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Harvoni

Generic Name: Ledipasvir and Sofosbuvir
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

Introduction

Antiviral;1 fixed combination containing ledipasvir (HCV NS5A replication complex inhibitor [NS5A inhibitor])1 5 6 and sofosbuvir (nucleotide analog HCV NS5B polymerase inhibitor).1

Uses for Harvoni

Chronic HCV Infection

Treatment of chronic HCV genotype 1, 4, 5, or 6 infection in treatment-naive (previously untreated) or previously treated adults, including those with cirrhosis (compensated or decompensated), liver transplant recipients, and those with HIV coinfection.1 2 3 4 9 10 119

Used alone or in conjunction with ribavirin, depending on HCV genotype and certain patient factors (e.g., presence of compensated or decompensated cirrhosis, liver transplantation).1 2 3 4 9 10 119

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information.119 Information from the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and International Antiviral Society–USA (IAS–USA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at .119

Harvoni Dosage and Administration

General

  • For treatment of chronic HCV infection, ledipasvir/sofosbuvir is used alone or in conjunction with ribavirin.1

  • Base specific regimen and duration of treatment on HCV genotype and certain patient factors (e.g., presence of compensated or decompensated cirrhosis, liver transplantation).1 Consider that relapse rates following treatment are affected by baseline host and viral factors and differ between treatment durations for certain subgroups.1

  • Prior to and during treatment, perform appropriate laboratory tests to evaluate liver function, especially in patients with decompensated cirrhosis receiving a regimen of ledipasvir/sofosbuvir in conjunction with ribavirin.1 (See Hepatic Impairment under Cautions.)

Administration

Oral Administration

Administer orally once daily without regard to food.1

Dosage

Available as fixed-combination tablets containing 90 mg of ledipasvir and 400 mg of sofosbuvir.1

Adults

Treatment of Chronic HCV Infection
HCV Genotype 1 Infection
Oral

1 tablet (ledipasvir 90 mg and sofosbuvir 400 mg) once daily.1

Use alone in patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A);1 use in conjunction with ribavirin in those with decompensated cirrhosis (Child-Pugh class B or C) and in liver transplant recipients.1 Treatment duration of 12 weeks recommended for most patients;1 treatment duration of 24 weeks recommended in previously treated patients with compensated cirrhosis (Child-Pugh class A).1 (See Table 1.)

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.1 Some experts state that treatment duration <12 weeks should be used with caution and at the clinician's discretion.119

Previously treated defined as patients who failed treatment with peginterferon alfa and ribavirin with or without an HCV protease inhibitor.1

Alternatively, a regimen of ledipasvir/sofosbuvir and ribavirin for a duration of 12 weeks can be considered in previously treated patients with cirrhosis who are eligible to receive ribavirin.1

In patients 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 <75 kg or up to 1.2 g daily for those ≥75 kg); give ribavirin daily dosage in 2 divided doses with food.1 If ribavirin starting dosage not well tolerated, reduce dosage as clinically indicated based on hemoglobin levels.1

Use weight-based ribavirin dosage (1 g daily for patients ≥75 kg or 1.2 g daily for those ≥75 kg); give ribavirin daily dosage in 2 divided doses with food.1

Table 1. Recommended Treatment Regimen and Duration of Ledipasvir/Sofosbuvir for HCV Genotype 1 Infection.1

Patient Type

Treatment Regimen

Duration of Treatment

Treatment-naive without cirrhosis

Ledipasvir/sofosbuvir

12 weeks

Treatment-naive with compensated cirrhosis (Child-Pugh class A)

Ledipasvir/sofosbuvir

12 weeks

Previously treated without cirrhosis

Ledipasvir/sofosbuvir

12 weeks

Previously treated with compensated cirrhosis (Child-Pugh class A)

Ledipasvir/sofosbuvir

24 weeks

Treatment-naive or previously treated with decompensated cirrhosis (Child-Pugh class B or C)

Ledipasvir/sofosbuvir and ribavirin

12 weeks

Treatment-naive or previously treated liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh class A)

Ledipasvir/sofosbuvir and ribavirin

12 weeks

HCV Genotype 4 Infection
Oral

1 tablet (ledipasvir 90 mg and sofosbuvir 400 mg) once daily.1

Use alone in patients without cirrhosis or in those with compensated cirrhosis (Child-Pugh class A);1 use in conjunction with ribavirin in liver transplant recipients.1 (See Table 2.)

Previously treated defined as patients who failed treatment with peginterferon alfa and ribavirin with or without an HCV protease inhibitor.1

Use weight-based ribavirin dosage (1 g daily for patients <75 kg or 1.2 g daily for those ≥75 kg); give ribavirin daily dosage in 2 divided doses with food.1

Table 2. Recommended Treatment Regimen and Duration of Ledipasvir/Sofosbuvir for HCV Genotype 4 Infection.1

Patient Type

Treatment Regimen

Duration of Treatment

Treatment-naive without cirrhosis or with compensated cirrhosis (Child-Pugh class A)

Ledipasvir/sofosbuvir

12 weeks

Previously treated without cirrhosis or with compensated cirrhosis (Child-Pugh class A)

Ledipasvir/sofosbuvir

12 weeks

Treatment naive or previously treated liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh class A)

Ledipasvir/sofosbuvir and ribavirin

12 weeks

HCV Genotype 5 or 6 Infection
Oral

1 tablet (ledipasvir 90 mg and sofosbuvir 400 mg) once daily for 12 weeks.1 (See Table 3.)

Previously treated defined as patients who failed treatment with peginterferon alfa and ribavirin with or without an HCV protease inhibitor.1

Table 3. Recommended Treatment Regimen and Duration of Ledipasvir/Sofosbuvir for HCV Genotype 5 or 6 Infection.1

Patient Type

Treatment Regimen

Duration of Treatment

Treatment-naive without cirrhosis or with compensated cirrhosis (Child-Pugh class A)

Ledipasvir/sofosbuvir

12 weeks

Previously treated without cirrhosis or with compensated cirrhosis (Child-Pugh class A)

Ledipasvir/sofosbuvir

12 weeks

HCV-infected with HIV Coinfection.
Oral

HCV genotype 1, 4, 5, or 6: Use same ledipasvir/sofosbuvir dosage and same HCV genotype-specific multiple-drug regimen and duration of treatment recommended for HCV-infected patients without HIV coinfection.1 (See Table 1, Table 2, and Table 3.)

Special Populations

Hepatic Impairment

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C): Dosage adjustments not needed.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment: Dosage adjustments not needed.1

Severe renal impairment (estimated GFR <30 mL/minute per 1.73 m2) or end-stage renal disease (ESRD): Dosage recommendations not available;1 safety and efficacy not established in such patients.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustments not needed.1

Cautions for Harvoni

Contraindications

  • If ledipasvir/sofosbuvir used in conjunction with ribavirin, the contraindications to ribavirin also apply.1 (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Rash, sometimes with blisters or angioedema-like swelling, reported during postmarketing experience.1

Cardiovascular Effects

Postmarketing reports of symptomatic bradycardia, including cases requiring pacemaker intervention, in patients receiving amiodarone concomitantly with ledipasvir/sofosbuvir.1 23 Fatal cardiac arrest reported in one patient.1

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.1 Mechanism for this adverse cardiovascular effect unknown.1

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.1

Concomitant use of amiodarone with ledipasvir/sofosbuvir not recommended.1

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.1 Perform cardiac monitoring in an inpatient setting during first 48 hours of concomitant use of amiodarone and ledipasvir/sofosbuvir;1 heart rate monitoring should then be performed daily (outpatient or self-monitoring) through at least the first 2 weeks of concomitant use.1 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.1

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.1

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.1 (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.1 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for both ledipasvir and sofosbuvir.1

Do not use ledipasvir/sofosbuvir concomitantly with any other preparation containing sofosbuvir.1

When used in conjunction with ribavirin, consider that ribavirin may cause fetal toxicity and/or death.349 377 Extreme care must be taken to avoid pregnancy in female patients and female partners of male patients receiving a ribavirin-containing regimen.349 377 Obtain a negative pregnancy test for female patients of childbearing potential immediately prior to initiating ribavirin;349 377 perform pregnancy tests monthly during and for 6 months after ribavirin treatment is completed.349 377 Women of childbearing potential (and their male partners) and male patients (and their female partners) must use at least 2 forms of effective contraception during and for 6 months after ribavirin treatment is completed.349 377

Specific Populations

Pregnancy

Adequate data regarding use of ledipasvir/sofosbuvir in pregnant women not available.1 In animal studies, neither ledipasvir nor sofosbuvir affected fetal development at dosages tested.1

When used in conjunction with ribavirin, consider that ribavirin is contraindicated in pregnant women and male partners of pregnant women.1 349 377 (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

Lactation

Not known whether ledipasvir/sofosbuvir and metabolites distributed into human milk.1

Predominant metabolite of sofosbuvir (GS-331007) distributed into milk in rats;1 ledipasvir detected in plasma of suckling rat pups.1 No apparent effects on the nursing pups.1

Consider benefits of breast-feeding and importance of the drug to the woman;1 also consider potential adverse effects on the breast-fed child from the drug or underlying maternal condition.1

When used in conjunction with ribavirin,1 consider potential for adverse reactions to ribavirin in nursing infants and discontinue nursing or the ribavirin-containing regimen.349 377 (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

Geriatric Use

No overall differences in safety and efficacy in patients ≥65 years of age compared with younger adults,1 but increased sensitivity in some older individuals cannot be ruled out.1

Hepatic Impairment

Severe hepatic impairment (Child-Pugh class C) without HCV infection: Ledipasvir exposure similar to exposure in individuals similar to exposure in individuals with normal hepatic function.1

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.1

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 is recommended as clinically indicated.1

Renal Impairment

Severe renal impairment (estimated GFR <30 mL/minute per 1.73 m2) or ESRD requiring hemodialysis: Safety and efficacy not established.1

Severe renal impairment without HCV infection: Ledipasvir exposure similar to exposure in healthy individuals;1 substantially increased sofosbuvir and GS-331007 exposures compared with exposures in individuals with normal renal function.1

HCV-infected with HIV Coinfection

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

Common Adverse Effects

Ledipasvir/sofosbuvir: Fatigue,1 2 3 4 9 10 headache,1 2 3 4 9 10 nausea,1 2 3 4 9 diarrhea,1 2 3 4 9 10 abdominal pain,10 insomnia or sleep disorder,1 2 3 4 9 irritability,1 2 9 rash,2 4 pruritus,2 dry skin,9 arthralgia,3 4 9 10 myalgia,1 9 10 back pain,9 asthenia,2 9 10 cough,1 2 4 9 10 upper respiratory tract infection,4 9 10 dizziness.1 4 10

Ledipasvir/sofosbuvir in conjunction with ribavirin: Fatigue,9 headache,1 9 nausea,9 diarrhea,9 insomnia,9 asthenia,1 9 cough,1 9 bronchitis,9 dyspnea,1 irritability,1 9 pruritus,9 dry skin,9 myalgia,9 decreased hemoglobin.1

Interactions for Harvoni

Ledipasvir inhibits P-gp transport system.1 Ledipasvir and sofosbuvir are substrates of P-gp.1

Ledipasvir inhibits breast cancer resistance protein (BCRP).1 Ledipasvir and sofosbuvir are substrates of BCRP.1

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

The following drug interactions are based on studies using ledipasvir/sofosbuvir, ledipasvir alone, or sofosbuvir alone.1 When ledipasvir/sofosbuvir used, consider interactions associated with both drugs in the fixed combination.1

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.1

P-gp inducers: Possible decreased ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect.1 Concomitant use not recommended.1

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.1

Inhibitors of BCRP: Possible increased plasma concentrations of ledipasvir and sofosbuvir without increase in plasma concentrations of GS-331007.1

Specific Drugs

Drug

Interaction

Comments

Abacavir

Abacavir: Clinically important pharmacokinetic interactions not expected1

Fixed combination of abacavir and lamivudine (abacavir/lamivudine): No clinically important effects on pharmacokinetics of abacavir, lamivudine, ledipasvir, or sofosbuvir8

Antacids (aluminum, magnesium hydroxide)

Decreased ledipasvir concentrations expected;1 increased gastric pH decreases ledipasvir solubility1

Take antacids 4 hours before or after ledipasvir/sofosbuvir1

Antiarrhythmic agents (amiodarone)

Amiodarone: Concomitant use with ledipasvir/sofosbuvir may result in serious symptomatic bradycardia1 23 (mechanism unknown);1 effect on amiodarone, ledipasvir, and sofosbuvir concentrations unknown1

Amiodarone: Concomitant use with ledipasvir/sofosbuvir not recommended;1 if concomitant use required, patient counseling and cardiac monitoring required1 (see Cardiovascular Effects under Cautions)

Anticonvulsants (carbamazepine, oxcarbazepine, phenytoin, phenobarbital)

Carbamazepine, oxcarbazepine, phenytoin, phenobarbital: Decreased ledipasvir and sofosbuvir concentrations expected;1 may lead to reduced therapeutic effect1

Carbamazepine, oxcarbazepine, phenytoin, phenobarbital: Concomitant use with ledipasvir/sofosbuvir not recommended1

Antimycobacterial agents (rifabutin, rifampin, rifapentine)

Rifabutin, rifampin, rifapentine: Decreased ledipasvir and sofosbuvir concentrations expected;1 may lead to reduced therapeutic effect1

Rifabutin, rifampin, rifapentine: Concomitant use with ledipasvir/sofosbuvir not recommended1

Atazanavir

Ritonavir-boosted atazanavir: Increased atazanavir and ledipasvir AUCs; no clinically important effects on pharmacokinetics of sofosbuvir1 200

Fixed combination of atazanavir and cobicistat (atazanavir/cobicistat): Clinically important pharmacokinetic interactions not expected200

HIV antiretroviral regimens that include tenofovir disoproxil fumarate (tenofovir DF) and ritonavir-boosted atazanavir or atazanavir/cobicistat: Possible increased tenofovir concentrations if used with ledipasvir/sofosbuvir;1 200 safety of increased tenofovir concentrations not established1

Ritonavir-boosted atazanavir: Dosage adjustments not needed200

Atazanavir/cobicistat: Dosage adjustments not needed200

HIV antiretroviral regimens that include tenofovir DF and ritonavir-boosted atazanavir or atazanavir/cobicistat: Consider alternative HCV treatment or alternative antiretroviral therapy;1 200 if concomitant use necessary, monitor for tenofovir-associated adverse effects1 200

Darunavir

Ritonavir-boosted darunavir: No clinically important effects on pharmacokinetics of darunavir, ritonavir, ledipasvir, or sofosbuvir1 200

Fixed combination of darunavir and cobicistat (darunavir/cobicistat): Clinically important pharmacokinetic interactions not expected200

HIV antiretroviral regimens that include tenofovir DF and ritonavir-boosted darunavir or darunavir/cobicistat: Possible increased tenofovir concentrations if used with ledipasvir/sofosbuvir;1 200 safety of increased tenofovir concentrations not established1

Ritonavir-boosted darunavir: Dosage adjustments not needed200

Darunavir/cobicistat: Dosage adjustments not needed200

HIV antiretroviral regimens that include tenofovir DF and ritonavir-boosted darunavir or darunavir/cobicistat: Consider alternative HCV treatment or alternative antiretroviral therapy;1 200 if concomitant use necessary, monitor for tenofovir-associated adverse effects1 200

Digoxin

Possible increased digoxin concentrations1

Therapeutic concentration monitoring of digoxin recommended1

Dolutegravir

Dolutegravir: Clinically important pharmacokinetic interactions not expected1

HIV antiretroviral regimen of dolutegravir in conjunction with fixed combination of emtricitabine and tenofovir DF (emtricitabine/tenofovir DF): Increased tenofovir concentrations and AUC expected1

Efavirenz

Efavirenz: Possible decreased concentrations and AUC of ledipasvir;200 no clinically important effects on sofosbuvir or efavirenz pharmacokinetics1 200

Fixed combination of efavirenz, emtricitabine, and tenofovir DF (efavirenz/emtricitabine/tenofovir DF): Decreased ledipasvir concentrations and AUC and increased tenofovir concentrations and AUC;1 200 no clinically important effects on pharmacokinetics of efavirenz or sofosbuvir1 200

Efavirenz: Dosage adjustments not needed if efavirenz and ledipasvir/sofosbuvir used concomitantly200

HIV antiretroviral regimen that includes efavirenz in conjunction with emtricitabine and tenofovir DF: Monitor for tenofovir-associated adverse effects200

Elvitegravir

Elvitegravir with cobicistat (cobicistat-boosted elvitegravir): Increased concentrations and AUC of ledipasvir and cobicistat;8 no clinically important effects on pharmacokinetics of elvitegravir or sofosbuvir8

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir DF (EFV/c/FTC/TDF): Increased tenofovir and ledipasvir concentrations expected;1 200 safety of increased tenofovir concentrations not established1

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (EFV/c/FTC/TAF): No clinically important effects on any of the drugs1

Single-entity elvitegravir used in conjunction with a ritonavir-boosted HIV PI: Clinically important effect on elvitegravir concentrations not expected200

EVG/c/FTC/TDF: Concomitant use with ledipasvir/sofosbuvir not recommended1 200

Single-entity elvitegravir used in conjunction with a ritonavir-boosted HIV PI: Refer to dosage recommendations for the HIV PI200

Emtricitabine

Clinically important pharmacokinetic interactions not expected1

Estrogens/progestins

Oral contraceptive containing ethinyl estradiol and norgestimate: No clinically important effects on pharmacokinetics of ethinyl estradiol or norgestimate and its active metabolites (norelgestromin, norgestrel) when used concomitantly with ledipasvir or sofosbuvir;1 7 efficacy of the oral contraceptive not expected to be affected7

Etravirine

Clinically important interactions not expected200

Dosage adjustments not needed if etravirine and ledipasvir/sofosbuvir used concomitantly200

Fosamprenavir

HIV antiretroviral regimens that include ritonavir-boosted fosamprenavir and tenofovir DF: Possible increased tenofovir concentrations if used with ledipasvir/sofosbuvir;200 safety of increased tenofovir concentrations not established1

HIV antiretroviral regimens that include ritonavir-boosted fosamprenavir and tenofovir DF: Consider alternative HCV treatment or alternative antiretroviral therapy;200 if concomitant use necessary, monitor for tenofovir-associated adverse effects200

Histamine H2-receptor antagonists

Decreased ledipasvir concentrations expected;1 increased gastric pH decreases ledipasvir solubility1

Administer H2-antagonists concomitantly with or 12 hours apart from ledipasvir/sofosbuvir;1 do not exceed H2-antagonist dosages comparable to famotidine 40 mg twice daily1

HMG-CoA reductase inhibitors (statins)

Pravastatin: Clinically important interactions not expected1

Rosuvastatin: Possible increased rosuvastatin concentrations and increased risk of myopathy and rhabdomyolysis1

Rosuvastatin: Concomitant use with ledipasvir/sofosbuvir not recommended1

Immunosuppressants (cyclosporine, tacrolimus)

Cyclosporine: Pharmacokinetics of cyclosporine not affected by ledipasvir or sofosbuvir;1 clinically important interactions not expected if used with ledipasvir/sofosbuvir1

Tacrolimus: Clinically important interactions not expected1

Lamivudine

Lamivudine: Clinically important pharmacokinetic interactions not expected1

Abacavir/lamivudine: No clinically important effects on pharmacokinetics of abacavir, lamivudine, ledipasvir, or sofosbuvir8

Lopinavir

HIV antiretroviral regimens that include fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) and tenofovir DF: Possible increased tenofovir concentrations if used concomitantly with ledipasvir/sofosbuvir;1 200 safety of increased tenofovir concentrations not established1

HIV antiretroviral regimens that include lopinavir/ritonavir and tenofovir DF: Consider alternative HCV treatment or alternative antiretroviral therapy;1 200 if concomitant use necessary, monitor for tenofovir-associated adverse effects1 200

Maraviroc

Clinically important effect on maraviroc pharmacokinetics not expected200

Some experts recommend maraviroc 300 mg twice daily in those receiving ledipasvir/sofosbuvir200

Methadone

Methadone pharmacokinetics not affected by ledipasvir or sofosbuvir;1 clinically important interactions not expected if used with ledipasvir/sofosbuvir1

Nevirapine

Clinically important drug interactions not expected200

Dosage adjustments not needed if nevirapine and ledipasvir/sofosbuvir used concomitantly200

Proton-pump inhibitors

Decreased ledipasvir concentrations expected;1 increased gastric pH decreases ledipasvir solubility1

Administer proton-pump inhibitors concomitantly with ledipasvir/sofosbuvir under fasting conditions;1 do not exceed proton-pump inhibitor dosages comparable to 20 mg of omeprazole once daily1

Raltegravir

No clinically important effects on pharmacokinetics of raltegravir, ledipasvir, or sofosbuvir1

Rilpivirine

Rilpivirine: No clinically important effects on pharmacokinetics of rilpivirine, ledipasvir, or sofosbuvir1

Fixed combination of emtricitabine, rilpivirine, and tenofovir DF (emtricitabine/rilpivirine/tenofovir DF): Increased tenofovir concentrations and AUC1 200

Rilpivirine: Dosage adjustments not needed if rilpivirine and ledipasvir/sofosbuvir used concomitantly200

HIV antiretroviral regimens that include emtricitabine/rilpivirine/tenofovir DF: Monitor for tenofovir-associated adverse effects200

Saquinavir

HIV antiretroviral regimens that include ritonavir-boosted saquinavir and tenofovir DF: Possible increased tenofovir concentrations if used with ledipasvir/sofosbuvir;200 safety of increased tenofovir concentrations not established1

HIV antiretroviral regimens that include ritonavir-boosted saquinavir and tenofovir DF: Consider alternative HCV treatment or alternative antiretroviral therapy;200 if concomitant use necessary, monitor for tenofovir-associated adverse effects200

Simeprevir

Increased ledipasvir and simeprevir concentrations1

Concomitant use of ledipasvir/sofosbuvir and simeprevir not recommended1

Sofosbuvir

Do not use ledipasvir/sofosbuvir with any other preparation containing sofosbuvir1

St. John's wort (Hypericum perforatum)

Decreased ledipasvir and sofosbuvir concentrations;1 may result in loss of therapeutic effect of ledipasvir/sofosbuvir1

Concomitant use with ledipasvir/sofosbuvir not recommended1

Tenofovir

EVG/c/FTC/TDF: Possible increased tenofovir concentrations if used with ledipasvir/sofosbuvir;1 safety of increased tenofovir concentrations not established1

HIV antiretroviral regimens that include tenofovir DF and a ritonavir-boosted HIV PI, atazanavir/cobicistat, or darunavir/cobicistat: Possible increased tenofovir concentrations if used with ledipasvir/sofosbuvir;1 200 safety of increased tenofovir concentrations not established1

EVG/c/FTC/TDF: Concomitant use with ledipasvir/sofosbuvir not recommended1 200

HIV antiretroviral regimens that include tenofovir DF and a ritonavir-boosted HIV PI, atazanavir/cobicistat, or darunavir/cobicistat: Consider alternative HCV treatment or alternative antiretroviral therapy;1 200 if concomitant use necessary, monitor for tenofovir-associated adverse effects1 200

HIV antiretroviral regimens that include tenofovir DF without a ritonavir-boosted HIV PI or cobicistat: Monitor for tenofovir-associated adverse effects1 200

Tipranavir

Ritonavir-boosted tipranavir: Decreased concentrations of ledipasvir and sofosbuvir expected;1 may lead to reduced therapeutic effect of ledipasvir/sofosbuvir1

Ritonavir-boosted tipranavir: Concomitant use with ledipasvir/sofosbuvir not recommended1 200

Verapamil

Clinically important interactions not expected1

Harvoni 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.1 Peak plasma concentrations and AUC of ledipasvir are 32 and 24% lower, respectively, in HCV-infected adults compared with healthy adults.1

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;1 GS-331007 accounts for >90% of total systemic exposure.1 Peak plasma concentrations and AUC of sofosbuvir and GS-331007 are similar in HCV-infected and healthy adults.1

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;1 sofosbuvir peak plasma concentrations not affected, but AUC is increased approximately twofold.1

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.1

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;1 GS-331007 AUC is 18 or 9% higher, respectively.1

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.1

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;1 GS-331007 AUC is 55, 88, or 451% higher, respectively.1

Population pharmacokinetic analysis in HCV-infected individuals indicates cirrhosis does not substantially affect ledipasvir, sofosbuvir, or GS-331007 exposures.1

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;1 not considered clinically important.1 Gender did not affect sofosbuvir or GS-331007 exposures.1

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.1

Distribution

Plasma Protein Binding

Ledipasvir: >99.8%.1

Sofosbuvir: Approximately 61–65%;1 GS-331007 has minimal protein binding.1

Elimination

Metabolism

Ledipasvir: Slow oxidative metabolism occurs by unknown mechanism;1 systemic exposure is almost exclusively the parent drug.1

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).1 Results in formation of pharmacologically active metabolite, GS-461203.1 Desphosphorylation subsequently occurs leading to formation of GS-331007 (the predominant circulating metabolite);1 GS-331007 has no anti-HCV activity.1

Elimination Route

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

Sofosbuvir: Major route of elimination is renal clearance.1 Following single 400-mg oral dose, 80% eliminated in urine (mainly as GS-331007), 14% excreted in feces, and 2.5% in expired air.1

Half-life

Ledipasvir: 47 hours.1

Sofosbuvir: 0.5 hours;1 GS-331007 has half-life of 27 hours.1

Special Populations

Ledipasvir: Removal by hemodialysis unlikely since highly bound to plasma protein.1

Sofosbuvir: Hemodialysis (4-hour session) removes approximately 18% of dose.1

Stability

Storage

Oral

Film-coated Tablets

Room temperature <30ºC.1

Dispense only in original container.1

Actions and Spectrum

  • Ledipasvir/sofosbuvir is a fixed combination of 2 HCV antivirals.1 Ledipasvir is an HCV NS5A replication complex inhibitor (NS5A inhibitor)1 5 6 and sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor.1

  • Ledipasvir and sofosbuvir are both direct-acting antivirals (DAAs) with activity against HCV.1 No in vitro evidence of antagonistic anti-HCV effects between the drugs in HCV replicon studies.1

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

  • 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;1 acts as RNA chain terminator.1 In vitro studies using biochemical and cell-based replicon assays indicate GS-461203 has activity against HCV genotypes 1a, 1b, 4a, 5a, and 6a.1

  • 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.1 6 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;1 some of these patients also had baseline NS5A polymorphisms at resistance-associated amino acid positions.1 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);1 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.1

  • 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.1 In all replicon genotypes tested, S282T substitution was associated with reduced susceptibility to sofosbuvir;1 in genotypes 5 and 6 replicons, M289L substitution developed along with the S282T substitution.1 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.1 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;1 treatment-emergent nucleotide inhibitor substitution M289I also reported in a patient with HCV genotype 5 relapse.1

  • Cross-resistance between ledipasvir and other NS5A inhibitors is expected;1 efficacy of ledipasvir/sofosbuvir not established in patients in whom previous treatment with other regimens that included an NS5A inhibitor failed.1 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).1

Advice to Patients

  • Advise patients to take ledipasvir/sofosbuvir once daily (with or without food) on a regular dosing schedule.1

  • Importance of taking recommended dosage of ledipasvir/sofosbuvir for the recommended duration of treatment;1 importance of not missing or skipping doses.1

  • 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.1 (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.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 If ledipasvir/sofosbuvir is used in conjunction with ribavirin, advise men and women of importance of using 2 forms of effective contraception during and for 6 months after ribavirin therapy.349 377 (See Precautions Related to Fixed Combinations and Multiple-drug Treatment Regimens under Cautions.)

  • Importance of informing patients of other important precautionary information.1 (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.

Ledipasvir and Sofosbuvir

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

Ledipasvir 90 mg and Sofosbuvir 400 mg

Harvoni

Gilead

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Gilead Sciences, Inc. Harvoni (ledipasvir and sofosbuvir) tablets prescribing information. Foster City, CA; 2016 Feb.

2. Afdhal N, Zeuzem S, Kwo P et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014; 370:1889-98. [PubMed 24725239]

3. Kowdley KV, Gordon SC, Reddy KR et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014; 370:1879-88. [PubMed 24720702]

4. Afdhal N, Reddy KR, Nelson DR et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014; 370:1483-93. [PubMed 24725238]

5. Link JO, Taylor JG, Xu L et al. Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection. J Med Chem. 2014; 57:2033-46. [PubMed 24320933]

6. Gentile I, Buonomo AR, Borgia F et al. Ledipasvir: a novel synthetic antiviral for the treatment of HCV infection. Expert Opin Investig Drugs. 2014; 23:561-71. [PubMed 24593285]

7. German P, Moorehead L, Pang P et al. Lack of a clinically important pharmacokinetic interaction between sofosbuvir or ledipasvir and hormonal oral contraceptives norgestimate/ethinyl estradiol in HCV-uninfected female subjects. J Clin Pharmacol. 2014; 54:1290-8. [PubMed 24925712]

8. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 205834Orig1s000. Clinical pharmacology and biopharmaceutics review. From FDA website.

9. Bourlière M, Bronowicki JP, de Ledinghen V et al. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS). Lancet Infect Dis. 2015; 15:397-404. [PubMed 25773757]

10. Abergel A, Asselah T, Metivier S et al. Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study. Lancet Infect Dis. 2016; :. [PubMed 26803446]

11. Naggie S, Cooper C, Saag M et al. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015; 373:705-13. [PubMed 26196665]

12. Efficacy and safety of ledipasvir/sofosbuvir fixed-dose combination in treatment-naive and treatment-experienced subjects with chronic genotype 4 or 5 infection. From ClinicalTrials.gov registry. Accessed 2014 Jun 5

23. US Food and Drug Administration. FDA drug safety communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir (Harvoni) or Sovaldi in combination with another direct acting antiviral. 2015 Mar 24. From FDA website.

119. American Association for the Study of Liver Diseases (AASLD). Recommendations for testing, managing, and treating hepatitis C. From the AASLD website. Accessed 2016 Mar 1.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (Jan 28, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website.

349. Merck Sharp & Dohme Corporation. Rebetol (ribavirin) capsules and oral solution prescribing information. Whitehouse Station, NJ; 2013 Nov.

377. Genentech. Copegus (ribavirin) tablets prescribing information. South San Francisco, CA; 2013 Feb.

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