Data from FDA - Curated by EPG Health - Last updated 31 December 2017

Indication(s)

1 INDICATIONS AND USAGE HARVONI is a fixed-dose combination of ledipasvir, a hepatitis C virus (HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor, and is indicated for the treatment of chronic hepatitis C virus (HCV) in: Adults with genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis Adults with genotype 1 infection with decompensated cirrhosis, in combination with ribavirin Adults with genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, in combination with ribavirin Pediatric patients 12 years of age and older or weighing at least 35 kg with genotype 1, 4, 5, or 6 without cirrhosis or with compensated cirrhosis. (1) Adult Patients: HARVONI is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) [see Dosage and Administration (2.2) and Clinical Studies (14)]: genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis genotype 1 infection with decompensated cirrhosis, for use in combination with ribavirin genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, for use in combination with ribavirin Pediatric Patients: HARVONI is indicated for the treatment of pediatric patients 12 years of age and older or weighing at least 35 kg with HCV genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis [see Dosage and Administration (2.3) and Clinical Studies (14.6)].

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Advisory information

contraindications
4 CONTRAINDICATIONS If HARVONI is administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen. Refer to the ribavirin prescribing information for a list of contraindications for ribavirin [see Dosage and Administration (2.2)]. If used in combination with ribavirin, all contraindications to ribavirin also apply to HARVONI combination therapy. (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see Warnings and Precautions (5.2)]. 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. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. If HARVONI is administered with ribavirin to adults, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions. Clinical Trials in Adult Subjects The safety assessment of HARVONI was based on pooled data from three randomized, open-label Phase 3 clinical trials (ION-3, ION-1, and ION-2) of subjects with genotype 1 HCV with compensated liver disease (with and without cirrhosis) including 215, 539, and 326 subjects who received HARVONI once daily by mouth for 8, 12 and 24 weeks, respectively [see Clinical Studies (14)]. The proportion of subjects who permanently discontinued treatment due to adverse events was 0%, less than 1%, and 1% for subjects receiving HARVONI for 8, 12, and 24 weeks, respectively. The most common adverse reactions (at least 10%) were fatigue and headache in subjects treated with 8, 12, or 24 weeks of HARVONI. Table 3 lists adverse reactions (adverse events assessed as causally related by the investigator, all grades) observed in at least 5% of subjects receiving 8, 12, or 24 weeks treatment with HARVONI in clinical trials. The majority of adverse reactions presented in Table 3 occurred at severity of grade 1. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs. Table 3 Adverse Reactions (All Grades) Reported in ≥5% of Subjects Receiving 8, 12, or 24 Weeks of Treatment with HARVONI HARVONI 8 weeks N=215 HARVONI 12 weeks N=539 HARVONI 24 weeks N=326 Fatigue 16% 13% 18% Headache 11% 14% 17% Nausea 6% 7% 9% Diarrhea 4% 3% 7% Insomnia 3% 5% 6% The safety assessment of HARVONI was also based on pooled data from three open-label trials (Study 1119, ION-4, and ELECTRON-2) in 118 subjects with chronic HCV genotype 4, 5, or 6 infection with compensated liver disease (with or without cirrhosis) [see Clinical Studies (14.3)]. The subjects received HARVONI once daily by mouth for 12 weeks. The safety profile in subjects with chronic HCV genotype 4, 5, or 6 infection with compensated liver disease was similar to that observed in subjects with chronic HCV genotype 1 infection with compensated liver disease. The most common adverse reactions occurring in at least 10% of subjects were asthenia (18%), headache (14%), and fatigue (10%). Adverse Reactions in Subjects with Cirrhosis The safety assessment of HARVONI with or without ribavirin was based on a randomized, double-blind and placebo-controlled trial in treatment-experienced genotype 1 subjects with compensated cirrhosis and was compared to placebo in the SIRIUS trial. Subjects were randomized to receive 24 weeks of HARVONI once daily by mouth without ribavirin or 12 weeks of placebo followed by 12 weeks of HARVONI once daily by mouth + ribavirin [see Clinical Studies (14.2)]. Table 4 presents the adverse reactions, as defined above, that occurred with at least 5% greater frequency in subjects treated with 24 weeks of HARVONI or 12 weeks of HARVONI + ribavirin, compared to those reported for 12 weeks of placebo. The majority of the adverse reactions presented in Table 4 were Grade 1 or 2 in severity. Table 4 Adverse Reactions with ≥5% Greater Frequency Reported in Treatment-Experienced Subjects with Cirrhosis Receiving HARVONI for 24 Weeks or HARVONI + RBV for 12 Weeks Compared to Placebo for 12 weeks HARVONI 24 weeks (N=78) HARVONI + RBV 12 weeks (N=76) Placebo 12 weeks (N=77) Asthenia 31% 36% 23% Headache 29% 13% 16% Fatigue 18% 4% 1% Cough 5% 11% 1% Myalgia 9% 4% 0 Dyspnea 3% 9% 1% Irritability 8% 7% 1% Dizziness 5% 1% 0 Adverse Reactions in Subjects Coinfected with HIV-1 The safety assessment of HARVONI was based on an open-label clinical trial in 335 genotype 1 or 4 subjects with HCV/HIV-1 coinfection who were on stable antiretroviral therapy in Study ION-4 [see Clinical Studies (14.4)]. The safety profile in HCV/HIV-1 coinfected subjects was similar to that observed in HCV mono-infected subjects. The most common adverse reactions occurring in at least 10% of subjects were headache (20%) and fatigue (17%). Adverse Reactions in Liver Transplant Recipients and/or Subjects with Decompensated Cirrhosis The safety assessment of HARVONI with ribavirin (RBV) in liver transplant recipients and/or those who had decompensated liver disease was based on pooled data from two Phase 2 open-label clinical trials including 336 subjects who received HARVONI plus RBV for 12 weeks. Subjects with Child-Pugh-Turcotte (CPT) scores greater than 12 were excluded from the trials [see Clinical Studies (14.5)]. The adverse events observed were consistent with the expected clinical sequelae of liver transplantation and/or decompensated liver disease, or the known safety profile of HARVONI and/or ribavirin. Decreases in hemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were observed in 38% and 13% of subjects treated with HARVONI plus RBV for 12 weeks, respectively. Ribavirin was permanently discontinued in 11% of subjects treated with HARVONI plus RBV for 12 weeks. Liver Transplant Recipients with Compensated Liver Disease: Among the 174 liver transplant recipients with compensated liver disease who received HARVONI with RBV for 12 weeks, 2 (1%) subjects permanently discontinued HARVONI due to an adverse event. Subjects with Decompensated Liver Disease: Among the 162 subjects with decompensated liver disease (pre- or post-transplant) who received HARVONI with RBV for 12 weeks, 7 (4%) subjects died, 4 (2%) subjects underwent liver transplantation, and 1 subject (<1%) underwent liver transplantation and died during treatment or within 30 days after discontinuation of treatment. Because these events occurred in patients with advanced liver disease who are at risk of progression of liver disease including liver failure and death, it is not possible to reliably assess the contribution of drug effect to outcomes. A total of 4 (2%) subjects permanently discontinued HARVONI due to an adverse event. Less Common Adverse Reactions Reported in Clinical Trials (less than 5%): The following adverse reactions occurred in less than 5% of subjects receiving HARVONI in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship. Psychiatric disorders: depression (including in subjects with pre-existing history of psychiatric illness). Depression (particularly in subjects with pre-existing history of psychiatric illness) occurred in subjects receiving sofosbuvir containing regimens. Suicidal ideation and suicide have occurred in less than 1% of subjects treated with sofosbuvir in combination with ribavirin or pegylated interferon/ribavirin in other clinical trials. Laboratory Abnormalities Bilirubin Elevations: Bilirubin elevations of greater than 1.5×ULN 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 1.5×ULN were observed in 3%, 11%, and 3% of subjects with compensated cirrhosis treated with placebo, HARVONI + ribavirin for 12 weeks and HARVONI for 24 weeks, respectively, in the SIRIUS trial. Lipase Elevations: Transient, asymptomatic lipase elevations of greater than 3×ULN 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 3× 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 10×ULN was observed in 1% of subjects treated with HARVONI for 12 weeks in the ION-4 trial and has also been previously reported in subjects treated with sofosbuvir in combination with ribavirin or peginterferon/ribavirin in other clinical trials. Adverse Reactions in Pediatric Subjects 12 Years of Age and Older The safety assessment of HARVONI in pediatric subjects 12 years of age and older is based on data from a Phase 2, open-label clinical trial (Study 1116) that enrolled 100 subjects without cirrhosis or with compensated cirrhosis who were treated with HARVONI for 12 weeks. The adverse reactions observed were consistent with those observed in clinical studies of HARVONI in adults. Limited safety data are available in pediatric subjects receiving HARVONI for 24 weeks. No Grade 3 or 4 adverse reactions or discontinuation due to an adverse reaction was observed in those pediatric subjects receiving HARVONI for 24 weeks [see Clinical Studies (14.6)]. 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 (5.2), Drug Interactions (7.2)]. Skin and Subcutaneous Tissue Disorders Skin rashes, sometimes with blisters or angioedema-like swelling Angioedema

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Testing Prior to the Initiation of Therapy: Test all patients for HBV infection by measuring HBsAg and anti-HBc. (2.1) Recommended adult and pediatric dosage: One tablet (90 mg of ledipasvir and 400 mg of sofosbuvir) taken orally once daily with or without food. (2.2, 2.3) HCV/HIV-1 coinfection: For adult and pediatric patients with HCV/HIV-1 coinfection, follow the dosage recommendations in the tables below, respectively. (2.2, 2.3) If used in combination with ribavirin, follow the recommendations for ribavirin dosing and dosage modifications. (2.2) Recommended adult treatment regimen and duration: (2.2) Adult Patient Population Regimen and Duration Genotype 1 Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) HARVONI 12 weeks Treatment-experienced without cirrhosis HARVONI 12 weeks Treatment-experienced with compensated cirrhosis (Child-Pugh A) HARVONI 24 weeks Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C) HARVONI + ribavirin 12 weeks Genotype 1 or 4 Treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis, or with compensated cirrhosis (Child-Pugh A) HARVONI + ribavirin 12 weeks Genotype 4, 5, or 6 Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A) HARVONI 12 weeks Recommended treatment duration for pediatric patients 12 years of age and older or weighing at least 35 kg. (2.3) Pediatric Patient Population 12 Years of Age and Older or Weighing at Least 35 Kg Regimen and Duration Genotype 1 Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) HARVONI 12 weeks Treatment-experienced without cirrhosis HARVONI 12 weeks Treatment-experienced with compensated cirrhosis (Child-Pugh A) HARVONI 24 weeks Genotype 4, 5, or 6 Treatment-naïve and treatment-experienced, without cirrhosis or with compensated cirrhosis (Child-Pugh A) HARVONI 12 weeks A dosage recommendation cannot be made for patients with severe renal impairment or end stage renal disease. (2.4) 2.1 Testing Prior to the Initiation of Therapy Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with HARVONI [see Warnings and Precautions (5.1)]. 2.2 Recommended Dosage in Adults The recommended dosage of HARVONI is one tablet (90 mg ledipasvir and 400 mg sofosbuvir) taken orally once daily with or without food [see Clinical Pharmacology (12.3)]. Relapse rates are affected by baseline host and viral factors and differ between treatment durations for certain subgroups [see Clinical Studies (14)]. Table 1 shows the recommended HARVONI treatment regimen and duration based on patient population. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1 [see Clinical Studies (14)]. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs. Table 1 Recommended Treatment Regimen and Duration for HARVONI in Adult Patients with Genotype 1, 4, 5, or 6 HCV Patient Population Treatment Regimen and Duration Genotype 1 Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) HARVONI 12 weeksHARVONI for 8 weeks can be considered in treatment-naïve genotype 1 patients without cirrhosis who have pretreatment HCV RNA less than 6 million IU/mL [see Clinical Studies (14.2)]. Treatment-experiencedTreatment-experienced patients have failed a peginterferon alfa + ribavirin based regimen with or without an HCV protease inhibitor. without cirrhosis HARVONI 12 weeks Treatment-experienced with compensated cirrhosis (Child-Pugh A) HARVONI 24 weeksHARVONI + ribavirin for 12 weeks can be considered in treatment-experienced genotype 1 patients with cirrhosis who are eligible for ribavirin [see Clinical Studies (14.2)]. See footnote ¶ for ribavirin dosage recommendations. Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C) HARVONI + ribavirinIn patients with decompensated cirrhosis, the starting dosage of ribavirin is 600 mg and can be titrated up to 1000 mg for patients <75 kg and 1200 mg for those ≥75 kg in two divided doses with food. If the starting dosage of ribavirin is not well tolerated, the dosage should be reduced as clinically indicated based on hemoglobin levels. 12 weeks Genotype 1 or 4 Treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis, or with compensated cirrhosis (Child-Pugh A) HARVONI + ribavirinThe 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. 12 weeks Genotype 4, 5, or 6 Treatment-naïve and treatment-experienced, without cirrhosis or with compensated cirrhosis (Child-Pugh A) HARVONI 12 weeks For further information on ribavirin dosing and dosage modifications, refer to the ribavirin prescribing information [see Clinical Studies (14.5)]. 2.3 Recommended Dosage in Pediatric Patients 12 Years of Age and Older or Weighing at Least 35 kg The recommended dosage of HARVONI in pediatric patients 12 years of age and older or weighing at least 35 kg is one tablet (90 mg ledipasvir and 400 mg sofosbuvir) taken orally once daily with or without food for 12 weeks [see Clinical Pharmacology (12.3) and Clinical Studies (14.6)]. Table 2 shows the recommended HARVONI duration based on pediatric patient population. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 2 [see Use in Specific Populations (8.4)]. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs. Table 2 Recommended Regimen and Duration for HARVONI in Pediatric Patients 12 Years of Age or Older or Weighing at Least 35 kg with Genotype 1, 4, 5, or 6 HCV without Cirrhosis or with Compensated Cirrhosis Patient Population Treatment Regimen and Duration Genotype 1 Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) HARVONI 12 weeks Treatment-experienced Treatment-experienced patients have failed an interferon based regimen with or without ribavirin. without cirrhosis HARVONI 12 weeks Treatment-experienced with compensated cirrhosis (Child-Pugh A) HARVONI 24 weeks Genotype 4, 5, or 6 Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A) HARVONI 12 weeks 2.4 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/1.73 m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary 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 ribavirin-associated risks of use during pregnancy. No adequate human data are available to establish whether or not HARVONI poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of HARVONI (ledipasvir or sofosbuvir) at exposures greater than those in humans at the recommended human dose (RHD) [see Data]. During organogenesis in the rat and rabbit, systemic exposures (AUC) to ledipasvir were approximately 4 (rats) and 2 (rabbits) times the exposure in humans at the RHD, while exposures to the predominant circulating metabolite of sofosbuvir (GS-331007) were ≥3 (rats) and 7 (rabbits) times the exposure in humans at the RHD. In rat pre/postnatal development studies, maternal systemic exposures (AUC) to ledipasvir and GS-331007 were approximately 5 and 7 times, respectively, the exposure in humans at the RHD. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. 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, and also to rats (oral doses up to 100 mg/kg/day) on gestation day 6 to lactation/post-partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. Systemic exposures (AUC) to ledipasvir were ≥4 (rats) and 2 (rabbits) times the exposure in humans at the RHD. 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, and also to rats (oral doses up to 500 mg/kg/day) on gestation day 6 to lactation/post-partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. Systemic exposures (AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) were ≥3 (rats) and 7 (rabbits) times the exposure in humans at the RHD, with exposures increasing during gestation from approximately 3 to 6 (rats) and 7 to 17 (rabbits) times the exposure in humans at the RHD. 8.2 Lactation Risk Summary It is not known whether ledipasvir or sofosbuvir, the components of HARVONI, or their metabolites are present in human breast milk, affect human milk production or have effects on the breastfed infant. When administered to lactating rats, ledipasvir was detected in the plasma of nursing pups likely due to the presence of ledipasvir in milk, without clear effects on nursing pups [see Data]. 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 child from HARVONI or from the underlying maternal condition. If HARVONI is administered with ribavirin, the nursing mother's information for ribavirin also applies to this combination regimen. Refer to the ribavirin prescribing information for more information on use during lactation. Data Ledipasvir: No effects of ledipasvir on growth and postnatal development were observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure (AUC) to ledipasvir was approximately 5 times the exposure in humans at the RHD. Although not measured directly, ledipasvir was likely present in the milk of lactating rats, since systemic exposure (AUC) to ledipasvir of approximately 25% that of maternal exposure was observed in nursing pups on lactation day 10. Sofosbuvir: No effects of sofosbuvir on growth and postnatal development were observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure (AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) was approximately 7 times the exposure in humans at the RHD, with exposure of approximately 2% that of maternal exposure observed in nursing pups on lactation day 10. In a lactation study, sofosbuvir metabolites (primarily GS-331007) were excreted into the milk of lactating rats following administration of a single oral dose of sofosbuvir (20 mg/kg) on lactation day 2, with milk concentrations of approximately 10% that of maternal plasma concentrations observed 1 hour post-dose. 8.3 Females and Males of Reproductive Potential If HARVONI is administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to ribavirin prescribing information for additional information. 8.4 Pediatric Use The safety, pharmacokinetics, and efficacy of HARVONI for treatment of HCV genotype 1 infection in treatment-naïve and treatment-experienced pediatric patients 12 years of age and older without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1116, N=100; 80 treatment-naïve, 20 treatment-experienced) and are comparable to that observed in adults. The safety and efficacy of HARVONI for treatment of HCV genotypes 4, 5, or 6 infection in pediatric patients 12 years of age and older or weighing at least 35 kg without cirrhosis or with compensated cirrhosis is supported by comparable ledipasvir, sofosbuvir, and GS-331007 exposures between adults and adolescents with HCV genotype 1 and similar efficacy and exposures across HCV genotypes 1, 4, 5, and 6 in adults [see Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3 and 14.6)]. The safety and efficacy of HARVONI have not been established in pediatric patients less than 12 years of age and weighing less than 35 kg, in pediatric patients with decompensated cirrhosis, or in pediatric liver transplant recipients. 8.5 Geriatric Use Clinical trials of HARVONI included 225 subjects aged 65 and over (9% of total number of subjects in the clinical studies). 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 less than 30 mL/min/1.73 m2) or ESRD requiring hemodialysis. No dosage recommendation can be given for patients with severe renal impairment or ESRD [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Refer to ribavirin prescribing information regarding use in patients with renal impairment. 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) [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) and Clinical Studies (14.5)]. Clinical and hepatic laboratory monitoring, as clinically indicated, is recommended for patients with decompensated cirrhosis receiving treatment with HARVONI and ribavirin [see Adverse Reactions (6.1)].

Interactions

7 DRUG INTERACTIONS Coadministration with amiodarone may result in serious symptomatic bradycardia. Use of HARVONI with amiodarone is not recommended. (5.2, 6.2, 7.2) P-gp inducers (e.g., rifampin, St. John's wort): May alter concentrations of ledipasvir and sofosbuvir. Use of HARVONI with P-gp inducers is not recommended. (5.3, 7, 12.3) Frequent monitoring of international normalized ratio (INR) values is recommended in patients receiving warfarin. (7.1) Consult the full prescribing information prior to use for potential drug interactions. (5.2, 5.3, 7, 12.3) 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 (5.3)]. Fluctuations in INR values may occur in patients receiving warfarin concomitant with HCV treatment, including treatment with HARVONI. Frequent monitoring of INR values is recommended during treatment and post-treatment follow-up. 7.2 Established and Potentially Significant Drug Interactions Table 5 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 (5.2, 5.3) and Clinical Pharmacology (12.3)]. Table 5 Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted InteractionThis table is not all inclusive. Concomitant Drug Class: Drug Name Effect on Concentration↓ = decrease, ↑ = increase Clinical Comment tenofovir DF = tenofovir disoproxil fumarate Acid Reducing Agents: ↓ ledipasvir Ledipasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease concentration of ledipasvir. Antacids (e.g., aluminum and magnesium hydroxide) It is recommended to separate antacid and HARVONI administration by 4 hours. H2-receptor antagonistsThese interactions have been studied in healthy adults. (e.g., famotidine) 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 inhibitors (e.g., omeprazole) Proton-pump inhibitor doses comparable to omeprazole 20 mg or lower can be administered simultaneously with HARVONI under fasted conditions. Antiarrhythmics: amiodarone Effect on amiodarone, ledipasvir, and sofosbuvir concentrations unknown 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 (5.2), Adverse Reactions (6.2)]. digoxin ↑ digoxin Coadministration of HARVONI with digoxin may increase the concentration of digoxin. Therapeutic concentration monitoring of digoxin is recommended when coadministered with HARVONI. Anticonvulsants: carbamazepine phenytoin phenobarbital oxcarbazepine ↓ ledipasvir ↓ sofosbuvir 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. Antimycobacterials: rifabutin rifampin rifapentine ↓ ledipasvir ↓ sofosbuvir 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 (5.3)]. HIV Antiretrovirals: Regimens containing tenofovir DF without an HIV protease inhibitor/ritonavir or cobicistat ↑ tenofovir Monitor for tenofovir-associated adverse reactions in patients receiving HARVONI concomitantly with a regimen containing tenofovir DF without an HIV protease inhibitor/ritonavir or cobicistat. Refer to VIREAD or TRUVADA prescribing information for recommendations on renal monitoring. Regimens containing tenofovir DF and an HIV protease inhibitor/ritonavir or cobicistat atazanavir/ritonavir or cobicistat + emtricitabine/tenofovir DF darunavir/ritonavir or cobicistat + emtricitabine/tenofovir DF lopinavir/ritonavir + emtricitabine/tenofovir DF ↑ tenofovir The safety of increased tenofovir concentrations in the setting of HARVONI and an 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. elvitegravir, cobicistat, emtricitabine, tenofovir DF ↑ tenofovir 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. tipranavir/ritonavir ↓ ledipasvir ↓ sofosbuvir 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. HCV Products: simeprevir ↑ ledipasvir ↑ simeprevir Concentrations of ledipasvir and simeprevir are increased when simeprevir is coadministered with ledipasvir. Coadministration of HARVONI with simeprevir is not recommended. Herbal Supplements: St. John's wort (Hypericum perforatum) ↓ ledipasvir ↓ sofosbuvir Coadministration of HARVONI with St. John's wort, a P-gp inducer, is not recommended [see Warnings and Precautions (5.3)]. HMG-CoA Reductase Inhibitors: rosuvastatin ↑ rosuvastatin 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. atorvastatin ↑ atorvastatin Coadministration of HARVONI with atorvastatin may be associated with increased risk of myopathy, including rhabdomyolysis. Monitor closely for HMG-CoA reductase inhibitor-associated adverse reactions, such as myopathy and rhabdomyolysis. 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 5 for use of HARVONI with certain HIV antiretroviral regimens [see Drug Interactions (7.2)].

More information

Category Value
Authorisation number NDA205834
Agency product number WJ6CA3ZU8B
Orphan designation No
Product NDC 61958-1801
Date Last Revised 15-11-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1591943
Storage and handling Store at room temperature below 30 °C (86 °F). Dispense only in original container. Do not use if seal over bottle opening is broken or missing.
Marketing authorisation holder Gilead Sciences, Inc
Warnings WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HARVONI. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated [see Warnings and Precautions (5.1)]. WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV See full prescribing information for complete boxed warning. Hepatitis B virus (HBV) reactivation has been reported, in some cases resulting in fulminant hepatitis, hepatic failure, and death. (5.1)