Ledipasvir and Sofosbuvir

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Harvoni: Ledipasvir 45 mg and sofosbuvir 200 mg

Harvoni: Ledipasvir 90 mg and sofosbuvir 400 mg [contains fd&c yellow #6 aluminum lake]

Generic: Ledipasvir 90 mg and sofosbuvir 400 mg

Pharmacology

Mechanism of Action

Ledipasvir inhibits the HCV NS5A protein necessary for viral replication; sofosbuvir is a prodrug converted to its pharmacologically active form (GS-461203), inhibits NS5B RNA-dependent RNA polymerase, also essential for viral replication, and acts as a chain terminator.

Pharmacokinetics/Pharmacodynamics

Absorption

Ledipasvir and sofosbuvir are well absorbed

Metabolism

Ledipasvir: Slow oxidative metabolism via an unknown mechanism; Sofosbuvir: Hepatic; forms pharmacologically active nucleoside (uridine) analog triphosphate GS-461203; Dephosphorylation results in the formation of nucleoside inactive metabolite GS-331007

Excretion

Ledipasvir: Feces (~86%), urine (1%); Sofosbuvir: Urine (80%), feces (14%)

Time to Peak

Ledipasvir: 4 to 4.5 hours; Sofosbuvir: ~0.8 to 1 hour

Half-Life Elimination

Ledipasvir: 47 hours; Sofosbuvir: ~0.5 hours

Protein Binding

Ledipasvir: >99.8%; Sofosbuvir: ~61% to 65%

Use in Specific Populations

Special Populations: Renal Function Impairment

Sofosbuvir: Following a single 400 mg dose of sofosbuvir in HCV negative subjects with mild (eGFR ≥50 and <80 mL/minute/1.73 m²), moderate (eGFR ≥30 and <50 mL/minute/1.73 m²), severe renal impairment (eGFR <30 mL/minute/1.73 m²), and subjects with ESRD requiring hemodialysis the sofosbuvir AUC_0-∞ was 61%, 107%, and 171% higher in mild, moderate, and severe renal impairment than in subjects with normal renal function.

Use: Labeled Indications

Chronic hepatitis C: Treatment of chronic hepatitis C virus genotype 1, 4, 5, or 6 infection in adult and pediatric patients ≥3 years of age, without cirrhosis or with compensated cirrhosis; genotype 1 in adult patients with decompensated cirrhosis, in combination with ribavirin; and genotype 1 or 4 in adult liver transplant patients without cirrhosis or with compensated cirrhosis, in combination with ribavirin.

Use: Off Label

Chronic hepatitis C, genotype 1 or 4 (kidney transplant recipients)yes

Based on the AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, ledipasvir and sofosbuvir is recommended and effective for treatment of hepatitis C virus genotype 1 or 4 infection in kidney transplant recipients without cirrhosis or with compensated cirrhosis. Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Chronic hepatitis C, genotype 4, 5, or 6 (with decompensated cirrhosis)yes

Based on the AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, ledipasvir and sofosbuvir, with or without concomitant ribavirin, is recommended and effective for treatment of hepatitis C virus genotype 4, 5, or 6 infection in patients with decompensated cirrhosis, including patients who have prior sofosbuvir-based treatment failure. Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Chronic hepatitis C, genotype 5 or 6 (liver transplant recipients)yes

Based on the AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, ledipasvir and sofosbuvir, with concomitant ribavirin, is recommended and effective for treatment of hepatitis C virus genotype 5 or 6 infection in liver transplant recipients with or without cirrhosis (including decompensated cirrhosis). Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Contraindications

There are no contraindications listed in the US manufacturer’s labeling. If ledipasvir/sofosbuvir is administered with ribavirin, the contraindications to ribavirin also apply. See ribavirin manufacturer's information.

Canadian labeling: Hypersensitivity to any component of the formulation.

Dosage and Administration

Dosing: Adult

Chronic hepatitis C infection (monoinfection or coinfected with HIV-1): Oral:

Genotype 1:

Treatment-naive patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A) or peginterferon/ribavirin treatment-experienced patients without cirrhosis: One tablet once daily for 12 weeks. Note: Treatment-naive patients without cirrhosis who have hepatitis C virus RNA <6 million units/mL, are HIV uninfected, and nonblack may be considered for therapy of 8 weeks duration (AASLD/IDSA 2018).

Peginterferon/ribavirin treatment-experienced patients with compensated cirrhosis (Child-Pugh class A) (alternative regimen): One tablet once daily with concomitant ribavirin for 12 weeks (AASLD/IDSA 2018).

NS3 protease inhibitor + peginterferon/ribavirin treatment-experienced patients:

Without cirrhosis: One tablet once daily for 12 weeks (AASLD/IDSA 2018).

With compensated cirrhosis (Child-Pugh class A) (alternative regimen): One tablet once daily with concomitant ribavirin for 12 weeks (AASLD/IDSA 2018).

Non-NS5A inhibitor, sofosbuvir-containing regimen-experienced patients without cirrhosis (except in cases of simeprevir failure) (alternative regimen): One tablet once daily with concomitant ribavirin for 12 weeks (AASLD/IDSA 2018).

Decompensated cirrhosis (Child-Pugh class B or C): One tablet once daily with concomitant ribavirin for 12 weeks; if ribavirin ineligible, one tablet once daily for 24 weeks (AASLD/IDSA 2018).

Decompensated cirrhosis (Child-Pugh class B or C) in patients with prior sofosbuvir treatment failure: One tablet once daily with concomitant ribavirin for 24 weeks (AASLD/IDSA 2018).

Liver transplant recipients (treatment naive and treatment experienced) without cirrhosis or with compensated cirrhosis (Child-Pugh class A): One tablet once daily with concomitant ribavirin for 12 weeks (AASLD/IDSA 2018).

Liver transplant recipients with decompensated cirrhosis (Child-Pugh class B or C) (off-label use): One tablet once daily with concomitant ribavirin for 12 weeks (AASLD/IDSA 2018).

Kidney transplant recipients (treatment naive and treatment experienced) without cirrhosis or with compensated (Child-Pugh class A) cirrhosis (off-label use): One tablet once daily for 12 weeks (AASLD/IDSA 2018).

Genotype 4:

Treatment-naive patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A) and peginterferon/ribavirin treatment-experienced patients without cirrhosis: One tablet once daily for 12 weeks.

Peginterferon/ribavirin treatment-experienced patients with compensated cirrhosis (Child-Pugh class A) (alternative regimen): One tablet once daily with concomitant ribavirin for 12 weeks (AASLD/IDSA 2018).

Decompensated cirrhosis (Child-Pugh class B or C) (off-label use): One tablet once daily with concomitant ribavirin for 12 weeks; if ribavirin ineligible, one tablet once daily for 24 weeks (AASLD/IDSA 2018).

Decompensated cirrhosis (Child-Pugh class B or C) in patients with sofosbuvir treatment failure (off-label use): One tablet once daily with concomitant ribavirin for 24 weeks (AASLD/IDSA 2018).

Liver transplant recipients (treatment naive and treatment experienced) with compensated (Child-Pugh class A) cirrhosis or without cirrhosis: One tablet once daily with concomitant ribavirin for 12 weeks (AASLD/IDSA 2018).

Liver transplant recipients (treatment naive and treatment experienced) with decompensated cirrhosis (Child-Pugh class B or C) (off-label use): One tablet once daily with concomitant ribavirin for 12 weeks (AASLD/IDSA 2018).

Kidney transplant recipients (treatment naive and treatment experienced) without cirrhosis or with compensated (Child-Pugh class A) cirrhosis (off-label use): One tablet once daily for 12 weeks (AASLD/IDSA 2018).

Genotype 5 or 6:

Treatment-naive and peginterferon/ribavirin treatment-experienced patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A): One tablet once daily for 12 weeks (AASLD/IDSA 2018).

Decompensated cirrhosis (Child-Pugh class B or C) (off-label use): One tablet once daily with concomitant ribavirin for 12 weeks; if ribavirin ineligible, one tablet once daily for 24 weeks (AASLD/IDSA 2018).

Decompensated cirrhosis (Child-Pugh class B or C) in patients with sofosbuvir treatment failure: One tablet once daily with concomitant ribavirin for 24 weeks (AASLD/IDSA 2018).

Liver transplant recipients (treatment naive and treatment experienced) with or without cirrhosis, including decompensated cirrhosis (off-label use): One tablet once daily with concomitant ribavirin for 12 weeks (AASLD/IDSA 2018).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Prior to initiating therapy, test patient for evidence of hepatitis B infection (current or prior).

Chronic hepatitis C infection (monoinfection or co-infected with HIV-1): Children ≥3 years and Adolescents:

Patient weight:

<17 kg: Pellets: Oral: 33.75 mg ledipasvir/150 mg sofosbuvir once daily.

17 to <35 kg:Pellets, tablets: Oral: 45 mg ledipasvir/200 mg sofosbuvir once daily.

≥35 kg: Pellets, tablets: Oral: 90 mg ledipasvir/400 mg sofosbuvir once daily.

Duration of therapy dependent upon multiple factors (eg, genotype, hepatic function [cirrhosis/compensation], previous treatment and response). Note: Treatment-experienced patients are defined as those who have failed an interferon-based regimen.

Genotype 1:

Treatment-naive patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A) or treatment-experienced patients without cirrhosis: 12 weeks.

Treatment-experienced patients with compensated cirrhosis (Child-Pugh class A): 24 weeks.

Treatment-naive or treatment-experienced with decompensated cirrhosis (Child-Pugh class B or C): 12 weeks in combination with ribavirin.

Genotype 1 or 4: Treatment-naive or treatment-experienced liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 12 weeks in combination with ribavirin.

Genotype 4, 5, or 6: Treatment-naive and treatment-experienced patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 12 weeks.

Administration

Oral:

Tablets: Administer with or without food.

Pellets: Administer with or without food. May be sprinkled on 1 or more spoonfuls of nonacidic soft foods (eg, pudding, chocolate syrup, mashed potatoes, ice cream) at or below room temperature; gently mix. Swallow entire contents within 30 minutes of mixing; do not chew to avoid bitter aftertaste.

Storage

Tablets and pellets: Store below 30°C (86°F). Dispense in original packaging.

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. If used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Alpelisib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. Consider therapy modification

Amiodarone: Sofosbuvir may enhance the bradycardic effect of Amiodarone. Avoid combination

Antacids: May decrease the serum concentration of Ledipasvir. Management: Separate the administration of ledipasvir and antacids by 4 hours. Consider therapy modification

Antidiabetic Agents: Direct Acting Antiviral Agents (HCV) may enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Asunaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir. Avoid combination

AtorvaSTATin: Ledipasvir may enhance the adverse/toxic effect of AtorvaSTATin. Monitor therapy

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy

Cladribine: BCRP/ABCG2 Inhibitors may increase the serum concentration of Cladribine. Management: Avoid concomitant use of BCRP inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider dose reduction of the BCRP inhibitor and separation in the timing of administration. Consider therapy modification

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Monitor therapy

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Elagolix: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix. Avoid combination

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Monitor therapy

Grazoprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Grazoprevir. Avoid combination

Histamine H2 Receptor Antagonists: May decrease the serum concentration of Ledipasvir. Consider therapy modification

Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

Lefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Consider therapy modification

Lumacaftor and Ivacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor and Ivacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Modafinil: May decrease the serum concentration of Sofosbuvir. Avoid combination

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

OXcarbazepine: May decrease the serum concentration of Sofosbuvir. Avoid combination

OXcarbazepine: May decrease the serum concentration of Ledipasvir. Avoid combination

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Sofosbuvir. Avoid combination

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Ledipasvir. Avoid combination

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide. Monitor therapy

PHENobarbital: May decrease the serum concentration of Ledipasvir. Avoid combination

PHENobarbital: May decrease the serum concentration of Sofosbuvir. Avoid combination

Primidone: May decrease the serum concentration of Ledipasvir. Avoid combination

Primidone: May decrease the serum concentration of Sofosbuvir. Avoid combination

Proton Pump Inhibitors: May decrease the serum concentration of Ledipasvir. Management: PPI doses equivalent to omeprazole 20 mg or lower may be given with ledipasvir under fasted conditions. Administration with higher doses of PPIs, 2 hours after a PPI, or in combination with food and PPIs may reduce ledipasvir bioavailability. Consider therapy modification

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Revefenacin: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin. Avoid combination

Rifabutin: May decrease the serum concentration of Sofosbuvir. Avoid combination

Rifabutin: May decrease the serum concentration of Ledipasvir. Avoid combination

Rifapentine: May decrease the serum concentration of Sofosbuvir. Avoid combination

Rifapentine: May decrease the serum concentration of Ledipasvir. Avoid combination

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Rosuvastatin: Ledipasvir may increase the serum concentration of Rosuvastatin. Avoid combination

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Monitor therapy

Simeprevir: May increase the serum concentration of Ledipasvir. Ledipasvir may increase the serum concentration of Simeprevir. Avoid combination

Tacrolimus (Systemic): Ledipasvir may decrease the serum concentration of Tacrolimus (Systemic). Monitor therapy

Tacrolimus (Systemic): Sofosbuvir may decrease the serum concentration of Tacrolimus (Systemic). Monitor therapy

Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs. Monitor therapy

Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Monitor therapy

Tegaserod: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. Monitor therapy

Tenofovir Alafenamide: Sofosbuvir may increase the serum concentration of Tenofovir Alafenamide. Monitor therapy

Tenofovir Disoproxil Fumarate: Ledipasvir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Management: Avoidance of this combination is recommended under some circumstances. Refer to full monograph for details. Consider therapy modification

Tipranavir: May decrease the serum concentration of Ledipasvir. Avoid combination

Tipranavir: May decrease the serum concentration of Sofosbuvir. Avoid combination

Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Ubrogepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (if needed) of 50 mg when used with a P-gp inhibitor. Consider therapy modification

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vitamin K Antagonists (eg, warfarin): Direct Acting Antiviral Agents (HCV) may diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir. Avoid combination

Adverse Reactions

>10%:

Nervous system: Headache (11% to 29%), fatigue (10% to 18%)

Neuromuscular & skeletal: Asthenia (18% to 31%)

1% to 10%:

Gastrointestinal: Nausea (6% to 9%), increased serum lipase (>3 x ULN: ≤9%), diarrhea (3% to 7%)

Hepatic: Hyperbilirubinemia (>1.5 x ULN: ≤3%)

Nervous system: Irritability (8%), insomnia (3% to 6%), dizziness (5%), depression (<5%; including in subjects with preexisting history of psychiatric illness)

Neuromuscular & skeletal: Myalgia (9%), increased serum creatine kinase (≥10 x ULN: 1%)

Respiratory: Cough (5%), dyspnea (3%)

<1%, postmarketing, and/or case reports: Angioedema, reactivation of HBV, skin rash

Warnings/Precautions

Disease-related concerns:

• Diabetes: Rapid reduction in hepatitis C viral load during direct-acting antiviral (DAA) therapy for hepatitis C may lead to improvement in glucose metabolism in patients with diabetes, potentially resulting in symptomatic hypoglycemia if antidiabetic agents are continued at the same dose. Monitor for changes in glucose tolerance and inform patients of the risk of hypoglycemia during DAA therapy, particularly within the first 3 months. Modification of antidiabetic therapy may be necessary (Ciancio 2018; Dawood 2017; Hum 2017).
• Hepatitis B virus reactivation: [US Boxed Warning]: Hepatitis B virus (HBV) reactivation has been reported in hepatitis C virus (HCV)/HBV coinfected patients who were receiving or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy; some cases have resulted in fulminant hepatitis, hepatic failure, and death. Test all patients for evidence of current or prior HBV infection prior to initiation of ledipasvir/sofosbuvir; monitor HCV/HBV co-infected patients for hepatitis flare or HBV reactivation during treatment and post-treatment follow-up. Initiate treatment for HBV infection as clinically indicated. HBV reactivation has been reported in HBsAg positive patients and in patients with serologic evidence of resolved HBV infection (ie, HBsAg negative and anti-HBc positive) and is characterized by an abrupt increase in HBV replication manifested as a rapid increase in serum HBV DNA level; reappearance of HBsAg may occur in patients with resolved HBV infection. Risk of HBV reactivation may be increased in patients receiving certain immunosuppressants or chemotherapeutic agents.

Concurrent drug therapy issues:

• Amiodarone: Symptomatic bradycardia (some requiring pacemaker intervention) and fatal cardiac arrest has occurred in patients receiving amiodarone and ledipasvir/sofosbuvir. Bradycardia generally occurred within hours to days following coadministration, however some cases have occurred 2 weeks following the initiation of HCV treatment. The risk of bradycardia may be increased in patients taking beta blockers or patients with underlying cardiac comorbidities and/or advanced liver disease. Bradycardia generally resolves following discontinuation of ledipasvir/sofosbuvir. Coadministration of amiodarone and ledipasvir/sofosbuvir is not recommended. However, if patients have no treatment alternatives, patients should have inpatient cardiac monitoring for the first 48 hours, followed by daily outpatient or self-monitoring of heart rate for at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, cardiac monitoring (as described) is also recommended if amiodarone was discontinued just prior to beginning treatment with ledipasvir/sofosbuvir. Patients should seek medical attention immediately if they experience fainting or near-fainting, dizziness, lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems.
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Baseline (within 12 weeks prior to treatment initiation) CBC, INR, hepatic function (albumin, total and direct bilirubin, ALT, AST, alkaline phosphatase), calculated GFR; baseline (obtain any time prior to treatment initiation) hepatitis C virus (HCV) genotype and subtype, quantitative HCV viral load. During treatment, monitor CBC, serum creatinine, calculated GFR, hepatic function panel (after 4 weeks of therapy and as clinically indicated); quantitative HCV viral load testing (after 4 weeks of therapy and at 12 weeks after completion of therapy). If quantitative HCV viral load is detectable at treatment week 4, repeat testing is recommended after 2 additional weeks of treatment (treatment week 6) (AASLD/IDSA 2018). If used in combination with amiodarone (or in patients who discontinued amiodarone just prior to initiating ledipasvir/sofosbuvir), inpatient cardiac monitoring for the first 48 hours of coadministration, then outpatient or self-monitoring of heart rate daily through at least the first 2 weeks of treatment.

Hepatitis B surface antigen and hepatitis B core antibody prior to initiation; in patients with serologic evidence of hepatitis B virus (HBV) infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during treatment and during posttreatment follow-up.

Pregnancy

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies using ledipasvir or sofosbuvir.

Treatment of hepatitis C is not currently recommended to treat maternal infection or to decrease the risk of mother-to-child transmission during pregnancy (Tran 2016). HCV-infected females of childbearing potential should consider postponing pregnancy until therapy is complete to reduce the risk of HCV transmission (AASLD/IDSA 2018). When HCV infection is detected during pregnancy, treatment should be deferred until after delivery. Direct-acting antiviral medications should not be used in pregnant females outside of clinical trials until safety and efficacy information is available (SMFM [Hughes 2017]).

If used in combination with ribavirin, all warnings related to the use of ribavirin and pregnancy and/or contraception should be followed. Refer to the ribavirin monograph for additional information.

Patient Education

What is this drug used for?

• It is used to treat hepatitis C infection.

Frequently reported side effects of this drug

• Loss of strength and energy
• Headache
• Nausea
• Diarrhea
• Trouble sleeping
• Cough
• Muscle pain
• Irritability
• Dizziness

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.