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
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
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Recommended dosage: One tablet (90 mg of ledipasvir and 400 mg of sofosbuvir) taken orally once daily with or without food (2.1)
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Recommended treatment duration (2.1):
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Treatment-naïve with or without cirrhosis: 12 weeks
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Treatment-experienced without cirrhosis: 12 weeks
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Treatment-experienced with cirrhosis: 24 weeks
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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 (4)
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.
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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)
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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
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
HARVONI is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults.
2 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)].
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 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.
4 CONTRAINDICATIONS
None
5 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.
6 ADVERSE REACTIONS
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.
Laboratory Abnormalities
Bilirubin Elevations: Bilirubin elevations of greater than 1.5×ULN 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 3×ULN 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.
7 DRUG INTERACTIONS
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.
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)].
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)].
8 USE IN SPECIFIC POPULATIONS
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 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)].
10 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 [(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:
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:
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 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 eva luated 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 doe
