NDC 72626-2601 Ledipasvir And Sofosbuvir

Ledipasvir And Sofosbuvir

NDC Product Code 72626-2601

NDC CODE: 72626-2601

Proprietary Name: Ledipasvir And Sofosbuvir What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Ledipasvir And Sofosbuvir What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Product Characteristics

Color(s):
ORANGE (C48331)
Shape: DIAMOND (C48338)
Size(s):
20 MM
Imprint(s):
ASE;9875
Score: 1

NDC Code Structure

  • 72626 - Asegua Therapeutics Llc

NDC 72626-2601-1

Package Description: 2 BLISTER PACK in 1 CARTON > 14 TABLET, FILM COATED in 1 BLISTER PACK

NDC Product Information

Ledipasvir And Sofosbuvir with NDC 72626-2601 is a a human prescription drug product labeled by Asegua Therapeutics Llc. The generic name of Ledipasvir And Sofosbuvir is ledipasvir and sofosbuvir. The product's dosage form is tablet, film coated and is administered via oral form.

Labeler Name: Asegua Therapeutics Llc

Dosage Form: Tablet, Film Coated - A solid dosage form that contains medicinal substances with or without suitable diluents and is coated with a thin layer of a water-insoluble or water-soluble polymer.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Ledipasvir And Sofosbuvir Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • LEDIPASVIR 90 mg/1
  • SOFOSBUVIR 400 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • ALCOHOL (UNII: 3K9958V90M)
  • COPOVIDONE K25-31 (UNII: D9C330MD8B)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • WATER (UNII: 059QF0KO0R)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • POLYETHYLENE GLYCOL 3350 (UNII: G2M7P15E5P)
  • TALC (UNII: 7SEV7J4R1U)
  • FD&C YELLOW NO. 6 (UNII: H77VEI93A8)
  • POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Hepatitis C Virus NS5A Inhibitor - [EPC] (Established Pharmacologic Class)
  • P-Glycoprotein Inhibitors - [MoA] (Mechanism of Action)
  • Breast Cancer Resistance Protein Inhibitors - [MoA] (Mechanism of Action)
  • Hepatitis C Virus Nucleotide Analog NS5B Polymerase Inhibitor - [EPC] (Established Pharmacologic Class)
  • RNA Replicase Inhibitors - [MoA] (Mechanism of Action)
  • Nucleoside Analog - [EXT]

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Asegua Therapeutics Llc
Labeler Code: 72626
FDA Application Number: NDA205834 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA AUTHORIZED GENERIC - A product marketed as a “generic” drug under an approved New Drug Application (NDA), rather than an Abbreviated New Drug Application (ANDA),. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 01-01-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

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Information for Patients

Ledipasvir and Sofosbuvir

Ledipasvir and Sofosbuvir is pronounced as (le dip' as vir) and (soe fos' bue vir)

Why is ledipasvir and sofosbuvir medication prescribed?
The combination of ledipasvir and sofosbuvir is used alone or in combination with ribavirin (Copegus, Rebetol, Ribasphere, others) to treat certain types of chronic hepat...
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* Please review the disclaimer below.

Ledipasvir And Sofosbuvir Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Warning: Risk Of Hepatitis B Virus Reactivation In Patients Coinfected With Hcv And Hbv

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with ledipasvir and sofosbuvir tablets. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated [see Warnings and Precautions (5.1)].

Other

  • Adult Patients:Ledipasvir and sofosbuvir tablets are indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) [see Dosage and Administration (2.2) and Clinical Studies (14)]:genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosisgenotype 1 infection with decompensated cirrhosis, for use in combination with ribaviringenotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, for use in combination with ribavirin

Pediatric Patients:Ledipasvir and sofosbuvir tablets are indicated for the treatment of pediatric patients 12 years of age and older or weighing at least 35 kg with HCV genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis [see Dosage and Administration (2.3) and Clinical Studies (14.6)].

Clinical Trials in Adult SubjectsThe safety assessment of ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets.Table 3 lists adverse reactions (adverse events assessed as causally related by the investigator, all grades) observed in at least 5% of subjects receiving 8, 12, or 24 weeks treatment with ledipasvir and sofosbuvir tablets in clinical trials. The majority of adverse reactions presented in Table 3 occurred at severity of grade 1. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.Table 3 Adverse Reactions (All Grades) Reported in ≥5% of Subjects Receiving 8, 12, or 24 Weeks of Treatment with Ledipasvir and Sofosbuvir TabletsLedipasvir and Sofosbuvir Tablets8 weeksN=215Ledipasvir and Sofosbuvir Tablets12 weeksN=539Ledipasvir and Sofosbuvir Tablets24 weeksN=326Fatigue16%13%18%Headache11%14%17%Nausea6%7%9%Diarrhea4%3%7%Insomnia3%5%6%The safety assessment of ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets 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 CirrhosisThe safety assessment of ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets once daily by mouth without ribavirin or 12 weeks of placebo followed by 12 weeks of ledipasvir and sofosbuvir tablets once daily by mouth + ribavirin [see Clinical Studies (14.2)]. Table 4 presents the adverse reactions, as defined above, that occurred with at least 5% greater frequency in subjects treated with 24 weeks of ledipasvir and sofosbuvir tablets or 12 weeks of ledipasvir and sofosbuvir tablets + ribavirin, compared to those reported for 12 weeks of placebo. The majority of the adverse reactions presented in Table 4 were Grade 1 or 2 in severity.Table 4 Adverse Reactions with ≥5% Greater Frequency Reported in Treatment-Experienced Subjects with Cirrhosis Receiving Ledipasvir and Sofosbuvir Tablets for 24 Weeks or Ledipasvir and Sofosbuvir Tablets + RBV for 12 Weeks Compared to Placebo for 12 weeks Ledipasvir and Sofosbuvir Tablets24 weeks(N=78)Ledipasvir and Sofosbuvir Tablets + RBV12 weeks(N=76)Placebo12 weeks(N=77)Asthenia31%36%23%Headache29%13%16%Fatigue18%4%1%Cough5%11%1%Myalgia9%4%0Dyspnea3%9%1%Irritability8%7%1%Dizziness5%1%0

Adverse Reactions in Subjects Coinfected with HIV-1The safety assessment of ledipasvir and sofosbuvir tablets was based on an open-label clinical trial in 335 genotype 1 or 4 subjects with HCV/HIV-1 coinfection who were on stable antiretroviral therapy in Study ION-4 [see Clinical Studies (14.4)]. The safety profile in HCV/HIV-1 coinfected subjects was similar to that observed in HCV mono-infected subjects. The most common adverse reactions occurring in at least 10% of subjects were headache (20%) and fatigue (17%).

Adverse Reactions in Liver Transplant Recipients and/or Subjects with Decompensated CirrhosisThe safety assessment of ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets plus RBV for 12 weeks, respectively. Ribavirin was permanently discontinued in 11% of subjects treated with ledipasvir and sofosbuvir tablets plus RBV for 12 weeks.

Liver Transplant Recipients with Compensated Liver Disease:Among the 174 liver transplant recipients with compensated liver disease who received ledipasvir and sofosbuvir tablets with RBV for 12 weeks, 2 (1%) subjects permanently discontinued ledipasvir and sofosbuvir tablets due to an adverse event.

Subjects with Decompensated Liver Disease:Among the 162 subjects with decompensated liver disease (pre- or post-transplant) who received ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship.

Psychiatric disorders: depression (including in subjects with pre-existing history of psychiatric illness).Depression (particularly in subjects with pre-existing history of psychiatric illness) occurred in subjects receiving sofosbuvir containing regimens. Suicidal ideation and suicide have occurred in less than 1% of subjects treated with sofosbuvir in combination with ribavirin or pegylated interferon/ribavirin in other clinical trials.

Laboratory Abnormalities

Bilirubin Elevations: Bilirubin elevations of greater than 1.5×ULN were observed in 3%, less than 1%, and 2% of subjects treated with ledipasvir and sofosbuvir tablets for 8, 12, and 24 weeks, respectively. Bilirubin elevations of greater than 1.5×ULN were observed in 3%, 11%, and 3% of subjects with compensated cirrhosis treated with placebo, ledipasvir and sofosbuvir tablets + ribavirin for 12 weeks and ledipasvir and sofosbuvir tablets for 24 weeks, respectively, in the SIRIUS trial.

Lipase Elevations: Transient, asymptomatic lipase elevations of greater than 3×ULN were observed in less than 1%, 2%, and 3% of subjects treated with ledipasvir and sofosbuvir tablets for 8, 12, and 24 weeks, respectively. Transient, asymptomatic lipase elevations of greater than 3×ULN were observed in 1%, 3%, and 9% of subjects with compensated cirrhosis treated with placebo, ledipasvir and sofosbuvir tablets + ribavirin for 12 weeks, and ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets. Creatine kinase was assessed in the ION-4 trial. Isolated, asymptomatic creatine kinase elevations of greater than or equal to 10×ULN was observed in 1% of subjects treated with ledipasvir and sofosbuvir tablets for 12 weeks in the ION-4 trial and has also been previously reported in subjects treated with sofosbuvir in combination with ribavirin or peginterferon/ribavirin in other clinical trials.

Adverse Reactions in Pediatric Subjects 12 Years of Age and OlderThe safety assessment of ledipasvir and sofosbuvir tablets in pediatric subjects 12 years of age and older is based on data from a Phase 2, open-label clinical trial (Study 1116) that enrolled 100 subjects without cirrhosis or with compensated cirrhosis who were treated with ledipasvir and sofosbuvir tablets for 12 weeks. The adverse reactions observed were consistent with those observed in clinical studies of ledipasvir and sofosbuvir tablets in adults. Limited safety data are available in pediatric subjects receiving ledipasvir and sofosbuvir tablets for 24 weeks. No Grade 3 or 4 adverse reactions or discontinuation due to an adverse reaction was observed in those pediatric subjects receiving ledipasvir and sofosbuvir tablets for 24 weeks [see Clinical Studies (14.6)].

Cardiac DisordersSerious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with ledipasvir and sofosbuvir tablets [see Warnings and Precautions (5.2), Drug Interactions (7.2)].

Skin and Subcutaneous Tissue DisordersSkin rashes, sometimes with blisters or angioedema-like swellingAngioedema

Risk SummaryIf ledipasvir and sofosbuvir tablets are 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 ledipasvir and sofosbuvir tablets pose a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of ledipasvir and sofosbuvir tablets (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.

Risk SummaryIt is not known whether ledipasvir or sofosbuvir, the components of ledipasvir and sofosbuvir tablets, 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 ledipasvir and sofosbuvir tablets and any potential adverse effects on the breastfed child from ledipasvir and sofosbuvir tablets or from the underlying maternal condition.If ledipasvir and sofosbuvir tablets are 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.

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 37°C and is slightly soluble in water.

Cardiac ElectrophysiologyThorough 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.

AbsorptionThe 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 ledipasvir and sofosbuvir tablets, 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 FoodRelative to fasting conditions, the administration of a single dose of ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets with food or without food. Ledipasvir and sofosbuvir tablets can be administered without regard to food.

DistributionLedipasvir 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.

EliminationFollowing 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 ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets 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, sofosbuvir, and GS-331007 were determined in 100 pediatric subjects 12 years of age and older infected with HCV genotype 1 receiving a daily dose of ledipasvir and sofosbuvir tablets (90 mg ledipasvir and 400 mg sofosbuvir). The pharmacokinetic properties of ledipasvir, sofosbuvir, and GS-331007 in pediatric subjects 12 years of age and older are provided in Table 6. Exposures in pediatric subjects were similar to those observed in adults.Table 6 Pharmacokinetic Properties of the Components of Ledipasvir and Sofosbuvir Tablets in Pediatric Subjects 12 Years of Age and OlderPopulation PK derived parametersGeometric MeanLedipasvirLedipasvir N=100; Sofosbuvir N=72; GS-331007 N=100SofosbuvirGS-331007AUCtau (ng∙hr/mL)11200135013600Cmax (ng/mL)550660921The pharmacokinetics of ledipasvir or sofosbuvir have not been established in pediatric patients less than 12 years of age [see Use in Specific Populations (8.4), and Clinical Studies (14.6)].

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 (2.3) 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 StudiesLedipasvir 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 ledipasvir and sofosbuvir tablets, and the use with P-gp inducers is not recommended with ledipasvir and sofosbuvir tablets [see Warnings and Precautions (5.3)]. Coadministration with drugs that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets 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 7 [see Drug Interactions (7.2)]. Table 7 Drug Interactions: Changes in Pharmacokinetic Parameters for Ledipasvir, Sofosbuvir, and the Predominant Circulating Metabolite GS-331007 in the Presence of the Coadministered DrugAll interaction studies conducted in healthy volunteers.Coadministered DrugDose of Coadministered Drug(mg)Ledi-pasvir Dose(mg)Sofos-buvir Dose(mg)NMean Ratio (90% CI) of Ledipasvir, Sofosbuvir, and GS-331007 PK With/Without Coadministered DrugNo Effect=1.00CmaxAUCCminNA = not available/not applicable, ND = not dosed.tenofovir DF = tenofovir disoproxil fumarateAtazanavir/ ritonavir + emtricitabine/ tenofovir DFData generated from simultaneous dosing with ledipasvir and sofosbuvir tablets. Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir DF or darunavir/ritonavir + emtricitabine/tenofovir DF and ledipasvir and sofosbuvir tablets provided similar results.,The effects of atazanavir/ritonavir on ledipasvir and sofosbuvir are similar with or without the presence of emtricitabine/tenofovir DF. 300/100 + 200/300 once daily90 once daily400 once daily24ledipasvir1.68 (1.54, 1.84)1.96 (1.74, 2.21)2.18 (1.91, 2.50)sofosbuvir1.01 (0.88, 1.15)1.11 (1.02, 1.21)NAGS-3310071.17 (1.12, 1.23)1.31 (1.25, 1.36)1.42 (1.34, 1.49)Cyclosporine600 single doseND400 single dose19sofosbuvir2.54(1.87, 3.45)4.53(3.26, 6.30)NAGS-3310070.60 (0.53, 0.69)1.04 (0.90, 1.20)NADarunavir/ ritonavir800/100 once daily90 once dailyND23ledipasvir1.45 (1.34, 1.56)1.39 (1.28, 1.49)1.39 (1.29, 1.51)ND400 single dose18sofosbuvir1.45 (1.10, 1.92)1.34(1.12, 1.59)NAGS-3310070.97 (0.90, 1.05)1.24(1.18, 1.30)NADarunavir/ ritonavir + emtricitabine/ tenofovir DF800/100 + 200/300 once daily90 once daily400 once daily23ledipasvir1.11 (0.99, 1.24)1.12 (1.00, 1.25)1.17 (1.04, 1.31)sofosbuvir0.63 (0.52, 0.75)0.73 (0.65, 0.82)NAGS-3310071.10 (1.04, 1.16)1.20 (1.16, 1.24)1.26 (1.20, 1.32)Efavirenz/ emtricitabine/ tenofovir DFAdministered as Atripla® (efavirenz, emtricitabine, tenofovir DF).600/200/300 once daily90 once daily400 once daily14ledipasvir0.66 (0.59, 0.75)0.66 (0.59, 0.75)0.66 (0.57, 0.76)sofosbuvir1.03 (0.87, 1.23)0.94 (0.81, 1.10)NAGS-3310070.86 (0.76, 0.96)0.90 (0.83, 0.97)1.07 (1.02, 1.13)Elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide150/150/200/10 once daily90 once daily400 once daily30ledipasvir1.65 (1.53, 1.78)1.79 (1.64, 1.96)1.93 (1.74, 2.15)sofosbuvir1.28 (1.13, 1.47)1.47(1.35, 1.59)NAGS-3310071.29 (1.24, 1.35)1.48 (1.44, 1.53)1.66 (1.60, 1.73)Famotidine40 single dose simultaneously with ledipasvir and sofosbuvir tablets90 single dose400 single dose12ledipasvir0.80 (0.69, 0.93)0.89 (0.76, 1.06)NAsofosbuvir1.15 (0.88, 1.50)1.11 (1.00, 1.24)NAGS-3310071.06 (0.97, 1.14)1.06 (1.02, 1.11)NA40 single dose 12 hours prior to ledipasvir and sofosbuvir tablets12ledipasvir0.83 (0.69, 1.00)0.98 (0.80, 1.20)NAsofosbuvir1.00 (0.76, 1.32)0.95 (0.82, 1.10)NAGS-3310071.13 (1.07, 1.20)1.06 (1.01, 1.12)NAMethadone30 to 130 dailyND400 once daily14sofosbuvir0.95 (0.68, 1.33)1.30 (1.00, 1.69)NAGS-3310070.73 (0.65, 0.83)1.04(0.89, 1.22)NAOmeprazole20 once daily simultaneously with ledipasvir and sofosbuvir tablets90 single dose400 single dose16ledipasvir0.89(0.61, 1.30)0.96(0.66, 1.39)NAsofosbuvir1.12(0.88, 1.42)1.00(0.80, 1.25)NAGS-3310071.14(1.01, 1.29)1.03(0.96, 1.12)NA20 once daily 2 hours prior to ledipasvir30 single doseND17ledipasvir0.52(0.41, 0.66)0.58(0.48, 0.71)NARifampin600 once daily90 single doseThis study was conducted in the presence of two other investigational HCV direct-acting agents.ND31ledipasvir0.65(0.56, 0.76)0.41(0.36, 0.48)NAND400 single dose17sofosbuvir0.23 (0.19, 0.29)0.28(0.24, 0.32)NAGS-3310071.23(1.14, 1.34)0.95(0.88, 1.03)NASimeprevir150 once daily30 once dailyND22ledipasvir1.81(1.69, 2.94)1.92(1.77, 2.07)NATacrolimus5 single doseND400 single dose16sofosbuvir0.97(0.65, 1.43)1.13(0.81, 1.57)NAGS-3310070.97(0.83, 1.14)1.00(0.87, 1.13)NANo 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 8 [see Drug Interactions (7.2)].Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Ledipasvir, Sofosbuvir, or Ledipasvir and Sofosbuvir TabletsAll interaction studies conducted in healthy volunteers.Coadministered DrugDose of Coadministered Drug (mg)Ledi-pasvir Dose (mg)Sofos-buvir Dose (mg)NMean Ratio (90% CI) of Coadministered Drug PK With/Without Ledipasvir, Sofosbuvir, or Ledipasvir and Sofosbuvir TabletsNo Effect=1.00CmaxAUCCminNA = not available/not applicable, ND = not dosed.tenofovir DF = tenofovir disoproxil fumarateAtazanavir/ ritonavir + emtricitabine /tenofovir DFData generated from simultaneous dosing with ledipasvir and sofosbuvir tablets. Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir DF or darunavir/ritonavir + emtricitabine/tenofovir DF and ledipasvir and sofosbuvir tablets provided similar results.,The effects of ledipasvir and sofosbuvir tablets on atazanavir and ritonavir are similar with or without the presence of emtricitabine/tenofovir DF.,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 + ledipasvir and sofosbuvir tablets or tenofovir DF + darunavir/ritonavir + ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets.atazanavir 300 once daily90 once daily400 once daily241.07 (0.99, 1.14)1.27 (1.18, 1.37)1.63 (1.45, 1.84)ritonavir 100 once daily0.86 (0.79, 0.93)0.97 (0.89, 1.05)1.45 (1.27, 1.64)tenofovir DF 300 once daily1.47 (1.37, 1.58)1.35 (1.29, 1.42)1.47 (1.38, 1.57)Darunavir/ ritonavir + emtricitabine/ tenofovir DF,darunavir 800 once daily90 once daily400 once daily231.01 (0.96, 1.06)1.04 (0.99, 1.08)1.08 (0.98, 1.20)ritonavir 100 once daily1.17 (1.01, 1.35)1.25 (1.15, 1.36)1.48 (1.34, 1.63)tenofovir DF 300 once daily1.64 (1.54, 1.74)1.50 (1.42, 1.59)1.59 (1.49, 1.70)Elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamideelvitegravir 150 once daily90 once daily400 once daily300.98 (0.90, 1.07)1.11 (1.02, 1.20)1.46 (1.28, 1.66)cobicistat 150 once daily1.23 (1.15, 1.32)1.53 (1.45, 1.62)3.25 (2.88, 3.67)tenofovir alafenamide 10 once daily0.90 (0.73, 1.11)0.86 (0.78, 0.95)NANorelgestrominnorgestimate 0.180/0.215/0.25/ethinyl estradiol 0.025 once daily90 once dailyND151.02 (0.89, 1.16)1.03 (0.90, 1.18)1.09 (0.91, 1.31)ND400 once daily1.07 (0.94, 1.22)1.06 (0.92, 1.21)1.07 (0.89, 1.28)Norgestrel90 once dailyND1.03 (0.87, 1.23)0.99 (0.82, 1.20)1.00 (0.81, 1.23)ND400 once daily1.18 (0.99, 1.41)1.19 (0.98, 1.45)1.23 (1.00, 1.51)Ethinyl estradiol90 once dailyND1.40 (1.18, 1.66)1.20 (1.04, 1.39)0.98 (0.79, 1.22)ND400 once daily1.15 (0.97, 1.36)1.09 (0.94, 1.26)0.99 (0.80, 1.23)Raltegravir400 twice daily90 once dailyND280.82 (0.66, 1.02)0.85(0.70, 1.02)1.15 (0.90, 1.46)ND400 single dose190.57 (0.44, 0.75)0.73 (0.59, 0.91)0.95 (0.81, 1.12)Simeprevir150 once daily30 once dailyND222.61 (2.39, 2.86)2.69 (2.44, 2.96)NATacrolimus5 single doseND400 single dose160.73 (0.59, 0.90)1.09 (0.84, 1.40)NATenofovir DF300 once dailyAdministered as Atripla (efavirenz, emtricitabine, tenofovir DF). The effects of ledipasvir and sofosbuvir tablets on tenofovir exposures are similar when tenofovir is administered as Atripla, Complera®, or Truvada + dolutegravir.90 once daily400 once daily151.79 (1.56, 2.04)1.98 (1.77, 2.23)2.63 (2.32, 2.97)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.

Mechanism of ActionLedipasvir 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 ActivityIn 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 from treatment-naïve HCV-infected subjects were 0.02 nM for genotype 1a (range 0.007–1.0 nM; N=23) and 0.006 nM for genotype 1b (range 0.002–1.0 nM; N=34). Ledipasvir had median EC50 values ranging between 0.002 nM to 0.16 nM against 11 genotype 4 subtypes (4a, 4d, 4n, 4r, 4o, 4c, 4f, 4k, 4l, 4m and 4t). The median EC50 value for subtype 4b was 199.6 nM (range 0.66–1799 nM; N=3); the two 4b isolates with EC50 values greater than 100 nM had NS5A resistance-associated polymorphisms L30S+M31M+P58S+Y93H. The median EC50 value of ledipasvir was 0.03 nM against genotype 5a isolates (range 0.008–0.081 nM; N=35). For genotype 6, the EC50 values for ledipasvir varied by subtype. Subtypes 6a and 6h had median EC50 values of 0.55 and 0.17 nM, respectively. For subtypes 6e, 6l, 6n, 6q, 6k and 6m, the median EC50 values ranged from 60.6 nM to 430.1 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 CultureHCV 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 1In a pooled analysis of subjects who received ledipasvir and sofosbuvir tablets 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 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 ledipasvir and sofosbuvir tablets in a Phase 2 trial.

Genotype 4, 5 or 6Resistance 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 ledipasvir and sofosbuvir tablets 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 SubstitutionsNo 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

Adults

Genotype 1Analyses 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 ledipasvir and sofosbuvir tablets. 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 ledipasvir and sofosbuvir tablets. 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 ledipasvir and sofosbuvir tablets. 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 ledipasvir and sofosbuvir tablets + RBV compared to 2/15 (13%) subjects treated with 24 weeks of ledipasvir and sofosbuvir tablets.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 ledipasvir and sofosbuvir tablets 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 6Phylogenetic 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 ledipasvir and sofosbuvir tablets 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.

PediatricsIn Study 1116, the presence of NS5A and NS5B resistance-associated polymorphisms did not impact treatment outcome; all pediatric subjects 12 years of age and older with baseline NS5A or NS5B nucleoside inhibitor resistance-associated polymorphisms (18%; 17/96) achieved SVR following 12 weeks treatment with ledipasvir and sofosbuvir tablets.

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.

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.

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): ledipasvir and sofosbuvir tablets for 8 weeks, ledipasvir and sofosbuvir tablets for 12 weeks, or ledipasvir and sofosbuvir tablets + 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 10 presents the SVR12 for the ledipasvir and sofosbuvir treatment groups in the ION-3 trial after 8 and 12 weeks of ledipasvir and sofosbuvir treatment. Ribavirin was not shown to increase the SVR12 observed with ledipasvir and sofosbuvir tablets. Therefore, the ledipasvir and sofosbuvir tablets + ribavirin arm is not presented in Table 10.Table 10 Study ION-3: SVR12 after 8 and 12 Weeks of Treatment in Treatment-Naïve Non-Cirrhotic Subjects with Genotype 1 HCVLedipasvir and Sofosbuvir Tablets8 Weeks(N=215)Ledipasvir and Sofosbuvir Tablets12 Weeks(N=216)SVR1294% (202/215)96% (208/216)Outcome for Subjects without SVR  On-Treatment Virologic Failure0/2150/216  RelapseThe denominator for relapse is the number of subjects with HCV RNA
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 ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets for 12 weeks, ledipasvir and sofosbuvir tablets + ribavirin for 12 weeks, ledipasvir and sofosbuvir tablets for 24 weeks, or ledipasvir and sofosbuvir tablets + 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 12 presents the SVR12 for the treatment group of ledipasvir and sofosbuvir tablets for 12 weeks in the ION-1 trial. Ribavirin was not shown to increase SVR12 observed with ledipasvir and sofosbuvir tablets. Therefore, the ledipasvir and sofosbuvir tablets + ribavirin arm is not presented in Table 12.Table 12 Study ION-1: SVR12 after 12 Weeks of Treatment in Treatment-Naïve Subjects with Genotype 1 HCV with and without CirrhosisLedipasvir and Sofosbuvir Tablets12 Weeks(N=214)SVR12Excluding one subject with genotype 4 infection.99% (210/213)Outcome for Subjects without SVR  On-Treatment Virologic Failure0/213  Relapse,The denominator for relapse is the number of subjects with HCV RNA
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 ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets for 12 weeks, ledipasvir and sofosbuvir tablets + ribavirin for 12 weeks, ledipasvir and sofosbuvir tablets for 24 weeks, or ledipasvir and sofosbuvir tablets + 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 14 presents the SVR12 for the ledipasvir and sofosbuvir treatment groups in the ION-2 trial. Ribavirin was not shown to increase SVR12 observed with ledipasvir and sofosbuvir tablets. Therefore, the ledipasvir and sofosbuvir tablets + ribavirin arms are not presented in Table 14.Table 14 Study ION-2: SVR12 after 12 and 24 Weeks of Treatment in Subjects with Genotype 1 HCV with or without Cirrhosis Who Failed Prior TherapyLedipasvir and Sofosbuvir Tablets12 Weeks(N=109)Ledipasvir and Sofosbuvir Tablets24 Weeks(N=109)SVR1294% (102/109)99% (108/109)Outcome for Subjects without SVR  On-Treatment Virologic Failure0/1090/109  RelapseThe denominator for relapse is the number of subjects with HCV RNA
Previously-Treated Adults with Cirrhosis – SIRIUS (Study 0121)SIRIUS was a randomized, double-blind and placebo-controlled trial that evaluated the efficacy of ledipasvir and sofosbuvir tablets + ribavirin for 12 weeks or ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets + ribavirin for 12 weeks or ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets + ribavirin for 12 weeks and ledipasvir and sofosbuvir tablets for 24 weeks without ribavirin, respectively. All 5 subjects who did not achieve SVR12 relapsed.

Genotype 4In two open-label studies (Study 1119 and ION-4), ledipasvir and sofosbuvir tablets were administered for 12 weeks to treatment-naïve and previously-treated adult subjects with genotype 4 HCV infection. Study 1119 enrolled 44 treatment-naïve or previously-treated subjects with genotype 4 HCV, with or without cirrhosis. ION-4 enrolled 4 treatment-naïve and 4 previously-treated subjects with genotype 4 HCV infection who were coinfected with HIV-1, none of whom had cirrhosis.In Study 1119, the overall SVR12 rate was 93% (41/44). SVR12 was similar based upon prior HCV treatment history and cirrhosis status. In ION-4, all 8 subjects achieved SVR12.

Genotype 5In the open-label 1119 trial, ledipasvir and sofosbuvir tablets were administered for 12 weeks to 41 treatment-naïve or previously-treated adult subjects with genotype 5 HCV infection, with or without cirrhosis. The overall SVR12 was 93% (38/41). SVR12 was similar based upon prior HCV treatment history and cirrhosis status.

Genotype 6In the open-label ELECTRON-2 trial, ledipasvir and sofosbuvir tablets were administered for 12 weeks to 25 treatment-naïve or previously-treated adult subjects with genotype 6 HCV infection, with or without cirrhosis. The overall SVR12 was 96% (24/25). SVR12 was similar based upon prior HCV treatment history and cirrhosis status. The single subject who relapsed discontinued study treatment early (at approximately Week 8).

Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBVInform patients that HBV reactivation can occur in patients coinfected with HBV during or after treatment of HCV infection. Advise patients to tell their healthcare provider if they have a history of HBV infection [see Warnings and Precautions (5.1)].

Serious Symptomatic Bradycardia When Coadministered with Amiodarone Advise patients to seek medical evaluation immediately for symptoms of bradycardia such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems [see Warnings and Precautions (5.2), Adverse Reactions (6.2), and Drug Interactions (7.2)].

Drug InteractionsInform patients that ledipasvir and sofosbuvir tablets may interact with other drugs. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products including St. John's wort [see Warnings and Precautions (5.2, 5.3) and Drug Interactions (7)].

PregnancyAdvise patients to avoid pregnancy during combination treatment with ledipasvir and sofosbuvir tablets 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)].

AdministrationAdvise patients to take ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets for the duration that is recommended by the physician.

Manufactured for:Asegua Therapeutics LLCAn affiliate of Gilead Sciences, Inc.Foster City, CA 94404Asegua is a trademark of Asegua Therapeutics LLC. All other trademarks referenced herein are the property of their respective owners.205834-AG-007

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 ledipasvir and sofosbuvir tablets [see Warnings and Precautions (5.1)].

2.2 Recommended Dosage In Adults

The recommended dosage of ledipasvir and sofosbuvir tablets is one tablet (90 mg ledipasvir and 400 mg sofosbuvir) taken orally once daily with or without food [see Clinical Pharmacology (12.3)].Relapse rates are affected by baseline host and viral factors and differ between treatment durations for certain subgroups [see Clinical Studies (14)].Table 1 shows the recommended ledipasvir and sofosbuvir tablets treatment regimen and duration based on patient population.For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1 [see Clinical Studies (14)]. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs.Table 1 Recommended Treatment Regimen and Duration for Ledipasvir and Sofosbuvir Tablets in Adult Patients with Genotype 1, 4, 5, or 6 HCVPatient PopulationTreatment Regimen and DurationGenotype 1Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A)Ledipasvir and sofosbuvir tablets12 weeksLedipasvir and sofosbuvir tablets for 8 weeks can be considered in treatment-naïve genotype 1 patients without cirrhosis who have pretreatment HCV RNA less than 6 million IU/mL [see Clinical Studies (14.2)].Treatment-experiencedTreatment-experienced patients have failed a peginterferon alfa + ribavirin based regimen with or without an HCV protease inhibitor. without cirrhosisLedipasvir and sofosbuvir tablets12 weeksTreatment-experienced with compensated cirrhosis (Child-Pugh A)Ledipasvir and sofosbuvir tablets24 weeksLedipasvir and sofosbuvir tablets + ribavirin for 12 weeks can be considered in treatment-experienced genotype 1 patients with cirrhosis who are eligible for ribavirin [see Clinical Studies (14.2)]. See footnote ¶ for ribavirin dosage recommendations.Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C)Ledipasvir and sofosbuvir tablets+ ribavirinIn patients with decompensated cirrhosis, the starting dosage of ribavirin is 600 mg and can be titrated up to 1000 mg for patients <75 kg and 1200 mg for those ≥75 kg in two divided doses with food. If the starting dosage of ribavirin is not well tolerated, the dosage should be reduced as clinically indicated based on hemoglobin levels. 12 weeksGenotype 1 or 4Treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis, or with compensated cirrhosis (Child-Pugh A)Ledipasvir and sofosbuvir tablets+ ribavirinThe daily dosage of ribavirin is weight-based (1000 mg for patients <75 kg and 1200 mg for those ≥75 kg) administered orally in two divided doses with food.12 weeksGenotype 4, 5, or 6Treatment-naïve and treatment-experienced, without cirrhosis or with compensated cirrhosis (Child-Pugh A)Ledipasvir and sofosbuvir tablets12 weeksFor further information on ribavirin dosing and dosage modifications, refer to the ribavirin prescribing information [see Clinical Studies (14.5)].

2.3 Recommended Dosage In Pediatric Patients 12 Years Of Age And Older Or Weighing At Least 35 Kg

The recommended dosage of ledipasvir and sofosbuvir tablets in pediatric patients 12 years of age and older or weighing at least 35 kg is one tablet (90 mg ledipasvir and 400 mg sofosbuvir) taken orally once daily with or without food for 12 weeks [see Clinical Pharmacology (12.3) and Clinical Studies (14.6)].Table 2 shows the recommended ledipasvir and sofosbuvir tablets duration based on pediatric patient population.For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 2 [see Use in Specific Populations (8.4)]. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs.Table 2 Recommended Regimen and Duration for Ledipasvir and Sofosbuvir Tablets in Pediatric Patients 12 Years of Age or Older or Weighing at Least 35 kg with Genotype 1, 4, 5, or 6 HCV without Cirrhosis or with Compensated CirrhosisPatient PopulationTreatment Regimenand DurationGenotype 1Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A)Ledipasvir and sofosbuvir tablets12 weeksTreatment-experiencedTreatment-experienced patients have failed an interferon based regimen with or without ribavirin. without cirrhosisLedipasvir and sofosbuvir tablets12 weeksTreatment-experienced with compensated cirrhosis (Child-Pugh A)Ledipasvir and sofosbuvir tablets24 weeksGenotype 4, 5, or 6Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A)Ledipasvir and sofosbuvir tablets12 weeks

2.4 Severe Renal Impairment And End Stage Renal Disease

No dosage recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate [eGFR] less than 30 mL/min/1.73 m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

3 Dosage Forms And Strengths

Ledipasvir and sofosbuvir tablets are available as orange colored, diamond shaped, film-coated tablets debossed with "ASE" on one side and "9875" on the other side of the tablet. Each tablet contains 90 mg ledipasvir and 400 mg sofosbuvir.

4 Contraindications

If ledipasvir and sofosbuvir tablets are 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)].

5.1 Risk Of Hepatitis B Virus Reactivation In Patients Coinfected With Hcv And Hbv

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressants or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection, reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with ledipasvir and sofosbuvir tablets. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with ledipasvir and sofosbuvir tablets and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

5.2 Serious Symptomatic Bradycardia When Coadministered With Amiodarone

  • Postmarketing cases of symptomatic bradycardia, as well as fatal cardiac arrest and cases requiring pacemaker intervention, have been reported when amiodarone is coadministered with ledipasvir and sofosbuvir tablets. 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 ledipasvir and sofosbuvir tablets is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered ledipasvir and sofosbuvir tablets:Counsel patients about the risk of serious symptomatic bradycardiaCardiac 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 ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets should also undergo similar cardiac monitoring as outlined above.Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems [see Adverse Reactions (6.2), Drug Interactions (7.2)].

5.3 Risk Of Reduced Therapeutic Effect Due To Use With P-Gp Inducers

The concomitant use of ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir. Therefore, the use of ledipasvir and sofosbuvir tablets with P-gp inducers (e.g., rifampin or St. John's wort) is not recommended [see Drug Interactions (7.2)].

5.4 Risks Associated With Ribavirin Combination Treatment

If ledipasvir and sofosbuvir tablets are administered with ribavirin, the warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin [see Dosage and Administration (2.2)].

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)].

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 ledipasvir and sofosbuvir tablets are administered with ribavirin to adults, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of ledipasvir and sofosbuvir tablets. 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.

7.1 Potential For Drug Interaction

As ledipasvir and sofosbuvir tablets contain ledipasvir and sofosbuvir, any interactions that have been identified with these agents individually may occur with ledipasvir and sofosbuvir tablets.After oral administration of ledipasvir and sofosbuvir tablets, 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 ledipasvir and sofosbuvir, and the use with P-gp inducers is not recommended with ledipasvir and sofosbuvir tablets [see Warnings and Precautions (5.3)].Fluctuations in INR values may occur in patients receiving warfarin concomitant with HCV treatment, including treatment with ledipasvir and sofosbuvir tablets. Frequent monitoring of INR values is recommended during treatment and post-treatment follow-up.

7.2 Established And Potentially Significant Drug Interactions

  • Table 5 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either ledipasvir and sofosbuvir tablets, the components of ledipasvir and sofosbuvir tablets (ledipasvir and sofosbuvir) as individual agents, or are predicted drug interactions that may occur with ledipasvir and sofosbuvir tablets [see Warnings and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3)].Table 5Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted InteractionThis table is not all inclusive.Concomitant Drug Class: Drug NameEffect on Concentration↓ = decrease, ↑ = increaseClinical Commenttenofovir DF = tenofovir disoproxil fumarateAcid Reducing Agents:↓ ledipasvirLedipasvir 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 ledipasvir and sofosbuvir tablet administration by 4 hours.H2-receptor antagonistsThese interactions have been studied in healthy adults. (e.g., famotidine)H2-receptor antagonists may be administered simultaneously with or 12 hours apart from ledipasvir and sofosbuvir tablets at a dose that does not exceed doses comparable to famotidine 40 mg twice daily.Proton-pump inhibitors (e.g., omeprazole)Proton-pump inhibitor doses comparable to omeprazole 20 mg or lower can be administered simultaneously with ledipasvir and sofosbuvir tablets under fasted conditions.Antiarrhythmics:amiodaroneEffect on amiodarone, ledipasvir, and sofosbuvir concentrations unknownCoadministration of amiodarone with ledipasvir and sofosbuvir tablets may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with ledipasvir and sofosbuvir tablets is not recommended; if coadministration is required, cardiac monitoring is recommended [see Warnings and Precautions (5.2), Adverse Reactions (6.2)].digoxin↑ digoxinCoadministration of ledipasvir and sofosbuvir tablets with digoxin may increase the concentration of digoxin. Therapeutic concentration monitoring of digoxin is recommended when coadministered with ledipasvir and sofosbuvir tablets.Anticonvulsants:carbamazepinephenytoinphenobarbitaloxcarbazepine↓ ledipasvir↓ sofosbuvirCoadministration of ledipasvir and sofosbuvir tablets with carbamazepine, phenytoin, phenobarbital, or oxcarbazepine is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of ledipasvir and sofosbuvir. Coadministration is not recommended.Antimycobacterials:rifabutinrifampinrifapentine↓ ledipasvir↓ sofosbuvirCoadministration of ledipasvir and sofosbuvir tablets with rifabutin or rifapentine is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of ledipasvir and sofosbuvir. Coadministration is not recommended.Coadministration of ledipasvir and sofosbuvir tablets with rifampin, a P-gp inducer, is not recommended [see Warnings and Precautions (5.3)].HIV Antiretrovirals:Regimens containing tenofovir DF without an HIV protease inhibitor/ritonavir or cobicistat↑ tenofovirMonitor for tenofovir-associated adverse reactions in patients receiving ledipasvir and sofosbuvir tablets concomitantly with a regimen containing tenofovir DF without an HIV protease inhibitor/ritonavir or cobicistat. Refer to Viread® or Truvada® prescribing information for recommendations on renal monitoring.Regimens containing tenofovir DF and an HIV protease inhibitor/ritonavir or cobicistatatazanavir/ritonavir or cobicistat + emtricitabine/tenofovir DFdarunavir/ritonavir or cobicistat + emtricitabine/tenofovir DFlopinavir/ritonavir + emtricitabine/tenofovir DF↑ tenofovirThe safety of increased tenofovir concentrations in the setting of ledipasvir and sofosbuvir tablets and an HIV protease inhibitor/ritonavir or cobicistat has not been established.Consider alternative HCV or antiretroviral therapy to avoid increases in tenofovir exposures. If coadministration is necessary, monitor for tenofovir-associated adverse reactions. Refer to Viread or Truvada prescribing information for recommendations on renal monitoring.elvitegravir, cobicistat, emtricitabine, tenofovir DF↑ tenofovirThe safety of increased tenofovir concentrations in the setting of ledipasvir and sofosbuvir tablets and the combination of elvitegravir, cobicistat, emtricitabine and tenofovir DF has not been established. Coadministration is not recommended.tipranavir/ritonavir↓ ledipasvir↓ sofosbuvirCoadministration of ledipasvir and sofosbuvir tablets with tipranavir/ritonavir is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of ledipasvir and sofosbuvir. Coadministration is not recommended.HCV Products:simeprevir↑ ledipasvir↑ simeprevirConcentrations of ledipasvir and simeprevir are increased when simeprevir is coadministered with ledipasvir. Coadministration of ledipasvir and sofosbuvir tablets with simeprevir is not recommended.Herbal Supplements:St. John's wort (Hypericum perforatum)↓ ledipasvir↓ sofosbuvirCoadministration of ledipasvir and sofosbuvir tablets with St. John's wort, a P-gp inducer, is not recommended [see Warnings and Precautions (5.3)].HMG-CoA Reductase Inhibitors:rosuvastatin↑ rosuvastatinCoadministration of ledipasvir and sofosbuvir tablets with rosuvastatin may significantly increase the concentration of rosuvastatin which is associated with increased risk of myopathy, including rhabdomyolysis. Coadministration of ledipasvir and sofosbuvir tablets with rosuvastatin is not recommended.atorvastatin↑ atorvastatinCoadministration of ledipasvir and sofosbuvir tablets with atorvastatin may be associated with increased risk of myopathy, including rhabdomyolysis. Monitor closely for HMG-CoA reductase inhibitor-associated adverse reactions, such as myopathy and rhabdomyolysis.

7.3 Drugs Without Clinically Significant Interactions With Ledipasvir And Sofosbuvir

Based on drug interaction studies conducted with the components of ledipasvir and sofosbuvir tablets (ledipasvir or sofosbuvir) or ledipasvir and sofosbuvir tablets, no clinically significant drug interactions have been either observed or are expected when ledipasvir and sofosbuvir tablets are used with the following drugs [see Clinical Pharmacology (12.3)]: abacavir, atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, dolutegravir, efavirenz, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, lamivudine, methadone, oral contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus, or verapamil. See Table 5 for use of ledipasvir and sofosbuvir tablets with certain HIV antiretroviral regimens [see Drug Interactions (7.2)].

8.3 Females And Males Of Reproductive Potential

If ledipasvir and sofosbuvir tablets are administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to ribavirin prescribing information for additional information.

8.4 Pediatric Use

The safety, pharmacokinetics, and efficacy of ledipasvir and sofosbuvir tablets for treatment of HCV genotype 1 infection in treatment-naïve and treatment-experienced pediatric patients 12 years of age and older without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1116, N=100; 80 treatment-naïve, 20 treatment-experienced) and are comparable to that observed in adults.The safety and efficacy of ledipasvir and sofosbuvir tablets for treatment of HCV genotypes 4, 5, or 6 infection in pediatric patients 12 years of age and older or weighing at least 35 kg without cirrhosis or with compensated cirrhosis is supported by comparable ledipasvir, sofosbuvir, and GS-331007 exposures between adults and adolescents with HCV genotype 1 and similar efficacy and exposures across HCV genotypes 1, 4, 5, and 6 in adults [see Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3 and 14.6)].The safety and efficacy of ledipasvir and sofosbuvir tablets have not been established in pediatric patients less than 12 years of age and weighing less than 35 kg, in pediatric patients with decompensated cirrhosis, or in pediatric liver transplant recipients.

8.5 Geriatric Use

Clinical trials of ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets is warranted in geriatric patients [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

No dosage adjustment of ledipasvir and sofosbuvir tablets is required for patients with mild or moderate renal impairment. The safety and efficacy of ledipasvir and sofosbuvir tablets have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or ESRD requiring hemodialysis. No dosage recommendation can be given for patients with severe renal impairment or ESRD [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Refer to ribavirin prescribing information regarding use in patients with renal impairment.

8.7 Hepatic Impairment

No dosage adjustment of ledipasvir and sofosbuvir tablets is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) and Clinical Studies (14.5)].Clinical and hepatic laboratory monitoring, as clinically indicated, is recommended for patients with decompensated cirrhosis receiving treatment with ledipasvir and sofosbuvir tablets and ribavirin [see Adverse Reactions (6.1)].

10 Overdosage

No specific antidote is available for overdose with ledipasvir and sofosbuvir tablets. If overdose occurs, the patient must be monitored for evidence of toxicity. Treatment of overdose with ledipasvir and sofosbuvir tablets 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

Ledipasvir and sofosbuvir 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 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.

12.1 Mechanism Of Action

Ledipasvir and sofosbuvir tablets are a fixed-dose combination of ledipasvir and sofosbuvir which are direct-acting antiviral agents against the hepatitis C virus [see Microbiology (12.4)].

14.1 Description Of Clinical Trials

The efficacy and safety of ledipasvir and sofosbuvir tablets were evaluated in four trials in genotype 1 HCV mono-infected subjects including one trial exclusively in treatment-experienced subjects with compensated cirrhosis (Child-Pugh A), one trial in genotype 1 or 4 HCV/HIV-1 coinfected subjects, two trials in genotype 4, 5, or 6 HCV mono-infected subjects, two trials in genotype 1 or 4 HCV infected pretransplant subjects with decompensated cirrhosis (Child-Pugh B and C) or post-transplant with Metavir F0–F3 fibrosis, compensated cirrhosis, decompensated cirrhosis, or fibrosing cholestatic hepatitis (FCH), and one trial in genotype 1 HCV pediatric subjects 12 years of age and older without cirrhosis or with compensated cirrhosis, as summarized in Table 9 [see Clinical Studies (14.2, 14.3, 14.4, 14.5, and 14.6)]:Table 9 Trials Conducted with Ledipasvir and Sofosbuvir Tablets with or without Ribavirin in Subjects with Chronic HCV Genotype 1, 4, 5 or 6 InfectionTrialPopulationStudy Arms (Number of Subjects Treated)TN: Treatment-naïve subjectsTE: Treatment-experienced subjects including those who have failed a peginterferon alfa + ribavirin based regimen with or without an HCV protease inhibitor.ION-3(open-label)GT1, TN without cirrhosisLedipasvir and sofosbuvir tablets 8 weeks (215)Ledipasvir and sofosbuvir tablets + RBV 8 weeks (216)Ledipasvir and sofosbuvir tablets 12 weeks (216)ION-1 (open-label)GT1, TN with or without cirrhosisLedipasvir and sofosbuvir tablets 12 weeks (214)Ledipasvir and sofosbuvir tablets + RBV 12 weeks (217)Ledipasvir and sofosbuvir tablets 24 weeks (217)Ledipasvir and sofosbuvir tablets + RBV 24 weeks (217)ION-2 (open-label)GT1, TE with or without cirrhosisLedipasvir and sofosbuvir tablets 12 weeks (109)Ledipasvir and sofosbuvir tablets + RBV 12 weeks (111)Ledipasvir and sofosbuvir tablets 24 weeks (109)Ledipasvir and sofosbuvir tablets + RBV 24 weeks (111)SIRIUS(double-blind)GT1, TE with cirrhosisLedipasvir and sofosbuvir tablets + RBV 12 Weeks (77)Ledipasvir and sofosbuvir tablets 24 weeks (77)ION-4 (open-label)GT1 and GT4 HCV/HIV-1 coinfectedTN and TE with or without cirrhosisLedipasvir and sofosbuvir tablets 12 Weeks(N=327 for GT1; N=8 for GT4)Study 1119(open-label)GT4 and GT5, TN and TE with or without cirrhosisLedipasvir and sofosbuvir tablets 12 Weeks(N=44 for GT4; N=41 for GT5)ELECTRON-2 (open-label)GT6, TN and TE with or without cirrhosisLedipasvir and sofosbuvir tablets 12 Weeks (25)SOLAR-1 and SOLAR-2(open-label)GT1 and GT4 pre-transplant with decompensated cirrhosis or post-transplant with Metavir F0–F3 fibrosis, compensated cirrhosis, decompensated cirrhosis, or FCHLedipasvir and sofosbuvir tablets + RBV 12 Weeks (336)Ledipasvir and sofosbuvir tablets + RBV 24 weeks (334)Study 1116(open-label)GT1 with or without cirrhosis in pediatric subjects 12 years of age and olderLedipasvir and sofosbuvir tablets 12 Weeks (100)Ledipasvir and sofosbuvir tablets were administered once daily by mouth in these trials. For subjects without cirrhosis or with compensated cirrhosis who received ribavirin (RBV), the RBV dosage was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing at least 75 kg. For subjects with decompensated cirrhosis in SOLAR-1 and SOLAR-2 studies, the starting RBV dosage was 600 mg per day regardless of transplantation status. RBV dose adjustments were performed according to the RBV labeling.Serum HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System in ION-3, ION-1, ION-2, SIRIUS, and ION-4 studies or the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) in ELECTRON-2, 1119, SOLAR-1, SOLAR-2, and 1116 studies. The COBAS TaqMan HCV test (version 2.0) for use with the High Pure System has a lower limit of quantification (LLOQ) of 25 IU per mL and the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) has a LLOQ of 15 IU per mL. Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in studies in adults and the key efficacy endpoint in the study in pediatric subjects 12 years of age and older. Relapse was a secondary endpoint, which was defined as HCV RNA greater than or equal to LLOQ with 2 consecutive values or last available post-treatment measurement during the post-treatment period after achieving HCV RNA less than LLOQ at end of treatment.

14.3 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.

14.4 Clinical Trials In Subjects Coinfected With Hcv And Hiv-1

ION-4 was an open-label clinical trial that evaluated the safety and efficacy of 12 weeks of treatment with ledipasvir and sofosbuvir tablets without ribavirin in HCV treatment-naïve and previously-treated adult subjects with genotype 1 or 4 HCV infection who were coinfected with HIV-1. Treatment-experienced subjects had failed prior treatment with Peg-IFN + RBV, Peg-IFN + RBV + an HCV protease inhibitor or sofosbuvir + RBV. Subjects were on a stable HIV-1 antiretroviral therapy that included emtricitabine + tenofovir disoproxil fumarate, administered with efavirenz, rilpivirine, or raltegravir.Of the 335 treated subjects, the median age was 52 years (range: 26 to 72); 82% of the subjects were male; 61% were White; 34% were Black; mean body mass index was 27 kg/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 17 presents the SVR12 in the ION-4 trial after 12 weeks of ledipasvir and sofosbuvir treatment.Table 17 Study ION-4: SVR12 in Subjects with Genotype 1 or 4 HCV Coinfected with HIV-1Ledipasvir and Sofosbuvir Tablets12 Weeks(N=335)SVR1296% (321/335)Outcome for Subjects without SVR  On-Treatment Virologic Failure<1% (2/335)  RelapseThe denominator for relapse is the number of subjects with HCV RNA

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 ledipasvir and sofosbuvir tablets in combination with ribavirin in HCV treatment-naïve and previously-treated adult subjects with genotype 1 and 4 infection who had undergone liver transplantation and/or who had decompensated liver disease. The two trials were identical in study design. Subjects were enrolled in one of the seven groups in the trials based on liver transplantation status and severity of hepatic impairment (see Table 16). Subjects with a CPT score greater than 12 were excluded. Within each group, subjects were randomized in a 1:1 ratio to receive ledipasvir and sofosbuvir tablets + RBV for 12 weeks or ledipasvir and sofosbuvir tablets + 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 18 presents the pooled SVR12 rates for SOLAR-1 and SOLAR-2 in subjects with genotype 1 HCV treated with ledipasvir and sofosbuvir tablets + RBV for 12 weeks. The SVR12 rates observed with 24 weeks of ledipasvir and sofosbuvir tablets + RBV were similar to the SVR12 rates observed with 12 weeks of treatment. Therefore, the results for the ledipasvir and sofosbuvir tablets + RBV 24 weeks arm are not presented in Table 18.Table 18 Studies SOLAR-1 and SOLAR-2: SVR12 and Relapse Rates After 12 Weeks of Treatment with Ledipasvir and Sofosbuvir Tablets and Ribavirin in Subjects with Genotype 1 HCV Who Were Post Liver Transplant and/or Who Had Decompensated Liver DiseaseLedipasvir and Sofosbuvir Tablets + RBV 12 weeksN=307SVR12 (N=300)Five subjects transplanted prior to post-treatment Week 12 with HCV RNA

14.6 Clinical Trial In Pediatric Subjects

The efficacy of ledipasvir and sofosbuvir tablets was evaluated in an open-label trial (Study 1116) that evaluated 12 weeks of treatment with ledipasvir and sofosbuvir tablets once daily in genotype 1 HCV treatment-naïve (N=80) and treatment-experienced (N=20) pediatric subjects 12 years of age and older without cirrhosis or with compensated cirrhosis.Demographics and baseline characteristics were balanced across treatment-naïve and treatment-experienced subjects (patients had failed an interferon based regimen with or without ribavirin). Of the 100 treated subjects, the median age was 15 years (range: 12 to 17); 63% of the subjects were female; 90% were White, 7% were Black, and 2% were Asian; 13% were Hispanic/Latino; mean body mass index was 23 kg/m2 (range: 13.1 to 36.6 kg/m2); mean weight was 61 kg (range 33 to 126 kg); 55% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 81% had genotype 1a HCV infection; 76% had non-CC IL28B alleles (CT or TT). One subject had known compensated cirrhosis. The majority of subjects (84%) had been infected through vertical transmission.The SVR12 rate was 98% overall (98% [78/80] in treatment-naïve subjects and 100% [20/20] in treatment-experienced subjects). No subject experienced on-treatment virologic failure or relapse. Two subjects were lost to follow-up.

16 How Supplied/Storage And Handling

Ledipasvir and sofosbuvir tablets are orange, diamond-shaped, film-coated, debossed with "ASE" on one side and "9875" on the other side of the tablet. Each blister pack contains 28 tablets (2 blister cards each containing 14 tablets) (NDC 72626-2601-1).

Storage And Handling

Store at room temperature below 30 °C (86 °F).

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Spl Patient Package Insert

  • This Patient Information has been approved by the U.S. Food and Drug AdministrationRevised: 11/2018Patient Information Ledipasvir and Sofosbuvir(led" i pas' vir and soe fos' bue vir)TabletsAuthorized generic of Harvoni®Important: If you take ledipasvir and sofosbuvir tablets with ribavirin, you should also read the Medication Guide for ribavirin.What is the most important information I should know about ledipasvir and sofosbuvir tablets?Ledipasvir and sofosbuvir tablets can cause serious side effects, including,Hepatitis B virus reactivation: Before starting treatment with ledipasvir and sofosbuvir tablets, your healthcare provider will do blood tests to check for hepatitis B virus infection. If you have ever had hepatitis B virus infection, the hepatitis B virus could become active again during or after treatment of hepatitis C virus with ledipasvir and sofosbuvir tablets. Hepatitis B virus becoming active again (called reactivation) may cause serious liver problems including liver failure and death. Your healthcare provider will monitor you if you are at risk for hepatitis B virus reactivation during treatment and after you stop taking ledipasvir and sofosbuvir tablets.For more information about side effects, see the section "What are the possible side effects of ledipasvir and sofosbuvir tablets?"What are ledipasvir and sofosbuvir tablets?Ledipasvir and sofosbuvir tablets are a prescription medicine used to treat adults with chronic (lasting a long time) hepatitis C virus (HCV):genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosisgenotype 1 infection with advanced cirrhosis (decompensated) in combination with ribaviringenotype 1 or 4 infection without cirrhosis or with compensated cirrhosis who have had a liver transplant, in combination with ribavirinLedipasvir and sofosbuvir tablets are used to treat children 12 years of age and older or weighing at least 77 pounds (at least 35 kg) with chronic HCV genotype 1, 4, 5, or 6 without cirrhosis or with compensated cirrhosis.It is not known if ledipasvir and sofosbuvir tablets are safe and effective in children with HCV under 12 years of age and weighing less than 77 pounds (less than 35 kg), with advanced cirrhosis (decompensated), or who have had a liver transplant.Before taking ledipasvir and sofosbuvir tablets, tell your healthcare provider about all of your medical conditions, including if you: have ever had hepatitis B virus infectionhave liver problems other than hepatitis C infectionhave had a liver transplanthave severe kidney problems or you are on dialysishave HIV infectionare pregnant or plan to become pregnant. It is not known if ledipasvir and sofosbuvir tablets will harm your unborn baby.Males and females who take ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir pass into your breast milk.Talk to your healthcare provider about the best way to feed your baby during treatment with ledipasvir and sofosbuvir tablets.Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Ledipasvir and sofosbuvir tablets and other medicines may affect each other. This can cause you to have too much or not enough ledipasvir and sofosbuvir or other medicines in your body. This may affect the way ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir.Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take ledipasvir and sofosbuvir tablets with other medicines.How should I take ledipasvir and sofosbuvir tablets? Take ledipasvir and sofosbuvir tablets 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 ledipasvir and sofosbuvir tablets without first talking with your healthcare provider.Take 1 ledipasvir and sofosbuvir tablet one time each day and at the same time each day.Take ledipasvir and sofosbuvir tablets with or without food.It is important that you do not miss or skip doses of ledipasvir and sofosbuvir tablets during treatment.If you take too much ledipasvir and sofosbuvir tablets, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of ledipasvir and sofosbuvir tablets?Ledipasvir and sofosbuvir tablets can cause serious side effects, including:Hepatitis B virus reactivation. See "What is the most important information I should know about ledipasvir and sofosbuvir tablets?"Slow heart rate (bradycardia). Ledipasvir and sofosbuvir 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 ledipasvir and sofosbuvir tablets. Get medical help right away if you take amiodarone with ledipasvir and sofosbuvir tablets and get any of the following symptoms:fainting or near-faintingdizziness or lightheadednessnot feeling wellweaknessextreme tirednessshortness of breathchest painsconfusionmemory problemsThe most common side effects of ledipasvir and sofosbuvir tablets include:tirednessheadacheweaknessThese are not all the possible side effects of ledipasvir and sofosbuvir tablets. 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 ledipasvir and sofosbuvir tablets?Store ledipasvir and sofosbuvir tablets at room temperature below 86 °F (30 °C).Keep ledipasvir and sofosbuvir tablets and all medicines out of the reach of children.General information about the safe and effective use of ledipasvir and sofosbuvir tabletsMedicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ledipasvir and sofosbuvir tablets for a condition for which it was not prescribed. Do not give ledipasvir and sofosbuvir tablets to other people, even if they have the same symptoms you have. It may harm them.You can ask your healthcare provider or pharmacist for information about ledipasvir and sofosbuvir tablets that is written for health professionals. What are the ingredients in ledipasvir and sofosbuvir tablets?Active ingredients: ledipasvir and sofosbuvirInactive 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 for:Asegua Therapeutics LLC, an affiliate of Gilead Sciences, Inc., Foster City, CA 94404For more information, call 1-800-445-3235 or go to www.asegua.com.Asegua is a trademark of Asegua Therapeutics LLC. All other trademarks referenced herein are the property of their respective owners.205834-AG-007

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