Lepidipavir sofosbuvir tablets instruction

Date of approval.
Date of revision.
 Lepidipavir Sofosbuvir Tablets Instructions
Please read the instructions carefully and use under the guidance of a doctor
Drug Name
Generic name: Ledipavir Sofosbuvir Tablets
Trade name: Xafanin® Harvoni®
English name: Ledipasvir and Sofosbuvir tablets
Hanyu Pinyin Name: Laidipaiwei Suolinbuwei Pian
Ingredients
This product is a compound preparation, the composition of which is: each tablet contains 90 mg of Ledipasvir and 400 mg of Sofosbuvir.
Sofosbuvir
Chemical name: L-alanine, N-[[P(S),2’R]-2′-deoxy-2′-fluoro-2′-methyl-P-phenyl-5′-uridyl]-, 1-methylethyl ester
Chemical structure formula.
Molecular formula: C22H29FN3O9P
Molecular weight: 529.45
 Ledipavir
Chemical name: carbamic acid,N-[(1S)-1-[[(6S)-6-[5-[9,9-difluoro-7-[2-[(1R,3S,4S)-2-[(2S)-2-[(methylmethyl)amino]-3-methyl-1-oxobutyl]-2-azabicyclo[2.2.1]hept-3-yl]-1H-benzimidazol-6-yl]-9H-fluoren-2- base]-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl]carbonyl]-2-methylpropyl]]-,methyl ester complexed with 2-acetone (1:1) (LDVAS)
Chemical structure formula.
Molecular formula: C52H60F2N8O7
Molecular weight: 947.08 (LDV:889, acetone:58.08)
【Properties】.
This product is an orange film-coated tablet. After removing the coating, it appears off-white.
The tablet is diamond-shaped, with “GSI” engraved on one side and “7985” engraved on the other side.
Indications
This product is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults and adolescents aged 12 to < 18 years (see [Dosage], [Precautions] and [Pharmacology and Toxicology]).
 For hepatitis C virus (HCV) genotype-specific activity, see [Precautions] and [Pharmacologic Toxicology].
Specification
Each tablet contains 90 mg of Ledipavir and 400 mg of Sofosbuvir.
Dosage]
Treatment with this product should be initiated and monitored by a physician with extensive experience in the treatment of patients with chronic HCV infection.
 Dosage
Adults and adolescents 12 to < 18 years of age
 The recommended dose of this product is one tablet once daily with or without food (see [Pharmacokinetics]).
 Table 1: Recommended Duration of Therapy for HCV Genotype 1, 2, 4, 5, or 6 HCV Mono-infection and HCV/HIV-1 Co-infection in Adults and Adolescents (12 to < 18 Years of Age)
 Patient Population
（Adults and adolescents aged 12 years or older with genotype 1, 4, 5, or 6 HCV (including HIV co-infected patients) Treatment and Duration
 Patients without cirrhotic infection 12 weeks Lepidipavir sofosbuvir tablets Treatment.
-For    
For patients with genotype 1 infection who have not received prior treatment, consider
8 weeks of leidipivir sofosbuvir tablets.
 
 
 12 weeks of Ledipasvir sofosbuvir tablets + ribavirin A in patients with compensated cirrhosis
or
24 weeks Ledipasvir sofosbuvir tablets (not combined with ribavirin)
 – For patients considered to be at low risk of clinical disease progression and with options for subsequent retreatment, 12 weeks of ledipasvir sofosbuvir tablets (without ribavirin) may be considered.
 12 weeks of Ledipasvir sofosbuvir tablets + ribavirin A in post-transplant patients without cirrhosis or with compensated cirrhosis
– Consider 12 weeks for patients who are not indicated or intolerant to ribavirin
(in patients without cirrhosis) or 24 weeks (in patients with cirrhosis)
Lepidipavir sofosbuvir tablets (not combined with ribavirin) treatment.
 In patients with decompensated cirrhosis (regardless of graft status) 12 weeks of leidipasvir sofosbuvir tablets + ribavirin B
– 24 weeks may be considered for patients who are unsuitable or intolerant to ribavirin
Lepidipavir sofosbuvir tablets (not in combination with ribavirin) for the treatment of adults with genotype 3 HCV and patients aged 12 years or older
Adult patients with genotype 2 HCV and adolescent patients 12 years of age or older with compensated cirrhosis and/or prior treatment failure 24 weeks Lepidipavir sofosbuvir tablets + ribavirin A. Adult patients with genotype 2 HCV Adult patients with genotype 2 HCV 12 weeks Lepidipavir sofosbuvir tablets A Adult: weight-based ribavirin (< 75 kg = 1,000 mg, ≥ 75 kg = 1,200 mg) kg = 1,200 mg), divided into two doses
orally with food. Adolescents: See Table 3 below for ribavirin dosing recommendations.
 B For ribavirin dosing recommendations in patients with decompensated cirrhosis, see Table 2 below.
 Table 2: Ribavirin dosing recommendations when administered in combination with Ledipavir sofosbuvir tablets to patients with decompensated cirrhosis
 Patient Ribavirin Dose* Pre-transplant Child-Pugh-Turcotte (CPT)
Grade B cirrhosis for patients weighing < 75 kg, a dose of 1,000 mg/day.
For patients weighing ≥ 75 kg, 1,200 mg/day for pre-transplant CPT grade C cirrhosis
 Starting dose of 600 mg for post-transplant CPT grade B or C cirrhosis, with the possibility of upward dose adjustment if well tolerated
Up to 1,000/1,200 mg (for patients weighing < 75 kg, the dose is
1,000 mg for patients weighing ≥ 75 kg; 1,200 mg for patients weighing ≥ 75 kg).
If the starting dose is not well tolerated, the dose should be reduced based on hemoglobin levels as clinically indicated
Dose reduction based on hemoglobin levels* – If a more normalized ribavirin dose (by weight and renal function) cannot be achieved for tolerability reasons, then 24 weeks should be considered
Lederpivir/sofosbuvir + ribavirin therapy to minimize the risk of relapse.
 When combining leidipavir sofosbuvir tablets with ribavirin, please also refer to the instructions for ribavirin.
 For adolescent patients 12 to <18 years of age, the following ribavirin dosing regimen is recommended, with ribavirin doses given twice daily with food.
Table 3. Ribavirin dosing guidelines when administered in combination with lidipavir sofosbuvir tablets to adolescent patients aged 12 to < 18 years
 Body weight kg Ribavirin dose*< 4715 mg/kg/day 47-49600 mg/day 50-65800 mg/day 66-741000 mg/day > or = 751200 mg/day * Ribavirin dose is given orally with food in two divided doses.  
 Dose adjustment for adults taking 1,0001,200 mg of ribavirin daily
If Ledipavir sofosbuvir tablets are used in combination with ribavirin and the patient experiences a serious adverse reaction that may be related to ribavirin, the ribavirin dose should be adjusted or discontinued (if appropriate) until the serious adverse reaction resolves or decreases in severity. Table 4 provides guidelines for dose adjustment and discontinuation based on the patient’s hemoglobin concentration and cardiac function status.
 Table 4: Guidelines for Ribavirin Dose Adjustment in Adults When Combined with Ledipavir Sofosbuvir Tablets
Reduce ribavirin dose to 600 mg/day if laboratory test values: Discontinue ribavirin if: hemoglobin levels in patients without cardiac disease< 10 g/dL< 8.5 g/dL hemoglobin levels in patients with a history of stable cardiac disease have decreased by ≥ 2 g/dL during any 4-week treatment period despite the 4-week treatment Levels < 12 g/dL despite dose reduction during 4 weeks of therapy
 After ribavirin has been discontinued due to abnormal laboratory tests or abnormal clinical presentation, restarting ribavirin at a dose of 600 mg per day and further increasing the dose to 800 mg per day may be attempted; however, increasing ribavirin to the initially assigned dose (1,000 mg to 1,200 mg per day) is not recommended.
 Age < 12 years in children
The safety and efficacy of Ledipavir sofosbuvir tablets have not been established in pediatric patients aged < 12 years.
 Missed Doses
Patients should be instructed to take a replacement tablet if vomiting occurs within 5 hours of dosing. If vomiting occurs after more than 5 hours of administration, no make-up dose is required (see [Pharmacology and Toxicology]).
 If a dose is missed but still within 18 hours of the normal dosing time, the patient should be instructed to take the tablet as soon as possible, after which the patient should take the next dose at the usual dosing time. If more than 18 hours have elapsed, the patient should be instructed to wait until the usual dosing time for the next dose. Patients should be instructed not to take twice the dose.
 Geriatric patients
In elderly patients, no dose adjustment is necessary (see [Pharmacokinetics]).
 Renal Impairment
In patients with mild or moderate renal impairment, no dose adjustment of Ledipavir sofosbuvir tablets is required. The safety of Ledipavir Sofosbuvir Tablets has not been evaluated in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) or end-stage renal disease (ESRD) requiring hemodialysis (see [Pharmacokinetics]).
 Hepatic Impairment
No dose adjustment of Ledipavir sofosbuvir tablets is required for patients with mild, moderate, or severe hepatic impairment (ChildPughTurcotte [CPT] class A, B, or C) (see [Pharmacokinetics]). The safety and efficacy of Ledipavir sofosbuvir tablets in patients with decompensated cirrhosis have not been established (see [Pharmacology and Toxicology]).
 Method of Administration
For oral administration.
 Patients should be instructed to swallow the tablets whole, with or without food. Due to the bitter taste, it is recommended not to chew or crush the film-coated tablets (see [Pharmacokinetics]).
Adverse Reactions]
Summary of adult safety profile from overseas studies
The safety profile of Ledipavir sofosbuvir tablets was evaluated based on pooled data from three overseas phase 3 clinical studies (ION3, ION1, and ION2), which included 215, 539, and 326 patients who received 8, 12, and 24 weeks of Ledipavir sofosbuvir tablets; and 216, 328, and 328 patients who received 8, 12, and 24 weeks of Ledipavir sofosbuvir tablets + ribavirin combination, respectively. 216, 328, and 328 patients receiving 8, 12, and 24 weeks of combination therapy with leidipivir sofosbuvir + ribavirin. These studies did not include any controls who did not receive leidipasvir sofosbuvir tablets. Further data include a double-blind comparison of the safety of leidipivir sofosbuvir tablets (12 weeks) and placebo in 155 patients with cirrhosis (see [Pharmacology and Toxicology]).
 The proportion of patients who permanently discontinued treatment due to adverse events was 0%, < 1%, and 1% in patients receiving 8, 12, and 24 weeks of ledipavir sofosbuvir tablets, respectively, and was < 1%, 0%, and 2% in patients receiving 8, 12, and 24 weeks of ledipavir/sofosbuvir + ribavirin combination therapy, respectively.
 In the clinical study, fatigue and headache were more common in patients treated with ledipavir sofosbuvir tablets than in those receiving placebo. In the study of leidipasvir sofosbuvir tablets in combination with ribavirin, the most common adverse drug reactions to the combination of leidipasvir sofosbuvir tablets + ribavirin were consistent with the known safety profile of ribavirin and did not increase in frequency or severity compared with expectations.
 The following adverse drug reactions have been identified with the use of lidipavir sofosbuvir tablets (Table 5). The adverse reactions are listed below by body system organ and frequency of occurrence. The frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), rare (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), or very rare (< 1/10,000).
 Table 5: Adverse drug reactions found with Harvoni
FrequencyAdverse drug reactionsNeurological disorders: very commonHeadacheDermal and subcutaneous tissue disorders: commonRashUnknown angioedemaSystemic disorders: very commonFatigueLedipavir sofosbuvir tablets in patients with genotype 2, 3, 4, 5, or 6 CHC have a safety profile generally similar to that observed in overseas phase 3 clinical studies.
 Summary of Safety Profile in Chinese Adult Patients with Chronic Genotype 1 HCV Infection
 The safety profile of lidipavir sofosbuvir tablets in Chinese subjects with untreated or treated genotype 1 chronic HCV infection was generally similar to that observed in the overseas phase 3 clinical study.
 For Chinese subjects, the most common treatment-related adverse events (reported in 2/206 subjects (1.0%) each) were nausea, gastroesophageal reflux disease, fatigue, fever, headache, and ALT elevation. No other treatment-related adverse events were reported in more than 1 subject.
 Special Populations
 Adults with decompensated cirrhosis and/or awaiting liver transplantation or post-liver transplantation
The safety profile of adults with decompensated liver disease and/or post-liver transplantation treated with 12 or 24 weeks of Harvoni + ribavirin was determined based on data from two open-label studies (SOLAR1 and SOLAR-2). No new adverse drug reactions were identified in patients with decompensated cirrhosis and/or after liver transplantation and in those receiving lidipavir/sofosbuvir and ribavirin. Although the frequency of adverse events, including serious adverse events, was higher in this study than in those studies excluding patients with decompensated disease and/or after liver transplantation, the adverse events observed were the expected clinical sequelae of advanced liver disease and/or transplantation or were consistent with the known safety profile of ribavirin (for more information on this study, see [Pharmacology and Toxicology]).
 Among patients receiving the combination of ledipavir/sofosbuvir and ribavirin, 39% and 13%, respectively, experienced a decrease in hemoglobin to < 10 g/dL and < 8.5 g/dL during treatment. ribavirin was discontinued in 15% of patients.
 Immunosuppression adjustments were required in 7% of liver transplant patients.
 Pediatric Population
The safety and efficacy of ledipavir sofosbuvir tablets in adolescents aged 12 to < 18 years were determined based on data from a phase 2, open-label clinical trial (Study 1116) enrolling 100 patients with genotype 1 HCV infection treated with 12 weeks of ledipavir sofosbuvir tablets. The adverse reactions observed were consistent with those observed in the adult clinical study of leidipivir sofosbuvir tablets (see Table 5).
 Description of Selected Adverse Reactions
Cardiac Arrhythmias
Cases of severe bradycardia and heart block have been observed when ledipavir/sofosbuvir is combined with amiodarone and/or other drugs that can lower the heart rate (see [Precautions] and [Drug Interactions]).
 Report of suspected adverse reactions
It is important to report suspected adverse reactions after the drug has been marketed. This allows for continuous monitoring of the benefit/risk balance of the use of the drug. In China, healthcare professionals are required to report any suspected adverse reactions through the national reporting system.
Contraindications
Hypersensitivity reactions to the active ingredient or any of the excipients listed below.
 Tablet core: copovidone, lactose monohydrate, microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, colloidal silicon dioxide, magnesium stearate.
Film coating: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, FD&C yellow #6/sunset yellow FCF aluminum precipitate.
 Combined with Rosuvastatin (see [Drug Interactions]).
 Combination with potent P-gp inducers
Intestinal potent P-glycoprotein (P-gp) inducer drugs (rifampin, rifabutin, St. John’s wort [Hypericum perforatum], carbamazepine, phenobarbital, and phenytoin). Co-administration significantly reduces the plasma concentrations of leidipavir and sofosbuvir and may result in a loss of efficacy of leidipavir sofosbuvir tablets (see [Drug Interactions]).
Precautions]
This product should not be used in combination with other drugs containing sofosbuvir.
 Genotype-Specific Activity
For recommended treatment regimens for different HCV genotypes, see Dosage and Administration. For genotype-specific virologic and clinical activity, see [Pharmacology and Toxicology].
 There are limited clinical data supporting the use of leidipavir sofosbuvir tablets in adults infected with genotype 3 HCV. The relative efficacy of a 12-week dosing regimen containing leidipivir sofosbuvir tablets + ribavirin compared with a 24-week dosing regimen of sofosbuvir + ribavirin has not been studied. Conservative treatment for 24 weeks is recommended for all treated genotype 3 patients and for untreated genotype 3 cirrhotic patients. In genotype 3-infected patients, use of Ledipavir sofosbuvir tablets (always in combination with ribavirin) should be considered only in patients who are considered to be at high risk for clinical disease progression and for whom no alternative treatment options are available.
 Clinical data supporting the use of Ledipavir sofosbuvir tablets in adults with HCV genotype 6 infection are limited (see [Pharmacology and Toxicology]).
 Severe bradycardia and heart block
Cases of severe bradycardia and heart block have been observed with the combination of Ledipavir sofosbuvir tablets and amiodarone (with or without other heart rate lowering agents). The mechanism has not been determined.
 Limit co-administration of amiodarone throughout the clinical development of sofosbuvir plus direct-acting antiviral (DAA) drugs. Amiodarone should be used in patients receiving leidipavir sofosbuvir tablets only if other alternative antiarrhythmic therapy is not tolerated or contraindicated due to potentially life-threatening conditions. In patients who are also taking beta-blockers or have underlying cardiac disease and/or advanced liver disease, there may be an increased risk of symptomatic bradycardia when combined with amiodarone.
 If co-administration of amiodarone is deemed necessary, close monitoring of the patient at the time of initiation of treatment with Ledipavir sofosbuvir tablets is recommended.
Patients identified as being at high risk for bradyarrhythmias should be monitored continuously for 48 hours in an appropriate clinical setting and then daily in the clinic or on their own for at least the first 2 weeks of the treatment period.
 Due to the long half-life of amiodarone, appropriate monitoring should also be performed in patients who have discontinued amiodarone within the past few months and are about to start treatment with leidipavir sofosbuvir tablets.
 In addition, all patients receiving ledipasvir sofosbuvir tablets in combination with amiodarone (with or without other heart rate lowering agents) should be reminded of the presence of bradycardia and heart block and should be advised to seek immediate medical attention if they develop such symptoms.
 Treatment of Patients Previously Exposed to HCV Direct-Acting Antivirals
Selection for NS5A resistance mutations that substantially reduce susceptibility to leidipavir has been identified in most cases in patients who have failed treatment with leidipavir sofosbuvir tablets (see Pharmacology). The limited data suggest that such NS5A mutations do not recover during long-term follow-up. There are no data to support the efficacy of retreatment with subsequent regimens containing NS5A inhibitors in patients who have failed treatment with ledipavir/sofosbuvir. Similarly, there are no data to support the effectiveness of NS3/4A protease inhibitors in patients who have failed prior therapy with NS3/4A-containing protease inhibitors. These patients may therefore be dependent on other types of drugs to clear HCV infection. Therefore, longer-term therapy should be considered for patients in whom subsequent retreatment options are uncertain.
 Renal impairment
In patients with mild or moderate renal impairment, no dose adjustment of Ledipavir sofosbuvir tablets is required. The safety of Ledipavir sofosbuvir tablets has not been evaluated in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) or in patients with end-stage renal disease (ESRD) requiring hemodialysis. For patients with creatinine clearance (CrCl) < 50 mL/min, see also the prescribing information for ribavirin (see [Pharmacokinetics]) when combining Ledipasvir sofosbuvir Tablets with ribavirin.
 Adults with decompensated cirrhosis and/or awaiting liver transplantation or after liver transplantation
The efficacy of Ledipavir sofosbuvir tablets has not been studied in patients with genotype 5 and genotype 6 HCV infection in decompensated cirrhosis and/or awaiting liver transplantation or after liver transplantation. Treatment with Ledipavir sofosbuvir tablets should be guided by an individual patient assessment of potential benefit and risk.
 Combination with Moderate P-gp Inducers
Enteral moderate Pgp-inducing agents such as oxcarbazepine may reduce the efficacy of Ledipavir sofosbuvir tablets by decreasing the plasma concentration of Ledipavir and sofosbuvir. Combining these drugs with Ledipavir sofosbuvir Tablets is not recommended (see Drug Interactions).
 Use in combination with specific HIV antiretroviral regimens
Ledipavir sofosbuvir tablets have been shown to increase tenofovir exposure, especially when used in combination with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic booster (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate has not been established in the context of the use of letdipavir sofosbuvir tablets with a pharmacokinetic booster. The potential risks and benefits of combining ledipavir sofosbuvir tablets with a fixed-dose combination tablet containing everolimus/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate with an enhanced HIV protease inhibitor (e.g., atazanavir or dirinavir) should be considered, particularly in patients at increased risk of renal insufficiency. Patients receiving leidipavir sofosbuvir tablets in combination with everolimus/cobicistat/emtricitabine/tenofovir disoproxil fumarate or in combination with tenofovir disoproxil fumarate and an enhanced HIV protease inhibitor should be monitored for adverse reactions associated with tenofovir. See Tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxil fumarate, or everolimus/cobicistat/emtricitabine/tenofovir disoproxil fumarate prescribing information for recommendations on renal monitoring.
 Combination with HMG-CoA reductase inhibitors
The combination of Ledipavir sofosbuvir tablets with HMGCoA reductase inhibitors (statins) can significantly increase statin concentrations, thereby increasing the risk of myopathy and rhabdomyolysis (see [Drug Interactions]).
 HCV/HBV (hepatitis B virus) co-infection
Cases of hepatitis B virus (HBV) reactivation, including some fatal cases, have been reported during or after treatment with direct-acting antivirals. Patients with HBV/HCV co-infection are at risk for HBV reactivation and should be monitored and managed according to current clinical guidelines.
 Pediatric population
Ledipavir sofosbuvir tablets are not recommended for pediatric patients age < 12 years because the safety and efficacy of the drug in this population have not been established.
 Excipients
Ledipavir sofosbuvir tablets contain the nitrogen coloring agent sunset yellow FCF aluminum precipitate (E110), which may cause allergic reactions. It also contains lactose. Therefore, patients with galactose intolerance, Lapp lactase deficiency or a rare genetic problem of glucose-galactose malabsorption should not take this drug.
For pregnant and lactating women]
Contraception for women of childbearing age/men and women
Extreme caution must be exercised when Lepidipavir sofosbuvir tablets are used in combination with ribavirin to avoid pregnancy in female patients and female partners of male patients. Significant teratogenic and/or embryonic effects have been demonstrated in all animal species exposed to ribavirin. Females of childbearing potential and their male partners must use effective contraception as recommended in the ribavirin prescribing information during and for some time after treatment. For additional information, see the Prescribing Information for Ribavirin.
 Pregnancy
There are no or very limited data on the use of ledipavir, sofosbuvir, or ledipavir sofosbuvir tablets in pregnant women (fewer than 300 pregnancy outcomes).
 Animal studies have not demonstrated direct adverse effects in terms of reproductive toxicity. No significant effects on fetal development have been observed in rats and rabbits using either leidipavir or sofosbuvir. However, it is not possible to adequately estimate the boundary ratio of sofosbuvir exposure achieved in rats relative to human exposure at recommended clinical doses (see [Pharmacologic Toxicology]).
 As a precautionary measure, it is best not to use Ledipavir sofosbuvir tablets during pregnancy.
 Lactation
It is not known whether leidipavir or sofosbuvir and its metabolites are excreted into human breast milk. Risks to the newborn/infant cannot be excluded. Therefore, leidipavir/sofosbuvir should not be used during breast-feeding.
 Animal pharmacokinetic data indicate that the metabolites of Ledipavir and Sofosbuvir are secreted into breast milk (see [Pharmacology and Toxicology]).
 Fertility
No data are available on the effect of leidipavir sofosbuvir tablets on human fertility. Animal studies have not shown harmful effects of either ledipavir or sofosbuvir on fertility.
 If ribavirin is used in combination with Ledipavir Sofosbuvir Tablets, the same contraindications to the use of ribavirin during pregnancy and breast-feeding apply (see also Ribavirin Prescribing Information).
Pediatric Use]
The safety and efficacy of Ledipavir sofosbuvir tablets in pediatric patients aged 12 years have not been established. No data are available for pediatric patients aged 12 years.
Geriatric Use]
A population pharmacokinetic analysis in HCV-infected patients showed no clinically relevant effect of age on exposure to ledipavir, sofosbuvir and GS-331007 in the age range analyzed (18 to 80 years). The overseas clinical study of leidipavir sofosbuvir tablets included 235 subjects aged 65 years and older.
Drug Interactions]
Since Ledipavir Sofosbuvir Tablets contain both Ledipavir and Sofosbuvir, any interactions found with these active ingredients alone may occur with the use of Ledipavir Sofosbuvir Tablets.
 Potential for Ledipavir Sofosbuvir Tablets to Affect Other Drugs
Ledipavir is an in vitro inhibitor of the drug transporters Pgp and breast cancer resistance protein (BCRP) and may increase the intestinal absorption of co-administered substrates of these transporters.
 Potential for Other Drugs to Affect Ledipavir Sofosbuvir Tablets
Ledipavir and sofosbuvir are substrates of the drug transporters Pgp and BCRP, while GS331007 is not.
 Potent P-gp inducers (rifampicin, rifabutin, St. John’s wort, carbamazepine, phenobarbital, and phenytoin) may significantly reduce the plasma concentrations of leidipavir and sofosbuvir, resulting in reduced efficacy of leidipavir sofosbuvir tablets, and should therefore be contraindicated with the use of leidipavir sofosbuvir tablets (see [Contraindications]). Moderate enteral Pgp inducers (e.g., oxcarbazepine) may reduce the efficacy of Ledipavir sofosbuvir Tablets by decreasing the plasma concentration of Ledipavir and sofosbuvir. Combination of these drugs is not recommended with Ledipavir sofosbuvir tablets (see [Precautions]). Combination with drugs that inhibit P-gp and/or BCRP may increase plasma concentrations of Ledipavir and sofosbuvir, but not GS331007; Ledipavir sofosbuvir tablets may be combined with P-gp and/or BCRP inhibitors. Clinically significant drug interactions mediated by CYP450 or UGT1A1 enzymes are not anticipated with Ledipavir sofosbuvir tablets.
 Patients treated with vitamin K antagonists
Close monitoring of the International Normalized Ratio (INR) is recommended due to possible changes in liver function during treatment with Ledipasvir Sofosbuvir Tablets.
 Interactions between Ledipavir Sofosbuvir Tablets and other drugs
Table 6 provides a list of drug interactions that have been identified or are likely to be clinically significant (where the 90% confidence interval [CI] for the geometric mean least squares [GLSM] ratio is labeled as follows: within a predefined equivalence threshold “↔”, above this range “↑” or below this range “↓”). The drug-drug interactions described are based on studies conducted with Ledipavir Sofosbuvir Tablets or Ledipavir and Sofosbuvir as separate drugs, or on possible drug-drug interactions predicted with the use of Ledipavir Sofosbuvir Tablets. This table is not exhaustive.
 Table 6: Interactions between Ledipavir Sofosbuvir Tablets and Other Drugs
Effect of drugs on drug levels by therapeutic area.
Mean ratios (90% confidence interval) for AUC, Cmax, Cmina, b Suggested acidulants for combination with Ledipavir Sofosbuvir Tablets The solubility of Ledipavir decreases with increasing pH. Drugs that increase the pH in the stomach are expected to decrease the concentration of leidipavir. Antacids such as aluminum hydroxide or magnesium hydroxide; calcium carbonate have not been studied for interaction.
Expected to.
↓ Ledipavir
↔ Sofosbuvir
↔ GS331007
 (elevated intragastric pH) Separate administration of antacids and leidipavir sofosbuvir tablets at 4-hour intervals is recommended. H2 receptor antagonist Famotidine
(40 mg single dose)/ledipavir (90 mg single dose)c/sofosbuvir (400 mg single dose)c, d
 Famotidine administered concomitantly with Harvonid
 
 Cimetidine e
Nizatidine e
Ranitidine e Ledipavir
↓ Cmax 0.80 (0.69, 0.93)
↔ AUC 0.89 (0.76, 1.06)
 Sofosbuvir
↑ Cmax 1.15 (0.88, 1.50)
↔ AUC 1.11 (1.00, 1.24)
 GS331007
↔ Cmax 1.06 (0.97, 1.14)
↔ AUC 1.06 (1.02, 1.11)
 (Increased intragastric pH) H2 receptor antagonists may be administered concurrently with or staggered with levidipavir sofosbuvir tablets, but not in doses greater than 40 mg of famotidine twice daily. Famotidine
(40 mg single dose)/Ledipivir (90 mg single dose)c/Sofosbuvir (400 mg single dose)c, d
 Famotidine given 12 hours prior to Harvoni dosingd Ledipavir
↓ Cmax 0.83 (0.69, 1.00)
↔ AUC 0.98 (0.80, 1.20)
 Sofosbuvir
Sofosbuvir ↔ Cmax 1.00 (0.76, 1.32)
Sofosbuvir ↔ AUC 0.95 (0.82, 1.10)
 GS331007.
GS331007 ↔ Cmax 1.13 (1.07, 1.20)
↔ AUC 1.06 (1.01, 1.12)
 (elevated intragastric pH) Proton pump inhibitor Omeprazole
(20 mg once daily) / Ledipavir (90 mg single dose)c / Sofosbuvir (400 mg single dose)c
 Omeprazole administered concomitantly with Harvoni
 Lansoprazolee
Rabeprazolee
Pantoprazolee
Esomeprazolee Ledipavir
↓ Cmax 0.89 (0.61, 1.30)
↓ AUC 0.96 (0.66, 1.39)
 Sofosbuvir
Sofosbuvir ↔ Cmax 1.12 (0.88, 1.42)
Sofosbuvir ↔ AUC 1.00 (0.80, 1.25)
 GS331007.
↔ Cmax 1.14 (1.01, 1.29)
↔ AUC 1.03 (0.96, 1.12)
 (elevated intragastric pH) Proton pump inhibitors comparable to omeprazole 20 mg doses may be administered concomitantly with Ledipavir sofosbuvir tablets. Proton pump inhibitors should not be administered prior to the administration of Ledipavir Sofosbuvir Tablets. Interactions have not been studied with the antiarrhythmic drug amiodarone. Use only if no other alternative medication is available. Close monitoring is recommended if this drug is used in combination with Ledipavir Sofosbuvir Tablets (see [Precautions] and [Adverse Reactions]). Digoxin has not been studied for interactions.
Expected.
↑ Digoxin
↔ Ledipavir
↔ Sofosbuvir
↔ GS331007
 (Pgp inhibition) Ledipavir sofosbuvir tablets in combination with digoxin may increase digoxin concentrations. Caution should be exercised when combining Ledipavir sofosbuvir tablets with digoxin and monitoring of therapeutic concentrations of digoxin is recommended. Interactions have not been studied with the anticoagulant dabigatranate.
Expected.
↑ Dabigatran
↔ Ledipavir
↔ Sofosbuvir
↔ GS331007
 (Pgp inhibition) Clinical monitoring is recommended when dabigatran ester is used in combination with leidipavir sofosbuvir tablets to look for signs of bleeding and anemia. Coagulation testing can help identify patients at increased risk of bleeding due to increased dabigatran exposure. Vitamin K Antagonists Not Studied Interactions Close monitoring of the INR is recommended when combining with all vitamin K antagonists. The reason for this is that liver function may change during treatment with leidipavir sofosbuvir tablets. Anticonvulsants Carbamazepine
Phenobarbital
Phenytoin Interactions were not studied.
Expected.
↓ Ledipavir
↓ sofosbuvir
↔ GS331007
 (Pgp induction) Combination of Ledipavir sofosbuvir tablets with carbamazepine, phenobarbital, and phenytoin (potent enteral Pgp inducers) is prohibited (see [Contraindications]). Oxcarbazepine has not been studied for interaction.
Expected.
↓ Ledipavir
↓ sofosbuvir
↔ GS331007
 (Pgp induction) Combination of Ledipavir Sofosbuvir Tablets with oxcarbazepine is expected to decrease the concentration of Ledipavir and Sofosbuvir, resulting in decreased efficacy of Ledipavir Sofosbuvir Tablets. Such combinations are not recommended (see [Precautions]). The interaction of the antibranchial drug rifampicin (600 mg once daily)/leldipavir (90 mg single dose)d was not studied.
Expected.
Rifampicin
↔ Cmax
↔ AUC
Cmin ↔ Cmin
 Observation.
Raltegravir
↓ Cmax 0.65 (0.56, 0.76)
↓ AUC 0.41 (0.36, 0.48)
 (Pgp induction) Combination of eldapivir sofosbuvir tablets with rifampin, a potent enteric P-gp inducer, is prohibited (see [Contraindications]). Rifampin (600 mg once daily)/sofosbuvir (400 mg single dose)d interaction not studied.
Expected.
Rifampicin
↔ Cmax
↔ AUC
Cmin ↔ Cmin
 Observation.
Sofosbuvir
↓ Cmax 0.23 (0.19, 0.29)
↓ AUC 0.28 (0.24, 0.32)
 GS331007
↔ Cmax 1.23 (1.14, 1.34)
↔ AUC 0.95 (0.88, 1.03)
 (Pgp induction) Rifabutin
Rifapentine interactions were not studied.
Expected.
↓ Ledipavir
↓ sofosbuvir
↔ GS331007
(Pgp induction)
 
 
 Combination of eldipavir sofosbuvir tablets with rifabutin, a potent intestinal P-gp inducer, is prohibited (see [Contraindications]).
 The combination of Ledipavir sofosbuvir tablets with rifapentine is expected to decrease the concentration of Ledipavir and sofosbuvir, resulting in a decrease in the efficacy of Ledipavir sofosbuvir tablets. Such combinations are not recommended. Sedative/sleeping medication midazolam (2.5 mg, single dose)/Ledipipavir (90 mg/single dose)
 
 
 Lederpivir (90 mg once daily) Observation.
Midazolam
↔ Cmax 1.07 (1.00, 1.04)
↔ AUC 0.09 (0.95, 1.04)
(CYP3A inhibitor)
 Midazolam.
Cmax 0.95 (0.87, 1.04) ↔ Cmax 0.95 (0.87, 1.04)
↔ AUC 0.89 (0.84, 0.95)
(CYP3A inhibitors)
 Expected.
↔ Sofosbuvir.
↔ GS331007 No dose adjustment for leidipivir sofosbuvir tablets or midazolam required. hcv product simeprevir (150 mg once daily)/leidiprevir (30 mg once daily) simeprevir
↑ Cmax 2.61 (2.39, 2.86)
↑ AUC 2.69 (2.44, 2.96)
 Ledipavir
↑ Cmax 1.81 (1.69, 2.94)
↑ AUC 1.92 (1.77, 2.07) When simeprevir was combined with ledipavir/sofosbuvir tablets, the concentrations of ledipavir, sofosbuvir and simeprevir were increased. Combined use is not recommended. Simeprevir h Simeprevir
↔ Cmax 0.96 (0.71, 1.30)
↔ AUC 0.94 (0.67, 1.33)
 Sofosbuvir
↑ Cmax 1.91 (1.26, 2.90)
↑ AUC 3.16 (2.25, 4.44)
 GS331007
↓ Cmax 0.69 (0.52, 0.93)
↔ AUC 1.09 (0.87, 1.37) HIV antivirals: reverse transcriptase inhibitors efavirenz/emtricitabine/tenofovir disoproxil fumarate
(600 mg/200 mg/300 mg/daily)/ledipavir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d efavirenz
↔ Cmax 0.87 (0.79, 0.97)
↔ AUC 0.90 (0.84, 0.96)
Cmin 0.91 (0.83, 0.99) ↔ Cmin 0.91 (0.83, 0.99)
 Emtricitabine.
Cmax 1.08 (0.97, 1.21) ↔ Cmax 1.08 (0.97, 1.21)
↔ AUC 1.05 (0.98, 1.11)
Cmin 1.04 (0.98, 1.11) ↔ Cmin 1.04 (0.98, 1.11)
 Tenofovir
↑ Cmax 1.79 (1.56, 2.04)
↑ AUC 1.98 (1.77, 2.23)
↑ Cmin 2.63 (2.32, 2.97)
 Ledipavir
↓ Cmax 0.66 (0.59, 0.75)
↓ AUC 0.66 (0.59, 0.75)
↓ Cmin 0.66 (0.57, 0.76)
 Sofosbuvir
Sofosbuvir ↔ Cmax 1.03 (0.87, 1.23)
↔ AUC 0.94 (0.81, 1.10)
 GS331007.
GS331007 ↔ Cmax 0.86 (0.76, 0.96)
GS331007 ↔ AUC 0.90 (0.83, 0.97)
↔ Cmin 1.07 (1.02, 1.13) No dose adjustment for leidipavir sofosbuvir tablets or efavirenz/emtricitabine/tenofovir disoproxil fumarate is required. Emtricitabine/ rilpivirine/ tenofovir disoproxil fumarate
(200 mg/ 25 mg/ 300 mg once daily)/ Ledipavir (90 mg once daily)c/ Sofosbuvir (400 mg once daily)c, d Emtricitabine
↔ Cmax 1.02 (0.98, 1.06)
↔ AUC 1.05 (1.02, 1.08)
Cmin 1.06 (0.97, 1.15) ↔ Cmin 1.06 (0.97, 1.15)
 Rilpivirine.
Ripivirine ↔ Cmax 0.97 (0.88, 1.07)
Ripivirine ↔ AUC 1.02 (0.94, 1.11)
Ripivirine ↔ Cmin 1.12 (1.03, 1.21)
 Tenofovir.
↔ Cmax 1.32 (1.25, 1.39)
↑ AUC 1.40 (1.31, 1.50)
↑ Cmin 1.91 (1.74, 2.10)
 Ledipavir
↔ Cmax 1.01 (0.95, 1.07)
Ledipavir ↔ AUC 1.08 (1.02, 1.15)
Lepidipavir ↔ Cmin 1.16 (1.08, 1.25)
 Sofosbuvir.
Sofosbuvir ↔ Cmax 1.05 (0.93, 1.20)
Sofosbuvir ↔ AUC 1.10 (1.01, 1.21)
 GS331007.
↔ Cmax 1.06 (1.01, 1.11)
GS331007 ↔ AUC 1.15 (1.11, 1.19)
↔ Cmin 1.18 (1.13, 1.24) No dose adjustment for Ledipavir sofosbuvir tablets or emtricitabine/ribivirine/tenofovir disoproxil fumarate is required. Abacavir/Lamivudine
(600 mg/ 300 mg once daily)/Ledipavir (90 mg once daily)c/ Sofosbuvir (400 mg once daily)c, d Abacavir
↔ Cmax 0.92 (0.87, 0.97)
↔ AUC 0.90 (0.85, 0.94)
 Lamivudine.
Lamivudine ↔ Cmax 0.93 (0.87, 1.00)
Lamivudine ↔ AUC 0.94 (0.90, 0.98)
Lamivudine ↔ Cmin 1.12 (1.05, 1.20)
 Ledipavir.
Ledipavir ↔ Cmax 1.10 (1.01, 1.19)
Ledipavir ↔ AUC 1.18 (1.10, 1.28)
Lepidipavir ↔ Cmin 1.26 (1.17, 1.36)
 Sofosbuvir.
Sofosbuvir ↔ Cmax 1.08 (0.85, 1.35)
Sofosbuvir ↔ AUC 1.21 (1.09, 1.35)
 GS331007.
GS331007 ↔ Cmax 1.00 (0.94, 1.07)
GS331007 ↔ AUC 1.05 (1.01, 1.09)
HIV antivirals: HIV protease inhibitor atazanavir augmented by ritonavir (300 mg/100 mg once daily) ↔ Cmin 1.08 (1.01, 1.14) ↔ No dose adjustment required for lidipavir sofosbuvir tablets or abacavir/lamivudine.
(300 mg/ 100 mg once daily)/ledipavir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d atazanavir
↔ Cmax 1.07 (1.00, 1.15)
↔ AUC 1.33 (1.25, 1.42)
↑ Cmin 1.75 (1.58, 1.93)
 Ledipavir
↑ Cmax 1.98 (1.78, 2.20)
↑ AUC 2.13 (1.89, 2.40)
↑ Cmin 2.36 (2.08, 2.67)
 Sofosbuvir
Sofosbuvir ↔ Cmax 0.96 (0.88, 1.05)
↔ AUC 1.08 (1.02, 1.15)
 GS331007.
↔ Cmax 1.13 (1.08, 1.19)
GS331007 ↔ AUC 1.23 (1.18, 1.29)
↔ Cmin 1.28 (1.21, 1.36) No dose adjustment for leidipavir sofosbuvir tablets or atazanavir (boosted by ritonavir) is required.
 See below for more information on the combination of tenofovir/emtricitabine + atazanavir/ritonavir. atazanavir (300 mg/100 mg once daily) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg once daily)/ledipavir (90 mg once daily)c/sofosbuvir (400 mg once daily)c, d as boosted by ritonavir
 Concurrent administrationf of atazanavir
↔ Cmax 1.07 (0.99, 1.14)
↔ AUC 1.27 (1.18, 1.37)
↑ Cmin 1.63 (1.45, 1.84)
 Ritonavir.
Ritonavir ↔ Cmax 0.86 (0.79, 0.93)
↔ AUC 0.97 (0.89, 1.05)
↑ Cmin 1.45 (1.27, 1.64)
 Emtricitabine
↔ Cmax 0.98 (0.94, 1.02)
↔ AUC 1.00 (0.97, 1.04)
Cmin 1.04 (0.96, 1.12) ↔ Cmin 1.04 (0.96, 1.12)
 Tenofovir
↑ Cmax 1.47 (1.37, 1.58)
↔ AUC 1.35 (1.29, 1.42)
↑ Cmin 1.47 (1.38, 1.57)
 Ledipavir
↑ Cmax 1.68 (1.54, 1.84)
↑ AUC 1.96 (1.74, 2.21)
↑ Cmin 2.18 (1.91, 2.50)
 Sofosbuvir
Sofosbuvir ↔ Cmax 1.01 (0.88, 1.15)
↔ AUC 1.11 (1.02, 1.21)
 GS331007.
↔ Cmax 1.17 (1.12, 1.23)
↔ AUC 1.31 (1.25, 1.36)
↑ Cmin 1.42 (1.34, 1.49) If tenofovir disoproxil fumarate is co-administered with atazanavir/ritonavir, eldipivir/sofosbuvir tablets will increase tenofovir concentrations.
 The safety of tenofovir disoproxil fumarate has not been established in the context of the use of ledipavir sofosbuvir tablets with a pharmacokinetic enhancer such as ritonavir or cobicistat.
 This combination should be used with caution and frequent renal monitoring if no other treatment options are available (see [Precautions].)
 Atazanavir concentrations are also elevated and are associated with increased bilirubin levels/risk of jaundice. This risk is higher if ribavirin is used as part of HCV therapy. Ritonavir-boosted dirinavir
(800 mg/ 100 mg once daily) / Ledipavir (90 mg once daily) dirinavir
↔ Cmax 1.02 (0.88, 1.19)
↔ AUC 0.96 (0.84, 1.11)
Cmin 0.97 (0.86, 1.10) ↔ Cmin 0.97 (0.86, 1.10)
 Ledipavir.
↑ Cmax 1.45 (1.34, 1.56)
↑ AUC 1.39 (1.28, 1.49)
↑ Cmin 1.39 (1.29, 1.51) No dose adjustment for leidipavir sofosbuvir tablets or dirinavir (boosted by ritonavir) is required.
 See below for more information on the combination of tenofovir/emtricitabine + dirinavir/ritonavir. Ritonavir-Enhanced Dirinavir
(800 mg/ 100 mg once daily)/sofosbuvir (400 mg once daily) Dirinavir
↔ Cmax 0.97 (0.94, 1.01)
↔ AUC 0.97 (0.94, 1.00)
Cmin 0.86 (0.78, 0.96) ↔ Cmin 0.86 (0.78, 0.96)
 Sofosbuvir
↑ Cmax 1.45 (1.10, 1.92)
↑ AUC 1.34 (1.12, 1.59)
 GS331007
↔ Cmax 0.97 (0.90, 1.05)
↔ AUC 1.24 (1.18, 1.30) trans-ritonavir-boosted dirinavir (800 mg/100 mg once daily) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg once daily)/letidipavir (90 mg once daily)c/sofosbuvir (400 mg once daily)c, d
 Concurrent administration of f-dirinavir
↔ Cmax 1.01 (0.96, 1.06)
↔ AUC 1.04 (0.99, 1.08)
Cmin 1.08 (0.98, 1.20) ↔ Cmin 1.08 (0.98, 1.20)
 Ritonavir.
Ritonavir ↔ Cmax 1.17 (1.01, 1.35)
↔ AUC 1.25 (1.15, 1.36)
↑ Cmin 1.48 (1.34, 1.63)
 Emtricitabine
↔ Cmax 1.02 (0.96, 1.08)
↔ AUC 1.04 (1.00, 1.08)
Cmin 1.03 (0.97, 1.10) ↔ Cmin 1.03 (0.97, 1.10)
 Tenofovir
↑ Cmax 1.64 (1.54, 1.74)
↑ AUC 1.50 (1.42, 1.59)
↑ Cmin 1.59 (1.49, 1.70)
 Ledipavir
↔ Cmax 1.11 (0.99, 1.24)
Ledipavir ↔ AUC 1.12 (1.00, 1.25)
Lepidipavir ↔ Cmin 1.17 (1.04, 1.31)
 Sofosbuvir
↓ Cmax 0.63 (0.52, 0.75)
↓ AUC 0.73 (0.65, 0.82)
 GS331007
↔ Cmax 1.10 (1.04, 1.16)
GS331007 ↔ AUC 1.20 (1.16, 1.24)
↔ Cmin 1.26 (1.20, 1.32) If combined with ledipavir sofosbuvir tablets on top of dirinavir/ritonavir co-administered with tenofovir disoproxil fumarate, ledipavir sofosbuvir tablets will increase tenofovir concentrations.
 The safety of tenofovir disoproxil fumarate has not been established in the setting of the use of ledipavir sofosbuvir tablets with a pharmacokinetic enhancer such as ritonavir or cobicistat.
 This combination should be used with caution and frequent renal monitoring if no other treatment options are available (see [Precautions]). Lopinavir + emtricitabine/tenofovir disoproxil fumarate enhanced by ritonavir was not studied for interaction.
Expected.
↑ Lopinavir
↑ Ritonavir
 ↔ Emtricitabine
↑ Tenofovir
 ↑ Ledipavir
↔ Sofosbuvir
↔ GS331007 If combined with lopinavir/ritonavir and tenofovir disoproxil fumarate coadministered on top of leidipivir sofosbuvir tablets, leidipivir sofosbuvir tablets would be expected to increase tenofovir concentrations.
 The safety of tenofovir disoproxil fumarate in the context of the use of ledipavir sofosbuvir tablets with a pharmacokinetic enhancer such as ritonavir or cobicistat has not been established.
 This combination should be used with caution and frequent renal monitoring if no other treatment options are available (see [Precautions]). Interactions have not been studied with ritonavir-boosted tipranavir.
Expected.
↓ Ledipavir
↓ sofosbuvir
↔ GS331007
 (Pgp induction) Combination of Ledipavir sofosbuvir tablets with tipranavir (boosted with ritonavir) is expected to decrease the concentration of Ledipavir, resulting in decreased efficacy of Ledipavir sofosbuvir tablets. HIV antivirals: the integrase inhibitor raltegravir
(400 mg twice daily)/ledipavir (90 mg once daily)d raltegravir
↓ Cmax 0.82 (0.66, 1.02)
↔ AUC 0.85 (0.70, 1.02)
↑ Cmin 1.15 (0.90, 1.46)
 Ledipavir.
Lepidipavir ↔ Cmax 0.92 (0.85, 1.00)
Ledipavir ↔ AUC 0.91 (0.84, 1.00)
Lepidipavir ↔ Cmin 0.89 (0.81, 0.98) No dose adjustment is required for either Lepidipavir sofosbuvir tablets or raltegravir. Raltegravir
(400 mg twice daily)/sofosbuvir (400 mg once daily)d raltegravir
↓ Cmax 0.57 (0.44, 0.75)
↓ AUC 0.73 (0.59, 0.91)
↔ Cmin 0.95 (0.81, 1.12)
 Sofosbuvir
Sofosbuvir ↔ Cmax 0.87 (0.71, 1.08)
Sofosbuvir ↔ AUC 0.95 (0.82, 1.09)
 GS331007.
GS331007 ↔ Cmax 1.09 (0.99, 1.19)
GS331007 ↔ AUC 1.02 (0.97, 1.08) Elvitegravir/cobicistat/emtricitabine/propofol tenofovir (150 mg/150 mg/200 mg/10 mg once daily)/letidipavir (90 mg once daily)c/sofosbuvir (400 mg once daily)c
Observations: everolimus ↔ Cmax 0.98 (0.90, 1.07) ↔ AUC 1.11 (1.02, 1.20) ↑ Cmin 1.46 (1.28, 1.66) cobicistat ↔ Cmax 1.23 (1.15, 1.32) ↑ AUC 1.53 (1.45, 1.62) ↑ Cmin 3.25 (2.88, 3.67 ) Emtricitabine ↔ Cmax 1.03 (0.96, 1.11) ↔ AUC 0.97 (0.93, 1.00) ↔ Cmin 0.95 (0.91, 0.99) Propofol tenofovir ↑ Cmax 0.90 (0.73, 1.11) ↑ AUC 0.86 (0.78, 0.95) Ledipavir ↑ Cmax 1.65 (1.53, 1.78)↑ AUC 1.79 (1.64, 1.96)↑ Cmin 1.93 (1.74, 2.15)Sofosbuvir ↑ Cmax 1.28 (1.13, 1.47)↑ AUC 1.47 (1.35, 1.59)GS-331007 ↑ Cmax 1.29 (1.24, 1.35)↑ AUC 1.48 (1.44, 1.53)↑ Cmin 1.66 (1.60, 1.73) No dose adjustment for levidipamivir sofosbuvir tablets or everolimus/cobicistat/emtricitabine/propofol tenofovir was required. Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate
(150 mg/ 150 mg/ 200 mg/ 300 mg once daily)/Ledipipavir (90 mg once daily)c/ Sofosbuvir (400 mg once daily)c Interactions were not studied.
Expected.
↔ Emtricitabine
↑ Tenofovir
 Observed results.
Efavirevir
↔ Cmax 0.88 (0.82, 0.95)
↔ AUC 1.02 (0.95, 1.09)
↑ Cmin 1.36 (1.23, 1.49)
 Cobicistat.
↔ Cmax 1.25 (1.18, 1.32)
↑ AUC 1.59 (1.49, 1.70)
↑ Cmin 4.25 (3.47, 5.22)
 Ledipavir
↑ Cmax 1.63 (1.51, 1.75)
↑ AUC 1.78 (1.64, 1.94)
↑ Cmin 1.91 (1.76, 2.08)
 Sofosbuvir
↑ Cmax 1.33 (1.14, 1.56)
↑ AUC 1.36 (1.21, 1.52)
 GS331007
↑ Cmax 1.33 (1.22, 1.44)
↑ AUC 1.44 (1.41, 1.48)
↑ Cmin 1.53 (1.47, 1.59) In combination with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate, eredipavir sofosbuvir tablets are expected to increase tenofovir concentrations.
 The safety of tenofovir disoproxil fumarate has not been established in the context of the use of ledipavir sofosbuvir tablets with a pharmacokinetic enhancer such as ritonavir or cobicistat.
 This combination should be used with caution and frequent renal monitoring if no other treatment options are available (see [Precautions]). Dortilavir
(50 mg once daily) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg once daily)/letidipavir (90 mg once daily)c/sofosbuvir (400 mg once daily)c Dotiravir
↔ Cmax 1.15 (1.07, 1.23)
↔ AUC 1.13 (1.06, 1.20)
Cmin 1.13 (1.06, 1.21) ↔ Cmin 1.13 (1.06, 1.21)
 Emtricitabine.
Cmax 1.02 (0.95, 1.08) ↔ Cmax 1.02 (0.95, 1.08)
Emtricitabine ↔ AUC 1.07 (1.04, 1.10)
Cmin 1.05 (1.02, 1.09) ↔ Cmin 1.05 (1.02, 1.09)
 Tenofovir
↑ Cmax 1.61 (1.51, 1.72)
↑ AUC 1.65 (1.59, 1.71)
↑ Cmin 2.15 (2.05, 2.26)
 Ledipavir
↑ Cmax 0.85 (0.81, 0.90)
↑ AUC 0.89 (0.84, 0.95)
↑ Cmin 0.89 (0.84, 0.95)
 Sofosbuvir
↑ Cmax 1.06 (0.92, 1.21)
↑ AUC 1.09 (1.00, 1.19)
 GS331007
↑ Cmax 0.99 (0.95, 1.03)
↑ AUC 1.06 (1.03, 1.09)
↑ Cmin 1.06 (1.03, 1.09) No dose adjustment required. Dortilavir interactions were not studied.
Expected.
↔ Dortilavir
↔ Ledipavir
↔ Sofosbuvir
↔ GS331007 does not require dose adjustment. Interactions were not studied for the herbal supplement St. John’s Wort.
Expected.
↓ Ledipavir
↓ Sofosbuvir
↔ GS331007
 (Pgp induction) Ledipavir/sofosbuvir is prohibited in combination with St. John’s wort, a potent enteric Pgp inducer (see [Contraindications]). HMG-CoA reductase inhibitor risulvastating ↑ risulvastatin
 (inhibition of drug transporters OATP and BCRP) Ledipivir sofosbuvir tablets in combination with resulvastatin significantly increases the concentration of resulvastatin (multifold increase in AUC), which is associated with an increased risk of myopathy, including rhabdomyolysis. Combination of lidipivir sofosbuvir tablets with resulvastatin is prohibited (see [Contraindications]). Pravastatin g↑ Pravastatin does not require dose adjustment for either Ledipavir sofosbuvir tablets or pravastatin. Other statins are expected to.
↑ No dose adjustment is required for statins for ledipivir sofosbuvir tablets or other statins. Narcotic analgesic methadone was not studied for interaction.
Expected.
↔ No dose adjustment for Ledipavir sofosbuvir tablets or methadone is required for Ledipavir sofosbuvir. Methadone
(methadone maintenance [30 to 130 mg/day])/sofosbuvir (400 mg once daily) dR methadone
↔ Cmax 0.99 (0.85, 1.16)
↔ AUC 1.01 (0.85, 1.21)
Cmin 0.94 (0.77, 1.14) ↔ Cmin 0.94 (0.77, 1.14)
 S methadone
S methadone ↔ Cmax 0.95 (0.79, 1.13)
S methadone ↔ AUC 0.95 (0.77, 1.17)
S methadone ↔ Cmin 0.95 (0.74, 1.22)
 Sofosbuvir
↓ Cmax 0.95 (0.68, 1.33)
↑ AUC 1.30 (1.00, 1.69)
 GS331007
↓ Cmax 0.73 (0.65, 0.83)
↔ AUC 1.04 (0.89, 1.22) Immunosuppressant cyclosporine g Interactions were not studied.
Expected.
↑ Ledipavir
↔ No dose adjustment for leidipavir sofosbuvir tablets or cyclosporine is required for cyclosporine. Cyclosporine
(600 mg single dose)/sofosbuvir (400 mg single dose)h cyclosporine
↔ Cmax 1.06 (0.94, 1.18)
↔ AUC 0.98 (0.85, 1.14)
 Sofosbuvir
↑ Cmax 2.54 (1.87, 3.45)
↑ AUC 4.53 (3.26, 6.30)
 GS331007
↓ Cmax 0.60 (0.53, 0.69)
↔ AUC 1.04 (0.90, 1.20) Tacrolimus interactions were not studied.
Expected.
↔ No dose adjustment for ledipivir sofosbuvir tablets or tacrolimus is required for ledipivir. Tacrolimus.
(5 mg single dose)/sofosbuvir (400 mg single dose) h Tacrolimus
↓ Cmax 0.73 (0.59, 0.90)
↑ AUC 1.09 (0.84, 1.40)
 sofosbuvir
↓ Cmax 0.97 (0.65, 1.43)
↑ AUC 1.13 (0.81, 1.57)
 GS331007
↔ Cmax 0.97 (0.83, 1.14)
↔ AUC 1.00 (0.87, 1.13) Oral contraceptives norgestimate/ethinyl estradiol (norgestimate 0.180 mg/0.215 mg/0.25 mg/ethinyl estradiol 0.025 mg)/ledipavir (90 mg once daily) d methyl progesterone
↔ Cmax 1.02 (0.89, 1.16)
↔ AUC 1.03 (0.90, 1.18)
Cmin 1.09 (0.91, 1.31) ↔ Cmin 1.09 (0.91, 1.31)
 Methylnortriptyline
↔ Cmax 1.03 (0.87, 1.23)
Methandienone ↔ AUC 0.99 (0.82, 1.20)
Cmin 1.00 (0.81, 1.23) ↔ Cmin 1.00 (0.81, 1.23)
 Ethinylestradiol
↑ Cmax 1.40 (1.18, 1.66)
↔ AUC 1.20 (1.04, 1.39)
↔ Cmin 0.98 (0.79, 1.22) No dose adjustment is required for oral contraceptives. Norgestrel/ethinyl estradiol (Norgestrel 0.180 mg/0.215 mg/0.25 mg/ethinyl estradiol 0.025 mg)/sofosbuvir (400 mg once daily) d methyl progesterone
↔ Cmax 1.07 (0.94, 1.22)
↔ AUC 1.06 (0.92, 1.21)
Cmin 1.07 (0.89, 1.28) ↔ Cmin 1.07 (0.89, 1.28)
 Methylnortriptyline
↔ Cmax 1.18 (0.99, 1.41)
↑ AUC 1.19 (0.98, 1.45)
↑ Cmin 1.23 (1.00, 1.51)
 Ethinylestradiol
↔ Cmax 1.15 (0.97, 1.36)
↔ AUC 1.09 (0.94, 1.26)
↔ Cmin 0.99 (0.80, 1.23) a. Combined drug pharmacokinetic mean ratio (90% CI) for study drugs alone or in combination. No effect = 1.00.
b. All interaction studies were conducted in healthy volunteers.
c. Dosed with Harvoni.
d. The cut-off for no pharmacokinetic interactions ranges from 70-143%.
e. These drugs fall into the category where similar interactions can be predicted.
f. Similar results were obtained for atazanavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate, or dirunavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate with Harvoni administered at staggered intervals (12 hours apart).
g. This study was conducted with two other direct-acting antiviral agents.
h. The bioequivalence/equivalence cut-off range is 80- 125%.
[Drug overdose].
The highest documented doses of ledipavir and sofosbuvir were 120 mg twice daily for 10 consecutive days and a single dose of 1,200 mg. In these healthy volunteer studies, no adverse effects were observed at these dose levels, and the frequency and severity of reported adverse effects were similar to those in the placebo group. The effects of higher doses are not known.
 There is no specific antidote for overdose with leidipavir sofosbuvir tablets. If an overdose occurs, patients must be monitored for signs of toxicity. Treatment of an overdose with leidipavir sofosbuvir tablets requires general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Hemodialysis is unlikely to significantly clear leidipavir due to its high binding rate to plasma proteins. Hemodialysis was effective in removing GS331007, the major circulating metabolite of sofosbuvir, with an extraction rate of 53%.
Clinical Trials]
Clinical Efficacy in Chinese Adult Patients with Chronic Genotype 1 HCV Infection (Study 0131)
 The efficacy of ledipavir/sofosbuvir was studied in an international multicenter, open-label clinical study including China, which evaluated the safety and efficacy of 12 weeks of ledipavir/sofosbuvir treatment in untreated or treated subjects with genotype 1 chronic HCV infection.
 The mean age of treated subjects (n = 206) was 47 years (range: 21 to 72); 50.0% of subjects were male and all subjects (100%) were Chinese; mean body mass index was 23.4 kg/m2 (range: 14.4 to 33.5 kg/m2) and 27.7% had a BMI ≥ 25 kg/m2. Thirty-two/206 subjects (15.5%) had compensated cirrhosis at baseline, and 100/206 subjects (48.5%) had prior HCV treatment. Among the 100 subjects with prior HCV treatment experience, reasons for prior treatment failure were relapse/breakthrough (47%; 47 subjects), non-response (25%; 25 subjects), and interferon intolerance (28%; 28 subjects). The majority of subjects carried the IL28B CC allele (76.2%). The overall mean (SD) baseline HCV RNA was 6.3 (0.63) log10 IU/mL, with 82.5% of subjects having a baseline HCV RNA value of ³ 800,000 IU/mL.
 SVR12 was achieved in all 206 subjects (100.0%) (95% CI: 98.2% to 100.0%). The SVR12 rate in untreated subjects (100%; 95% CI: 96.6% to 100.0%) was significantly greater than the historical SVR rate of 57.0% (p < 0.001), meeting the pre-specified criteria for superiority.
 Clinical Efficacy and Safety in Overseas Studies
 The efficacy of ledipavir/sofosbuvir has been evaluated in three overseas open-label Phase 3 studies with data from a total of 1,950 patients with genotype 1 chronic HCV infection treated with ledipavir/sofosbuvir. The three phase 3 studies include one study in untreated patients without cirrhosis (ION3); one study in untreated patients with and without cirrhosis (ION1); and one study in patients with and without cirrhosis who have failed prior treatment with interferon-based regimens, including HCV protease inhibitor-containing regimens (ION2). study (ION2). Patients in these studies had compensated liver disease. All three phase 3 studies evaluated the efficacy of ledipavir/sofosbuvir in combination with or without ribavirin.
 In addition, the efficacy of ledipavir/sofosbuvir was evaluated in a phase 2 and a phase 3 study in patients previously treated with sofosbuvir + ribavirin ± pegylated interferon (studies 1118 and ION-4); a phase 3 study in patients with genotype 2 HCV infection (study 1903); a phase 2 study in patients with genotype 3 HCV infection (study 1701); and a phase 2 study in patients with genotype 2 HCV infection (study 1701). (study 1701); two phase 2 studies in patients with genotype 4, 5, and 6 HCV infection (studies 1119 and ELECTRON-2); and one phase 3 and three phase 2 studies in specific populations (ION-4 [HIV co-infection], SOLAR-1 and SOLAR-2 [post-transplant and decompensated cirrhosis], and Study 1116 [adolescents aged 12 to <18 years]).
 The duration of treatment was fixed for each study. Serum HCV RNA values were measured during the clinical studies using the COBAS TaqMan HCV assay (version 2.0) (used in combination with the High Pure System). The lower limit of quantification (LLOQ) of this assay is 25 IU/mL. SVR12 is the primary endpoint for determining HCV cure rate, defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment.
 Overseas study in adults without cirrhosis who have not received treatment: ION3 (Study 0108) – Genotype 1
ION3 evaluated 8 weeks of Ledipavir/sofosbuvir in combination with or without ribavirin and 12 weeks of Ledipavir/sofosbuvir in non-cirrhotic patients with genotype 1 CHC who had not received treatment. Patients were randomized in a 1:1:1 ratio to one of three treatment groups and stratified by HCV genotype (1a vs. 1b).
 Table 7: Demographic information and baseline characteristics in study ION3
Patient distribution LDV/SOF
8 weeks
(n = 215) LDV/SOF+RBV
8 weeks
(n = 216) LDV/SOF
12 weeks
(n = 216) Total
 (n = 647) Age (years): median (range) 53 (2275)51 (2171)53 (2071)52 (2075) Male 60% (130) 54% (117)59% (128)58% (375) Race: Black/African American 21% (45)17% (36)19% (42)19% (123) White 76% (164)81% (176)77% (167)78% (507) Genotype 1a80% (171)80% (172)80% (172)80% (515)aIL28CC Genotype 26% (56)28% (60)26% (56)27% (172) Metavir score as measured by FibroTestb F0F133% (72)38% (81)33% (72)35% (225) F230% (65)28% (61)30% (65)30% (191) F3F436% (77)33% (71)37% (79)35% (227) Unreadable< 1% (1)1% (3)0% (0)< 1% (4)a . One patient in the LDV/SOF 8-week treatment group without a confirmed genotype 1 subtype.
b. Mapping of non-deficient FibroTest results to Metavir scores according to the following conditions: 00.31 = F0F1; 0.320.58 = F2; 0.591.00 = F3F4.
 Table 8: Study of response rates in ION3
 LDV/SOF
8 weeks
(n = 215) LDV/SOF+RBV
8 weeks
(n = 216)LDV/SOF
12 weeks
(n = 216)SVR 94% (202/215)93% (201/216)96% (208/216)Outcome of patients who did not achieve SVR Virological failure during treatment 0/2150/2160/216 Relapsea 5% (11/215)4% (9/214)1% (3/216) Otherb< 1% (2/215)3% ( 6/216)2% (5/216) Genotype Genotype 1a93% (159/171)92% (159/172)96% (165/172) Genotype 1b98% (42/43)95% (42/44)98% (43/44)a. The denominator for relapse is the number of patients with HCV RNA < LLOQ at the last evaluation during treatment number of people.
b. Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).
 Eight weeks of ledipavir/sofosbuvir treatment without ribavirin was not inferior to eight weeks of ledipavir/sofosbuvir treatment with ribavirin (treatment difference 0.9%; 95% confidence interval: 3.9% to 5.7%) and 12 weeks of ledipavir/sofosbuvir treatment (treatment difference 2.3%; 97.5% confidence interval: 7.2% to 3.6%). Among patients with baseline HCV RNA < 6 million IU/mL, the SVR12 was 97% (119/123) for 8 weeks of treatment with ledipavir/sofosbuvir and the corresponding value was 96% (126/131) for 12 weeks of treatment with ledipavir/sofosbuvir.
 Table 9: Relapse rates in the ION3 study presented by baseline characteristics, virologic failure population*
 LDV/SOF
8 weeks
(n = 213) LDV/SOF+RBV
8 weeks
(n = 210) LDV/SOF
12 weeks
(n = 211)Sex Male 8% (10/129)7% (8/114)2% (3/127) Female 1% (1/84)1% (1/96)0% (0/84)IL28 genotype CC4% (2/56)0% (0/57)0% (0/54) Non-CC6% (9/157)6% (9/153)2% (3/157)Baseline HCV RNAa HCV RNA < 6 million IU/mL2% (2/121)2% (3/136)2% (2/128) HCV RNA ≥ 6 million IU/mL10% (9/92)8% (6/74)1% (1/83)* Excluding patients who were lost to follow-up or withdrew consent.
a. HCV RNA values were determined using Roche TaqMan analysis; patients’ HCV RNA may vary between visits.
 Overseas study in adults with and without cirrhosis and not treated: ION1 (Study 0102) – Genotype 1
ION1 is a randomized, open-label study evaluating 12 and 24 weeks of Ledipavir/sofosbuvir treatment with or without ribavirin in 865 treatment-naïve patients with genotype 1 chronic HCV infection, including patients with cirrhosis (randomized 1:1:1:1). Randomized groups were stratified by presence of cirrhosis and HCV genotype (1a versus 1b).
 Table 10: Demographic information and baseline characteristics in study ION1
Patient distribution LDV/SOF
12 weeks
(n = 214) LDV/SOF + RBV 12 weeks
(n = 217)LDV/SOF
24 weeks
(n = 217)LDV/SOF + RBV 24 weeks
(n = 217)Total
 (n = 865) Age (years): median (range) 52 (1875)52 (1878)53 (2280)53 (2477)52 (1880) Male 59% (127)59% (128)64% (139)55% (119)59% (513) Race: Black/African American 11% (24)12% (26)15% (32)12% (26)12% (108) White 87% (187)87% (188)82% (177)84% (183)85% (735) Genotype 1aa68% (145)68% (148)67% (146)66% (143)67% (582) IL28CC Genotype 26% (55)35% (76) 24% (52)34% (73)30% (256) Metavir score as determined by FibroTestb F0F127% (57)26% (56)29% (62)30% (66)28% (241) F226% (56)25% (55)22% (47)28% (60)25% (218) F3F447% ( 100)48% (104)49% (107)42% (91)46% (402) Unreadable< 1% (1)1% (2)< 1% (1)0% (0)< 1% (4)a. Two patients in the LDV/SOF 12-week treatment group, one patient in the LDV/SOF+RBV 12-week treatment group, one patient in the LDV/SOF 24-week treatment group, and two patients in the LDV/SOF+RBV 24-week treatment group without a confirmed genotype 1 subtype.
b. Mapping of non-missing FibroTest results to Metavir scores according to: 00.31 = F0F1; 0.320.58 = F2; 0.591.00 = F3F4.
 Table 11: Study of response rates in ION1
 LDV/SOF
12 weeks
(n = 214)LDV/SOF+RBV 12 weeks
(n = 217)LDV/SOF
24 weeks
(n = 217)LDV/SOF+RBV 24 weeks
(n = 217)SVR99% (210/213) 97% (211/217)98% (213/217)99% (215/217)Outcome of patients who did not achieve SVR Virologic failure during treatment 0/213a0/217< 1% (1/217)0/216 Relapseb< 1% (1/212)0/217&lt ; 1% (1/215)0/216 Otherc< 1% (2/213)3% (6/217)< 1% (2/217)< 1% (2/217)< 1% (2/217) SVR rates for selected subgroups Genotype Genotype 1a98% (142/145)97% (143/148)99% (144/146)99% (141/143 ) Genotype 1b100% (67/67)99% (67/68)97% (67/69)100% (72/72) cirrhosisd No 99% (176/177)97% (177/183)98% (181/184)99% (178/180) Yes 94% (32/34)100% (33/33)97% (32/ 33)100% (36/36) a. One patient was excluded from the LDV/SOF 12-week treatment group and one patient was excluded from the LDV/SOF+RBV 24-week treatment group because both patients had genotype 4 chronic HCV infection.
b. The denominator for relapse is the number of patients with HCV RNA < LLOQ at the last assessment during treatment.
c. Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).
Patients with missing cirrhosis status were excluded from this subgroup analysis. d. Patients with missing cirrhosis status were excluded from this subgroup analysis.
 Overseas study in adults with or without cirrhosis and previously treated: ION2 (Study 0109) – Genotype 1
ION2 is a randomized, open-label study evaluating 12 and 24 weeks of Ledipavir/sofosbuvir treatment with or without ribavirin in patients with cirrhosis and genotype 1 HCV infection without cirrhosis who have failed prior therapy with interferon-based regimens, including HCV protease inhibitor-containing regimens (in 1:1:1:1 randomized groups). Randomization groups were stratified by presence of cirrhosis, HCV genotype (1a vs. 1b), and response to prior HCV therapy (relapse/breakthrough or no response).
Table 12: Demographic information and baseline characteristics in study ION2
Patient distribution LDV/SOF
 12 weeks
(n = 109) LDV/SOF+
RBV
12 weeks
(n = 111)LDV/SOF
 24 weeks
(n = 109)LDV/SOF+
RBV
24 weeks
(n = 111) Total
 
 (n = 440) Age (years): median (range) 56 (2467)57 (2775)56 (2568)55 (2870)56 (2475) Male 68% (74)64% (71)68% (74)61% (68)65% (287) Race: Black/African American 22% (24)14% (16)16% (17) 18% (20)18% (77) White 77% (84)85% (94)83% (91)80% (89)81% (358) Genotype 1a79% (86)79% (88)78% (85)79% (88)79% (347) Past HCV Treatment PEGIFN+RBV39% (43)42% (47)53% (58 ) 53% (59)47% (207)a HCV protease inhibitor + PEGIFN+RBV61% (66)58% (64)46% (50)46% (51)53% (231)aIL28CC genotype9% (10)10% (11)14% (16)16% (18)13% (55)FibroTest assayed Metavir scoreb F0F114% (15)10% (11)12% (13)16% (18)13% (57) F228% (31)26% (29)28% (31)30% (33)28% (124) F3F458% (63)64% (71)58% (63)54% (60)58% (257) Unable to Interpretation 0% (0)0% (0)2% (2)0% (0)< 1% (2) a. One patient in the LDV/SOF 24-week treatment arm and one patient in the LDV/SOF+RBV 24-week treatment arm failed prior treatment with a non-polyethylene glycol interferon-based regimen.
b. Non-missing FibroTest results were mapped to Metavir scores according to the following conditions: 00.31 = F0F1; 0.320.58 = F2; 0.591.00 = F3F4.
 Table 13: Study of response rates in ION2
 LDV/SOF
12 weeks
(n = 109) LDV/SOF+RBV
12 weeks
(n = 111)LDV/SOF
24 weeks
(n = 109)LDV/SOF+RBV
24 weeks
(n = 111)SVR94% (102/109)96% (107/111)99% (108/109)99% (110/111)Outcome of patients who did not achieve SVR Virological failure during treatment 0/1090/1110/109< 1% (1/111) Relapsea6% (7/108)4% (4/111)0/ 1090/110 Otherb0/1090/111< 1% (1/109)0/111 SVR rates for selected subgroups Genotype Genotype 1a95% (82/86)95% (84/88)99% (84/85)99% (87/88) Genotype 1b87% (20/23)100% (23/23)100% (24/ 24)100% (23/23) cirrhosis no 95% (83/87)100% (88/88)c99% (85/86)c99% (88/89) yesd86% (19/22)82% (18/22)100% (22/22)100% (22/22) previous HCV treatment PEGIFN+RBV 93% (40/ 43)96% (45/47)100% (58/58)98% (58/59) HCV protease inhibitor + PEGIFN+RBV94% (62/66)97% (62/64)98% (49/50)100% (51/51)a. The denominator for relapse is the number of patients with HCV RNA < LLOQ at the last evaluation during treatment. number of patients.
b. Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).
c. Patients with missing cirrhotic status were excluded from this subgroup analysis.
d. Liver biopsy showed Metavir score = 4 or Ishak score ≥ 5, or FibroTest score > 0.75 and (APRI) > 2.
 Table 14 shows relapse rates for 12-week regimens (with or without ribavirin) in selected subgroups (see also the previous section, “Impact of baseline HCV resistance-associated variants on treatment outcomes”). In non-cirrhotic patients, relapse occurred during treatment with ledipavir/sofosbuvir without ribavirin only in the presence of NS5A RAV at baseline. In patients with cirrhosis, relapses occurred with both treatment regimens and with and without the presence of NS5A RAV at baseline.
 Table 14: Relapse rates in selected subgroups of study ION2
 LDV/SOF
12 weeks
(n = 109) LDV/SOF+RBV
12 weeks
(n = 111)LDV/SOF
24 weeks
(n = 109)LDV/SOF+RBV
24 weeks
(n = 111) Number of responders at end of treatment 108111109110 cirrhosis No 5% (4/86)a0% (0/88)b0% (0/86)b0% (0/88) Yes 14% (3/22)18% (4/22)0% (0/22)0% (0/22)0% (0/22) Presence of baseline NS5A resistance-related substitutionc No 3% (3/91) d2% (2/94)0% (0/96)0% (0/95)f Yes24% (4/17)e12% (2/17)0% (0/13)0% (0/14) a. Baseline NS5A resistance-associated polymorphisms were present in all 4 of these non-cirrhotic relapsers.
b. Patients with missing cirrhotic status were excluded from this subgroup analysis.
c. Analysis (using deep sequencing) included NS5A resistance-associated polymorphisms that caused a > 2.5-fold change in EC50 (K24G/N/R, M28A/G/T, Q30E/G/H/L/K/R/T, L31I/F/M/V, P32L, S38F, H58D, A92K/T, and Y93C/F/S for genotype 1a HCV infection), while Y93C/F/H/N/S for genotype 1a HCV infection. /(L31I/F/M/V, P32L, P58D, A92K and Y93C/H/N/S for genotype 1b HCV infection).
d. All 3 patients had cirrhosis.
e. All 4 patients did not have cirrhosis.
f. One patient who achieved viral load < LLOQ at the end of treatment had missing baseline NS5A data and was therefore excluded from the analysis.
 
 Overseas Studies in Previously Treated Adults Who Failed Sofosbuvir + Ribavirin ± PEG-IFN Therapy (Studies 1118 and ION-4)
A total of two clinical studies supported the efficacy of Ledipavir/sofosbuvir treatment in patients who had failed prior treatment with sofosbuvir + ribavirin ± pegylated interferon. In Study 1118, 44 genotype 1 infected patients (including 12 with cirrhosis) who had failed prior treatment with sofosbuvir + ribavirin + PEG-IFN or sofosbuvir + ribavirin received 12 weeks of treatment with ledipavir/sofosbuvir + ribavirin; SVR was 100% (44/44). HIV1 co-infected patients (including 1 with cirrhosis) who had failed a previous regimen of sofosbuvir + ribavirin; SVR was 100% (13/13) after 12 weeks of treatment with ledipavir/sofosbuvir in these patients.
 
 Overseas study in Japanese adults with and without cirrhosis: (Study 1903) – Genotype 2
Study 1903 is a randomized, open-label study conducted in Japan to evaluate the effect of 12 weeks of treatment with Ledipavir/sofosbuvir compared to 12 weeks of treatment with sofosbuvir + ribavirin in Japanese subjects with chronic genotype 2 (2a and 2b) HCV infection with or without compensated cirrhosis (including subjects who had failed prior interferon therapy or pegylated interferon-based regimens) who had not received treatment or who had received treatment. The efficacy and safety of the study in Japanese subjects with chronic genotype 2 (2a and 2b) HCV infection (including subjects who failed prior interferon therapy or pegylated interferon-based regimens). The results of the study are shown in Table 15.
 
 
 Table 15: Response Rate in Study 1903
 12 weeks (N=131)SOF+RBV12 weeks (N=108)SVR12126/131 (96.2%)103/108 (95.4%)Outcome in subjects who did not achieve SVR Virologic failure (breakthrough, rebound, or no response) during the treatment period0/1310/108 Relapsea4/131 (3.1%)4/107 (3.7%)Otherb1 /131 (0.8%)1/108 (0.9%)cirrhosisd No 97% (110/113)95% (87/92)Yes 89% (16/18)100% (16/16)LDV: Ledipavir, SOF: Sofosbuvir, RBV: Ribavirin
a. For relapse cases, denominator is the number of subjects with HCV RNA < LLOQ at the last assessment during treatment.
b. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria.
* Cirrhosis as determined by liver biopsy, Fibroscan results > 12.5 kPa or FibroTest® score > 0.75 and AST:platelet ratio index (APRI) > 2.
 
 Overseas study in adults with and without cirrhosis who have not received treatment: (Study 1701) – Genotype 3
Study 1701 is an open-label study designed to evaluate the efficacy and safety of 12-week lidipivir/sofosbuvir + ribavirin treatment in chronically genotype 3 HCV-infected subjects with and without compensated cirrhosis who have not received treatment. The SVR12 rate was 89.2% (99/111 subjects).
 Table 16: Response rate in genotype 3 infected patients (SVR12) (Study 1701)
 LDV/SOF+RBV
12 weeks
(n = 111) SVR 89% (99/111) Outcome in patients who did not achieve SVR Treatment-phase virologic failure 0% Relapsea7% (8/111) Otherb4% (4/111) Cirrhosisc Yes 79% (31/39) No 94% (66/70) Missing 100% (2/2) a. Relapse = HCV RNA &lt. achieved at final treatment-phase visit LLOQ, but HCV RNA ≥ LLOQ confirmed at post-treatment phase.
b. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria.
c. Cirrhosis as determined by liver biopsy, Fibroscan results > 12.5 kPa or FibroTest® score > 0.75 and AST:platelet ratio index (APRI) > 2.
Overseas studies in treated and untreated adults with and without cirrhosis: (ELECTRON-2) – Genotype 3
 Table 17: Response rates in patients with genotype 3 infection (SVR12) (ELECTRON-2)
 LDV/SOF+RBV
12 weeks LDV/SOF
12 weeks SVR relapse aSVR relapsea untreated 100% (26/26)0% (0/26)64% (16/25)33% (8/24) Patients without cirrhosis 100% (20/20)0% (0/21)71% (15/21)25% (5/20) Patients with cirrhosis 100% (6/6)0% (0/5)25% ( 1/4)75% (3/4)Treated 82% (41/50)16% (8/49)NSNS Patients without cirrhosis 89% (25/28)7% (2/27)NSNS Patients with cirrhosis 73% (16/22)27% (6/22)NSNSNS: Not studied.
a. Denominator for relapse is the number of patients with HCV RNA < LLOQ at the last evaluation during treatment.
 Overseas studies in adults with and without cirrhosis from Study 1119 and ELECTRON-2 (Study 0122 Cohort 2, Group 5) – Genotypes 4, 5, 6
Studies 1119 and ELECTRON-2 (Study 0122 Cohort 2, Group 5) enrolled patients with or without cirrhosis who had not received treatment or had failed prior treatment with PEGIFN + ribavirin +/- an HCV protease inhibitor.
 The treatment regimen was 12 weeks of Ledipavir/sofosbuvir without ribavirin (Table 18).
 Table 18: Response rates in patients with genotypes 4, 5 and 6 HCV infection treated with 12 weeks of Ledipavir/sofosbuvir (SVR12)
Study GTnTEaSVR12 Relapseb Overall cirrhosis Study 1119 44450% (22/44)93% (41/44)100% (10/10)7% (3/44)Study 111954149% (20/41)93% (38/41)89% (8/9)5% (2/40)Study 0122 (ELECTRON2 ) 6250% (0/25) 96% (24/25) 100% (2/2) 4% (1/25) a. TE: number of patients treated.
b. Denominator for relapse is the number of patients with HCV RNA < LLOQ at the last evaluation during treatment.
 Overseas study in HCV/HIV co-infected adults: ION4 (Study 0115)
ION4 is an open-label clinical study evaluating the safety and efficacy of 12 weeks of treatment with Lepivir/sofosbuvir without ribavirin in HCV-treated and HCV-treated patients with genotype 1 or 4 chronic HCV infection and co-infection with HIV1. Treated patients had failed prior treatment with PEGIFN + ribavirin ± an HCV protease inhibitor or sofosbuvir + ribavirin ± PEGIFN. Patients were receiving stable HIV1 antiretroviral therapy with a regimen that included emtricitabine/tenofovir disoproxil fumarate in combination with efavirenz, rilpivirine, or raltegravir.
 The median age was 52 years (range: 26 to 72); 82% of patients were male; 61% were Caucasian; 34% were black; 75% had genotype 1a HCV infection; 2% had genotype 4 infection; 76% had a non-CC IL28B allele (CT or TT); and 20% had compensated cirrhosis. Fifty-five percent (55%) of patients were treated.
 Table 19: Response rates in study ION-4
 LDV/SOF
12 weeks
(n = 335) SVR 96% (321/335)a Outcome of patients not achieving SVR Virological failure during treatment< 1% (2/335) Relapseb3% (10/333) Otherc< 1% (2/335) SVR rate in selected subgroups Patients with cirrhosis 94% (63/67) Previously treated patients with cirrhosis 98% (46/47) ) a. Eight patients with genotype 4 HCV infection were included in the study, all of whom achieved SVR12.
b. The denominator for relapse was the number of patients with HCV RNA < LLOQ at the last evaluation during treatment.
c. Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g., missed visits).
HCV/HIV co-infected adults – ERADICATE
ERADICATE is an open-label study to evaluate 12 weeks of Ledipavir/sofosbuvir treatment in 50 patients with genotype 1 CHC co-infected with HIV. All patients were HCV-free and did not have cirrhosis, 26% (13/50) were not receiving HIV antiretroviral therapy, and 74% (37/50) were receiving co-administered HIV antiretroviral therapy. At interim analysis, 40 patients had reached 12 weeks post-treatment, with an SVR12 of 98% (39/40).
 Overseas studies in patients awaiting liver transplantation and post-transplantation: SOLAR1 and SOLAR-2
SOLAR-1 and SOLAR-2 are two open-label clinical studies evaluating 12 and 24 weeks of Ledipavir/sofosbuvir in combination with ribavirin in genotype 1 and 4 HCV-infected subjects who have undergone liver transplantation and/or have decompensated liver disease. The study design was the same for both studies. Subjects were entered into one of the groups (of seven) based on liver transplant status and severity of liver impairment (see Table 19). Subjects with CPT scores > 12 were excluded. Within each group, subjects were randomized in a 1:1 ratio to receive 12 or 24 weeks of lidipivir/sofosbuvir + ribavirin, respectively.
 Demographic information and baseline characteristics were well balanced across treatment groups. Of the 670 treated subjects, the median age was 59 years (range: 21 to 81 years); 77% were male; 91% were white; the 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; and 78% had failed prior HCV therapy. Among subjects with decompensated cirrhosis (pre- or post-transplant), the proportion of subjects with CPT grade B and C at screening was 64% and 36%, respectively, and 24% had a baseline model for end-stage liver disease (MELD) score greater than 15.
 Table 20: Pooled response rates for genotype 1 HCV-infected subjects from studies SOLAR1 and SOLAR-2 (SVR12)
 LDV/SOF+RBV
12 weeks
(n = 307)a,bLDV/SOF+RBV
24 weeks
(n = 307)a,b SVRSVR pre-transplant CPT B87% (45/52)92% (46/50)CPT C88% (35/40)83% (38/46)Post-transplant Metavir score F0-F395% (94/99)99% (99/100)CPT Ac98% (55/56)96% (51/53) CPT Bc89% (41/46)96% (43/45)CPT Cc57% (4/7)78% (7/9)FCH100% (7/7)100% (4/4)a. Twelve subjects who received transplantation prior to week 12 post-treatment and had HCV RNA < LLOQ at the last measurement prior to transplantation were excluded.
b. Two subjects who did not have decompensated cirrhosis and did not receive a liver transplant were excluded because they did not meet the inclusion criteria for either treatment group.
CPT A = CPT score 5-6 (compensated), CPT B = CPT score 7-9 (decompensated), CPT C = CPT score 10-12 (decompensated). c. CPT = Child-Pugh-Turcotte, FCH = fibrosing biliary hepatitis. d. CPT A = CPT score 5-6 (compensated), CPT B = CPT score 7-9 (decompensated), CPT C = CPT score 10-12 (decompensated).
 The SOLAR-1 and SOLAR-2 studies included 40 subjects with genotype 4 chronic HCV infection, and the SVR 12 was 92% (11/12) and 100% (10/10) in post-transplant subjects without decompensated cirrhosis after 12 or 24 weeks of treatment, respectively, and 60% ( 6/10) and 75% (6/8) for subjects with decompensated cirrhosis (pre- and post-liver transplantation), respectively. Of the 7 subjects who did not achieve SVR12, 3 relapsed, all 3 had decompensated cirrhosis and were treated with 12 weeks of Ledipavir/sofosbuvir + ribavirin.
 Changes in MELD and CPT scores from baseline to week 12 post-treatment were analyzed in all patients (pre- or post-transplant) with decompensated cirrhosis who achieved SVR12 and for whom data were available (n = 123) to assess the effect of SVR12 on liver function.
 Change in MELD scores: Among subjects treated with 12 weeks of ledipavir/sofosbuvir + ribavirin who achieved SVR12, 57% (70/123) and 19% (23/123) had improved or no change in MELD scores from baseline to week 12 post-treatment, respectively; among the 32 subjects with MELD scores ≥ 15 at baseline, 59% ( The main reason for the observed improvement in MELD score was an improvement in total bilirubin.
 Change in CPT score and grading: Among subjects treated with 12 weeks of lidipavir/sofosbuvir + ribavirin who achieved SVR12, the proportion of subjects with improved or no change in CPT score from baseline to week 12 post-treatment was 60% (74/123) and 34% (42/123), respectively; of the 32 subjects with CPT C cirrhosis at baseline, 53% (17/32) had CPT C at week 12 post-treatment. (17/32) had CPT B cirrhosis at week 12 post-treatment; of the 88 subjects with CPT B cirrhosis at baseline, 25% (22/88) had CPT A cirrhosis at week 12 post-treatment. The main reason for the observed improvement in CPT scores was improvement in total bilirubin and albumin.
 Overseas studies in untreated and treated adolescent patients aged 12 to < 18 years: (Study 1116)
A phase 2 open-label clinical trial (Study 1116) evaluated leidipavir/sofosbuvir in 100 patients with genotype 1 chronic HCV infection, in which the efficacy of leidipavir/sofosbuvir was assessed in HCV-infected adolescents aged 12 to < 18 years. A total of 80 patients (80%) were untreated and 20 patients (20%) were treated. All patients in the trial received 12 weeks of treatment with Ledipavir/sofosbuvir.
 Demographic information and baseline characteristics were balanced between untreated and treated patients. Of the 100 treated patients, the median age was 15 years (range: 12 to 17); 63% were female; 90% were white; 7% were black; 2% were Asian; and 13% were Hispanic/Latino; the mean weight was 61.3 kg (range: 33.0 to 126.0 kg); 55% had baseline HCV RNA levels greater than or equal to 800, 000 IU/mL; 81% had genotype 1a HCV infection; 76% had a non-CC IL28B allele (CT or TT), and 1% had known cirrhosis. Most patients (84%) were infected through vertical transmission.
 The overall SVR12 rate was 98% (98% [78/80] in untreated patients and 100% [20/20] in treated patients). A total of 2/100 patients (2%, neither patient was treated) did not achieve SVR12 (due to missed visits). No patients experienced virologic failure.
[Pharmacology and Toxicology].
Pharmacological effects
Ledipavir is an inhibitor of HCV NS5A protein (required for HCV virosomal RNA replication and assembly). The inhibitory effect of Ledipavir on NS5A has not been confirmed biochemically because NS5A is not enzymatically functional. In vitro resistance selection and cross-resistance studies suggest that the mechanism of action of ledipavir is to target NS5A.
Sofosbuvir is an inhibitor of HCV NS5B RNA-dependent RNA polymerase (required for viral replication). Sofosbuvir is a nucleotide precursor drug that is metabolized intracellularly to the pharmacologically active uridine analogue triphosphate (GS 461203), which can be embedded in HCV RNA by NS5B polymerase to terminate replication. A biochemical analysis showed that GS-461203 inhibited the polymerase activity of recombinant NS5B of genotypes 1b, 2a, 3a and 4a HCV at 50% inhibitory concentrations (IC50) of 0.7-2.6 μM. GS-461203 is neither a human DNA and RNA polymerase inhibitor nor a mitochondrial RNA polymerase inhibitor.
Antiviral activity
The EC50 values of leidipavir and sofosbuvir against full-length or chimeric replicons encoding the NS5A and NS5B sequences in clinical isolates are detailed in Table 21 below. 40% human serum had no effect on the anti-HCV activity of sofosbuvir, but reduced the anti-HCV activity of leidipavir against genotype 1a replicons by 12-fold.
Table 21: Activity of Ledipavir and Sofosbuvir against chimeric replicons
Genotypic replicons Ledipavir activity (EC50, nM) Sofosbuvir activity (EC50, nM) Stable replicons NS5A Transient replicons median value (range)a Stable replicons NS5B Transient replicons median value (range)a Genotype 1a0.0310.018 (0.0090.085)4062 (29128) Genotype 1b0.0040. 006 (0.0040.007)110102 (45170) genotype 2a21249-5029 (1481) genotype 2b16530b-15b-genotype 3a168-5081 (24181) genotype 4a0.39-40-genotype 4d0.60-genotype 5a0.15b-15b-genotype 6a1.1b-14b-genotype 6e264b— a. Transient replicons carrying NS5A or NS5B from patient isolates.
b. Lepidipavir using chimeric replicas carrying NS5A genes derived from genotypes 2b, 5a, 6a, and 6e, and sofosbuvir using chimeric replicas carrying NS5B genes derived from genotypes 2b, 5a, or 6a.
Drug resistance
HCV replicons with reduced susceptibility to leidipavir have been screened in cell cultures of genotypes 1a and 1b. In genotypes 1a and 1b, reduced susceptibility to leidipavir was associated with Y93H substitution in the major NS5A. In addition, Q30E substitutions were seen in genotype 1a replicons. targeted mutagenesis of NS5A RAV showed that substitutions causing a fold change in sensitivity to ledipavir of > 100 and ≤ 1,000 included Q30H/R, L31I/M/V, P32L and Y93T in genotype 1a, and P58D and Y93S in genotype 1b; substitutions causing a fold change of > 1,000 substitutions, including M28A/G, Q30E/G/K, H58D and Y93C/H/N/S in genotype 1a, and A92K and Y93H in genotype 1b.
HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell cultures of multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. In all replicon genotypes examined, reduced susceptibility to sofosbuvir was associated with substitution of primary NS5B for S282T. Among replicons of the eight genotypes, targeted mutagenesis of the S282T substitution resulted in a 2- to 18-fold reduction in susceptibility to sofosbuvir and an 89% to 99% reduction in viral replication capacity compared with the corresponding wild type. In biochemical analyses, recombinant NS5B polymerase from genotypes 1b, 2a, 3a, and 4a expressing the S282T substitution showed reduced susceptibility to GS-461203 compared to the corresponding wild type.
Cross-resistance
Ledipavir was fully active against the sofosbuvir resistance-associated substitution S282T in NS5B, whereas all of the ledipavir resistance-associated substitutions in NS5A were fully susceptible to sofosbuvir. Both sofosbuvir and ledipavir were fully active for resistance-associated substitutions of other types of direct-acting antivirals with different mechanisms of action, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. Substitution of NS5A that is resistant to Ledipavir may reduce the antiviral activity of other NS5A inhibitors.
Toxicological studies
Genotoxicity
Negative results in the Ames test for leidipavir or sofosbuvir, the human peripheral blood lymphocyte chromosome aberration test, and the mouse micronucleus test.
Reproductive toxicity
No adverse effects on mating and fertility were observed in rats at doses of 10, 30, and 100 mg/kg/day of Ledipavir. Only female rats at 100 mg/kg/day (approximately 3 times the human clinical dose exposure) showed a slight reduction in the number of corpus luteum, the number of implantations and the number of viable embryos, which was associated with transient maternal weight loss and reduced food intake. In embryo-fetal developmental toxicity tests, no teratogenic effects were observed in rats and rabbits at doses of 100 mg/kg/day and 180 mg/kg/day (approximately 4 and 2 times the human clinical dose exposure, respectively). In perinatal toxicity tests in rats, no significant maternal toxicity or embryo-fetal developmental toxicity was observed at doses up to 100 mg/kg/day. Lepidipavir is secreted through breast milk.
Sofosbuvir did not affect embryo-fetal development or fertility in rats at doses of 20, 100, or 500 mg/kg/day, and exposure to the major circulating metabolite (GS-331007) at 500 mg/kg/day was approximately 8 times greater than exposure at the human clinical dose. At the highest dose, no teratogenic effects were observed in rats (500 mg/kg/day) and rabbits (300 mg/kg/day), and the exposure of GS-331007 in pregnant rats and rabbits increased with the duration of administration, corresponding to 5-10 and 12-28 times the human clinical dose, respectively. No effect on fetus was observed.
Carcinogenicity
Ledipavir
Ledipavir was tested for carcinogenicity in transgenic mice for 6 months and no carcinogenicity was observed. In a 2-year rat carcinogenicity study, no significant increase in drug-associated tumor incidence was observed in male and female rats at doses of 100 mg/kg/day and 30 mg/kg/day, respectively, and exposure at high doses in rats was 10 times (male) and 4 times (female) the daily human dose exposure.
Sofosbuvir
In 2-year carcinogenicity tests in mice and rats, no carcinogenicity was observed in males and females at doses up to 600 mg/kg/day and 200 mg/kg/day, respectively, and in rats at doses up to 750 mg/kg/day in both sexes.GS-331007 exposure in mice was equivalent to 7 times (male) and 30 times (female) the human clinical dose exposure, respectively, and in rats The exposure in rats was 13 times (male) and 17 times (female) of the human daily dose exposure.
Pharmacokinetics]
Absorption
Following oral administration of Ledipavir/sofosbuvir to HCV-infected patients, median peak plasma concentrations of Ledipavir were observed at 4 hours post-dose. Sofosbuvir was rapidly absorbed and median peak plasma concentrations were observed at approximately 1 hour post-dose. Median peak plasma concentrations of GS331007 were observed at 4 hours post-dose.
 Based on a population pharmacokinetic analysis of HCV-infected patients, the geometric mean steady-state AUC024 was 8,530, 1,380, and 12,500 ng-h/mL for leidipavir (n = 2,113), sofosbuvir (n = 1,542), and GS331007 (n = 2,113), respectively. The AUC024 and Cmax of sofosbuvir and GS331007 were similar in healthy adult subjects as in HCV-infected patients. 24% lower AUC024 was observed in HCV-infected patients than in healthy subjects (n = 191).
Based on population PK analysis in Chinese subjects (n = 206), the steady-state AUC0-24 was 11,400, 1,590, and 14,200 ng-h/mL for ledipavir (n = 206), sofosbuvir (n = 56), and GS-331007 (n = 206), respectively.
 Food effects
The AUC0inf of sofosbuvir was approximately 2-fold higher with a single dose of leidipivir/sofosbuvir administered with a moderate fat meal or a high fat meal relative to fasting, but did not significantly affect sofosbuvir Cmax. neither meal type altered GS331007 and leidipivir exposure. Therefore, Harvoni can be given regardless of food.
 Distribution
Neither ledipavir nor sofosbuvir is a substrate of the hepatic uptake transporters (organic cation transporter (OCT) 1, organic cation transport polypeptide (OATP) 1B1 or OATP1B3). GS331007 is not a substrate of the renal transporters including organic anion transporter (OAT) 1 or OAT3 or OCT2. At concentrations achieved in clinical studies, Ledipavir is not an inhibitor of hepatic transporters including OATP 1B1 or 1B3, BSEP, OCT1, OCT2, OAT1, OAT3, multidrug and toxicant efflux (MATE) 1 transporters, multidrug resistance protein (MRP) 2 or MRP4. Sofosbuvir and GS331007 are not inhibitors of the drug transporters Pgp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1, and GS331007 is not an inhibitor of OAT1, OCT2, or MATE1.
 The binding rate of Ledipavir to human plasma proteins > 99.8%. Following a single administration of 90 mg of [14C]ledipavir to healthy subjects, the blood to plasma ratio of [14C]radioactivity ranged from 0.51 to 0.66.
 The binding of sofosbuvir to human plasma proteins was approximately 6165% over a range of 1 µg/mL to 20 µg/mL, independent of drug concentration. In human plasma, the protein binding of GS331007 was extremely low. After a single administration of 400 mg [14C]sofosbuvir to healthy subjects, the blood to plasma ratio of [14C]radioactivity was approximately 0.7.
 Biotransformation
In vitro, the metabolism of leidipavir by human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 was not detected. Signs of slow oxidative metabolism by an unknown mechanism have been observed. After a single dose of 90 mg [14C]ledipavir, systemic exposure was almost exclusively derived from the parent drug (> 98%). No change in Ledipavir was also the predominant type in the feces.
 Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analogue triphosphate GS-461203. no active metabolites were observed. The metabolic activation pathway consists of sequential hydrolysis of the carbonylster fraction catalyzed by human histone A or carboxylesterase 1 and phosphoramidate cleavage by histidine trimer nucleoside-binding protein 1, followed by phosphorylation via the pyrimidine nucleotide biosynthetic pathway. Dephosphorylation results in the nucleotide metabolite GS331007, which cannot be efficiently dephosphorylated and lacks in vitro anti-HCV activity. Within leidipavir/sofosbuvir, GS331007 accounts for approximately 85% of the total systemic exposure. Sofosbuvir and GS331007 are not substrates or inhibitors of UGT1A1 or CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 enzymes.
 Elimination
The mean total recovery of [14C]radioactivity in feces and urine following a single oral administration of 90 mg of [14C]Ledipavir was 87%, with the majority of the radioactive dose recovered from feces (86%). Excretion of unchanged Ledipavir into the feces accounted for an average of 70% of the administered dose, and the oxidized metabolite M19 accounted for 2.2% of the dose. These data suggest that biliary excretion of unchanged Ledipavir is the primary route of drug elimination, while renal excretion is the secondary route of elimination (approximately 1%). The median terminal half-life of ledipavir/sofosbuvir in healthy volunteers was 47 hours following fasting administration of ledipavir/sofosbuvir.
 After a single oral dose of 400 mg [14C] sofosbuvir, the mean total dose recovery was >92%, with urinary, fecal and expiratory recoveries of approximately 80%, 14% and 2.5%, respectively. The majority of the sofosbuvir dose recovered in urine was GS331007 (78%), with an additional 3.5% recovered as sofosbuvir. This data suggests that the primary route of elimination of GS331007 is renal, with most of it being actively secreted. The median terminal half-lives of sofosbuvir and GS331007 after leidipavir/sofosbuvir administration were 0.5 and 27 hours, respectively.
 Neither ledipavir nor sofosbuvir is a substrate for hepatic uptake transporters (organic cation transporter (OCT) 1, organic cation transport polypeptide (OATP) 1B1, or OATP1B3). GS-331007 is not a substrate for renal transporters (including organic anion transporter (OAT) 1 or OAT3) or OCT2.
 Potential for Ledipavir/Sofosbuvir to affect other drugs in vitro
At concentrations achieved in clinical studies, ledipavir is not an inhibitor of hepatic transporters including OATP 1B1 or 1B3, BSEP, OCT1, OCT2, OAT1, OAT3, multidrug and toxic compound efflux (MATE) 1 transporters, multidrug resistance protein (MRP) 2 or MRP4. Sofosbuvir and GS-331007 are not inhibitors of the drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1, and GS-331007 is not an inhibitor of OAT1, OCT2, or MATE1.
Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzymes.
 Pharmacokinetics in Special Populations
Race and gender
No clinically relevant pharmacokinetic differences due to race were identified for ledipavir, sofosbuvir, or GS331007. No clinically relevant pharmacokinetic differences due to gender were identified for sofosbuvir or GS331007. AUC and Cmax were 77% and 58% higher, respectively, in women compared to men; however, the relationship between gender and leidipavir exposure was not considered to be clinically relevant.
 Older adults
Population pharmacokinetic analysis in HCV-infected patients showed no clinically relevant effect of age on exposure to ledipavir, sofosbuvir, or GS331007 in the age range analyzed (18 to 80 years). The clinical study of ledipavir/sofosbuvir included 235 patients (8.6% of patients) aged 65 years and older.
 Renal impairment
The pharmacokinetics of a single dose of 90 mg of ledipavir was studied in HCV-negative patients with severe renal impairment (Cockcroft-Gault method yielding eGFR < 30 mL/min and median [range] CrCl of 22 [1729] mL/min). No clinically relevant differences in the pharmacokinetics of ledipavir were observed in healthy subjects and patients with severe renal impairment.
 The pharmacokinetics of 400 mg of Ledipavir were studied in mild (eGFR ≥ 50 and < 80 mL/min/1.73 m2), moderate (eGFR ≥ 30 and < 50 mL/min/1.73 m2), severe renal impairment (eGFR < 30 mL/min/1.73 m2), and HCV-negative patients with ESRD requiring hemodialysis. The pharmacokinetics of sofosbuvir after a single dose of sofosbuvir were studied in HCV-negative patients with ESRD requiring hemodialysis. Compared to patients with normal renal function (eGFR > 80 mL/min/1.73m2), sofosbuvir AUC0inf was 61%, 107% and 171% higher in patients with mild, moderate and severe renal impairment, respectively, and GS331007 AUC0inf was 55%, 88% and 451% higher, respectively. Compared to patients with normal renal function, sofosbuvir AUC0inf was 28% higher when given 1 hour before hemodialysis and 60% higher when given 1 hour after hemodialysis in patients with ESRD. GS331007 was effectively removed by hemodialysis with an extraction factor of approximately 53%. After a single dose of sofosbuvir 400 mg, hemodialysis removes 18% of the administered dose of sofosbuvir at 4 hours. The safety and efficacy of sofosbuvir have not been established in patients with severe renal impairment or ESRD.
 Hepatic Impairment
The pharmacokinetics of leidipivir with a single dose of 90 mg leidipivir were studied in HCV-negative patients with severe hepatic impairment (CPT class C). Population pharmacokinetic analysis of HCV-infected patients showed no clinically relevant effect of cirrhosis (including decompensated cirrhosis) on leidipavir exposure.
 The pharmacokinetics of sofosbuvir were studied after 7 days of 400 mg sofosbuvir administration in HCV-infected patients with moderate and severe hepatic impairment (CPT classes B and C). The population pharmacokinetic analysis of HCV-infected patients showed no clinically relevant effect of cirrhosis (including decompensated cirrhosis) on sofosbuvir and GS331007 exposure. The effect of sofosbuvir and GS331007 exposure was not clinically relevant.
 Pediatric population
Following leidipavir/sofosbuvir (90 mg/400 mg) administration, exposure to leidipavir, sofosbuvir, and GS-331007 in adolescents aged 12 to < 18 years was similar to the corresponding values in adults in the Phase 2/3 study. The pharmacokinetics of ledipavir, sofosbuvir, and GS-331007 in pediatric patients aged < 12 years have not been determined (see Dosage).
Storage
Store at 30°C or below.
Packaging
High-density polyethylene (HDPE) bottle with a polypropylene continuous threaded child-resistant cap with induction-activated aluminum foil liner, containing 28 film-coated tablets with silica gel desiccant and polyester cotton stopper.
 Each box contains 1 bottle, each containing 28 film-coated tablets.
Expiration date
48 months
Execution Standard
Import Registration Standard: JX20160413
Approval number
Imported drug registration certificate no.
【Manufacturing Company
Gilead Sciences Ireland UC
IDA Business & Technology Park, Carrigtohill, County Cork, Ireland
Tel: 00353 214825913
Fax: 00353 214825518
 
 Adverse Drug Reaction Reports
Gilead (Shanghai) Pharmaceutical Technology Co.
Domestic contact name: Gilead (Shanghai) Pharmaceutical Technology Co.
Domestic contact address: 31F, No. 1198 Century Avenue, China (Shanghai) Pilot Free Trade Zone
Tel: 4008201135