Harvoni

1 INDICATIONS AND USAGE HARVONI is indicated for the treatment of adults and pediatric patients 3 years of age and older with chronic hepatitis C virus (HCV) [see Dosage and Administration (2.2 and 2.3) and Clinical Studies (14) ] : genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis genotype 1 infection with decompensated cirrhosis, for use in combination with ribavirin genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, for use in combination with ribavirin HARVONI is a fixed-dose combination of ledipasvir, a hepatitis C virus (HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor, and is indicated for the treatment of chronic hepatitis C virus (HCV) in adults and pediatric patients 3 years of age and older: Genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis Genotype 1 infection with decompensated cirrhosis, in combination with ribavirin Genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, in combination with ribavirin. ( 1 )

2 DOSAGE AND ADMINISTRATION Testing prior to the initiation of therapy: Test all patients for HBV infection by measuring HBsAg and anti-HBc. ( 2.1 ) Recommended treatment regimen and duration in patients 3 years of age and older: ( 2.2 ) HCV Genotype Patient Population Regimen and Duration Genotype 1 Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) HARVONI 12 weeks Treatment-experienced without cirrhosis HARVONI 12 weeks Treatment-experienced with compensated cirrhosis (Child-Pugh A) HARVONI 24 weeks Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C) HARVONI + ribavirin 12 weeks Genotype 1 or 4 Treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis, or with compensated cirrhosis (Child-Pugh A) HARVONI + ribavirin 12 weeks Genotype 4, 5, or 6 Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A) HARVONI 12 weeks Recommended dosage in adults: One tablet (90 mg of ledipasvir and 400 mg of sofosbuvir) taken orally once daily with or without food. ( 2.3 ) Recommended dosage in pediatric patients 3 years and older: Recommended dosage of HARVONI in pediatric patients 3 years of age and older is based on weight. Refer to Table 2 of the full prescribing information for specific dosing guidelines based on body weight. ( 2.4 ) Instructions for Use should be followed for preparation and administration of HARVONI oral pellets. ( 2.5 ) HCV/HIV-1 coinfection: For adult and pediatric patients with HCV/HIV-1 coinfection, follow the dosage recommendations in the tables in the full prescribing information. ( 2.3 , 2.4 ) If used in combination with ribavirin, follow the recommendations for ribavirin dosing and dosage modifications. ( 2.3 , 2.4 ) For patients with any degree of renal impairment, including end stage renal disease on dialysis, no HARVONI dosage adjustment is recommended. ( 2.6 ) 2.1 Testing Prior to the Initiation of Therapy Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with HARVONI [see Warnings and Precautions (5.1) ] . 2.2 Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older with Genotype 1, 4, 5, or 6 HCV Table 1 shows the recommended HARVONI treatment regimen and duration based on patient population . Relapse rates are affected by baseline host and viral factors and differ between treatment durations for certain subgroups [see Clinical Studies (14) ]. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1 [see Clinical Studies (14) ]. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs. Table 1 Recommended Treatment Regimen and Duration for HARVONI in Patients 3 Years of Age and Older with Genotype 1, 4, 5, or 6 HCV HCV Genotype Patient Population Treatment Regimen and Duration Genotype 1 Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) HARVONI 12 weeks HARVONI for 8 weeks can be considered in treatment-naïve genotype 1 patients without cirrhosis who have pretreatment HCV RNA less than 6 million IU/mL [see Clinical Studies (14.2) ] . Treatment-experienced Treatment-experienced adult and pediatric subjects have failed a peginterferon alfa +/- ribavirin based regimen with or without an HCV protease inhibitor. without cirrhosis HARVONI 12 weeks Treatment-experienced with compensated cirrhosis (Child-Pugh A) HARVONI 24 weeks HARVONI + ribavirin for 12 weeks can be considered in treatment-experienced genotype 1 patients with cirrhosis who are eligible for ribavirin [see Dosage and Administration (2.3 and 2.4) and Clinical Studies (14.2) ]. Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C) HARVONI + ribavirin See Dosage and Administration 2.3 and 2.4 for ribavirin dosage rec …

3 DOSAGE FORMS AND STRENGTHS HARVONI is available as tablets or pellets for oral use. Each dosage form is available in two dose strengths. 90 mg/400 mg Tablets: orange, 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. 45 mg/200 mg Tablets: white, capsule-shaped, film-coated tablets, debossed with "GSI" on one side and "HRV" on the other side. Each tablet contains 45 mg ledipasvir and 200 mg sofosbuvir. 45 mg/200 mg Pellets: orange pellets in unit-dose packets. Each packet contains 45 mg ledipasvir and 200 mg sofosbuvir. 33.75 mg/150 mg Pellets: orange pellets in unit-dose packets. Each packet contains 33.75 mg ledipasvir and 150 mg sofosbuvir. Tablets: 90 mg of ledipasvir and 400 mg of sofosbuvir; 45 mg of ledipasvir and 200 mg of sofosbuvir. ( 3 ) Oral Pellets: 45 mg of ledipasvir and 200 mg of sofosbuvir; 33.75 mg of ledipasvir and 150 mg of sofosbuvir. ( 3 )

4 CONTRAINDICATIONS If HARVONI is administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen. Refer to the ribavirin prescribing information for a list of contraindications for ribavirin [see Dosage and Administration (2.2) ] . If used in combination with ribavirin, all contraindications to ribavirin also apply to HARVONI combination therapy. ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see Warnings and Precautions (5.2) ]. The most common adverse reactions (incidence greater than or equal to 10%, all grades) observed with treatment with HARVONI were fatigue, headache, and asthenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. If HARVONI is administered with ribavirin to adults, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions. Clinical Trials in Adult Subjects The safety assessment of HARVONI was based on pooled data from three randomized, open-label Phase 3 clinical trials (ION-3, ION-1, and ION-2) of subjects with genotype 1 HCV with compensated liver disease (with and without cirrhosis) including 215, 539, and 326 subjects who received HARVONI once daily by mouth for 8, 12, and 24 weeks, respectively [see Clinical Studies (14) ]. The proportion of subjects who permanently discontinued treatment due to adverse events was 0%, less than 1%, and 1% for subjects receiving HARVONI for 8, 12, and 24 weeks, respectively. The most common adverse reactions (at least 10%) were fatigue and headache in subjects treated with 8, 12, or 24 weeks of HARVONI. Table 4 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 of treatment with HARVONI in clinical trials. The majority of adverse reactions presented in Table 4 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 4 Adverse Reactions (All Grades) Reported in ≥5% of Subjects Receiving 8, 12, or 24 Weeks of Treatment with HARVONI HARVONI 8 weeks (N=215) HARVONI 12 weeks (N=539) HARVONI 24 weeks (N=326) Fatigue 16% 13% 18% Headache 11% 14% 17% Nausea 6% 7% 9% Diarrhea 4% 3% 7% Insomnia 3% 5% 6% The safety assessment of HARVONI was also based on pooled data from three open-label trials (Study 1119, ION-4, and ELECTRON-2) in 118 subjects with chronic HCV genotype 4, 5, or 6 infection with compensated liver disease (with or without cirrhosis) [see Clinical Studies (14.3) ] . The subjects received HARVONI once daily by mouth for 12 weeks. The safety profile in subjects with chronic HCV genotype 4, 5, or 6 infection with compensated liver disease was similar to that observed in subjects with chronic HCV genotype 1 infection with compensated liver disease. The most common adverse reactions occurring in at least 10% of subjects were asthenia (18%), headache (14%), and fatigue (10%). Adverse Reactions in Subjects with Cirrhosis The safety assessment of HARVONI with or without ribavirin was based on a randomized, double-blind and placebo-controlled trial in treatment-experienced genotype 1 subjects with compensated cirrhosis and was compared to placebo in the SIRIUS trial . Subjects were randomized to receive 24 weeks of HARVONI once daily by mouth without ribavirin or 12 weeks of placebo followed by 12 weeks of HARVONI once daily by mouth + ribavirin [see Clinical Studies (14.2) ] . Table 5 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 5 were Grade 1 or 2 in severity. Table 5 Adverse …

7 DRUG INTERACTIONS Coadministration with amiodarone may result in serious symptomatic bradycardia. Use of HARVONI with amiodarone is not recommended. ( 5.2 , 6.2 , 7.2 ) P-gp inducers (e.g., rifampin, St. John's wort): May alter concentrations of ledipasvir and sofosbuvir. Use of HARVONI with P-gp inducers is not recommended. ( 5.3 , 7 , 12.3 ) Consult the full prescribing information prior to use for potential drug interactions. ( 5.2 , 5.3 , 7 , 12.3 ) Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact safe and effective use of concomitant medications. Frequent monitoring of relevant laboratory parameters (INR or blood glucose) and dose adjustments of certain concomitant medications may be necessary. ( 7.2 ) 7.1 Potential for Drug Interaction As HARVONI contains ledipasvir and sofosbuvir, any interactions that have been identified with these agents individually may occur with HARVONI. After oral administration of HARVONI, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic extraction. In clinical pharmacology studies, both sofosbuvir and the inactive metabolite GS-331007 were monitored for purposes of pharmacokinetic analyses. Ledipasvir is an inhibitor of the drug transporters P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters. Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. P-gp inducers (e.g., rifampin, St. John's wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of HARVONI, and the use with P-gp inducers is not recommended with HARVONI [see Warnings and Precautions (5.3) ] . 7.2 Established and Potentially Significant Drug Interactions Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment. Frequent monitoring of relevant laboratory parameters (e.g., International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with a narrow therapeutic index (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary. Table 6 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either HARVONI, the components of HARVONI (ledipasvir and sofosbuvir) as individual agents, or are predicted drug interactions that may occur with HARVONI [see Warnings and Precautions (5.2 , 5.3) and Clinical Pharmacology (12.3) ] . Table 6 Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction This table is not all inclusive. Concomitant Drug Class: Drug Name Effect on Concentration ↓ = decrease, ↑ = increase Clinical Comment tenofovir DF = tenofovir disoproxil fumarate Acid Reducing Agents: ↓ ledipasvir Ledipasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease concentration of ledipasvir. Antacids (e.g., aluminum and magnesium hydroxide) It is recommended to separate antacid and HARVONI administration by 4 hours. H 2 -receptor antagonists These interactions have been studied in healthy adults. (e.g., famotidine) H 2 -receptor antagonists may be administered simultaneousl …

8 USE IN SPECIFIC POPULATIONS Pediatric Use: No data are available regarding the safety of HARVONI in pediatric patients with renal impairment. ( 8.4 ) 8.1 Pregnancy Risk Summary If HARVONI is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on ribavirin-associated risks of use during pregnancy. No adequate human data are available to establish whether or not HARVONI poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of HARVONI (ledipasvir or sofosbuvir) at exposures greater than those in humans at the recommended human dose (RHD) [see Data ] . During organogenesis in the rat and rabbit, systemic exposures (AUC) to ledipasvir were approximately 4 (rats) and 2 (rabbits) times the exposure in humans at the RHD, while exposures to the predominant circulating metabolite of sofosbuvir (GS-331007) were ≥3 (rats) and 7 (rabbits) times the exposure in humans at the RHD. In rat pre/postnatal development studies, maternal systemic exposures (AUC) to ledipasvir and GS-331007 were approximately 5 and 7 times, respectively, the exposure in humans at the RHD. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data Ledipasvir: Ledipasvir was administered orally to pregnant rats (up to 100 mg/kg/day) and rabbits (up to 180 mg/kg/day) on gestation days 6 to 18 and 7 to 20, respectively, and also to rats (oral doses up to 100 mg/kg/day) on gestation day 6 to lactation/post-partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. Systemic exposures (AUC) to ledipasvir were ≥4 (rats) and 2 (rabbits) times the exposure in humans at the RHD. Sofosbuvir: Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day) and rabbits (up to 300 mg/kg/day) on gestation days 6 to 18 and 6 to 19, respectively, and also to rats (oral doses up to 500 mg/kg/day) on gestation day 6 to lactation/post-partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. Systemic exposures (AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) were ≥3 (rats) and 7 (rabbits) times the exposure in humans at the RHD, with exposures increasing during gestation from approximately 3 to 6 (rats) and 7 to 17 (rabbits) times the exposure in humans at the RHD. 8.2 Lactation Risk Summary It is not known whether ledipasvir or sofosbuvir, the components of HARVONI, or their metabolites are present in human breast milk, affect human milk production or have effects on the breastfed infant. When administered to lactating rats, ledipasvir was detected in the plasma of nursing pups likely due to the presence of ledipasvir in milk, without clear effects on nursing pups [see Data ]. The predominant circulating metabolite of sofosbuvir (GS-331007) was the primary component observed in the milk of lactating rats, without effect on nursing pups. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for HARVONI and any potential adverse effects on the breastfed child from HARVONI or from the underlying maternal condition. If HARVONI is administered with ribavirin, the nursing mother's information for ribavirin also applies to this combination regimen. Refer to the ribavirin prescribing information for more information on use during lactation. Data Ledipasvir: No effects of ledipasvir on growth and postnatal development were observed in nursing pups at t …

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) ].

11 DESCRIPTION Tablets HARVONI tablets are fixed-dose combination tablets 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 90 mg/400 mg 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. Each 45 mg/200 mg tablet contains 45 mg ledipasvir and 200 mg sofosbuvir. The tablets include the following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Pellets HARVONI oral pellets are for oral administration, supplied as small, orange pellets in unit-dose packets. Each unit-dose of HARVONI oral pellets contains either 45 mg ledipasvir and 200 mg sofosbuvir or 33.75 mg ledipasvir and 150 mg sofosbuvir and the following inactive ingredients: amino-methacrylate copolymer, colloidal silicon dioxide, copovidone, croscarmellose sodium, hypromellose, lactose monohydrate, iron oxide red, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide. Ledipasvir: The IUPAC name for ledipasvir is methyl [(2 S )-1-{(6 S )-6-[5-(9,9-difluoro-7-{2-[(1 R ,3 S ,4 S )-2-{(2 S )-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-1 H -benzimidazol-6-yl}-9 H -fluoren-2-yl)-1 H -imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate. It has a molecular formula of C 49 H 54 F 2 N 8 O 6 and a molecular weight of 889.00. It has the following structural formula: Ledipasvir is practically insoluble (less than 0.1 mg/mL) across the pH range of 3.0–7.5 and is slightly soluble below pH 2.3 (1.1 mg/mL). Chemical Structure Sofosbuvir: The IUPAC name for sofosbuvir is ( S )-isopropyl 2-(( S )-(((2 R ,3 R ,4 R ,5 R )-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2 H )-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of C 22 H 29 FN 3 O 9 P and a molecular weight of 529.45. It has the following structural formula: Sofosbuvir is a white to off-white crystalline solid with a solubility of at least 2 mg/mL across the pH range of 2–7.7 at 37°C and is slightly soluble in water. Chemical Structure

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%.

16 HOW SUPPLIED/STORAGE AND HANDLING Tablets HARVONI tablets 90 mg/400 mg 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 and polyester coil, and is closed with a child-resistant closure. HARVONI tablets, 45 mg/200 mg, are white, capsule-shaped, film-coated, debossed with "GSI" on one side and "HRV" on the other side of the tablet. Each bottle contains 28 tablets (NDC 61958-1803-1), a silica gel desiccant and polyester coil, and is closed with a child-resistant closure. Store below 30 °C (86 °F). Dispense only in original container. Do not use if seal over bottle opening is broken or missing. Oral Pellets HARVONI pellets, 45 mg/200 mg, are orange pellets supplied as unit-dose packets in cartons. Each carton contains 28 packets (NDC 61958-1804-1). HARVONI pellets, 33.75 mg/150 mg, are orange pellets supplied as unit-dose packets in cartons. Each carton contains 28 packets (NDC 61958-1805-1). Store below 30 °C (86 °F). Do not use if carton tamper-evident seal or packet seal is broken or damaged.