Ledipasvir and Sofosbuvir (Monograph)

Brand name: Harvoni
Drug class: HCV Replication Complex Inhibitors
Chemical name: N-[(1S)-1-[[(6S)-6-[5-[9,9-di fluoro-7-[2-[(1R,3S,4S)-2-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-azabicyclo[2.2.1]hept-3-yl]-1H-benzimidazol-6-yl]-9H-fluoren-2-yl]-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl]carbonyl]-2-methylpropyl]-carbamic acid methyl ester
Molecular formula: C₄₉H₅₄F₂N₈O₆C₂₂H₂₉FN₃O₉P
CAS number: 1256388-51-8

Medically reviewed by Drugs.com on Feb 13, 2024. Written by ASHP.

Introduction

Antiviral; fixed combination containing ledipasvir (HCV NS5A replication complex inhibitor [NS5A inhibitor]) and sofosbuvir (nucleotide analog HCV NS5B polymerase inhibitor).

Uses for Ledipasvir and Sofosbuvir

Chronic HCV Infection

Treatment of chronic HCV genotype 1 infection in treatment-naive (have not previously received HCV treatment) or previously treated adults and pediatric patients ≥3 years of age without cirrhosis or with compensated or decompensated cirrhosis (Child-Pugh class A, B, or C), including those with HIV coinfection and liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh class A).

Treatment of chronic HCV genotype 4 infection in treatment-naive or previously treated adults and pediatric patients ≥3 years of age without cirrhosis or with compensated cirrhosis (Child-Pugh class A), including those with HIV coinfection and liver transplant recipients.

Treatment of chronic HCV genotype 5 or 6 infection in treatment-naive or previously treated adults and pediatric patients ≥3 years of age without cirrhosis or with compensated cirrhosis (Child-Pugh class A), including those with HIV coinfection.

Used alone for treatment of chronic HCV infection in patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A); used in conjunction with ribavirin in those with decompensated cirrhosis (Child-Pugh class B or C) and in liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh class A).

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information. Information from the American Association for the Study of Liver Diseases (AASLD) and IDSA regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at [Web].

Ledipasvir and Sofosbuvir Dosage and Administration

General

Pretreatment Screening

• Prior to initiating HCV treatment, test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc).

• In patients with serologic evidence of HBV infection, measure baseline HBV DNA level.

• Perform appropriate laboratory tests to evaluate liver function, especially in patients with decompensated cirrhosis receiving a regimen of ledipasvir/sofosbuvir in conjunction with ribavirin.

• When used in conjunction with ribavirin, women of childbearing potential should have a negative pregnancy test immediately prior to initiating ribavirin therapy; perform pregnancy tests periodically during and for 6 months after completion of ribavirin therapy.

Patient Monitoring

• Perform appropriate laboratory tests to evaluate liver function during therapy, especially in patients with decompensated cirrhosis receiving a regimen of ledipasvir/sofosbuvir in conjunction with ribavirin.

• In all patients with evidence of current or prior HBV infection: Monitor for clinical and laboratory signs (i.e., HBsAg, HBV DNA levels, serum aminotransferase and bilirubin concentrations) of hepatitis flare or HBV reactivation during and after treatment with HCV DAAs.

Other General Considerations

• For treatment of chronic HCV infection, ledipasvir/sofosbuvir is used alone or in conjunction with ribavirin.

• Specific regimen and duration of treatment depend on HCV genotype and certain patient factors (e.g., presence of compensated or decompensated cirrhosis, liver transplantation). Consider that relapse rates following treatment are affected by baseline host and viral factors and differ between treatment durations for certain subgroups.

• If amiodarone is used concomitantly with ledipasvir/sofosbuvir, perform cardiac monitoring in an inpatient setting during the first 48 hours of concomitant use; perform heart rate monitoring daily (outpatient or self-monitoring) through at least the first 2 weeks of concomitant use. Similar cardiac monitoring is recommended in patients who discontinue amiodarone just prior to initiation of ledipasvir/sofosbuvir.

Administration

Oral Administration

Administer orally once daily with or without food.

Available as film-coated tablets and pellets for oral administration; use the pellets in pediatric patients who cannot swallow tablets.

Ledipasvir/sofosbuvir pellets taken with food: Add one or more spoonfuls of nonacidic soft food at or below room temperature (e.g., pudding, chocolate syrup, mashed potato, ice cream) to a bowl; sprinkle entire contents of the appropriate number of single-dose packets of pellets (see Table 1) onto the food and gently mix with a spoon. Ensure that no pellets remain in the packet(s). Ingest entire mixture containing the pellets within 30 minutes after preparation; swallow pellets in the mixture whole without chewing to avoid a bitter aftertaste.

Ledipasvir/sofosbuvir pellets taken without food: Pour entire contents of single-dose packet of pellets directly into the mouth and swallow pellets whole without chewing to avoid a bitter aftertaste. May drink water after swallowing the pellets, if needed. If 2 packets of pellets are indicated (see Table 1), repeat the process. Ensure that no pellets remain in the packet(s).

Dosage

Available as fixed-combination pellets containing 33.75 mg of ledipasvir and 150 mg of sofosbuvir, fixed-combination pellets containing 45 mg of ledipasvir and 200 mg of sofosbuvir, fixed-combination tablets containing 45 mg of ledipasvir and 200 mg of sofosbuvir, and fixed-combination tablets containing 90 mg of ledipasvir and 400 mg of sofosbuvir.

Pediatric Patients

Treatment of Chronic HCV Infection

HCV Genotype 1 Infection

Oral

Treatment-naive or previously treated pediatric patients ≥3 years of age: Dosage based on weight. (See Table 1.)

Use alone in patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A); use with ribavirin in those with decompensated cirrhosis (Child-Pugh class B or C) and in liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh class A). Treatment duration of 12 weeks recommended for most patients; treatment duration of 24 weeks recommended in previously treated patients with compensated cirrhosis (Child-Pugh class A). (See Table 2.)

Manufacturer states treatment duration of 8 weeks can be considered in treatment-naive patients without cirrhosis who have pretreatment HCV RNA levels less than 6 million IU/mL.

Previously treated defined as patients who failed treatment with peginterferon alfa (with or without ribavirin) with or without an HCV protease inhibitor.

Alternatively, a regimen of ledipasvir/sofosbuvir and ribavirin for a duration of 12 weeks can be considered in previously treated patients with compensated cirrhosis (Child-Pugh class A) who are eligible to receive ribavirin.

Use weight-based ribavirin dosage in pediatric patients ≥3 years of age (7.5 mg twice daily in those weighing <47 kg; 200 mg in a.m. and 400 mg in p.m. in those 47–49 kg; 400 mg twice daily in those 50–65 kg; 400 mg in a.m. and 600 mg in p.m. in those 66–80 kg; 600 mg twice daily in those >80 kg). Give each ribavirin dose with food.

HCV Genotype 4 Infection

Oral

Treatment-naive or previously treated pediatric patients ≥3 years of age: Dosage based on weight. (See Table 1.)

Use alone in patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A); use in conjunction with ribavirin in liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh class A). Treatment duration is 12 weeks. (See Table 3.)

Previously treated defined as patients who failed treatment with peginterferon alfa (with or without ribavirin) with or without an HCV protease inhibitor.

Use weight-based ribavirin dosage in pediatric patients ≥3 years of age (7.5 mg twice daily in those weighing <47 kg; 200 mg in a.m. and 400 mg in p.m. in those 47–49 kg; 400 mg twice daily in those 50–65 kg; 400 mg in a.m. and 600 mg in p.m. in those 66–80 kg; 600 mg twice daily in those >80 kg). Give each ribavirin dose with food.

HCV Genotype 5 or 6 Infection

Oral

Treatment-naive or previously treated pediatric patients ≥3 years of age: Dosage based on weight. (See Table 1.)

Use alone in patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A). Treatment duration is 12 weeks. (See Table 4.)

Previously treated defined as patients who failed treatment with peginterferon alfa (with or without ribavirin) with or without an HCV protease inhibitor.

HCV-infected with HIV Coinfection.

Oral

Treatment-naive or previously treated pediatric patients ≥3 years of age with HCV genotype 1, 4, 5, or 6 infection: Use same dosage and same HCV genotype-specific multiple-drug regimen and duration of treatment recommended for HCV-infected patients without HIV coinfection.

Adults

Treatment of Chronic HCV Infection

HCV Genotype 1 Infection

Oral

Treatment-naive or previously treated adults: 1 tablet containing ledipasvir 90 mg/sofosbuvir 400 mg once daily.

Use alone in patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A); use in conjunction with ribavirin in those with decompensated cirrhosis (Child-Pugh class B or C) and in liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh class A). Treatment duration of 12 weeks recommended for most patients; treatment duration of 24 weeks recommended in previously treated patients with compensated cirrhosis (Child-Pugh class A). (See Table 5.)

Decompensated cirrhosis (Child-Pugh class B or C): Treatment duration of 12 weeks recommended for most patients. Some experts recommend treatment duration of 24 weeks in those who cannot receive ribavirin. Referral to an expert (ideally at a liver transplant center) recommended.

Manufacturer states treatment duration of 8 weeks can be considered in treatment-naive patients without cirrhosis who have pretreatment HCV RNA levels <6 million IU/mL.

Previously treated defined as patients who failed treatment with peginterferon alfa (with or without ribavirin) with or without an HCV protease inhibitor.

Alternatively, a regimen of ledipasvir/sofosbuvir and ribavirin for a duration of 12 weeks can be considered in previously treated patients with compensated cirrhosis (Child-Pugh class A) who are eligible to receive ribavirin.

Use weight-based ribavirin dosage in adults without cirrhosis or with compensated cirrhosis (1 g daily for patients weighing <75 kg or 1.2 g daily for those weighing ≥75 kg). In adults with decompensated cirrhosis, starting ribavirin dosage is 600 mg daily and can be titrated up to weight-based ribavirin dosage (up to 1 g daily for patients weighing <75 kg or up to 1.2 g daily for those weighing ≥75 kg). Give ribavirin daily dosage in 2 divided doses with food. If ribavirin starting dosage not well tolerated, reduce dosage as clinically indicated based on hemoglobin concentrations.

HCV Genotype 4 Infection

Oral

Treatment-naive or previously treated adults: 1 tablet containing ledipasvir 90 mg/sofosbuvir 400 mg once daily.

Use alone in patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A); use in conjunction with ribavirin in liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh class A). Treatment duration is 12 weeks. (See Table 6.)

Decompensated cirrhosis^{† [off-label]} (Child-Pugh class B or C): Some experts recommend a 12-week regimen of ledipasvir/sofosbuvir given in a dosage of 1 tablet containing ledipasvir 90 mg/sofosbuvir 400 mg once daily in conjunction with ribavirin. If ledipasvir/sofosbuvir (without ribavirin) used in patients with decompensated cirrhosis who cannot receive ribavirin, these experts recommend treatment duration of 24 weeks. Referral to an expert (ideally at a liver transplant center) recommended.

Previously treated defined as patients who failed treatment with peginterferon alfa (with or without ribavirin) with or without an HCV protease inhibitor.

Use weight-based ribavirin dosage in adults without cirrhosis or with compensated cirrhosis (1 g daily for patients weighing <75 kg or 1.2 g daily for those weighing ≥75 kg). In adults with decompensated cirrhosis, starting ribavirin dosage is 600 mg daily and can be titrated up to weight-based ribavirin dosage (up to 1 g daily for patients weighing <75 kg or up to 1.2 g daily for those weighing ≥75 kg). Give ribavirin daily dosage in 2 divided doses with food. If ribavirin starting dosage not well tolerated, reduce dosage as clinically indicated based on hemoglobin concentrations.

HCV Genotype 5 or 6 Infection

Oral

Treatment-naive or previously treated adults: 1 tablet containing ledipasvir 90 mg/sofosbuvir 400 mg once daily.

Use alone in patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A). Treatment duration is 12 weeks. (See Table 7.)

Decompensated cirrhosis^{† [off-label]} (Child-Pugh class B or C): Some experts recommend a 12-week regimen of ledipasvir/sofosbuvir given in a dosage of 1 tablet containing ledipasvir 90 mg/sofosbuvir 400 mg once daily in conjunction with ribavirin. If ledipasvir/sofosbuvir (without ribavirin) used in patients with decompensated cirrhosis who cannot receive ribavirin, these experts recommend treatment duration of 24 weeks. Referral to an expert (ideally at a liver transplant center) recommended.

Previously treated defined as patients who failed treatment with peginterferon alfa (with or without ribavirin) with or without an HCV protease inhibitor.

HCV-infected with HIV Coinfection.

Oral

Treatment-naive or previously treated adults with HCV genotype 1, 4, 5, or 6: Use same dosage and same HCV genotype-specific multiple-drug regimen and duration of treatment recommended for HCV-infected patients without HIV coinfection.

Special Populations

Hepatic Impairment

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C): Dosage adjustments not needed. (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild, moderate, or severe renal impairment, including end-stage renal disease (ESRD) requiring dialysis: Dosage adjustments not needed. (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustments not needed.

Cautions for Ledipasvir and Sofosbuvir

Contraindications

• If ledipasvir/sofosbuvir used in conjunction with ribavirin, the contraindications to ribavirin also apply. (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

Warnings/Precautions

Warnings

Risk of HBV Reactivation in Patients Coinfected with HCV and HBV

Postmarketing reports of reactivation of HBV infection when DAAs were used for treatment of HCV infection in patients with HBV coinfection; fulminant hepatitis, hepatic failure, and death reported in some cases.

HBV reactivation (abrupt increase in HBV replication manifested as rapid increase in serum HBV DNA levels or detection of HBsAg in an individual who was previously HBsAg negative and anti-HBc positive) reported in patients with HCV and HBV coinfection receiving HCV treatment with a regimen that included HCV DAAs without interferon alfa. HBV reactivation usually occurred within 4–8 weeks after initiation of HCV treatment.

Patients with HBV reactivation heterogeneous in terms of HCV genotype and baseline HBV disease. Some patients were HBsAg positive; others had serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive).

HBV reactivation also reported in patients receiving certain immunosuppressant or chemotherapeutic drugs; risk of reactivation associated with HCV DAAs may be increased in such patients.

Mechanism for HBV reactivation in coinfected patients receiving HCV DAAs unknown. Although HCV DAAs not known to cause immunosuppression, HBV reactivation in coinfected patients may result from a complex interplay of host immunologic responses in the setting of infection with 2 hepatitis viruses.

Prior to initiating treatment with an HCV DAA, including ledipasvir/sofosbuvir, screen all patients for evidence of current or prior HBV infection by measuring HBsAg, anti-HBs, and anti-HBc. If there is serologic evidence of HBV infection, measure baseline HBV DNA level.

In all patients with evidence of current or prior HBV infection, monitor for clinical and laboratory signs (i.e., HBsAg, HBV DNA levels, serum aminotransferase and bilirubin concentrations) of hepatitis flare or HBV reactivation during and after treatment with HCV DAAs. Initiate appropriate management for HBV infection as clinically indicated.

Advise coinfected patients to immediately contact a clinician if they develop any signs or symptoms of serious liver injury. (See Advice to Patients.)

When making decisions regarding HBV monitoring or HBV treatment in coinfected patients, consult a clinician with expertise in managing HBV infection.

Sensitivity Reactions

Angioedema and rash, sometimes with blisters or angioedema-like swelling, reported during postmarketing experience.

Other Warnings/Precautions

Cardiovascular Effects

Postmarketing reports of symptomatic bradycardia, including cases requiring pacemaker intervention, in patients receiving amiodarone concomitantly with ledipasvir/sofosbuvir. Fatal cardiac arrest reported in one patient.

In most reported cases, bradycardia occurred within hours to days after HCV treatment initiated in patients receiving amiodarone (also has been observed up to 2 weeks after initiation of HCV treatment) and resolved after HCV treatment discontinued. Mechanism for this adverse cardiovascular effect unknown.

Patients who may be at increased risk for symptomatic bradycardia if amiodarone used concomitantly with ledipasvir/sofosbuvir include those also receiving a β-adrenergic blocking agent, those with underlying cardiac comorbidities, and/or those with advanced liver disease.

Concomitant use of amiodarone with ledipasvir/sofosbuvir not recommended.

If there are no alternative HCV treatment options and regimen of ledipasvir/sofosbuvir must be used in a patient receiving amiodarone, advise patient about the risk of serious bradycardia before initiating HCV treatment. Perform cardiac monitoring in an inpatient setting during first 48 hours of concomitant use of amiodarone and ledipasvir/sofosbuvir; heart rate monitoring should then be performed daily (outpatient or self-monitoring) through at least the first 2 weeks of concomitant use. Similar cardiac monitoring recommended in patients who discontinued amiodarone just prior to initiation of ledipasvir/sofosbuvir or if there are no other treatment options and amiodarone must be initiated in a patient already receiving ledipasvir/sofosbuvir.

Advise patients receiving amiodarone concomitantly with ledipasvir/sofosbuvir to immediately contact a clinician if signs or symptoms of bradycardia (e.g., near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, memory problems) develop.

Interactions

Concomitant use of ledipasvir/sofosbuvir and inducers of the P-glycoprotein (P-gp) transport system (e.g., rifampin, St. John's wort) not recommended. (See Interactions.)

Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens

Consider cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination (i.e., ledipasvir, sofosbuvir). Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for both drugs.

When used in conjunction with ribavirin, consider that ribavirin may cause fetal toxicity and/or death. Extreme care must be taken to avoid pregnancy in female patients and female partners of male patients receiving a ribavirin-containing regimen. Obtain a negative pregnancy test for female patients of childbearing potential immediately prior to initiating ribavirin; perform pregnancy tests periodically during and for 6 months after ribavirin treatment is completed. Women of childbearing potential (and their male partners) and male patients (and their female partners) must use effective contraception during and for 6 months after ribavirin treatment is completed.

Specific Populations

Pregnancy

Adequate data regarding use of ledipasvir/sofosbuvir in pregnant women not available. In animal studies, neither ledipasvir nor sofosbuvir affected fetal development at dosages tested.

When used in conjunction with ribavirin, consider that ribavirin is contraindicated in pregnant women and male partners of pregnant women. (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

Lactation

Not known whether ledipasvir, sofosbuvir, or their metabolites distribute into human milk, affect milk production, or affect breast-fed child.

Predominant metabolite of sofosbuvir (GS-331007) distributed into milk in rats; ledipasvir detected in plasma of suckling rat pups. No apparent effects on the nursing pups.

Consider benefits of breast-feeding and importance of the drug to the woman; also consider potential adverse effects on the breast-fed child from the drug or underlying maternal condition.

When used in conjunction with ribavirin, consider potential for adverse reactions to ribavirin in nursing infants. (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

Pediatric Use

Safety and efficacy not established in pediatric patients <3 years of age.

Safety and efficacy for treatment of HCV genotype 1 or 4 infection in treatment-naive and previously treated pediatric patients ≥3 years of age without cirrhosis or with compensated cirrhosis (Child-Pugh class A) have been established in an open-label clinical study.

Safety and efficacy for treatment of HCV genotype 1 infection in pediatric patients ≥3 years of age with decompensated cirrhosis (Child-Pugh class B or C) and for treatment of HCV genotype 1 or 4 infection in pediatric patients ≥3 years of age who are liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh class A) are supported by pharmacokinetic data indicating that ledipasvir, sofosbuvir, and GS-331007 exposures in pediatric patients ≥3 years of age with HCV genotype 1, 3, or 4 infection are similar to exposures in adults.

Safety and efficacy for treatment of HCV genotype 5 or 6 infection in pediatric patients ≥3 years of age are supported by pharmacokinetic data indicating that ledipasvir, sofosbuvir, and GS-331007 exposures in pediatric patients ≥3 years of age with HCV genotype 1, 3, or 4 infection are similar to exposures in adults.

Adverse effects in pediatric patients ≥3 years of age are similar to those observed in adults.

Data not available regarding safety and pharmacokinetics in pediatric patients with renal impairment.

Geriatric Use

No overall differences in safety and efficacy in patients ≥65 years of age compared with younger adults, but increased sensitivity in some older individuals cannot be ruled out.

Hepatic Impairment

Severe hepatic impairment (Child-Pugh class C) without HCV infection: Ledipasvir exposure similar to exposure in individuals with normal hepatic function.

HCV-infected individuals with moderate or severe hepatic impairment (Child-Pugh class B or C): Increased sofosbuvir and GS-331007 exposures compared with exposures in individuals with normal hepatic function.

When ledipasvir/sofosbuvir is used in conjunction with ribavirin in patients with decompensated cirrhosis (Child-Pugh class B or C), clinical and hepatic laboratory monitoring recommended as clinically indicated.

Data not available regarding safety of ledipasvir/sofosbuvir in patients with decompensated cirrhosis and severe renal impairment, including those requiring dialysis.

Renal Impairment

Severe renal impairment without HCV infection: Ledipasvir exposure similar to exposure in healthy individuals; substantially increased sofosbuvir and GS-331007 exposures compared with exposures in individuals with normal renal function.

Severe renal impairment or end-stage renal disease (ESRD) requiring hemodialysis without HCV infection: Sofosbuvir and GS-331007 plasma exposures substantially higher compared with exposures in individuals with normal renal function.

Data not available regarding safety of ledipasvir/sofosbuvir in patients with severe renal impairment, including those requiring dialysis, who also have decompensated cirrhosis.

HCV-infected with HIV Coinfection

Safety profile of ledipasvir/sofosbuvir in individuals with HCV genotype 1 or 4 infection and HIV-1 coinfection generally comparable to that reported in HCV-infected individuals without HIV-1 coinfection.

Common Adverse Effects

Ledipasvir/sofosbuvir (≥5%): Fatigue, headache, nausea, diarrhea, abdominal pain, insomnia or sleep disorder, irritability, rash, pruritus, dry skin, arthralgia, myalgia, back pain, asthenia, cough, upper respiratory tract infection, dizziness.

Ledipasvir/sofosbuvir in conjunction with ribavirin (≥5%): Fatigue, headache, nausea, diarrhea, insomnia, asthenia, cough, bronchitis, dyspnea, irritability, pruritus, dry skin, myalgia, decreased hemoglobin.

Drug Interactions

Ledipasvir inhibits P-gp transport system. Ledipasvir and sofosbuvir are substrates of P-gp.

Ledipasvir inhibits breast cancer resistance protein (BCRP). Ledipasvir and sofosbuvir are substrates of BCRP.

At concentrations exceeding those achieved in clinical settings, ledipasvir inhibits organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and the bile salt export pump (BSEP).

The following drug interactions are based on studies using ledipasvir/sofosbuvir, ledipasvir alone, or sofosbuvir alone. When ledipasvir/sofosbuvir used, consider interactions associated with both drugs in the fixed combination.

Drugs Affecting or Affected by P-glycoprotein Transport System

P-gp substrates: Concomitant use of ledipasvir and P-gp substrates may increase intestinal absorption of such drugs.

P-gp inducers: Possible decreased ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect. Concomitant use not recommended.

Drugs Affecting or Affected by Breast Cancer Resistance Protein

BCRP substrates: Concomitant use of ledipasvir and BCRP substrates may increase intestinal absorption of such drugs.

Inhibitors of BCRP: Possible increased plasma concentrations of ledipasvir and sofosbuvir without increase in plasma concentrations of GS-331007.

Specific Drugs

Ledipasvir and Sofosbuvir Pharmacokinetics

Absorption

Bioavailability

Following oral administration of ledipasvir/sofosbuvir in adults, peak plasma concentrations of ledipasvir occur approximately 4–4.5 hours after a dose. Peak plasma concentrations and AUC of ledipasvir are 32 and 24% lower, respectively, in HCV-infected adults compared with healthy adults.

Following oral administration of ledipasvir/sofosbuvir in adults, peak plasma concentrations of sofosbuvir and predominant sofosbuvir metabolite (GS-331007) occur approximately 0.8–1 and 3.5–4 hours, respectively, after a dose; GS-331007 accounts for >90% of total systemic exposure. Peak plasma concentrations and AUC of sofosbuvir and GS-331007 are similar in HCV-infected and healthy adults.

Food

Administration of ledipasvir/sofosbuvir with moderate-fat (approximately 600 kcal, 25–30% fat) or high-fat (approximately 1000 kcal, 50% fat) meal does not substantially affect ledipasvir or GS-331007 exposures relative to administration in fasting state; sofosbuvir peak plasma concentrations not affected, but AUC is increased approximately twofold.

Special Populations

Ledipasvir: In individuals with severe hepatic impairment (Child-Pugh class C) without HCV infection, AUC of ledipasvir after single 90-mg dose is similar to that observed in individuals with normal hepatic function.

Sofosbuvir: In HCV-infected individuals with moderate or severe hepatic impairment (Child-Pugh class B or C), sofosbuvir AUC is 126 or 143% higher, respectively, compared with individuals with normal hepatic function; GS-331007 AUC is 18 or 9% higher, respectively.

Ledipasvir: In individuals with severe renal impairment without HCV infection, no clinically important differences in ledipasvir pharmacokinetics after single 90-mg dose compared with healthy individuals.

Sofosbuvir: In individuals with mild, moderate, or severe renal impairment without HCV infection, sofosbuvir AUC after single 400-mg dose is 61, 107, or 171% higher, respectively, compared with individuals with normal renal function; GS-331007 AUC is 55, 88, or 451% higher, respectively.

Population pharmacokinetic analysis in HCV-infected individuals indicates cirrhosis does not substantially affect ledipasvir, sofosbuvir, or GS-331007 exposures.

Population pharmacokinetic analysis in HCV-infected individuals indicates peak plasma concentrations and AUC of ledipasvir are 58 and 77% higher, respectively, in females than in males; not considered clinically important. Gender did not affect sofosbuvir or GS-331007 exposures.

Population pharmacokinetic analysis indicates that age (range 18–80 years) and race do not have clinically important effects on ledipasvir, sofosbuvir, or GS-331007 exposures.

Pediatric patients ≥3 years of age with HCV genotype 1, 3, or 4 infection: Pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 comparable to those in adults. Pharmacokinetics not established in pediatric patients <3 years of age.

Distribution

Plasma Protein Binding

Ledipasvir: >99.8%.

Sofosbuvir: Approximately 61–65%; GS-331007 has minimal protein binding.

Elimination

Metabolism

Ledipasvir: Slow oxidative metabolism occurs by unknown mechanism; systemic exposure is almost exclusively the parent drug.

Sofosbuvir: Prodrug that undergoes intracellular metabolic activation in the liver (hydrolysis by human cathepsin A [CatA] or carboxylesterase 1 [CES1], phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 [HINT1], and phosphorylation by pyrimidine nucleotide biosynthesis pathway). Results in formation of pharmacologically active metabolite, GS-461203. Desphosphorylation subsequently occurs leading to formation of GS-331007 (the predominant circulating metabolite); GS-331007 has no anti-HCV activity.

Elimination Route

Ledipasvir: Major route of elimination is biliary excretion. Following single 90-mg oral dose, 86% excreted in feces (70% as unchanged ledipasvir, 2.2% as the oxidative metabolite); 1% excreted in urine.

Sofosbuvir: Major route of elimination is renal clearance. Following single 400-mg oral dose, 80% eliminated in urine (mainly as GS-331007), 14% excreted in feces, and 2.5% in expired air.

Half-life

Ledipasvir: 47 hours.

Sofosbuvir: 0.5 hours; GS-331007 has half-life of 27 hours.

Special Populations

Ledipasvir: Removal by hemodialysis unlikely since highly bound to plasma protein.

Sofosbuvir: Hemodialysis (4-hour session) removes approximately 18% of dose.

Stability

Storage

Oral

Film-coated Tablets

Room temperature <30ºC.

Dispense only in original container.

Pellets

Single-use packets: Room temperature <30ºC.

After mixing with soft food, use within 30 minutes; do not store or use any leftover mixture. (See Administration under Dosage and Administration.)

Actions and Spectrum

• Ledipasvir/sofosbuvir is a fixed combination of 2 HCV antivirals. Ledipasvir is an HCV NS5A replication complex inhibitor (NS5A inhibitor) and sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor.

• Ledipasvir and sofosbuvir are both direct-acting antivirals (DAAs) with activity against HCV. No in vitro evidence of antagonistic anti-HCV effects between the drugs in HCV replicon studies.

• Ledipasvir targets HCV NS5A protein, which is required for viral replication. In vitro studies using cell-based replicon assays indicate ledipasvir has activity against HCV genotypes 1a and 1b. Also has some antiviral activity against HCV genotypes 4a, 5a, and 6a, but substantially lower activity against HCV genotype 6e.

• Sofosbuvir is a prodrug that undergoes metabolic activation in the liver to a pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by NS5B polymerase; acts as RNA chain terminator. In vitro studies using biochemical and cell-based replicon assays indicate GS-461203 has activity against HCV genotypes 1a, 1b, 4a, 5a, and 6a.

• Certain amino acid substitutions in NS5A of HCV genotype 1a (e.g., Y93H, Q30E) and genotype 1b (e.g., Y93H) have been selected in cell culture and have been associated with reduced susceptibility to ledipasvir in vitro in replicon studies. Treatment-emergent NS5A ledipasvir resistance-associated substitutions, including K24R, M28T/V, Q30R/H/K/L, L31M/V, H58D/P, and/or Y93H/N/C in HCV genotype 1a and L31V/M/I, R30Q, and/or Y93H/N in HCV genotype 1b, have been detected in patients who experienced virologic failure in clinical trials; some of these patients also had baseline NS5A polymorphisms at resistance-associated amino acid positions. In clinical trials evaluating ledipasvir/sofosbuvir in patients with HCV genotype 4, 5, or 6 infection, patients with relapse who had NS5A sequencing data available had pretreatment NS5A resistance-associated polymorphisms (single or combinations at positions 24, 28, 30, 31 and 58); NS5A resistance-associated substitutions Y93C or L28V emerged posttreatment in a few of the patients with HCV genotype 4 relapse who also had NS5A polymorphisms pretreatment.

• Certain amino acid substitutions in NS5B polymerase of HCV genotypes 1b, 4a, 5a, and 6a have been selected in cell culture and have been associated with reduced susceptibility to sofosbuvir in vitro in replicon studies. In all replicon genotypes tested, S282T substitution was associated with reduced susceptibility to sofosbuvir; in genotypes 5 and 6 replicons, M289L substitution developed along with the S282T substitution. Although clinical importance unknown, treatment-emergent NS5B resistance-associated amino acid substitutions (e.g., L159, V321, D61G, A112T, E237G, S473T, S282T, L320V/I, V321I) were detected in clinical trials evaluating ledipasvir/sofosbuvir in patients with HCV genotype 1 infection. Treatment-emergent sofosbuvir resistance-associated NS5B substitution S282T reported at time of relapse in patients with HCV genotype 4, 5, or 6 infection who received ledipasvir/sofosbuvir in clinical trials; treatment-emergent nucleotide inhibitor substitution M289I also reported in a patient with HCV genotype 5 relapse.

• Cross-resistance between ledipasvir and other NS5A inhibitors is expected; efficacy of ledipasvir/sofosbuvir not established in patients in whom previous treatment with other regimens that included an NS5A inhibitor failed. Ledipasvir and sofosbuvir are both active against HCV with amino acid substitutions associated with resistance to other classes of HCV DAAs that have different mechanisms of action (e.g., HCV NS5B nonnucleoside inhibitors, NS3 protease inhibitors).

Advice to Patients

• Advise patients to take ledipasvir/sofosbuvir once daily (with or without food) on a regular dosing schedule.

• Inform patients that reactivation of HBV infection has occurred in coinfected patients being treated for HCV infection. Importance of informing clinician of any history of HBV infection or other liver problems (e.g., cirrhosis). Importance of immediately contacting a clinician if any signs or symptoms of serious liver injury (e.g., fatigue, weakness, loss of appetite, nausea and vomiting, yellowing of the eyes or skin, light-colored bowel movements) occur. (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Cautions.)

• Importance of taking recommended dosage of ledipasvir/sofosbuvir for the recommended duration of treatment; importance of not missing or skipping doses.

• If ledipasvir/sofosbuvir is used in a patient receiving amiodarone, advise patient about the risk of serious symptomatic bradycardia and importance of immediately contacting clinician if signs or symptoms of bradycardia (e.g., near-fainting or fainting, dizziness, lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, memory problems) occur. (See Cardiovascular Effects under Cautions.)

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. If ledipasvir/sofosbuvir is used in conjunction with ribavirin, advise men and women of importance of using effective contraception during and for 6 months after ribavirin therapy. (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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