosuvastatin
`
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`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 (5.1)].
`
`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.
`
`a. This table is not all inclusive.
`b. ↓ = decrease, ↑ = increase
`c. These interactions have been studied in healthy adults.
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`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
`individually [see Clinical Pharmacology (12.3)]: abacavir, atazanavir/ritonavir,
`cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, lamivudine, methadone, oral
`contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus, tenofovir disoproxil
`fumarate, or verapamil. See Table 3 for use of HARVONI with certain HIV antiretroviral
`regimens [see Drug Interactions (7.2)].
`
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`Reference ID: 3643151
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`Gilead Sciences
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`USE IN SPECIFIC POPULATIONS
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`8
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`8.1 Pregnancy
`Pregnancy Category B
`There are no adequate and well-controlled studies with HARVONI in pregnant women.
`Because animal reproduction studies are not always predictive of human response,
`HARVONI should be used during pregnancy only if the potential benefit justifies the
`potential risk to the fetus.
`
`Animal Data
`Ledipasvir: No effects on fetal development have been observed in rats and rabbits at
`the highest doses tested. In the rat and rabbit, AUC exposure to ledipasvir was
`approximately 4- and 2-fold, respectively, the exposure in humans at the recommended
`clinical dose.
`
`Sofosbuvir: No effects on fetal development have been observed in rats and rabbits at
`the highest doses tested. In the rat and rabbit, AUC exposure to the predominant
`circulating metabolite GS-331007 increased over the course of gestation from
`approximately 3- to 6-fold and 7- to 17-fold the exposure in humans at the
`recommended clinical dose, respectively.
`
`8.3 Nursing Mothers
`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. Ledipasvir had no clear effects on
`the 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 developmental 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 child from the drug or from the underlying maternal
`condition.
`
`8.4 Pediatric Use
`Safety and effectiveness of HARVONI have not been established in pediatric patients.
`
`8.5 Geriatric Use
`Clinical trials of HARVONI included 117 subjects aged 65 and over. No overall
`differences in safety or effectiveness were observed between these subjects and
`younger subjects, and other reported clinical experience has not identified differences in
`responses between the elderly and younger patients, but greater sensitivity of some
`older individuals cannot be ruled out. No dosage adjustment of HARVONI is warranted
`in geriatric patients [see Clinical Pharmacology (12.3)].
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`8.6 Renal Impairment
`No dosage adjustment of HARVONI is required for patients with mild or moderate renal
`impairment. The safety and efficacy of HARVONI have not been established in patients
`
`
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`Reference ID: 3643151
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`Gilead Sciences
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`7
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`with severe renal impairment (eGFR <30 lemin/1.73m2) or ESRD requiring
`hemodialysis. No dosage recommendation can be given for patients with severe renal
`impairment or ESRD [see Dosage and Administration (2.2) and Clinical Phannacology
`(12. 3)].
`
`Hepatic Impairment
`8.7
`No dosage adjustment of HARVONI is required for patients with mild, moderate, or
`severe hepatic impairment (Child-Pugh Class A, B, or C). Safety and efficacy of
`HARVONI have not been established in patients with decompensated cirrhosis [see
`Clinical Pharmacology (12. 3)].
`
`1o
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`OVERDOSAGE
`
`No specific antidote is available for overdose with HARVONI. If overdose occurs the
`patient must be monitored for evidence of toxicity. Treatment of overdose with
`HARVONI consists of general supportive measures including monitoring of vital signs
`as well as observation of the clinical status of the patient. Hemodialysis is unlikely to
`result in significant removal of ledipasvir since ledipasvir is highly bound to plasma
`protein. Hemodialysis can efficiently remove the predominant circulating metabolite of
`sofosbuvir, GS-331007, with an extraction ratio of 53%.
`
`11
`
`DESCRIPTION
`
`HARVONI is a fixed-dose combination tablet containing ledipasvir and sofosbuvir for
`oral administration. Ledipasvir is an HCV NS5A inhibitor and sofosbuvir is a nucleotide
`analog inhibitor of HCV NS5B polymerase.
`
`Each tablet contains 90 mg ledipasvir and 400 mg sofosbuvir. The tablets include the
`following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose
`sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The
`tablets are film-coated with a coating material containing the following inactive
`ingredients: FD&C yellow #6/sunset yellow FCF aluminum lake, polyethylene glycol,
`polyvinyl alcohol, talc, and titanium dioxide.
`
`Ledipasvir: The IUPAC name for ledipasvir is Methyl [(28)—1-{(68)-6-[5-(9,9-difluoro-7-
`{2-[(1 R,3S,4S)—2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoy|}-2-
`azabicyclo[2.2. 1]hept-3-yl]-1 H-benzimidazol-6-yl}-9H-fiuoren-2-yl )-1 H-imidazol-2-yl]-5-
`azaspiro[2.4]hept—5—yl}-3-methyl-1 -oxobutan-2—yl]carbamate.
`
`It has a molecular formula of C49H54F2N306 and a molecular weight of 889.00. It has the
`following structural formula:
`
`0
`
`H H,( S?
`F F
`H3COJLN\/(fo
`0c
`H; fi fit“ :1
`“
`N
`Vikfi/ O O O 041:? ”3
`
`Reference ID: 3643151
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`Gilead Sciences
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`8
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`Ledipasvir is practically insoluble (<0.1 mg/mL) across the pH range of 3.0—7.5 and is
`slightly soluble below pH 2.3 (1.1 mg/mL).
`
`Sofosbuvir: The IUPAC name for sofosbuvir is (S)-|sopropyl 2-((S)-(((2R,3R,4R,5R)-5-
`(2,4-dioxo-3,4-dihyd ropyrimidin-1 (2H)-yI)—4-fluoro-3-hyd roxy-4-methyltetrahyd rofu ran-2-
`yl)methoxy)—(phenoxy)phosphorylamino)propanoate. It has a molecular formula of
`C22H29FN309P and a molecular weight of 529.45. It has the following structural formula:
`
`>0 :5 o
`o O
`n
`mfifiTJ
`O
`
`o
`
`Sofosbuvir is a white to off-white crystalline solid with a solubility of 22 mg/mL across
`the pH range of 2—7.7 at 37°C and is slightly soluble in water.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`HARVONI is a fixed-dose combination of ledipasvir and sofosbuvir which are direct-
`acting antiviral agents against the hepatitis C virus [see Microbiology (12. 4)].
`
`12.2 Pharmacodynamics
`Cardiac Electrophysiology
`Thorough QT studies have been conducted for ledipasvir and sofosbuvir.
`The effect of ledipasvir 120 mg twice daily (2.67 times the maximum recommended
`dosage) for 10 days on QTc interval was evaluated in a randomized, multiple-dose,
`placebo-, and active-controlled (moxifloxacin 400 mg) three period crossover thorough
`QT trial in 59 healthy subjects. At the dose of 120 mg twice daily (2.67 times the
`maximum recommended dosage), ledipasvir does not prolong QTc interval to any
`clinically relevant extent.
`
`The effect of sofosbuvir 400 mg (maximum recommended dosage) and 1200 mg (three
`times the maximum recommended dosage) on QTc interval was evaluated in a
`randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four
`period crossover thorough QT trial in 59 healthy subjects. At a dose three times the
`maximum recommended dose, sofosbuvir does not prolong QTc to any clinically
`relevant extent.
`
`12.3 Pharmacokinetics
`
`Absorption
`The pharmacokinetic properties of ledipasvir, sofosbuvir, and the predominant
`circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in
`subjects with chronic hepatitis C. Following oral administration of HARVONI, ledipasvir
`median peak concentrations were observed 4 to 4.5 hours post-dose. Sofosbuvir was
`absorbed quickly and the peak median plasma concentration was observed ~0.8 to 1
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`hour post-dose. Median peak plasma concentration of GS-331007 was observed
`between 3.5 to 4 hours post-dose.
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`Based on the population pharmacokinetic analysis in HCV-infected subjects, geometric
`mean steady-state AUC0-24 for ledipasvir (N=2113), sofosbuvir (N=1542), and
`GS-331007 (N=2113) were 7290, 1320, and 12,000 ng•hr/mL, respectively. Steady-
`state Cmax for ledipasvir, sofosbuvir, and GS-331007 were 323, 618, and 707 ng/mL,
`respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult
`subjects and subjects with HCV infection. Relative to healthy subjects (N=191),
`ledipasvir AUC0-24 and Cmax were 24% lower and 32% lower, respectively, in
`HCV-infected subjects.
`
`Effect of Food
`Relative to fasting conditions, the administration of a single dose of HARVONI with a
`moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal
`increased sofosbuvir AUC0-inf by approximately 2-fold, but did not significantly affect
`sofosbuvir Cmax. The exposures of GS-331007 and ledipasvir were not altered in the
`presence of either meal type. The response rates in Phase 3 trials were similar in HCV-
`infected subjects who received HARVONI with food or without food. HARVONI can be
`administered without regard to food.
`
`Distribution
`Ledipasvir is >99.8% bound to human plasma proteins. After a single 90 mg dose of
`[14C]-ledipasvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity ranged
`between 0.51 and 0.66.
`
`Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding
`is independent of drug concentration over the range of 1 µg/mL to 20 µg/mL. Protein
`binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of
`[14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was
`approximately 0.7.
`
`Metabolism
`In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2,
`CYP2C8, CYP2C9, CYP 2C19, CYP2D6, and CYP3A4. Evidence of slow oxidative
`metabolism via an unknown mechanism has been observed. Following a single dose of
`90 mg [14C]-ledipasvir, systemic exposure was almost exclusively to the parent drug
`(>98%). Unchanged ledipasvir is the major species present in feces.
`
`Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active
`nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves
`sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A
`(CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad
`nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine
`nucleotide biosynthesis pathway. Dephosphorylation results in the formation of
`nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks
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`anti-HCV activity in vitro. After a single 400 mg oral dose of [14C]-sofosbuvir, GS-331007
`accounted for approximately >90% of total systemic exposure.
`
`Elimination
`Following a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the
`[14C]-radioactivity in feces and urine was approximately 87%, with most of the
`radioactive dose recovered from feces (approximately 86%). Unchanged ledipasvir
`excreted in feces accounted for a mean of 70% of the administered dose and the
`oxidative metabolite M19 accounted for 2.2% of the dose. These data indicate that
`biliary excretion of unchanged ledipasvir is a major route of elimination, with renal
`excretion being a minor pathway (approximately 1%). The median terminal half-life of
`ledipasvir following administration of HARVONI was 47 hours.
`
`Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose
`was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in
`urine, feces, and expired air, respectively. The majority of the sofosbuvir dose
`recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir.
`These data indicate that renal clearance is the major elimination pathway for
`GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following
`administration of HARVONI were 0.5 and 27 hours, respectively.
`
`Specific Populations
`Patients with Renal Impairment: The pharmacokinetics of ledipasvir were studied with a
`single dose of 90 mg ledipasvir in HCV negative subjects with severe renal impairment
`(eGFR <30 mL/min by Cockcroft-Gault). No clinically relevant differences in ledipasvir
`pharmacokinetics were observed between healthy subjects and subjects with severe
`renal impairment.
`
`The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild
`(eGFR ≥50 and <80 mL/min/1.73m2), moderate (eGFR ≥30 and <50 mL/min/1.73m2),
`severe renal impairment (eGFR <30 mL/min/1.73m2), and subjects with ESRD requiring
`hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with
`normal renal function (eGFR >80 mL/min/1.73m2), the sofosbuvir AUC0-inf was 61%,
`107%, and 171% higher in mild, moderate, and severe renal impairment, while the GS-
`331007 AUC0-inf was 55%, 88%, and 451% higher, respectively. In subjects with ESRD,
`relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC0-inf was
`28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis
`compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after
`hemodialysis, respectively. A 4 hour hemodialysis session removed approximately 18%
`of administered dose [see Dosage and Administration (2.2) and Use in Specific
`Populations (8.6)].
`
`Race: Population pharmacokinetics analysis in HCV-infected subjects indicated that
`race had no clinically relevant effect on the exposure of ledipasvir, sofosbuvir, and GS-
`331007.
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`Gilead Sciences
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`Gender: Population pharmacokinetics analysis in HCV-infected subjects indicated that
`gender had no clinically relevant effect on the exposure of sofosbuvir and GS-331007.
`AUC and Cmax of ledipasvir were 77% and 58% higher, respectively, in females than
`males; however, the relationship between gender and ledipasvir exposures was not
`considered clinically relevant, as high response rates (SVR >90%) were achieved in
`male and female subjects across the Phase 3 studies and the safety profiles are similar
`in females and males.
`
`Pediatric Patients: The pharmacokinetics of ledipasvir or sofosbuvir in pediatric patients
`has not been established [see Use in Specific Populations (8.4)].
`
`Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects
`showed that within the age range (18 to 80 years) analyzed, age did not have a
`clinically relevant effect on the exposure to ledipasvir, sofosbuvir, and GS-331007 [see
`Use in Specific Populations (8.5)].
`
`Patients with Hepatic Impairment: The pharmacokinetics of ledipasvir were studied with
`a single dose of 90 mg ledipasvir in HCV negative subjects with severe hepatic
`impairment (Child-Pugh Class C). Ledipasvir plasma exposure (AUC0-inf) was similar in
`subjects with severe hepatic impairment and control subjects with normal hepatic
`function. Population pharmacokinetics analysis in HCV-infected subjects indicated that
`cirrhosis had no clinically relevant effect on the exposure of ledipasvir [see Use in
`Specific Populations (8.7)].
`
`The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg
`sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment
`(Child-Pugh Class B and C). Relative to subjects with normal hepatic function, the
`sofosbuvir AUC0-24 were 126% and 143% higher in moderate and severe hepatic
`impairment, while the GS-331007 AUC0-24 were 18% and 9% higher, respectively.
`Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis
`had no clinically relevant effect on the exposure of sofosbuvir and GS-331007 [see Use
`in Specific Populations (8.7)].
`
`Drug Interaction Studies
`
`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 (5.1)]. Coadministration with drugs that inhibit P-gp and/or
`BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing
`GS-331007 plasma concentration; HARVONI may be coadministered with P-gp and/or
`BCRP inhibitors. Neither ledipasvir nor sofosbuvir is a substrate for hepatic uptake
`