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HIGHLIGHTS OF PRESCRIBING INFORMATION
• If used in combination with ribavirin, follow the recommendations for These highlights do not include all the information needed to use
ribavirin dosing and dosage modifications (2.1) HARVONI® safely and effectively. See full prescribing information
• A dosage recommendation cannot be made for patients with severe for HARVONI.
renal impairment or end stage renal disease (2.2)
HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use
-----------------------DOSAGE FORMS AND STRENGTHS--------------------
Initial U.S. Approval: 2014
Tablets: 90 mg ledipasvir and 400 mg sofosbuvir (3) ------------------------------RECENT MAJOR CHANGES -----------------------
Indications and Usage (1) 02/2016 If used in combination with ribavirin, all contraindications to ribavirin Dosage and Administration (2.1) 02/2016 also apply to HARVONI combination therapy (4) Contraindications (4) 11/2015 Warnings and Precautions (5.3) 11/2015 • Bradycardia with amiodarone coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone, particularly in HARVONI is a fixed-dose combination of ledipasvir, a hepatitis C virus patients also receiving beta blockers, or those with underlying (HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog cardiac comorbidities and/or advanced liver disease. NS5B polymerase inhibitor, and is indicated with or without ribavirin for Coadministration of amiodarone with HARVONI is not the treatment of chronic hepatitis C virus (HCV) genotype 1, 4, 5 or 6 recommended. In patients without alternative, viable treatment options, cardiac monitoring is recommended. (5.1, 6.2, 7.2) • Use with other drugs containing sofosbuvir is not recommended • Recommended dosage: One tablet (90 mg of ledipasvir and 400 mg of sofosbuvir) taken orally once daily with or without food (2.1) • Recommended treatment regimen and duration: (2.1) The most common adverse reactions (incidence greater than or equal to 10%, all grades) observed with treatment with HARVONI were Patient Population
fatigue, headache and asthenia (6.1) Duration
To report SUSPECTED ADVERSE REACTIONS, contact Gilead
Treatment-naïve without cirrhosis or with Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or
compensated cirrhosis (Child-Pugh A) Treatment-experienced without cirrhosis • Coadministration with amiodarone may result in serious Treatment-experienced with symptomatic bradycardia. Use of HARVONI with amiodarone is not compensated cirrhosis (Child-Pugh A) recommended (5.1, 6.2, 7.2) Treatment-naïve and treatment- • P-gp inducers (e.g., rifampin, St. John's wort): May alter experienced with decompensated concentrations of ledipasvir and sofosbuvir. Use of HARVONI with cirrhosis (Child-Pugh B or C) P-gp inducers is not recommended (5.2, 7, 12.3) Treatment-naïve and treatment- • Consult the full prescribing information prior to use for potential drug experienced liver transplant recipients interactions (5.1, 5.2, 7, 12.3) without cirrhosis, or with compensated cirrhosis (Child-Pugh A) See 17 for PATIENT COUNSELING INFORMATION and
Treatment-naïve and treatment- FDA-approved patient labeling.
experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A) Revised: 06/2016
• HCV/HIV-1 co-infection: For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in the table above (2.1) FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
8.3 Females and Males of Reproductive Potential 2 DOSAGE AND ADMINISTRATION
8.4 Pediatric Use 2.1 Recommended Dosage in Adults 8.5 Geriatric Use 2.2 Severe Renal Impairment and End Stage Renal Disease 8.6 Renal Impairment 3 DOSAGE FORMS AND STRENGTHS
8.7 Hepatic Impairment 4 CONTRAINDICATIONS
10 OVERDOSAGE
5 WARNINGS AND PRECAUTIONS
11 DESCRIPTION
5.1 Serious Symptomatic Bradycardia When Coadministered 12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action 5.2 Risk of Reduced Therapeutic Effect Due to Use with P-gp 12.2 Pharmacodynamics 12.3 Pharmacokinetics 5.3 Risks Associated with Ribavirin Combination Treatment 12.4 Microbiology 5.4 Related Products Not Recommended 13 NONCLINICAL TOXICOLOGY
6 ADVERSE REACTIONS
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 6.1 Clinical Trials Experience 14 CLINICAL STUDIES
6.2 Postmarketing Experience 14.1 Description of Clinical Trials 7 DRUG INTERACTIONS
14.2 Clinical Trials in Subjects with Genotype 1 HCV 7.1 Potential for Drug Interaction 14.3 Clinical Trials in Subjects with Genotype 4, 5, or 6 HCV 7.2 Established and Potentially Significant Drug Interactions 14.4 Clinical Trials in Subjects Co-infected with HCV and HIV-1 7.3 Drugs without Clinically Significant Interactions with 14.5 Clinical Trials in Liver Transplant Recipients and/or Subjects with Decompensated Cirrhosis 8 USE IN SPECIFIC POPULATIONS
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
HARVONI is indicated with or without ribavirin for the treatment of patients with chronic
hepatitis C virus (HCV) genotype 1, 4, 5, or 6 infection [see Dosage and Administration
(2) and Clinical Studies (14)].
2
DOSAGE AND ADMINISTRATION
Recommended Dosage
The recommended dosage of HARVONI is one tablet 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 co-infection, 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
Patients with Genotype 1, 4, 5 or 6 HCV
Treatment Regimen
Patient Population
and Duration
Treatment-naïve without cirrhosis or with compensated cirrhosis (Child- HARVONI 12 weeks* Treatment-experienced** without HARVONI 12 weeks Treatment-experienced** with HARVONI 24 weeks† compensated cirrhosis (Child-Pugh A) Treatment-naïve and treatment-experienced** with decompensated HARVONI + ribavirin‡ 12 weeks cirrhosis (Child-Pugh B or C) Treatment-naïve and treatment-experienced** liver transplant recipients HARVONI + ribavirin§ 12 weeks without cirrhosis, or with compensated cirrhosis (Child-Pugh A) Treatment-naïve and treatment- Genotype 4, 5 or 6 experienced**, without cirrhosis or with HARVONI 12 weeks compensated cirrhosis (Child-Pugh A) * 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 patients include those who have failed a peginterferon alfa + ribavirin based regimen with or without an HCV protease inhibitor. † 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. ‡ 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. § 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.
For further information on ribavirin dosing and dosage modifications, refer to the
ribavirin prescribing information [see Clinical Studies (14.5)].
2.2
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)].

3
DOSAGE FORMS AND STRENGTHS
HARVONI is available as an orange colored, diamond shaped, film-coated tablet
debossed with "GSI" on one side and "7985" on the other side of the tablet. Each tablet
contains 90 mg ledipasvir and 400 mg sofosbuvir.
4
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 (2.1)].
5
WARNINGS AND PRECAUTIONS
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)].
5.2
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)].
5.3
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 (2.1)].
5.4
Related Products Not Recommended
The use of HARVONI with other products containing sofosbuvir is not recommended.
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 (5.1)]. 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, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions. 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 2 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 2 occurred at severity of grade 1. The side-by-side tabulation is to simplify
presentation; direct comparison across trials should not be made due to differing trial
designs.
Table 2
Adverse Reactions (All Grades) Reported in ≥5% of Subjects
Receiving 8, 12, or 24 Weeks of Treatment with HARVONI
HARVONI HARVONI

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 3 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 3 were Grade 1 or 2 in severity. Table 3 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 + RBV
Adverse Reactions in Subjects Co-infected 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 co-infection who were on stable antiretroviral therapy in Study ION-4 [see Clinical Studies (14.4)]. The safety profile in HCV/HIV-1 co-infected 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 1.5xULN 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 1.5xULN 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 3xULN 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 3x 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 10xULN 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. 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 (5.1), Drug Interactions
(7.2)].
Skin and Subcutaneous Tissue Disorders
Skin rashes, sometimes with blisters or angioedema-like swelling
7
DRUG INTERACTIONS
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 (5.2)]. Established and Potentially Significant Drug Interactions
Table 4 provides a listing of established or potentially clinically significant drug
interactions. The drug interactions described are based on studies conducted with either
HARVONI, the components of HARVONI (ledipasvir and sofosbuvir) as individual
agents, or are predicted drug interactions that may occur with HARVONI [see Warnings
and Precautions (5.1, 5.2) and Clinical Pharmacology (12.3)].
Table 4
Potentially Significant Drug Interactions: Alteration in Dose or
Regimen May Be Recommended Based on Drug Interaction Studies
or Predicted Interactiona
Concomitant Drug
Effect on
Clinical Comment
Class: Drug Name
Acid Reducing Agents:
Ledipasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease concentration of ledipasvir. Antacids (e.g., aluminum It is recommended to separate antacid and HARVONI administration by 4 hours. H2-receptor antagonistsc H2-receptor antagonists may be administered (e.g., famotidine) 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 inhibitorsc Proton-pump inhibitor doses comparable to omeprazole (e.g., omeprazole) 20 mg or lower can be administered simultaneously with HARVONI under fasted conditions. 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 (5.1), Adverse Reactions (6.2)]. Coadministration of HARVONI with digoxin may increase the concentration of digoxin. Therapeutic concentration monitoring of digoxin is recommended when coadministered with HARVONI. Coadministration of HARVONI with carbamazepine, carbamazepine ↓ sofosbuvir phenytoin, phenobarbital, or oxcarbazepine is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of HARVONI. Coadministration is not recommended. Coadministration of HARVONI with rifabutin or rifapentine is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of HARVONI. Coadministration is not recommended. Coadministration of HARVONI with rifampin, a P-gp inducer, is not recommended [see Warnings and Precautions (5.2)]. HIV Antiretrovirals:
Regimens containing Monitor for tenofovir-associated adverse reactions in tenofovir DF without an patients receiving HARVONI concomitantly with a regimen containing tenofovir DF without an HIV protease inhibitor/ritonavir or inhibitor/ritonavir or cobicistat. Refer to VIREAD or TRUVADA prescribing information for recommendations on renal monitoring. Regimens containing The safety of increased tenofovir concentrations in the tenofovir DF and an HIV setting of HARVONI and an HIV protease protease inhibitor/ritonavir inhibitor/ritonavir or cobicistat has not been established. Consider alternative HCV or antiretroviral therapy to avoid • atazanavir/ritonavir or increases in tenofovir exposures. If coadministration is necessary, monitor for tenofovir-associated adverse emtricitabine/tenofovir reactions. Refer to VIREAD or TRUVADA prescribing information for recommendations on renal monitoring. • darunavir/ritonavir or cobicistat + emtricitabine/tenofovir DFc • lopinavir/ritonavir + emtricitabine/tenofovir DF elvitegravir, cobicistat, The safety of increased tenofovir concentrations in the emtricitabine, tenofovir setting of HARVONI and the combination of elvitegravir, cobicistat, emtricitabine and tenofovir DF has not been established. Coadministration is not recommended. tipranavir/ritonavir 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:
Concentrations of ledipasvir and simeprevir are increased when simeprevir is coadministered with ledipasvir. Coadministration of HARVONI with simeprevir is not Herbal Supplements:
Coadministration of HARVONI with St. John's wort, a P-gp inducer, is not recommended [see Warnings and (Hypericum perforatum) Precautions (5.2)]. HMG-CoA Reductase
↑ rosuvastatin Coadministration of HARVONI with rosuvastatin may Inhibitors:
significantly increase the concentration of rosuvastatin which is associated with increased risk of myopathy, including rhabdomyolysis. Coadministration of HARVONI with rosuvastatin is not recommended. tenofovir DF = tenofovir disoproxil fumarate a. This table is not all inclusive. b. ↓ = decrease, ↑ = increase c. These interactions have been studied in healthy adults. 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 4 for use of HARVONI with
certain HIV antiretroviral regimens [see Drug Interactions (7.2)].
8
USE IN SPECIFIC POPULATIONS
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 use in 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. Pediatric Use
Safety and effectiveness of HARVONI have not been established in pediatric patients.
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/1.73m2) or ESRD requiring
hemodialysis. No dosage recommendation can be given for patients with severe renal
impairment or ESRD [see Dosage and Administration (2.2) and Clinical Pharmacology
(12.3)]. 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 (2.1), 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)].
10
OVERDOSAGE
No specific antidote is available for overdose with HARVONI. If overdose occurs, the
patient must be monitored for evidence of toxicity. Treatment of overdose with
HARVONI consists of general supportive measures including monitoring of vital signs
as well as observation of the clinical status of the patient. Hemodialysis is unlikely to
result in significant removal of ledipasvir since ledipasvir is highly bound to plasma
protein. Hemodialysis can efficiently remove the predominant circulating metabolite of
sofosbuvir, GS-331007, with an extraction ratio of 53%.

11
DESCRIPTION
HARVONI is a fixed-dose combination tablet containing ledipasvir and sofosbuvir for oral administration. Ledipasvir is an HCV NS5A inhibitor and sofosbuvir is a nucleotide analog inhibitor of HCV NS5B polymerase. Each tablet contains 90 mg ledipasvir and 400 mg sofosbuvir. The tablets include the following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: FD&C yellow #6/sunset yellow FCF aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Ledipasvir: The IUPAC name for ledipasvir is Methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate. It has a molecular formula of C49H54F2N8O6 and a molecular weight of 889.00. It has the following structural formula: Ledipasvir is practically insoluble (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). Sofosbuvir: The IUPAC name for sofosbuvir is (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of C22H29FN3O9P and a molecular weight of 529.45. It has the following structural formula: Sofosbuvir is a white to off-white crystalline solid with a solubility of at least 2 mg/mL
across the pH range of 2–7.7 at 37oC and is slightly soluble in water.
12
CLINICAL PHARMACOLOGY

12.1 Mechanism of Action
HARVONI is a fixed-dose combination of ledipasvir and sofosbuvir which are direct-
acting antiviral agents against the hepatitis C virus [see Microbiology (12.4)].
12.2 Pharmacodynamics
Cardiac Electrophysiology
Thorough QT studies have been conducted for ledipasvir and sofosbuvir.
The effect of ledipasvir 120 mg twice daily (2.67 times the maximum recommended
dosage) for 10 days on QTc interval was evaluated in a randomized, multiple-dose,
placebo-, and active-controlled (moxifloxacin 400 mg) three period crossover thorough
QT trial in 59 healthy subjects. At the dose of 120 mg twice daily (2.67 times the
maximum recommended dosage), ledipasvir does not prolong QTc interval to any
clinically relevant extent.
The effect of sofosbuvir 400 mg (maximum recommended dosage) and 1200 mg (three
times the maximum recommended dosage) on QTc interval was evaluated in a
randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four
period crossover thorough QT trial in 59 healthy subjects. At a dose three times the
maximum recommended dose, sofosbuvir does not prolong QTc to any clinically
relevant extent.
12.3 Pharmacokinetics
Absorption
The pharmacokinetic properties of ledipasvir, sofosbuvir, and the predominant
circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in
subjects with chronic hepatitis C. Following oral administration of HARVONI, ledipasvir
median peak concentrations were observed 4 to 4.5 hours post-dose. Sofosbuvir was
absorbed quickly and the peak median plasma concentration was observed 0.8 to
1 hour post-dose. Median peak plasma concentration of GS-331007 was observed
between 3.5 to 4 hours post-dose.
Based on the population pharmacokinetic analysis in HCV-infected subjects, geometric
mean steady-state AUC0-24 for ledipasvir (N=2113), sofosbuvir (N=1542), and
GS-331007 (N=2113) were 7290, 1320, and 12,000 ng•hr/mL, respectively. Steady-
state Cmax for ledipasvir, sofosbuvir, and GS-331007 were 323, 618, and 707 ng/mL,
respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult
subjects and subjects with HCV infection. Relative to healthy subjects (N=191),
ledipasvir AUC0-24 and Cmax were 24% lower and 32% lower, respectively, in
HCV-infected subjects.
Effect of Food
Relative to fasting conditions, the administration of a single dose of HARVONI with a
moderate fat ( 600 kcal, 25% to 30% fat) or high fat ( 1000 kcal, 50% fat) meal
increased sofosbuvir AUC0-inf by approximately 2-fold, but did not significantly affect
sofosbuvir Cmax. The exposures of GS-331007 and ledipasvir were not altered in the
presence of either meal type. The response rates in Phase 3 trials were similar in HCV-
infected subjects who received HARVONI with food or without food. HARVONI can be
administered without regard to food.

Distribution
Ledipasvir is greater than 99.8% bound to human plasma proteins. After a single 90 mg
dose of [14C]-ledipasvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity
ranged between 0.51 and 0.66.
Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding
is independent of drug concentration over the range of 1 microgram/mL to
20 microgram/mL. Protein binding of GS-331007 was minimal in human plasma. After a
single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of
14C-radioactivity was approximately 0.7.

Metabolism
In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2,
CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Evidence of slow oxidative
metabolism via an unknown mechanism has been observed. Following a single dose of
90 mg [14C]-ledipasvir, systemic exposure was almost exclusively to the parent drug
(greater than 98%). Unchanged ledipasvir is the major species present in feces.
Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active
nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves
sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A
(CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad
nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine
nucleotide biosynthesis pathway. Dephosphorylation results in the formation of
nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks
anti-HCV activity in vitro. After a single 400 mg oral dose of [14C]-sofosbuvir, GS-331007
accounted for approximately greater than 90% of total systemic exposure.
Elimination
Following a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the
[14C]-radioactivity in feces and urine was approximately 87%, with most of the
radioactive dose recovered from feces (approximately 86%). Unchanged ledipasvir
excreted in feces accounted for a mean of 70% of the administered dose and the
oxidative metabolite M19 accounted for 2.2% of the dose. These data indicate that
biliary excretion of unchanged ledipasvir is a major route of elimination, with renal
excretion being a minor pathway (approximately 1%). The median terminal half-life of
ledipasvir following administration of HARVONI was 47 hours.
Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose
was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in
urine, feces, and expired air, respectively. The majority of the sofosbuvir dose
recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir.
These data indicate that renal clearance is the major elimination pathway for
GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following
administration of HARVONI were 0.5 and 27 hours, respectively.
Specific Populations Race: Population pharmacokinetics analysis in HCV-infected subjects indicated that race had no clinically relevant effect on the exposure of ledipasvir, sofosbuvir, and GS-331007. Gender: Population pharmacokinetics analysis in HCV-infected subjects indicated that gender had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. AUC and Cmax of ledipasvir were 77% and 58% higher, respectively, in females than males; however, the relationship between gender and ledipasvir exposures was not considered clinically relevant, as high response rates (SVR12 >90%) were achieved in male and female subjects across the Phase 3 studies and the safety profiles are similar in females and males. Pediatric Patients: The pharmacokinetics of ledipasvir or sofosbuvir in pediatric patients has not been established [see Use in Specific Populations (8.4)]. Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 80 years) analyzed, age did not have a clinically relevant effect on the exposure to ledipasvir, sofosbuvir, and GS-331007 [see Use in Specific Populations (8.5)]. Patients with Renal Impairment: The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative subjects with severe renal impairment (eGFR less than 30 mL/min by Cockcroft-Gault). No clinically relevant differences in ledipasvir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment. The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild (eGFR between 50 to less than 80 mL/min/1.73 m2), moderate (eGFR between 30 to less than 50 mL/min/1.73 m2), severe renal impairment (eGFR less than 30 mL/min/1.73 m2), and subjects with ESRD requiring hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR greater than 80 mL/min/1.73 m2), the sofosbuvir AUC0-inf was 61%, 107%, and 171% higher in mild, moderate, and severe renal impairment, while the GS-331007 AUC0-inf was 55%, 88%, and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC0-inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4 hour hemodialysis session removed approximately 18% of administered dose [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)]. Patients with Hepatic Impairment: The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative subjects with severe hepatic impairment (Child-Pugh Class C). Ledipasvir plasma exposure (AUC0-inf) was similar in subjects with severe hepatic impairment and control subjects with normal hepatic function. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of ledipasvir [see Use in Specific Populations (8.7)]. The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC0-24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 were 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of sofosbuvir and GS-331007 [see Use in Specific Populations (8.7) and Clinical Studies (14.5)]. Drug Interaction Studies Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. P-gp inducers (e.g., rifampin or St. John's wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of HARVONI, and the use with P-gp inducers is not recommended with HARVONI [see Warnings and Precautions (5.2)]. Coadministration with drugs that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; HARVONI may be coadministered with P-gp and/or BCRP inhibitors. Neither ledipasvir nor sofosbuvir is a substrate for hepatic uptake transporters OCT1, OATP1B1, or OATP1B3. GS-331007 is not a substrate for renal transporters, including organic anion transporter OAT1 or OAT3, or organic cation transporter OCT2. Ledipasvir is subject to slow oxidative metabolism via an unknown mechanism. In vitro, no detectable metabolism of ledipasvir by CYP enzymes has been observed. Biliary excretion of unchanged ledipasvir is a major route of elimination. Sofosbuvir is not a substrate for CYP and UGT1A1 enzymes. Clinically significant drug interactions with HARVONI mediated by CYP or UGT1A1 enzymes are not expected. The effects of coadministered drugs on the exposure of ledipasvir, sofosbuvir, and GS-331007 are shown in Table 5 [see Drug Interactions (7.2)]. Drug Interactions: Changes in Pharmacokinetic Parameters for
Ledipasvir, Sofosbuvir, and the Predominant Circulating Metabolite
GS-331007 in the Presence of the Coadministered Druga
Mean Ratio (90% CI) of Ledipasvir,
Dose of Co-
Sofosbuvir, and GS-331007 PK With/Without
pasvir -buvir
Coadministered Drug
No Effect=1.00
12 hours prior to NA = not available/not applicable, ND = not dosed. tenofovir DF = tenofovir disoproxil fumarate a. All interaction studies conducted in healthy volunteers. b. Data generated from simultaneous dosing with HARVONI. Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir DF or darunavir/ritonavir + emtricitabine/tenofovir DF and HARVONI provided similar results. c. The effects of atazanavir/ritonavir on ledipasvir and sofosbuvir are similar with or without the presence of emtricitabine/tenofovir DF. d. Administered as ATRIPLA® (efavirenz, emtricitabine, tenofovir DF). e. This study was conducted in the presence of two other investigational HCV direct-acting agents. No effect on the pharmacokinetic parameters of ledipasvir, sofosbuvir, and GS-331007 was observed with raltegravir and the combination of abacavir and lamivudine; emtricitabine, rilpivirine, and tenofovir disoproxil fumarate; or dolutegravir, emtricitabine, and tenofovir disoproxil fumarate. Ledipasvir is an inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters. Ledipasvir is an inhibitor of transporters OATP1B1, OATP1B3, and BSEP only at concentrations exceeding those achieved in clinic. Ledipasvir is not an inhibitor of transporters MRP2, MRP4, OCT2, OAT1, OAT3, MATE1, and OCT1. The drug-drug interaction potential of ledipasvir is primarily limited to the intestinal inhibition of P-gp and BCRP. Clinically relevant transporter inhibition by ledipasvir in the systemic circulation is not expected due to its high protein binding. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1,
OATP1B3, and OCT1, and GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1.
Ledipasvir, sofosbuvir, and GS-331007 are not inhibitors or inducers of CYP or UGT1A1
enzymes.
The effects of ledipasvir or sofosbuvir on the exposure of coadministered drugs are
shown in Table 6 [see Drug Interactions (7.2)].
Table 6
Drug Interactions: Changes in Pharmacokinetic Parameters for
Coadministered Drug in the Presence of Ledipasvir, Sofosbuvir, or
HARVONIa
Mean Ratio (90% CI) of
Coadministered Drug PK
With/Without Ledipasvir,
Dose of Co-
Sofosbuvir, or HARVONI
No Effect=1.00
Drug (mg)
/tenofovir DFb,c,d tenofovir DF 300 tenofovir DF 300 elvitegravir 150 ethinyl estradiol 0.025 once daily (1.18, 1.66) (1.04, 1.39) (0.79, 1.22) Ethinyl estradiol NA = not available/not applicable, ND = not dosed. tenofovir DF = tenofovir disoproxil fumarate a. All interaction studies conducted in healthy volunteers. b. Data generated from simultaneous dosing with HARVONI. Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir DF or darunavir/ritonavir + emtricitabine/tenofovir DF and HARVONI provided similar results. c. The effects of HARVONI on atazanavir and ritonavir are similar with or without the presence of emtricitabine/tenofovir DF. d. This magnitude of change in tenofovir exposure does not reflect the approximately 60–80% increase caused by the effects of an HIV PI/ritonavir and the effect of food. Therefore, tenofovir exposure is approximately 130% higher when administered as tenofovir DF + atazanavir/ritonavir + HARVONI or tenofovir DF + darunavir/ritonavir + HARVONI and with food as compared to the tenofovir exposure observed following fasted administration of tenofovir DF-based regimens that do not contain an HIV PI/ritonavir and HARVONI. e. Administered as ATRIPLA (efavirenz, emtricitabine, tenofovir DF). The effects of HARVONI on tenofovir exposures are similar when tenofovir is administered as ATRIPLA, COMPLERA, or TRUVADA + dolutegravir.
No effect on the pharmacokinetic parameters of the following coadministered drugs was
observed with ledipasvir or sofosbuvir: abacavir, cyclosporine, darunavir/ritonavir,
dolutegravir, efavirenz, emtricitabine, lamivudine, methadone, or rilpivirine.
12.4 Microbiology
Mechanism of Action
Ledipasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication.
Resistance selection in cell culture and cross-resistance studies indicate ledipasvir
targets NS5A as its mode of action.
Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is
required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes
intracellular metabolism to form the pharmacologically active uridine analog
triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B
polymerase and acts as a chain terminator. In a biochemical assay, GS-461203
inhibited the polymerase activity of the recombinant NS5B from HCV genotypes 1b and
4a with IC50 values of 3.3 and 2.7 microM, respectively. GS-461203 is neither an
inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA
polymerase.
Antiviral Activity
In HCV replicon assays, the EC50 values of ledipasvir against full-length replicons from
genotypes 1a and 1b were 0.031 nM and 0.004 nM, respectively. The median EC50
values of ledipasvir against chimeric replicons encoding NS5A sequences from clinical
isolates were 0.018 nM for genotype 1a (range 0.009–0.085 nM; N=30) and 0.006 nM
for genotype 1b (range 0.004–0.007 nM; N=3). Ledipasvir has less antiviral activity
compared to genotype 1 against genotypes 4a, 5a, and 6a, with EC50 values of
0.39 nM, 0.15 nM, and 1.1 nM, respectively, and substantially lower activity against
genotype 6e with an EC50 value of 264 nM.
In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from genotypes 1a, 1b, and 4a, and chimeric 1b replicons encoding NS5B from genotypes 5a or 6a ranged from 14–110 nM. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 62 nM for genotype 1a (range 29–128 nM; N=67) and 102 nM for genotype 1b (range 45–170 nM; N=29). In replication competent virus assays, the EC50 value of sofosbuvir against genotype 1a was 30 nM. Evaluation of sofosbuvir in combination with ledipasvir showed no antagonistic effect in reducing HCV RNA levels in replicon cells. Resistance In Cell Culture HCV replicons with reduced susceptibility to ledipasvir have been selected in cell culture for genotypes 1a and 1b. Reduced susceptibility to ledipasvir was associated with the primary NS5A amino acid substitution Y93H in both genotypes 1a and 1b. Additionally, a Q30E substitution emerged in genotype 1a replicons. Site-directed mutagenesis of the Y93H in both genotypes 1a and 1b, as well as the Q30E substitution in genotype 1a, conferred high levels of reduced susceptibility to ledipasvir (fold change in EC50 greater than 1000-fold). HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 4a, 5a, and 6a. Reduced susceptibility to sofosbuvir was associated with the NS5B substitution S282T in all replicon genotypes examined. An M289L substitution developed along with the S282T substitution in genotype 5 and 6 replicons. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir. In Clinical Trials Genotype 1 In a pooled analysis of subjects who received HARVONI in Phase 3 trials (ION-3, ION-1 and ION-2), 37 subjects (29 with genotype 1a HCV and 8 with genotype 1b HCV) qualified for resistance analysis due to virologic failure (35 with virologic relapse, 2 with breakthrough on-treatment due to documented non-adherence). Post-baseline NS5A and NS5B deep nucleotide sequence analysis data (assay sensitivity of 1%) were available for 37/37 and 36/37 subjects' viruses, respectively. Of the 29 genotype 1a virologic failure subjects, 55% (16/29) of subjects had virus with emergent NS5A resistance-associated substitutions K24R, M28T/V, Q30R/H/K/L, L31M, or Y93H/N at failure. Five of these 16 subjects' viruses also had baseline NS5A polymorphisms at resistance-associated amino acid positions. The most common substitutions detected at failure were Q30R, Y93H or N, and L31M. Of the 8 genotype 1b virologic failure subjects, 88% (7/8) had virus with emergent NS5A resistance-associated substitutions L31V/M/I or Y93H at failure. Virus from three of these 7 subjects also had baseline NS5A polymorphisms at resistance-associated positions. The most common substitution detected at failure was Y93H. At failure, 38% (14/37) of virologic failure subjects' viruses had 2 or more NS5A substitutions at resistance-associated positions. In the SOLAR-1 and SOLAR-2 trials (liver transplant recipients or subjects with decompensated liver disease), there were 24 virologic failures with genotype 1 infection (20 relapsers and 4 subjects who discontinued treatment prior to achieving HCV RNA <LLOQ). Treatment-emergent NS5A resistance-associated substitutions K24R, M28T, Q30R/H/K, L31V, H58D/P and/or Y93H/C were detected in 14/17 (82%) genotype 1a virologic failure subjects, and R30Q, L31M and/or Y93H/N were detected in 6/7 (86%) genotype 1b virologic failure subjects. In phenotypic analyses, post-baseline isolates from subjects who harbored NS5A resistance-associated substitutions at failure showed 20- to >243-fold reduced susceptibility to ledipasvir. Treatment-emergent NS5B substitutions L159 (n=1) and V321 (n=2) previously associated with sofosbuvir failure were detected in the Phase 3 trials (ION-3, ION-1 and ION-2). In addition, treatment-emergent NS5B substitutions at highly conserved positions D61G (n=3), A112T (n=2), E237G (n=2), and S473T (n=1) were detected at low frequency by next generation sequencing in treatment failure subjects infected with HCV genotype 1a. The D61G substitution was previously described in subjects infected with HCV genotype 1a in a liver pre-transplant trial. The E237G substitution was detected in 3 subjects infected with HCV GT1a in the SOLAR-1 and SOLAR-2 trials. The clinical significance of these substitutions is currently unknown. The sofosbuvir-associated resistance substitution S282T in NS5B was not detected in any failure isolate from the Phase 3 trials. NS5B substitutions S282T, L320V/I, and V321I in combination with NS5A substitutions L31M, Y93H, and Q30L were detected in one subject at failure following 8 weeks of treatment with HARVONI in a Phase 2 trial. Genotype 4, 5 or 6 Resistance analysis was performed for 6 relapse subjects infected with HCV genotype 4 (Study 1119 and ION-4, N=3), genotype 5 (Study 1119, N=2) or genotype 6 (ELECTRON-2; N=1) and treated with HARVONI for 12 weeks. All the relapse subjects with NS5A sequencing data (5 of 6) had pretreatment NS5A resistance-associated polymorphisms (single or combinations at positions 24, 28, 30, 31 and 58). NS5A resistance substitutions (Y93C or L28V) emerged in two of the genotype 4 relapse subjects post-treatment who also had NS5A polymorphisms pretreatment that were retained post-treatment. Two of the relapsers with genotype 4 HCV infection had an NS5B V321I substitution pretreatment, which was retained post-treatment. Three of the relapse subjects (1 each for genotype 4, 5, and 6) had virus with emergent sofosbuvir resistance-associated substitution S282T at relapse; the genotype 5 relapse subject also had emergent nucleotide inhibitor substitution M289I. Persistence of Resistance-Associated Substitutions No data are available on the persistence of ledipasvir or sofosbuvir resistance-associated substitutions. NS5A resistance-associated substitutions for other NS5A inhibitors have been found to persist for >1 year in some patients. The long-term clinical impact of the emergence or persistence of virus containing ledipasvir or sofosbuvir resistance-associated substitutions is unknown. Effect of Baseline HCV Polymorphisms on Treatment Response Genotype 1 Analyses were conducted to explore the association between pre-existing baseline NS5A polymorphisms at resistance-associated positions and relapse rates. In the pooled analysis of the Phase 3 trials, 23% (370/1589) of subjects' virus had baseline NS5A polymorphisms at resistance-associated positions (any change from reference at NS5A amino acid positions 24, 28, 30, 31, 58, 92, or 93) identified by population or analysis of deep nucleotide sequences with a 15% frequency threshold. In treatment-naïve subjects whose virus had baseline NS5A polymorphisms at resistance-associated positions in Studies ION-1 and ION-3, relapse rates were 6% (3/48) after 8 weeks and 1% (1/113) after 12 weeks of treatment with HARVONI. Relapse rates among subjects without baseline NS5A polymorphisms at resistance-associated positions were 5% (8/167) after 8 weeks and 1% (3/306) after 12 weeks treatment with HARVONI. In treatment-experienced subjects in Study ION-2 whose virus had baseline NS5A polymorphisms at resistance-associated positions, relapse rates were 22% (5/23) after 12 weeks and 0% (0/19) after 24 weeks of treatment with HARVONI. In another study in treatment-experienced subjects (SIRIUS), 0/15 (0%) subjects with NS5A polymorphisms at resistance-associated positions relapsed after 12 weeks of treatment with HARVONI + RBV compared to 2/15 (13%) subjects treated with 24 weeks of HARVONI. SVR was achieved in all 24 subjects (N=20 with L159F+C316N; N=1 with L159F; and N=3 with N142T) who had baseline polymorphisms associated with resistance to sofosbuvir and/or other NS5B nucleoside inhibitors. The NS5B S282T substitution associated with resistance to sofosbuvir was not detected in the baseline NS5B sequence of any subject in Phase 3 trials by population or deep nucleotide sequence analysis. In the SOLAR-1 and SOLAR-2 trials (liver transplant recipients or subjects with decompensated liver disease), after 12 weeks of treatment with HARVONI and RBV, relapse rates were 7% (5/71) and 5% (10/217) in genotype 1 subjects with and without baseline NS5A polymorphisms at resistance-associated positions, respectively. In the Phase 3 trials and SOLAR trials, the specific baseline NS5A resistance-associated polymorphisms observed among subjects who relapsed were M28T/V, Q30H/R, L31M, H58D/P, and Y93H/N in genotype 1a, and L28M, L31M, A92T, and Y93H in genotype 1b. Subjects with multiple NS5A polymorphisms at resistance-associated positions appeared to have higher relapse rates. Genotype 4, 5 or 6 Phylogenetic analysis of HCV sequences from genotype 4-infected subjects in Study 1119 (N=44) and ION-4 (N=8) identified 7 HCV genotype 4 subtypes (4a, 4b, 4d, 4f, 4m, 4o and 4r). Most subjects were infected with subtype 4a (N=32; 62%) or 4d (N=11; 21%); 1 to 3 subjects were infected with each of the other genotype 4 subtypes. There were 3 subjects with subtype 4r, 2 of whom experienced virologic relapse, and both had a combination of 2 pretreatment NS5A resistance-associated polymorphisms (L28M/V+L30R). Phylogenetic analysis of HCV sequences from genotype 5-infected subjects in Study 1119 showed almost all were subtype 5a (N=39) with one subject not having a subtype identified at screening or by analysis. Phylogenetic analysis of HCV sequences from genotype 6-infected subjects in ELECTRON-2 identified 7 HCV genotype 6 subtypes (6a, 6e, 6l, 6m, 6p, 6q and 6r). Thirty-two percent of the subjects had subtype 6a and 24% had subtype 6e. One to three subjects were infected with the other subtypes 6l, 6m, 6p, 6q, or 6r. The one subject who did not achieve SVR12 had subtype 6l. Although the data are limited, baseline HCV NS5A resistance-associated polymorphisms are not expected to impact the likelihood of achieving SVR when HARVONI is used as recommended to treat HCV genotype 4, 5, or 6-infected patients, based on the low virologic failure rate observed in Study 1119 and ELECTRON-2. The specific baseline polymorphisms observed in subjects with virologic failure were L28M/V, L30R, and P58T for genotype 4; L31M for genotype 5; and Q24K, F28V, R30A and T58P for genotype 6. Relapse occurred in 2 of 3 genotype 4 subjects who had baseline NS5B V321I, a polymorphism at a position associated with treatment failure to sofosbuvir and other nucleoside inhibitors; these two subjects also had baseline NS5A resistance-associated polymorphisms. For genotype 5 and 6, SVR12 was achieved in subjects who had baseline NS5B polymorphisms at positions associated with resistance to sofosbuvir and other nucleoside inhibitors (N=1 with N142T in genotype 5; N=1 with M289I in genotype 5; N=15 with M289L/I in genotype 6). The sofosbuvir resistance-associated substitution S282T was not detected in the baseline NS5B sequence of any subject with genotype 4, 5 or 6 HCV in clinical trials by population or deep nucleotide sequence analysis. Cross Resistance Based on resistance patterns observed in cell culture replicon studies and HCV-infected subjects, cross-resistance between ledipasvir and other NS5A inhibitors is expected. Both sofosbuvir and ledipasvir were fully active against substitutions associated with resistance to other classes of direct-acting antivirals with different mechanisms of action, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. The
efficacy of ledipasvir/sofosbuvir has not been established in patients who have
previously failed treatment with other regimens that include an NS5A inhibitor.
13
NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
Ledipasvir: Ledipasvir was not genotoxic in a battery of in vitro or in vivo assays,
including bacterial mutagenicity, chromosome aberration using human peripheral blood
lymphocytes, and in vivo rat micronucleus assays.
Ledipasvir was not carcinogenic in a 6-month rasH2 transgenic mouse study (up to
300 mg/kg/day). Similarly, ledipasvir was not carcinogenic in a 2-year rat study (up to
100 mg/kg/day in males and 30 mg/kg/day in females), resulting in exposures
approximately 10 and 4 times, respectively, higher than the exposure in humans at the
recommended human dose (RHD).
Sofosbuvir: Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays,
including bacterial mutagenicity, chromosome aberration using human peripheral blood
lymphocytes and in vivo mouse micronucleus assays.
Sofosbuvir was not carcinogenic in a 2-year mouse study (up to 200 mg/kg/day in males
and 600 mg/kg/day in females) and in a 2-year rat study (up to 750 mg/kg/day),
resulting in exposures of the predominant circulating metabolite GS-331007 of
approximately 4 and 18 times (in mice) and 8 and 10 times (in rats), in males and
females respectively, the exposure in humans at the RHD.
Impairment of Fertility
Ledipasvir: Ledipasvir had no adverse effects on mating and fertility. In female rats, the
mean number of corpora lutea and implantation sites were reduced slightly at maternal
exposures approximately 3 times the exposure in humans at the RHD. At the highest
dose levels without effects, exposures of ledipasvir were approximately 5 and 2 times,
in males and females, respectively, the exposure in humans at the RHD.
Sofosbuvir: Sofosbuvir had no effects on embryo-fetal viability or on fertility when
evaluated in rats. At the highest dose tested, exposure to the predominant circulating
metabolite GS-331007 was approximately 5 times the exposure in humans at the RHD.
14
CLINICAL STUDIES

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 co-
infected subjects, two trials in genotype 4, 5 or 6 HCV mono-infected subjects and 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), as summarized in Table 7 [see Clinical Studies (14.2, 14.3, 14.4 and 14.5)]: Trials Conducted with HARVONI with or without Ribavirin in
Subjects with Chronic HCV Genotype 1, 4, 5 or 6 Infection
Study Arms
Population
(Number of Subjects Treated)
HARVONI 8 weeks (215) GT1, TN without cirrhosis HARVONI + RBV 8 weeks (216) HARVONI 12 weeks (216) HARVONI 12 weeks (214) HARVONI + RBV 12 weeks (217) GT1, TN with or without cirrhosis HARVONI 24 weeks (217) HARVONI + RBV 24 weeks (217) HARVONI 12 weeks (109) HARVONI + RBV 12 weeks (111) GT1, TE with or without cirrhosis HARVONI 24 weeks (109) HARVONI + RBV 24 weeks (111) HARVONI + RBV 12 Weeks (77) GT1, TE with cirrhosis HARVONI 24 weeks (77) GT1 and GT4 HCV/HIV-1 co-infected HARVONI 12 Weeks TN and TE with or without cirrhosis (N=327 for GT1; N=8 for GT4) GT4 and GT5, TN and TE with or HARVONI 12 Weeks without cirrhosis (N=44 for GT4; N=41 for GT5) GT6, TN and TE with or without HARVONI 12 Weeks (25) GT1 and GT4 pre-transplant with decompensated cirrhosis or post- HARVONI + RBV 12 Weeks (336) transplant with Metavir F0-F3 fibrosis, compensated cirrhosis, HARVONI + RBV 24 weeks (334) decompensated cirrhosis, or FCH 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. 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 and SOLAR-2 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) was the primary endpoint and was defined as HCV RNA less than LLOQ at
12 weeks after the cessation of treatment. 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/m2 (range: 18 to 56 kg/m2); 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 8 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 8.
Study ION-3: SVR12 after 8 and 12 Weeks of Treatment in Treatment-
Naïve Non-Cirrhotic Subjects with Genotype 1 HCV
Outcome for Subjects without SVR On-Treatment Virologic Failure SVR by Genotypec a. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment b. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow- c. One subject without a confirmed subtype for genotype 1 infection was excluded from this subgroup analysis.
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 9.
Table 9
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
Number of Responders at End of Treatment Baseline HCV RNAa HCV RNA <6 million IU/mL HCV RNA ≥6 million IU/mL a. HCV RNA values were determined using the Roche TaqMan Assay; a subject's HCV RNA may vary from visit to 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/m2 (range: 18 to 48 kg/m2); 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 10 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 10.
Table 10
Study ION-1: SVR12 after 12 Weeks of Treatment in Treatment-Naïve
Subjects with Genotype 1 HCV with and without Cirrhosis
HARVONI 12 Weeks
Outcome for Subjects without SVR On-Treatment Virologic Failurea a. Excluding one subject with genotype 4 infection. b. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment c. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow- SVR12 for selected subgroups are presented in Table 11.
Table 11
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
a. One subject without a confirmed subtype for genotype 1 infection and one subject with genotype 4 infection were excluded from this subgroup analysis. b. Subjects with missing cirrhosis status were excluded from this subgroup analysis.

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/m2 (range: 19 to 50 kg/m2); 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 12 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 12.
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
Outcome for Subjects without SVR On-Treatment Virologic Failure a. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment b. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow- 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 13 and 14. Study ION-2: SVR12 for Selected Subgroups after 12 and 24 Weeks
of Treatment in Subjects with Genotype 1 HCV Who Failed Prior
Therapy
Prior HCV Therapy HCV protease inhibitor + Peg-IFN + RBV Response to Prior HCV Therapy Relapse/Breakthrough a. Subjects with missing cirrhosis status were excluded from this subgroup analysis.
Table 14
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
Number of Responders at End of Treatment Presence of Baseline NS5A Resistance-Associated Polymorphismsc a. Subjects with missing cirrhosis status were excluded from this subgroup analysis. b. These 4 non-cirrhotic relapsers all had baseline NS5A resistance-associated polymorphisms. c. NS5A resistance-associated polymorphisms include any change at NS5A positions 24, 28, 30, 31, 58, 92, or 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/m2
(range: 19 to 47 kg/m2); 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 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 co-infected 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 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 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 Co-infected 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 subjects with genotype 1 or 4 HCV infection who were co-infected 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/m2 (range: 18 to 66 kg/m2); 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 15 presents the SVR12 in the ION-4 trial after 12 weeks of HARVONI treatment.
Study ION-4: SVR12 in Subjects with Genotype 1 or 4 HCV
Co-infected with HIV-1
HARVONI 12 Weeks
Outcome for Subjects without SVR On-Treatment Virologic Failure a. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment b. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow- 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/mm3 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 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/m2 (range: 18
to 49 kg/m2); 94% and 6% had genotype 1 and 4 HCV infection, respectively; 78% of
the subjects failed a prior HCV therapy.
Table 16 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 16.
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
SVR12 (N=300)a,b Relapse (N=288)a,b,c Metavir score F0-F3 a. Five subjects transplanted prior to post-treatment Week 12 with HCV RNA<LLOQ at last measurement prior to transplant were excluded. b. 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). 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.
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.
16
HOW SUPPLIED/STORAGE AND HANDLING
HARVONI tablets are orange, 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 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. PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information). 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 (5.1), 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 (5.1, 5.2) 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. Manufactured and distributed by: Gilead Sciences, Inc. Foster City, CA 94404 Harvoni, Complera, Truvada and Viread are trademarks of Gilead Sciences, Inc., or its related companies. Atripla is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners. 2016 Gilead Sciences, Inc. All rights reserved. 205834-GS-004 Patient Information
HARVONI® (har-VOE-nee)
(ledipasvir and sofosbuvir)
Read this Patient Information before you start taking HARVONI and each time you get a refill. There may
be new information. This information does not take the place of talking with your healthcare provider
about your medical condition or your treatment. If you take HARVONI with ribavirin, you should also
read the Medication Guide for ribavirin.
What is HARVONI?
• HARVONI is a prescription medicine used with or without ribavirin to treat chronic (lasting a long time)
hepatitis C virus (HCV) genotype 1, 4, 5 or 6 infection. • HARVONI contains the prescription medicines ledipasvir and sofosbuvir. It is not known if HARVONI is safe and effective in children under 18 years of age. What should I tell my healthcare provider before taking HARVONI?
Before taking HARVONI, tell your healthcare provider if you:
• have liver problems other than hepatitis C infection
• have had a liver transplant
• have severe kidney problems or you are on dialysis • have HIV infection • have any other medical condition • are pregnant or plan to become pregnant. It is not known if HARVONI will harm your unborn baby. Males and females who take HARVONI in combination with ribavirin should also read
the ribavirin Medication Guide for important pregnancy, contraception, and infertility
information.
• are breastfeeding or plan to breastfeed. It is not known if HARVONI passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take
HARVONI.
Tell your healthcare provider about all of the medicines you take, including prescription and over-the-
counter medicines, vitamins, and herbal supplements. HARVONI and other medicines may affect each
other. This can cause you to have too much or not enough HARVONI or other medicines in your body.
This may affect the way HARVONI or your other medicines work, or may cause side effects. Keep a list
of your medicines to show your healthcare provider and pharmacist.
• You can ask your healthcare provider or pharmacist for a list of medicines that interact with
• Tell your healthcare provider if you take any medicines containing tenofovir disoproxil
fumarate (ATRIPLA®, COMPLERA®, STRIBILD®, TRUVADA®, VIREAD®).
• Do not start taking a new medicine without telling your healthcare provider. Your healthcare
provider can tell you if it is safe to take HARVONI with other medicines. How should I take HARVONI?
• Take HARVONI exactly as your healthcare provider tells you to take it. Do not change your dose
unless your healthcare provider tells you to. • Do not stop taking HARVONI without first talking with your healthcare provider. • Take 1 HARVONI tablet one time each day and at the same time each day. • Take HARVONI with or without food. • It is important that you do not miss or skip doses of HARVONI during treatment. • If you take too much HARVONI, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of HARVONI?
HARVONI may cause serious side effects, including:
• Slow heart rate (bradycardia). HARVONI treatment may result in slowing of the heart rate along
with other symptoms when taken with amiodarone (Cordarone®, Nexterone®, Pacerone®), a medicine used to treat certain heart problems. In some cases bradycardia has led to death or the need for a heart pacemaker when amiodarone is taken with HARVONI. Get medical help right away if you take amiodarone with HARVONI and get any of the following symptoms: fainting or near-fainting shortness of breath dizziness or lightheadedness not feeling well extreme tiredness The most common side effects of HARVONI include: • tiredness • headache • weakness Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of HARVONI. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store HARVONI?
• Store HARVONI at room temperature below 86°F (30°C).
• Keep HARVONI in its original container.
• Do not use HARVONI if the seal over the bottle opening is broken or missing.
Keep HARVONI and all medicines out of the reach of children.
General information about the safe and effective use of HARVONI
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.
Do not use HARVONI for a condition for which it was not prescribed. Do not give HARVONI to other
people, even if they have the same symptoms you have. It may harm them.
If you would like more information about HARVONI, talk with your healthcare provider. You can ask your
healthcare provider or pharmacist for information about HARVONI that is written for health professionals.
For more information, call 1-800-445-3235 or go to www.HARVONI.com.
What are the ingredients in HARVONI?
Active ingredients: ledipasvir and sofosbuvir
Inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate,
magnesium stearate, and microcrystalline cellulose.
The tablet film-coat contains: FD&C yellow #6/sunset yellow FCF aluminum lake, polyethylene glycol,
polyvinyl alcohol, talc, and titanium dioxide.
Manufactured and distributed by:
Gilead Sciences, Inc., Foster City, CA 94404
Harvoni, Complera, Sovaldi, Stribild, Truvada and Viread are trademarks of Gilead Sciences, Inc., or its related companies. Atripla is a trademark of
Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners.
2016 Gilead Sciences, Inc. All rights reserved.
205834-GS-004
This Patient Information has been approved by the U.S. Food and Drug Administration Revised: 06/2016

Source: https://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf