`
`
`
`-------------------------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 prescribing information prior to use for potential drug
`
`
`interactions (5.1, 7, 12.3)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`FDA-approved patient labeling.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 10/2014
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
` 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 inhibitor, 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
`
`
`
`
`
`
`
`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
`
`
`
`8.7 Hepatic Impairment
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1
`
`Reference ID: 3642283
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`DOSAGE AND ADMINISTRATION
`
` FULL PRESCRIBING INFORMATION
`
` 1
` INDICATIONS AND USAGE
`
`
`
`
`
`HARVONI is indicated for the treatment of chronic hepatitis C (CHC) genotype 1
`
`infection in adults.
`
`
`2
`
`
`
`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)].
`
`
`
`
`
`Table 1
`
`
`
`
`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)].
`
`
`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.
`
`
`
`
`
`Reference ID: 3642283
`
`
`Gilead Sciences
`
`
`2
`
`

`

`
`
`
`
`
`
`
`CONTRAINDICATIONS
`
`
`WARNINGS AND PRECAUTIONS
`
`
`
`4
`
`None
`
`
`5
`
`
` 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.
`
`
`6
`
`
`
`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.
`
`
`ADVERSE REACTIONS
`
`
`
`Reference ID: 3642283
`
`
`Gilead Sciences
`
`
`3
`
`

`

`
`
`
`
`
` Table 2
`
`
`
`
`
` Fatigue
`
`
` Headache
`
` Nausea
`
` Diarrhea
`
` Insomnia
`
`
`
`
`
`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%
`
`
`
`Laboratory Abnormalities
`
`
`
`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.
`
`
`DRUG INTERACTIONS
`
`
`
`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.
`
`
`
`
`Reference ID: 3642283
`
`
`Gilead Sciences
`
`
`4
`
`

`

`
`
`
`
`
`
`
`
`
` 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
`
`
`
`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:
`
`digoxin
`
`
`
`↑ digoxin
`
`
` Anticonvulsants:
`carbamazepine
`
`
` phenytoin
`
` phenobarbital
`
` oxcarbazepine
`Antimycobacterials:
`
`rifabutin
`
`rifampinc
`
`
`rifapentine
`
`↓ ledipasvir
`
`
`↓ sofosbuvir
`
`
`↓ GS-331007
`
`
`
`
`
`↓ ledipasvir
`
`
`↓ sofosbuvir
`
`
`↓ GS-331007
`
`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 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)].
`
`HIV Antiretrovirals:
`
`
`
`
`Reference ID: 3642283
`
`
`Gilead Sciences
`
`
`5
`
`

`

`
`
`
` 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
`
`
`tipranavir/ritonavir
`
`HCV Products:
`
`simeprevirc
`
`
`
`Herbal Supplements:
`
`
`St. John’s wort
`
`(Hypericum perforatum)
`HMG-CoA Reductase
`Inhibitors:
`
`rosuvastatin
`
`
`
`
` ↑ tenofovir
`
`
`
`
`
`↑ tenofovir
`
`
`
`
`
`
`
`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
`
`
`
`
`
`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.
`
`
`
`
`
` 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)].
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3642283
`
`
`Gilead Sciences
`
`
`6
`
`

`

`
`
`
`
`
`
`
` USE IN SPECIFIC POPULATIONS
`
`
`
`
` 8
`
`
`
`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)].
`
`
`
`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
`
`
`
`
`
`
`
`Reference ID: 3642283
`
`
`Gilead Sciences
`
`
`7
`
`

`

`
`
`
`
`
`
`
`with severe renal impairment (eGFR <30 mL/min/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 Pharmacology
`
`
`
` (12.3)].
`
`
`
`8.7 Hepatic Impairment
`
`
`
`
`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)].
`
`
`
`OVERDOSAGE
`10
`
`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%.
`
`
`
`DESCRIPTION
`11
`
`
`
`
`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 [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7­
`
`{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2­
`azabicyclo[2.2.1]hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5­
`
`azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate.
`
`
`
`It has a molecular formula of C49H54F2N8O6 and a molecular weight of 889.00. It has the
`
`
` following structural formula:
`
`
`
`
`
`O
`
`H3CO
`
`N
`H
`
`O
`
`N
`
`H
`N
`
`N
`
`F F
`
`
`
`
`
`Reference ID: 3642283
`
`H
`
`H
`N
`
`N
`
`O
`
`N
`
`H
`N OCH3
`O
`
`
`
`
`Gilead Sciences
`
`
`8
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5­
`(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2­
`
`
` yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of
` C22H29FN3O9P and a molecular weight of 529.45. It has the following structural formula:
`
`
`
`
`H
`O
`N O
`
`O
`
`O
`O HN P O
`O
`
`O
`
`N
`
`HO F
`
`
`
`CLINICAL PHARMACOLOGY
`
`
`
` Sofosbuvir is a white to off-white crystalline solid with a solubility of ≥2 mg/mL across
`
`
`
` the pH range of 2–7.7 at 37oC and is slightly soluble in water.
`
`
`
`12
`
`
`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
`
`
`
`Reference ID: 3642283
`
`
`Gilead Sciences
`
`
`9
`
`

`

`
`
`
`
`
`
`
`
`
` hour post-dose. Median peak plasma concentration of GS-331007 was observed
`
` between 3.5 to 4 hours post-dose.
`
`
`
`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
`
`
`
`
`
`
`
`
`Reference ID: 3642283
`
`
`Gilead Sciences
`
`
`10
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`Reference ID: 3642283
`
`
`Gilead Sciences
`
`
`11
`
`

`

`
`
`
`
`
`
`
`
`
`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 (S