Version May 2024
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.
Note: Prior to initiating therapy, test patient for evidence of hepatitis B infection (current or prior).
Chronic hepatitis C (monoinfection or co-infected with HIV-1):
Children ≥3 years and Adolescents:
<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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Altered kidney function:
Children ≥3 years and Adolescents:
Mild, moderate, and severe impairment: There are no pediatric-specific dosage adjustments provided in the manufacturer's labeling (has not been studied); based on information in adult patients, no dosage adjustment is required.
End-stage renal disease requiring hemodialysis: There are no pediatric-specific dosage adjustments provided in the manufacturer's labeling (has not been studied); based on information in adult patients, no dosage adjustment is required. Note: 18% of sofosbuvir dose was removed in a 4-hour dialysis session.
Children ≥3 years and Adolescents: Mild, moderate, or severe impairment (Child-Pugh class A, B, or C): No dosage adjustment necessary.
(For additional information see "Ledipasvir and sofosbuvir: Drug information")
Chronic hepatitis C: Oral:
Note: Compensated cirrhosis is defined as Child-Pugh class A and decompensated cirrhosis is defined as Child-Pugh class B or C (AASLD/IDSA 2021).
Genotype 1:
Note: Prior to initiating treatment for genotype 1a–infected, treatment-experienced patients with or without cirrhosis, consider NS5A RAS testing to determine if clinically important resistance exists (eg, ≥100-fold shift in in vitro EC50 to ledipasvir) necessitating use of an alternative regimen (AASLD/IDSA 2021).
Treatment-naive patients without cirrhosis or with compensated cirrhosis: Ledipasvir 90 mg/sofosbuvir 400 mg once daily for 12 weeks. Note: An 8-week duration may be considered in treatment-naive patients with favorable baseline characteristics (eg, no cirrhosis, hepatitis C virus [HCV] RNA <6 million units/mL, no HIV coinfection) (AASLD/IDSA 2021).
Decompensated cirrhosis: Ledipasvir 90 mg/sofosbuvir 400 mg once daily with concomitant ribavirin for 12 weeks; if ribavirin ineligible, ledipasvir 90 mg/sofosbuvir 400 mg once daily for 24 weeks (AASLD/IDSA 2021).
Decompensated cirrhosis in patients with prior sofosbuvir- or NS5A inhibitor–based treatment failure: Ledipasvir 90 mg/sofosbuvir 400 mg once daily with concomitant ribavirin for 24 weeks (AASLD/IDSA 2021).
Liver transplant recipients (treatment-naive and treatment-experienced) without cirrhosis or with compensated cirrhosis : Ledipasvir 90 mg/sofosbuvir 400 mg once daily for 12 weeks (AASLD/IDSA 2021).
Liver transplant recipients (treatment-naive and treatment-experienced) with decompensated cirrhosis (off-label use): Ledipasvir 90 mg/sofosbuvir 400 mg once daily with concomitant ribavirin for 12 weeks (treatment-naive) or 24 weeks (treatment-experienced) (AASLD/IDSA 2021).
Kidney transplant recipients (treatment- naive and non-direct-acting antiviral treatment–experienced) without cirrhosis or with compensated cirrhosis (off-label use): Ledipasvir 90 mg/sofosbuvir 400 mg once daily for 12 weeks (AASLD/IDSA 2021).
Genotype 4:
Treatment-naive patients without cirrhosis or with compensated cirrhosis: Ledipasvir 90 mg/sofosbuvir 400 mg once daily for 12 weeks. Note: An 8-week duration may be considered in treatment-naive patients with favorable baseline characteristics (eg, no cirrhosis, HCV RNA <6 million units/mL, no HIV coinfection, absence of genotype 4r) (AASLD/IDSA 2021).
Decompensated cirrhosis (off-label use): Ledipasvir 90 mg/sofosbuvir 400 mg once daily with concomitant ribavirin for 12 weeks; if ribavirin ineligible, ledipasvir 90 mg/sofosbuvir 400 mg once daily for 24 weeks (AASLD/IDSA 2021).
Decompensated cirrhosis in patients with sofosbuvir- or NS5A inhibitor–based treatment failure (off-label use) : Ledipasvir 90 mg/sofosbuvir 400 mg once daily with concomitant ribavirin for 24 weeks (AASLD/IDSA 2021).
Liver transplant recipients (treatment-naive and treatment-experienced) without cirrhosis or with compensated cirrhosis: Ledipasvir 90 mg/sofosbuvir 400 mg once daily for 12 weeks (AASLD/IDSA 2021).
Liver transplant recipients (treatment-naive and treatment-experienced) with decompensated cirrhosis (off-label use): Ledipasvir 90 mg/sofosbuvir 400 mg once daily for 12 weeks (treatment naive) or 24 weeks (treatment experienced) (AASLD/IDSA 2021).
Kidney transplant recipients (treatment-naive and non-direct-acting antiviral treatment–experienced) without cirrhosis or with compensated cirrhosis (off-label use): Ledipasvir 90 mg/sofosbuvir 400 mg once daily for 12 weeks (AASLD/IDSA 2021).
Genotype 5 or 6:
Treatment-naive patients without cirrhosis or with compensated cirrhosis: Ledipasvir 90 mg/sofosbuvir 400 mg once daily for 12 weeks. Note: Not recommended for treatment-naive patients with genotype 6e if subtype is known (AASLD/IDSA 2021).
Decompensated cirrhosis (off-label use): Ledipasvir 90 mg/sofosbuvir 400 mg once daily with concomitant ribavirin for 12 weeks; if ribavirin ineligible, ledipasvir 90 mg/sofosbuvir 400 mg once daily for 24 weeks (AASLD/IDSA 2021).
Decompensated cirrhosis in patients with sofosbuvir- or NS5A inhibitor–based treatment failure (off-label use) : Ledipasvir 90 mg/sofosbuvir 400 mg once daily with concomitant ribavirin for 24 weeks (AASLD/IDSA 2021).
Liver transplant recipients (treatment-naive and treatment-experienced) without cirrhosis or with compensated cirrhosis (off-label use): Ledipasvir 90 mg/sofosbuvir 400 mg once daily for 12 weeks (AASLD/IDSA 2021).
Liver transplant recipients (treatment-naive and treatment-experienced) with decompensated cirrhosis (off-label use): Ledipasvir 90 mg/sofosbuvir 400 mg once daily with concomitant ribavirin for 12 weeks (treatment-naive) or 24 weeks (treatment-experienced) (AASLD/IDSA 2021).
Kidney transplant recipients (treatment-naive and non-direct-acting antiviral treatment–experienced) without cirrhosis or with compensated cirrhosis (off-label use): Ledipasvir 90 mg/sofosbuvir 400 mg once daily for 12 weeks (AASLD/IDSA 2021).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Mild, moderate, or severe impairment: No dosage adjustment necessary.
End-stage renal disease requiring hemodialysis: No dosage adjustment necessary.
Preexisting hepatic impairment:
Mild, moderate, or severe impairment (Child-Pugh class A, B, or C): No dosage adjustment necessary.
Hepatoxicity during treatment:
Asymptomatic increases in ALT <10-fold: Closely monitor with repeat testing every 2 weeks. If persistent elevation remains, consider stopping therapy (AASLD/IDSA 2021).
<10-fold increase in ALT from baseline with weakness, nausea, vomiting, jaundice, or significantly increased bilirubin, alkaline phosphatase, or INR: Discontinue direct-acting antiviral (AASLD/IDSA 2021).
≥10-fold increase in ALT from baseline at any time during treatment: Discontinue direct-acting antiviral therapy, especially with signs and symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR (AASLD/IDSA 2021).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>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
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.
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Packet, Oral:
Harvoni: Ledipasvir 45 mg and sofosbuvir 200 mg (28 ea); Ledipasvir 33.75 mg and sofosbuvir 150 mg (28 ea)
Tablet, Oral:
Harvoni: Ledipasvir 45 mg and sofosbuvir 200 mg
Harvoni: Ledipasvir 90 mg and sofosbuvir 400 mg [contains fd&c yellow #6(sunset yellow)alumin lake]
Generic: Ledipasvir 90 mg and sofosbuvir 400 mg
May be product dependent
Pack (Harvoni Oral)
33.75-150 mg (per each): $1,350.00
45-200 mg (per each): $1,350.00
Tablets (Harvoni Oral)
45-200 mg (per each): $1,350.00
90-400 mg (per each): $1,350.00
Tablets (Ledipasvir-Sofosbuvir Oral)
90-400 mg (per each): $514.29
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
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(sunset yellow)alumin lake]
Oral:
Pellets: Administer with or without food. To avoid bitter aftertaste, do not chew pellets. May be sprinkled on 1 or more spoonfuls of non-acidic 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.
Tablets: Administer with or without food.
Oral:
Tablets: Administer with or without food.
Pellets: Administer with or without food. If administered without food, pour packet contents directly in the mouth and swallow without chewing to avoid bitter aftertaste; follow with water if needed. If administered with food, sprinkle packet contents on ≥1 spoonful 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.
Tablets and pellets: Store below 30°C (86°F). Dispense in original packaging.
Treatment of chronic hepatitis C virus genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis; treatment of chronic hepatitis C virus genotype 1 infection with decompensated cirrhosis in combination with ribavirin; treatment of chronic hepatitis C virus genotype 1 or 4 infection, in combination with ribavirin, in liver transplant recipients without cirrhosis or with compensated cirrhosis (All indications: FDA approved in ages ≥3 years and adults).
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: If combined, administer the P-gp inhibitor simultaneously with, or after, the dose of afatinib. Monitor closely for signs and symptoms of afatinib toxicity and if the combination is not tolerated, reduce the afatinib dose by 10 mg. Risk D: Consider therapy modification
Aliskiren: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Aliskiren. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Amiodarone: Sofosbuvir may enhance the bradycardic effect of Amiodarone. Management: Use alternative to a sofosbuvir-containing combo or to amiodarone when possible. If alternatives not possible, monitor in inpatient setting for first 48 hours of coadministration with daily outpatient monitoring for at least 2 weeks. Risk D: Consider therapy modification
Antacids: May decrease the serum concentration of Ledipasvir. Management: Separate the administration of ledipasvir and antacids by 4 hours. Risk D: Consider therapy modification
Antidiabetic Agents: Direct Acting Antiviral Agents (HCV) may enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Asunaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir. Risk X: Avoid combination
Atogepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Atogepant. Management: For episodic migraine, the recommended atogepant dose is 10 mg or 30 mg once daily if given with OATP1B1/1B3 inhibitors. For chronic migraine, the recommended atogepant dose is 30 mg once daily with OATP1B1/1B3 inhibitors. Risk D: Consider therapy modification
Atorvastatin: Ledipasvir may enhance the adverse/toxic effect of Atorvastatin. Risk C: Monitor therapy
Atorvastatin: Sofosbuvir may increase the serum concentration of Atorvastatin. Risk C: Monitor therapy
Berotralstat: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Berotralstat. Management: Decrease the berotralstat dose to 110 mg daily when combined with P-glycoprotein (P-gp) inhibitors. Risk D: Consider therapy modification
Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Risk X: Avoid combination
Brincidofovir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Brincidofovir. Management: Consider alternatives to OATP1B/1B3 inhibitors in patients treated with brincidofovir. If coadministration is required, administer OATP1B1/1B3 inhibitors at least 3 hours after brincidofovir and increase monitoring for brincidofovir adverse reactions. Risk D: Consider therapy modification
Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Risk C: 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. Risk D: 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: This combination is often contraindicated, but combined use may be permitted with dose adjustment and monitoring. Recommendations vary based on brand, indication, use of CYP3A4 inhibitors, and hepatic/renal function. See interaction monograph for details. Risk D: Consider therapy modification
Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Risk C: Monitor therapy
Digoxin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Digoxin. Management: Measure digoxin serum concentrations before initiating treatment with these P-glycoprotein (P-gp) inhibitors. Reduce digoxin concentrations by either reducing the digoxin dose by 15% to 30% or by modifying the dosing frequency. Risk D: Consider therapy modification
DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination
DOXOrubicin (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Liposomal). Risk C: Monitor therapy
Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Risk C: Monitor therapy
Elagolix: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix. Risk X: Avoid combination
Elagolix, Estradiol, and Norethindrone: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix, Estradiol, and Norethindrone. Specifically, concentrations of elagolix may be increased. Risk X: Avoid combination
Elbasvir and Grazoprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination
Eluxadoline: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with OATP1B1/1B3 inhibitors and monitor patients for increased eluxadoline effects/toxicities. Risk D: Consider therapy modification
Etoposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide. Risk C: Monitor therapy
Etoposide Phosphate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide Phosphate. Risk C: Monitor therapy
Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Risk C: Monitor therapy
Glecaprevir and Pibrentasvir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Glecaprevir and Pibrentasvir. Risk C: Monitor therapy
Histamine H2 Receptor Antagonists: May decrease the serum concentration of Ledipasvir. Management: Administer H2 receptor antagonist doses less than or comparable to famotidine 40 mg twice daily simultaneously or 12 hours prior to ledipasvir. The effect of administering H2 receptor antagonists at other time intervals is unknown and not recommended. Risk D: Consider therapy modification
Inhibitors of the Proton Pump (PPIs and PCABs): May decrease the serum concentration of Ledipasvir. Management: PPI or PCAB doses equivalent to omeprazole 20 mg or lower may be given with ledipasvir under fasted conditions. Use of ledipasvir with higher doses or with food, or 2 hours after a these agents, may reduce ledipasvir bioavailability. Risk D: Consider therapy modification
Lapatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lapatinib. Risk C: Monitor therapy
Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Lumacaftor and Ivacaftor: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may decrease the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Risk C: Monitor therapy
Modafinil: May decrease the serum concentration of Sofosbuvir. Risk X: Avoid combination
Momelotinib: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Momelotinib. Risk C: Monitor therapy
Morphine (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Morphine (Systemic). Risk C: Monitor therapy
Nadolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Nadolol. Risk C: Monitor therapy
Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Risk C: Monitor therapy
Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Risk C: Monitor therapy
OXcarbazepine: May decrease the serum concentration of Sofosbuvir. Risk X: Avoid combination
OXcarbazepine: May decrease the serum concentration of Ledipasvir. Risk X: Avoid combination
PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Risk X: Avoid combination
PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Risk X: Avoid combination
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Sofosbuvir. Risk X: Avoid combination
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Ledipasvir. Risk X: Avoid combination
PHENobarbital: May decrease the serum concentration of Ledipasvir. Risk X: Avoid combination
PHENobarbital: May decrease the serum concentration of Sofosbuvir. Risk X: Avoid combination
Pralsetinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Pralsetinib. Management: If this combo cannot be avoided, decrease pralsetinib dose from 400 mg daily to 300 mg daily; from 300 mg daily to 200 mg daily; and from 200 mg daily to 100 mg daily. Risk D: Consider therapy modification
Primidone: May decrease the serum concentration of Ledipasvir. Risk X: Avoid combination
Primidone: May decrease the serum concentration of Sofosbuvir. Risk X: Avoid combination
Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Risk C: Monitor therapy
Relugolix: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix. Management: Avoid coadministration of relugolix with oral P-gp inhibitors whenever possible. If combined, take relugolix at least 6 hours prior to the P-gp inhibitor and monitor patients more frequently for adverse reactions. Risk D: Consider therapy modification
Relugolix, Estradiol, and Norethindrone: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix, Estradiol, and Norethindrone. Management: Avoid use of relugolix/estradiol/norethindrone with P-glycoprotein (P-gp) inhibitors. If concomitant use is unavoidable, relugolix/estradiol/norethindrone should be administered at least 6 hours before the P-gp inhibitor. Risk D: Consider therapy modification
Repotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Repotrectinib. Risk X: Avoid combination
Revefenacin: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin. Risk X: Avoid combination
Rifabutin: May decrease the serum concentration of Sofosbuvir. Risk X: Avoid combination
Rifabutin: May decrease the serum concentration of Ledipasvir. Risk X: Avoid combination
Rifapentine: May decrease the serum concentration of Sofosbuvir. Risk X: Avoid combination
Rifapentine: May decrease the serum concentration of Ledipasvir. Risk X: Avoid combination
RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Risk C: Monitor therapy
Rimegepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rimegepant. Management: Avoid administration of another dose of rimegepant within 48 hours if given concomitantly with a P-glycoprotein (P-gp) inhibitor. Risk D: Consider therapy modification
RisperiDONE: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RisperiDONE. Risk C: Monitor therapy
RomiDEPsin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RomiDEPsin. Risk C: Monitor therapy
Rosuvastatin: Ledipasvir may increase the serum concentration of Rosuvastatin. Risk X: Avoid combination
Saquinavir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Saquinavir. Risk C: Monitor therapy
Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Risk C: Monitor therapy
Simeprevir: May increase the serum concentration of Ledipasvir. Ledipasvir may increase the serum concentration of Simeprevir. Risk X: Avoid combination
Sirolimus (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Conventional). Management: Avoid concurrent use of sirolimus with P-glycoprotein (P-gp) inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Monitor for increased sirolimus concentrations/toxicity if combined. Risk D: Consider therapy modification
Sirolimus (Protein Bound): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Protein Bound). Risk X: Avoid combination
Tacrolimus (Systemic): Direct Acting Antiviral Agents (HCV) may decrease the serum concentration of Tacrolimus (Systemic). Direct Acting Antiviral Agents (HCV) may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Risk C: Monitor therapy
Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Risk C: Monitor therapy
Taurursodiol: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Taurursodiol. Risk X: Avoid combination
Tegaserod (Withdrawn from US Market): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod (Withdrawn from US Market). Risk C: Monitor therapy
Teniposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Teniposide. Risk C: Monitor therapy
Tenofovir Disoproxil Fumarate: Ledipasvir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Management: Avoid this combination if TDF is used as part of the elvitegravir/cobicistat/emtricitabine/TDF product. Consider alternatives when TDF is used with a ritonavir or cobicistat boosted protease inhibitor. Monitor for increased TDF toxicities if combined. Risk D: Consider therapy modification
Tipranavir: May decrease the serum concentration of Ledipasvir. Risk X: Avoid combination
Tipranavir: May decrease the serum concentration of Sofosbuvir. Risk X: Avoid combination
Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Risk X: 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 (at least 2 hours later if needed) of 50 mg when used with a P-gp inhibitor. Risk D: Consider therapy modification
Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of a P-gp inhibitor. Risk D: Consider therapy modification
VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination
Vitamin K Antagonists (eg, warfarin): Direct Acting Antiviral Agents (HCV) may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir. Risk X: Avoid combination
Zavegepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Zavegepant. Risk X: Avoid combination
Patients with hepatitis C virus (HCV) infection should be treated before considering pregnancy to optimize maternal health and reduce the risk of HCV transmission (AASLD/IDSA 2021).
If used in combination with ribavirin, all warnings related to the use of ribavirin and contraception should be followed. Refer to the Ribavirin monograph for additional information.
Adverse events were not observed in animal reproduction studies using ledipasvir or sofosbuvir.
Pregnancy-induced physiologic changes were not found to alter the pharmacokinetic properties of ledipasvir and sofosbuvir in a clinically significant way (Chappell 2020).
Outcome data following maternal use of ledipasvir and sofosbuvir and other direct-acting antiviral (DAA) medications during pregnancy are limited. Use of a DAA is not currently recommended for the purpose of reducing mother to child transmission of hepatitis C virus due to a lack of safety and efficacy data. The decision to continue treatment in a patient who becomes pregnant while taking a DAA should be individualized after considering the potential benefits and risks of therapy. DAA medications should not be initiated during pregnancy outside of clinical trials until safety and efficacy data are available (AASLD/IDSA 2021; Chappell 2020; SMFM [Dotters-Katz 2021]).
If used in combination with ribavirin, all warnings related to the use of ribavirin and pregnancy should be followed. Refer to the Ribavirin monograph for additional information.
Management of hepatitis C virus (HCV) infection requires extensive monitoring; refer to current guidelines for additional guidance including response to abnormal laboratory parameters (AASLD/IDSA 2018).
Baseline (within 12 weeks prior to starting antiviral therapy): CBC, INR, hepatic function panel (albumin, total and direct bilirubin, ALT, AST, and alkaline phosphatase), SCr, calculated GFR. Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), 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. HCV genotype and subtype, quantitative HCV viral load (at any time prior to starting antiviral therapy) (AASLD/IDSA 2018).
During therapy: CBC, SCr, 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 sofosbuvir), inpatient cardiac monitoring for the first 48 hours of coadministration, then daily outpatient or self-monitoring of heart rate through at least the first 2 weeks of treatment.
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.
Note: The pharmacokinetic profile in pediatric patients ≥3 years of age is similar to adult patients.
Absorption: Ledipasvir and sofosbuvir are well absorbed.
Protein binding: Ledipasvir: >99.8%; Sofosbuvir: ~61% to 65%.
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.
Half-life elimination: Ledipasvir: 47 hours; Sofosbuvir: ~0.5 hours.
Time to peak: Median: Ledipasvir: 4 to 4.5 hours; Sofosbuvir: ~0.8 to 1 hour.
Excretion: Ledipasvir: Feces (~86%), urine (1%); Sofosbuvir: Urine (80%), feces (14%).
Altered kidney function: Sofosbuvir: Following a single 400 mg dose of sofosbuvir in hepatitis C virus 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 end-stage renal disease requiring hemodialysis the sofosbuvir AUC0-∞ was 61%, 107%, and 171% higher in mild, moderate, and severe renal impairment than in subjects with normal renal function. AUC0-inf was 28% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% higher when sofosbuvir was dosed 1 hour after hemodialysis.
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