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Ledipasvir and Sofosbuvir

Pronunciation

(le DIP as vir & soe FOS bue vir)

Index Terms

  • GS-5885
  • Ledipasvir/Sofosbuvir
  • Sofosbuvir and Ledipasvir

Dosage Forms

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

Tablet, Oral:

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

Brand Names: U.S.

  • Harvoni

Pharmacologic Category

  • Antihepaciviral, NS5A Inhibitor
  • Antihepaciviral, Polymerase Inhibitor (Anti-HCV)
  • NS5A Inhibitor
  • NS5B RNA Polymerase Inhibitor

Pharmacology

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.

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%

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 AUC0-inf 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 (HCV) genotype 1, 4, 5, or 6 infection in adult and pediatric patients ≥12 years or weighing ≥35 kg, 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.

Contraindications

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

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to any component of the formulation.

Dosing: Adult

Chronic hepatitis C (CHC) infection (monoinfection or co-infected with HIV-1): Oral: One tablet (ledipasvir 90 mg/sofosbuvir 400 mg) once daily.

Duration of therapy: Note: Treatment-experienced patients are defined as those in whom treatment has failed with a peginterferon alfa plus ribavirin based regimen with or without an HCV protease inhibitor.

Genotype 1:

Treatment-naive patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A) or treatment-experienced patients without cirrhosis: 12 weeks. Note: Treatment-naive patients without cirrhosis who have HCV RNA <6 million units/mL may be considered for therapy of 8 weeks duration.

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

Used without concomitant ribavirin: 24 weeks

Used with concomitant ribavirin in eligible patients: 12 weeks

Treatment-naive and treatment-experienced patients with decompensated cirrhosis (Child-Pugh class B or C): 12 weeks (with concomitant ribavirin)

Liver transplant recipients (treatment-naive and treatment-experienced) without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 12 weeks (with concomitant ribavirin)

Genotype 4:

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

Liver transplant recipients (treatment-naive and treatment-experienced) without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 12 weeks (with concomitant ribavirin)

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Chronic hepatitis C (CHC) infection (monoinfection or co-infected with HIV-1): Children and Adolescents ≥12 years or weighing ≥35 kg: Oral: 1 tablet (ledipasvir 90 mg/sofosbuvir 400 mg) once daily.

Duration of therapy: Note: Treatment-experienced patients are defined as those who have failed an interferon-based regimen with or without ribavirin.

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.

Genotype 4, 5, or 6:

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

Dosing: Renal Impairment

eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR <30 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling. However, sofosbuvir and metabolite accumulate in patients with severely impaired renal function.

End-stage renal disease (ESRD) , including those requiring intermittent hemodialysis (IHD): There are no dosage adjustments provided in the manufacturer's labeling However, sofosbuvir and metabolite accumulate in patients with severely impaired renal function. In a 4-hour dialysis session, 18% of sofosbuvir dose was removed.

Dosing: Hepatic Impairment

Mild, moderate, or severe impairment (Child-Pugh class A, B, or C): No dosage adjustment necessary.

Administration

Oral: Administer with or without food.

Storage

Store below 30°C (86°F). Dispense in original container.

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. 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

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. 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

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

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

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. Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

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 inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

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

Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor 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

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.). 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

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. Avoid combination

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

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

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

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

Vitamin K Antagonists (eg, warfarin): Antihepaciviral NS5B RNA Polymerase Inhibitors may diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Adverse Reactions

>10%:

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

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

1% to 10%:

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

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

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

Neuromuscular & skeletal: Myalgia (9%), increased creatine phosphokinase (1%)

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

<1%, postmarketing, and/or case reports: Angioedema, reactivation of HBV, skin rash (with blisters or angioedema-like swelling)

ALERT: U.S. Boxed Warning

Hepatitis B virus reactivation:

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

Warnings/Precautions

Disease-related concerns:

• 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

Manufacturer’s labeling:

Bilirubin, liver enzymes, and serum creatinine at baseline and periodically when clinically indicated. 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.

Serum HCV-RNA at baseline, during treatment, at the end of treatment, during treatment follow-up, and when clinically indicated.

Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) 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 post-treatment follow-up.

Alternate recommendations (AASLD/IDSA 2015):

Baseline (within 12 weeks prior to starting antiviral therapy): CBC, INR, hepatic function panel (albumin, total and direct bilirubin, ALT, AST, and alkaline phosphatase), calculated GFR

Baseline (at any time prior to starting antiviral therapy): HCV genotype and subtype, quantitative HCV viral load

During therapy: 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).

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies using ledipasvir or sofosbuvir. Also refer to the sofosbuvir monograph (and the ribavirin monograph if used in combination with ribavirin) for additional information.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience loss of strength and energy, headache, nausea, diarrhea, insomnia, cough, muscle pain, irritability, or dizziness. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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