Harvoni 90 MG / 400 MG Oral Tablet
DRUG INTERACTIONS
7 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 patient 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 Interaction This 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.
H 2-receptor antagonists These interactions have been studied in healthy adults.
(e.g., famotidine) H 2-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)] .
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: polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
Ledipasvir: The IUPAC name for ledipasvir is Methyl [(2 S)-1-{(6 S)-6-[5-(9,9-difluoro-7-{2-[(1 R,3 S,4 S)-2-{(2 S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-1 H-benzimidazol-6-yl}-9 H-fluoren-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 C 49H 54F 2N 😯 6 and a molecular weight of 889.00.
It has the following structural formula: Ledipasvir is practically insoluble (less than 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).
Chemical Structure Sofosbuvir: The IUPAC name for sofosbuvir is ( S)-Isopropyl 2-(( S)-(((2 R,3 R,4 R,5 R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2 H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate.
It has a molecular formula of C 22H 29FN 3O 9P 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 at least 2 mg/mL across the pH range of 2–7.7 at 37°C and is slightly soluble in water.
Chemical Structure
CLINICAL STUDIES
14 14.1 Description of Clinical Trials The efficacy and safety of HARVONI were evaluated in four trials in genotype 1 HCV mono-infected subjects including one trial exclusively in treatment-experienced subjects with compensated cirrhosis (Child-Pugh A), one trial in genotype 1 or 4 HCV/HIV-1 coinfected subjects, two trials in genotype 4, 5, or 6 HCV mono-infected subjects, two trials in genotype 1 or 4 HCV infected pretransplant subjects with decompensated cirrhosis (Child-Pugh B and C) or post-transplant with Metavir F0–F3 fibrosis, compensated cirrhosis, decompensated cirrhosis, or fibrosing cholestatic hepatitis (FCH), and one trial in genotype 1 HCV pediatric subjects 12 years of age and older without cirrhosis or with compensated cirrhosis, as summarized in Table 9 [see Clinical Studies (14.2, 14.3, 14.4, 14.5, and 14.6)]: Table 9 Trials Conducted with HARVONI with or without Ribavirin in Subjects with Chronic HCV Genotype 1, 4, 5 or 6 Infection Trial Population Study Arms (Number of Subjects Treated) TN: Treatment-naïve subjects TE: Treatment-experienced subjects including those who have failed a peginterferon alfa + ribavirin based regimen with or without an HCV protease inhibitor.
ION-3 (open-label) GT1, TN without cirrhosis HARVONI 8 weeks (215) HARVONI + RBV 8 weeks (216) HARVONI 12 weeks (216) ION-1 (open-label) GT1, TN with or without cirrhosis HARVONI 12 weeks (214) HARVONI + RBV 12 weeks (217) HARVONI 24 weeks (217) HARVONI + RBV 24 weeks (217) ION-2 (open-label) GT1, TE with or without cirrhosis HARVONI 12 weeks (109) HARVONI + RBV 12 weeks (111) HARVONI 24 weeks (109) HARVONI + RBV 24 weeks (111) SIRIUS (double-blind) GT1, TE with cirrhosis HARVONI + RBV 12 Weeks (77) HARVONI 24 weeks (77) ION-4 (open-label) GT1 and GT4 HCV/HIV-1 coinfected TN and TE with or without cirrhosis HARVONI 12 Weeks (N=327 for GT1; N=8 for GT4) Study 1119 (open-label) GT4 and GT5, TN and TE with or without cirrhosis HARVONI 12 Weeks (N=44 for GT4; N=41 for GT5) ELECTRON-2 (open-label) GT6, TN and TE with or without cirrhosis HARVONI 12 Weeks (25) SOLAR-1 and SOLAR-2 (open-label) GT1 and GT4 pre-transplant with decompensated cirrhosis or post-transplant with Metavir F0–F3 fibrosis, compensated cirrhosis, decompensated cirrhosis, or FCH HARVONI + RBV 12 Weeks (336) HARVONI + RBV 24 weeks (334) Study 1116 (open-label) GT1 with or without cirrhosis in pediatric subjects 12 years of age and older HARVONI 12 Weeks (100) HARVONI was administered once daily by mouth in these trials.
For subjects without cirrhosis or with compensated cirrhosis who received ribavirin (RBV), the RBV dosage was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing at least 75 kg.
For subjects with decompensated cirrhosis in SOLAR-1 and SOLAR-2 studies, the starting RBV dosage was 600 mg per day regardless of transplantation status.
RBV dose adjustments were performed according to the RBV labeling.
Serum HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System in ION-3, ION-1, ION-2, SIRIUS, and ION-4 studies or the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) in ELECTRON-2, 1119, SOLAR-1, SOLAR-2, and 1116 studies.
The COBAS TaqMan HCV test (version 2.0) for use with the High Pure System has a lower limit of quantification (LLOQ) of 25 IU per mL and the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) has a LLOQ of 15 IU per mL.
Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in studies in adults and the key efficacy endpoint in the study in pediatric subjects 12 years of age and older.
Relapse was a secondary endpoint, which was defined as HCV RNA greater than or equal to LLOQ with 2 consecutive values or last available post-treatment measurement during the post-treatment period after achieving HCV RNA less than LLOQ at end of treatment.
14.2 Clinical Trials in Subjects with Genotype 1 HCV Treatment-Naïve Adults without Cirrhosis ─ ION-3 (Study 0108) ION-3 was a randomized, open-label trial in treatment-naïve non-cirrhotic subjects with genotype 1 HCV.
Subjects were randomized in a 1:1:1 ratio to one of the following three treatment groups and stratified by HCV genotype (1a vs 1b): HARVONI for 8 weeks, HARVONI for 12 weeks, or HARVONI + ribavirin for 8 weeks.
Demographics and baseline characteristics were balanced across the treatment groups.
Of the 647 treated subjects, the median age was 55 years (range: 20 to 75); 58% of the subjects were male; 78% were White; 19% were Black; 6% were Hispanic or Latino; mean body mass index was 28 kg/m 2 (range: 18 to 56 kg/m 2); 81% had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 80% had genotype 1a HCV infection; 73% had non-C/C IL28B alleles (CT or TT).
Table 10 presents the SVR12 for the HARVONI treatment groups in the ION-3 trial after 8 and 12 weeks of HARVONI treatment.
Ribavirin was not shown to increase the SVR12 observed with HARVONI.
Therefore, the HARVONI + ribavirin arm is not presented in Table 10.
Table 10 Study ION-3: SVR12 after 8 and 12 Weeks of Treatment in Treatment-Naïve Non-Cirrhotic Subjects with Genotype 1 HCV HARVONI 8 Weeks (N=215) HARVONI 12 Weeks (N=216) SVR12 94% (202/215) 96% (208/216) Outcome for Subjects without SVR On-Treatment Virologic Failure 0/215 0/216 Relapse The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment.
5% (11/215) 1% (3/216) Other Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).
1% (2/215) 2% (5/216) SVR by Genotype One subject without a confirmed subtype for genotype 1 infection was excluded from this subgroup analysis.
Genotype 1a 93% (159/171) 96% (165/172) Genotype 1b 98% (42/43) 98% (43/44) The treatment difference between the 8-week treatment of HARVONI and 12-week treatment of HARVONI was –2.3% (97.5% confidence interval –7.2% to 2.5%).
Among subjects with a baseline HCV RNA less than 6 million IU per mL, the SVR12 was 97% (119/123) with 8-week treatment of HARVONI and 96% (126/131) with 12-week treatment of HARVONI.
Relapse rates by baseline viral load are presented in Table 11.
Table 11 Study ION-3: Relapse Rates by Baseline Viral Load after 8 and 12 Weeks of Treatment in Treatment-Naïve Non-Cirrhotic Subjects with Genotype 1 HCV HARVONI 8 Weeks (N=215) HARVONI 12 Weeks (N=216) Number of Responders at End of Treatment 215 216 Baseline HCV RNA HCV RNA values were determined using the Roche TaqMan Assay; a subject’s HCV RNA may vary from visit to visit.
HCV RNA <6 million IU/mL 2% (2/123) 2% (2/131) HCV RNA ≥6 million IU/mL 10% (9/92) 1% (1/85) Treatment-Naïve Adults with or without Cirrhosis ─ ION-1 (Study 0102) ION-1 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with HARVONI with or without ribavirin in 865 treatment-naïve subjects with genotype 1 HCV including those with cirrhosis.
Subjects were randomized in a 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI + ribavirin for 12 weeks, HARVONI for 24 weeks, or HARVONI + ribavirin for 24 weeks.
Randomization was stratified by the presence or absence of cirrhosis and HCV genotype (1a vs 1b).
Demographics and baseline characteristics were balanced across the treatment groups.
Of the 865 treated subjects, the median age was 54 years (range: 18 to 80); 59% of the subjects were male; 85% were White; 12% were Black; 12% were Hispanic or Latino; mean body mass index was 27 kg/m 2 (range: 18 to 48 kg/m 2); 79% had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 67% had genotype 1a HCV infection; 70% had non-C/C IL28B alleles (CT or TT); and 16% had cirrhosis.
Table 12 presents the SVR12 for the treatment group of HARVONI for 12 weeks in the ION-1 trial.
Ribavirin was not shown to increase SVR12 observed with HARVONI.
Therefore, the HARVONI + ribavirin arm is not presented in Table 12.
Table 12 Study ION-1: SVR12 after 12 Weeks of Treatment in Treatment-Naïve Subjects with Genotype 1 HCV with and without Cirrhosis HARVONI 12 Weeks (N=214) SVR12 Excluding one subject with genotype 4 infection.
99% (210/213) Outcome for Subjects without SVR On-Treatment Virologic Failure 0/213 Relapse , The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment.
<1% (1/212) Other , Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up).
1% (2/213) SVR12 for selected subgroups are presented in Table 13.
Table 13 Study ION-1: SVR12 for Selected Subgroups after 12 Weeks of Treatment in Treatment-Naïve Subjects with Genotype 1 HCV with and without Cirrhosis HARVONI 12 Weeks (N=214) Genotype One subject without a confirmed subtype for genotype 1 infection and one subject with genotype 4 infection were excluded from this subgroup analysis.
Genotype 1a 98% (142/145) Genotype 1b 100% (67/67) Cirrhosis Subjects with missing cirrhosis status were excluded from this subgroup analysis.
No 99% (176/177) Yes 94% (32/34) Previously-Treated Adults with or without Cirrhosis ─ ION-2 (Study 0109) ION-2 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with HARVONI with or without ribavirin in genotype 1 HCV-infected subjects with or without cirrhosis who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor.
Subjects were randomized in a 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI + ribavirin for 12 weeks, HARVONI for 24 weeks, or HARVONI + ribavirin for 24 weeks.
Randomization was stratified by the presence or absence of cirrhosis, HCV genotype (1a vs 1b) and response to prior HCV therapy (relapse/breakthrough vs nonresponse).
Demographics and baseline characteristics were balanced across the treatment groups.
Of the 440 treated subjects, the median age was 57 years (range: 24 to 75); 65% of the subjects were male; 81% were White; 18% were Black; 9% were Hispanic or Latino; mean body mass index was 28 kg/m 2 (range: 19 to 50 kg/m 2); 89% had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 79% had genotype 1a HCV infection; 88% had non-C/C IL28B alleles (CT or TT); and 20% had cirrhosis.
Forty-seven percent (47%) of the subjects failed a prior therapy of pegylated interferon and ribavirin.
Among these subjects, 49% were relapse/breakthrough and 51% were non-responder.
Fifty-three percent (53%) of the subjects failed a prior therapy of pegylated interferon and ribavirin with an HCV protease inhibitor.
Among these subjects, 62% were relapse/breakthrough and 38% were non-responder.
Table 14 presents the SVR12 for the HARVONI treatment groups in the ION-2 trial.
Ribavirin was not shown to increase SVR12 observed with HARVONI.
Therefore, the HARVONI + ribavirin arms are not presented in Table 14.
Table 14 Study ION-2: SVR12 after 12 and 24 Weeks of Treatment in Subjects with Genotype 1 HCV with or without Cirrhosis Who Failed Prior Therapy HARVONI 12 Weeks (N=109) HARVONI 24 Weeks (N=109) SVR12 94% (102/109) 99% (108/109) Outcome for Subjects without SVR On-Treatment Virologic Failure 0/109 0/109 Relapse The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment.
6% (7/108) 0/109 Other Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up).
0/109 1% (1/109) Among the subjects with available SVR12 and SVR24 data (206/218), all subjects who achieved SVR12 in the ION-2 study also achieved SVR24.
SVR12 and relapse rates for selected subgroups are presented in Tables 15 and 16.
Table 15 Study ION-2: SVR12 for Selected Subgroups after 12 and 24 Weeks of Treatment in Subjects with Genotype 1 HCV Who Failed Prior Therapy HARVONI 12 Weeks (N=109) HARVONI 24 Weeks (N=109) Genotype Genotype 1a 95% (82/86) 99% (84/85) Genotype 1b 87% (20/23) 100% (24/24) Cirrhosis Subjects with missing cirrhosis status were excluded from this subgroup analysis.
No 95% (83/87) 99% (85/86) Yes 86% (19/22) 100% (22/22) Prior HCV Therapy Peg-IFN + RBV 93% (40/43) 100% (58/58) HCV protease inhibitor + Peg-IFN + RBV 94% (62/66) 98% (49/50) Response to Prior HCV Therapy Relapse/Breakthrough 95% (57/60) 100% (60/60) Non-responder 92% (45/49) 98% (48/49) Table 16 Study ION-2: Relapse Rates for Selected Subgroups after 12 and 24 Weeks of Treatment in Subjects with Genotype 1 HCV Who Failed Prior Therapy HARVONI 12 Weeks (N=109) HARVONI 24 Weeks (N=109) Number of Responders at End of Treatment 108 109 Cirrhosis Subjects with missing cirrhosis status were excluded from this subgroup analysis.
No 5% (4/86) These 4 non-cirrhotic relapsers all had baseline NS5A resistance-associated polymorphisms.
0% (0/86) Yes 14% (3/22) 0% (0/22) Presence of Baseline NS5A Resistance-Associated Polymorphisms NS5A resistance-associated polymorphisms include any change at NS5A positions 24, 28, 30, 31, 58, 92, or 93.
No 2% (2/85) 0% (0/90) Yes 22% (5/23) 0% (0/19) IL28B Status C/C 0% (0/10) 0% (0/16) Non-C/C 7% (7/98) 0% (0/93) Previously-Treated Adults with Cirrhosis ─ SIRIUS (Study 0121) SIRIUS was a randomized, double-blind and placebo-controlled trial that evaluated the efficacy of HARVONI + ribavirin for 12 weeks or HARVONI without ribavirin for 24 weeks in genotype 1 HCV-infected subjects with compensated cirrhosis who failed prior therapy with a Peg-IFN + RBV regimen followed by a subsequent Peg-IFN + RBV + an HCV protease inhibitor regimen.
Subjects were randomized in a 1:1 ratio to receive placebo for 12 weeks followed by HARVONI + ribavirin for 12 weeks or HARVONI for 24 weeks.
Randomization was stratified by HCV genotype (1a vs 1b) and response to prior HCV therapy (never achieved HCV RNA less than LLOQ vs achieved HCV RNA less than LLOQ).
Demographics and baseline characteristics were balanced across the treatment groups.
Of the 155 randomized subjects, the median age was 56 years (range: 23 to 77); 74% of the subjects were male; 97% were White; mean body mass index was 27 kg/m 2 (range: 19 to 47 kg/m 2); 63% had genotype 1a HCV infection; 94% had non-C/C IL28B alleles (CT or TT).
One subject discontinued therapy while on placebo, and was not included in the efficacy analysis.
The SVR12 was 96% (74/77) and 97% (75/77) in subjects treated with HARVONI + ribavirin for 12 weeks and HARVONI for 24 weeks without ribavirin, respectively.
All 5 subjects who did not achieve SVR12 relapsed.
14.3 Clinical Trials in Subjects with Genotype 4, 5, or 6 HCV Below are trial descriptions, SVR12 and relapse data in the genotype 4, 5, and 6 HCV populations.
Trial results in the genotype 4, 5, and 6 HCV populations are based upon limited number of subjects in some subgroups, particularly in subjects who have been previously-treated and subjects with cirrhosis.
Genotype 4 In two open-label studies (Study 1119 and ION-4), HARVONI was administered for 12 weeks to treatment-naïve and previously-treated adult subjects with genotype 4 HCV infection.
Study 1119 enrolled 44 treatment-naïve or previously-treated subjects with genotype 4 HCV, with or without cirrhosis.
ION-4 enrolled 4 treatment-naïve and 4 previously-treated subjects with genotype 4 HCV infection who were coinfected with HIV-1, none of whom had cirrhosis.
In Study 1119, the overall SVR12 rate was 93% (41/44).
SVR12 was similar based upon prior HCV treatment history and cirrhosis status.
In ION-4, all 8 subjects achieved SVR12.
Genotype 5 In the open-label 1119 trial, HARVONI was administered for 12 weeks to 41 treatment-naïve or previously-treated adult subjects with genotype 5 HCV infection, with or without cirrhosis.
The overall SVR12 was 93% (38/41).
SVR12 was similar based upon prior HCV treatment history and cirrhosis status.
Genotype 6 In the open-label ELECTRON-2 trial, HARVONI was administered for 12 weeks to 25 treatment-naïve or previously-treated adult subjects with genotype 6 HCV infection, with or without cirrhosis.
The overall SVR12 was 96% (24/25).
SVR12 was similar based upon prior HCV treatment history and cirrhosis status.
The single subject who relapsed discontinued study treatment early (at approximately Week 8).
14.4 Clinical Trials in Subjects Coinfected with HCV and HIV-1 ION-4 was an open-label clinical trial that evaluated the safety and efficacy of 12 weeks of treatment with HARVONI without ribavirin in HCV treatment-naïve and previously-treated adult subjects with genotype 1 or 4 HCV infection who were coinfected with HIV-1.
Treatment-experienced subjects had failed prior treatment with Peg-IFN + RBV, Peg-IFN + RBV + an HCV protease inhibitor or sofosbuvir + RBV.
Subjects were on a stable HIV-1 antiretroviral therapy that included emtricitabine + tenofovir disoproxil fumarate, administered with efavirenz, rilpivirine, or raltegravir.
Of the 335 treated subjects, the median age was 52 years (range: 26 to 72); 82% of the subjects were male; 61% were White; 34% were Black; mean body mass index was 27 kg/m 2 (range: 18 to 66 kg/m 2); 75% had genotype 1a HCV infection; 2% had genotype 4 infection; 76% had non-C/C IL28B alleles (CT or TT); and 20% had compensated cirrhosis.
Fifty-five percent (55%) of the subjects were treatment-experienced.
Table 17 presents the SVR12 in the ION-4 trial after 12 weeks of HARVONI treatment.
Table 17 Study ION-4: SVR12 in Subjects with Genotype 1 or 4 HCV Coinfected with HIV-1 HARVONI 12 Weeks (N=335) SVR12 96% (321/335) Outcome for Subjects without SVR On-Treatment Virologic Failure <1% (2/335) Relapse The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment.
3% (10/333) Other Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up).
<1% (2/335) SVR12 rates were 94% (63/67) in subjects with cirrhosis and 98% (46/47) in subjects who were previously-treated and had cirrhosis.
The relapse rate in the ION-4 trial in Black subjects was 9% (10/115), all of whom were IL28B non-CC genotype, and none in non-Black subjects (0/220).
In the ION-1, ION-2, and ION-3 HCV mono-infection studies, relapse rates were 3% (10/305) in Black subjects and 2% (26/1637) in non-Black subjects.
No subject had HIV-1 rebound during the study.
The percentage of CD4+ cells did not change during treatment.
Median CD4+ cell count increase of 29 cells/mm 3 was observed at the end of treatment with HARVONI for 12 weeks.
14.5 Clinical Trials in Liver Transplant Recipients and/or Subjects with Decompensated Cirrhosis SOLAR-1 and SOLAR-2 were two open-label trials that evaluated 12 and 24 weeks of treatment with HARVONI in combination with ribavirin in HCV treatment-naïve and previously-treated adult subjects with genotype 1 and 4 infection who had undergone liver transplantation and/or who had decompensated liver disease.
The two trials were identical in study design.
Subjects were enrolled in one of the seven groups in the trials based on liver transplantation status and severity of hepatic impairment (see Table 16).
Subjects with a CPT score greater than 12 were excluded.
Within each group, subjects were randomized in a 1:1 ratio to receive HARVONI + RBV for 12 weeks or HARVONI + RBV for 24 weeks.
For subjects with decompensated cirrhosis in SOLAR-1 and SOLAR-2 studies, the starting RBV dosage was 600 mg per day regardless of transplantation status.
RBV dose adjustments were performed according to the RBV labeling [see Clinical Studies (14.1)] .
Demographics and baseline characteristics were balanced across the treatment groups.
Of the 670 treated subjects, the median age was 59 years (range: 21 to 81); 77% of the subjects were male; 91% were White; mean body mass index was 28 kg/m 2 (range: 18 to 49 kg/m 2); 94% and 6% had genotype 1 and 4 HCV infection, respectively; 78% of the subjects failed a prior HCV therapy.
Table 18 presents the pooled SVR12 rates for SOLAR-1 and SOLAR-2 in subjects with genotype 1 HCV treated with HARVONI + RBV for 12 weeks.
The SVR12 rates observed with 24 weeks of HARVONI + RBV were similar to the SVR12 rates observed with 12 weeks of treatment.
Therefore, the results for the HARVONI + RBV 24 weeks arm are not presented in Table 18.
Table 18 Studies SOLAR-1 and SOLAR-2: SVR12 and Relapse Rates After 12 Weeks of Treatment with HARVONI and Ribavirin in Subjects with Genotype 1 HCV Who Were Post Liver Transplant and/or Who Had Decompensated Liver Disease HARVONI + RBV 12 weeks N=307 SVR12 (N=300) Five subjects transplanted prior to post-treatment Week 12 with HCV RNA<LLOQ at last measurement prior to transplant were excluded.
, Two subjects were excluded due to failure to meet the inclusion criteria for any of the treatment groups (i.e., did not have decompensated cirrhosis and had also not received a liver transplant).
Relapse (N=288) , , Twelve subjects were excluded from relapse analysis because they died (N=11) or withdrew consent (N=1) prior to reaching the 12 week post-treatment follow-up visit.
Pre-transplant CPT B 87% (45/52) 12% (6/51) CPT C 88% (35/40) 5% (2/37) Post-transplant Metavir score F0–F3 95% (94/99) 3% (3/97) CPT A 98% (55/56) 0% (0/55) CPT B 89% (41/46) 2% (1/42) CPT C 57% (4/7) 33% (2/6) There were 7 subjects with fibrosing cholestatic hepatitis in the 12 week treatment arm, and all subjects achieved SVR12.
In genotype 4 HCV post-transplant subjects without cirrhosis or with compensated cirrhosis treated with HARVONI + RBV for 12 weeks (N=12), the SVR12 rate was similar to rates reported with genotype 1; no subjects relapsed.
Available data in subjects with genotype 4 HCV who had decompensated cirrhosis (pre- and post-liver transplantation) were insufficient for dosing recommendations; therefore, these results are not presented.
14.6 Clinical Trial in Pediatric Subjects The efficacy of HARVONI was evaluated in an open-label trial (Study 1116) that evaluated 12 weeks of treatment with HARVONI once daily in genotype 1 HCV treatment-naïve (N=80) and treatment-experienced (N=20) pediatric subjects 12 years of age and older without cirrhosis or with compensated cirrhosis.
Demographics and baseline characteristics were balanced across treatment-naïve and treatment-experienced subjects (patients had failed an interferon based regimen with or without ribavirin).
Of the 100 treated subjects, the median age was 15 years (range: 12 to 17); 63% of the subjects were female; 90% were White, 7% were Black, and 2% were Asian; 13% were Hispanic/Latino; mean body mass index was 23 kg/m 2 (range: 13.1 to 36.6 kg/m 2); mean weight was 61 kg (range 33 to 126 kg); 55% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 81% had genotype 1a HCV infection; 76% had non-CC IL28B alleles (CT or TT).
One subject had known compensated cirrhosis.
The majority of subjects (84%) had been infected through vertical transmission.
The SVR12 rate was 98% overall (98% [78/80] in treatment-naïve subjects and 100% [20/20] in treatment-experienced subjects).
No subject experienced on-treatment virologic failure or relapse.
Two subjects were lost to follow-up.
HOW SUPPLIED
16 /STORAGE AND HANDLING HARVONI tablets are white, diamond-shaped, film-coated, debossed with “GSI” on one side and “7985” on the other side of the tablet.
Each bottle contains 28 tablets (NDC 61958-1801-1), a silica gel desiccant, polyester coil, and is closed with a child-resistant closure.
Store below 30 °C (86 °F).
Dispense only in original container.
Do not use if seal over bottle opening is broken or missing.
RECENT MAJOR CHANGES
Boxed Warning 02/2017 Indications and Usage ( 1) 04/2017 Dosage and Administration ( 2.1) 02/2017 Dosage and Administration ( 2.3) 04/2017 Warnings and Precautions ( 5.1) 02/2017
GERIATRIC USE
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)] .
DOSAGE FORMS AND STRENGTHS
3 HARVONI is available as a white 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.
Tablets: 90 mg ledipasvir and 400 mg sofosbuvir.
( 3)
MECHANISM OF ACTION
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)].
INDICATIONS AND USAGE
1 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) : 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)] .
PEDIATRIC USE
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.
PREGNANCY
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.
BOXED WARNING
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)
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Risk of Hepatitis B Virus Reactivation: Test all patients for evidence of current or prior HBV infection before initiation of HCV treatment.
Monitor HCV/HBV coinfected patients for HBV reactivation and hepatitis flare during HCV treatment and post-treatment follow-up.
Initiate appropriate patient management for HBV infection as clinically indicated.
( 5.1) Bradycardia with amiodarone coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease.
Coadministration of amiodarone with HARVONI is not recommended.
In patients without alternative, viable treatment options, cardiac monitoring is recommended.
( 5.2, 6.2, 7.2) 5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy.
Some cases have resulted in fulminant hepatitis, hepatic failure, and death.
Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive).
HBV reactivation has also been reported in patients receiving certain immunosuppressants or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.
HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level.
In patients with resolved HBV infection, reappearance of HBsAg can occur.
Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level.
In patients with resolved HBV infection, reappearance of HBsAg can occur.
Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.
Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with HARVONI.
In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with HARVONI and during post-treatment follow-up.
Initiate appropriate patient management for HBV infection as clinically indicated.Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with HARVONI.
In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with HARVONI and during post-treatment follow-up.
Initiate appropriate patient management for HBV infection as clinically indicated.
5.2 Serious Symptomatic Bradycardia When Coadministered with Amiodarone Postmarketing cases of symptomatic bradycardia, as well as fatal cardiac arrest and cases requiring pacemaker intervention, have been reported when amiodarone is coadministered with HARVONI.
Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment.
Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease, may be at increased risk for symptomatic bradycardia with coadministration of amiodarone.
Bradycardia generally resolved after discontinuation of HCV treatment.
The mechanism for this effect is unknown.
Coadministration of amiodarone with HARVONI is not recommended.
For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered HARVONI: Counsel patients about the risk of serious symptomatic bradycardia Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.
Patients who are taking HARVONI who need to start amiodarone therapy due to no other alternative, viable treatment options should undergo similar cardiac monitoring as outlined above.
Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to starting HARVONI should also undergo similar cardiac monitoring as outlined above.
Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately.
Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems [see Adverse Reactions (6.2), Drug Interactions (7.2)] .
5.3 Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers The concomitant use of HARVONI and P-gp inducers (e.g., rifampin, St.
John’s wort) may significantly decrease ledipasvir and sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of HARVONI.
Therefore, the use of HARVONI with P-gp inducers (e.g., rifampin or St.
John’s wort) is not recommended [see Drug Interactions (7.2)] .
5.4 Risks Associated with Ribavirin Combination Treatment If HARVONI is administered with ribavirin, the warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, apply to this combination regimen.
Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin [see Dosage and Administration (2.2)].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).
Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV Inform patients that HBV reactivation can occur in patients coinfected with HBV during or after treatment of HCV infection.
Advise patients to tell their healthcare provider if they have a history of HBV infection [see Warnings and Precautions (5.1)] .
Serious Symptomatic Bradycardia When Coadministered with Amiodarone Advise patients to seek medical evaluation immediately for symptoms of bradycardia such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems [see Warnings and Precautions (5.2), Adverse Reactions (6.2), and Drug Interactions (7.2)].
Drug Interactions Inform patients that HARVONI may interact with other drugs.
Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products including St.
John’s wort [see Warnings and Precautions (5.2, 5.3) and Drug Interactions (7)].
Pregnancy Advise patients to avoid pregnancy during combination treatment with HARVONI and ribavirin and for 6 months after completion of treatment.
Inform patients to notify their healthcare provider immediately in the event of a pregnancy [see Use in Specific Populations (8.1)] .
Administration Advise patients to take HARVONI every day at the regularly scheduled time with or without food.
Inform patients that it is important not to miss or skip doses and to take HARVONI for the duration that is recommended by the physician.
DOSAGE AND ADMINISTRATION
2 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 weeks HARVONI 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-experienced Treatment-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 weeks HARVONI + ribavirin for 12 weeks can be considered in treatment-experienced genotype 1 patients with cirrhosis who are eligible for ribavirin [see Clinical Studies (14.2)] .
See footnote ¶ for ribavirin dosage recommendations.
Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C) HARVONI + ribavirin In 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 + ribavirin The daily dosage of ribavirin is weight-based (1000 mg for patients <75 kg and 1200 mg for those ≥75 kg) administered orally in two divided doses with food.
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 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 Refer to for dosage recommendations for concomitant HIV-1 antiviral drugs.
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 m 2) 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)] .