ledipasvir/sofosbuvir (Rx)

Brand and Other Names:Harvoni
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

ledipasvir/sofosbuvir

tablet

  • 90mg/400mg

Hepatitis C Virus Infection

Indicated for adults with chronic hepatitis C virus (HCV) genotypes 1, 4, 5, or 6 infection

1 tablet (90 mg/400 mg) PO qDay

Treatment duration

  • The following regimens also apply to HCV/HIV-1 coinfection
  • Genotype 1
    • Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A): 12 weeks; may consider 8 weeks in treatment-naïve patients without cirrhosis who have pretreatment HCV RNA <6 million IU/mL

    • Treatment-experienced (ie, those who have failed a peginterferon alfa + ribavirin based regimen with or without an HCV protease inhibitor) without cirrhosis: 12 weeks

    • Treatment-experienced with compensated cirrhosis (Child-Pugh A): 24 weeks; may also consider adding daily weight-based ribavirin

    • Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C), including those who have undergone liver transplantation: 12 weeks in combination with ribavirin

  • Genotypes 1 or 4
    • Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A), including those who have undergone liver transplantation: 12 weeks in combination with ribavirin
  • Genotypes 4, 5, or 6
    • Treatment-naïve and treatment-experienced, without cirrhosis or with compensated cirrhosis (Child-Pugh A): 12 weeks
  • Ribavirin dosing

    • <75 kg with or without decompensated cirrhosis: 1000 mg PO q12hr
    • ≥75 kg with or without decompensated cirrhosis: 1200 mg PO q12hr
    • If initial dose is not well tolerated, reduced dose as clinically indicated based on hemoglobin levels; refer to the ribavirin prescribing information for further information

Dosage Modifications

Renal impairment

  • Mild or moderate: No dosage adjustment required
  • Severe (eGFR <30 mL/min/1.73 m²) or ESRD: No dosage recommendation can be given owing to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite

Hepatic impairment

  • Mild, moderate, or severe: No dosage adjustment required
  • Decompensated cirrhosis: Safety and efficacy not established

Dosing Considerations

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HCV direct acting antivirals (DDAs)

Dosage Forms & Strengths

ledipasvir/sofosbuvir

tablet

  • 45mg/200mg
  • 90mg/400mg

oral pellets

  • 33.75mg/150mg per packet
  • 45mg/200mg per packet

Hepatitis C Virus Infection

Indicated for pediatric patients aged ≥3 yr with hepatitis C virus (HCV) genotype 1, 4, 5 or 6 infection

<3 years: Safety and efficacy not established

≥3 years

<17 kg: 1 packet (33.75 mg/150 mg) of pellets PO qDay

17 to <35kg: 1 tablet or packet (45 mg/200 mg) PO qDay

≥35 kg: 1 tablet (90 mg/400 mg) PO qDay or 2 tablets or packets (45 mg/200 mg) PO qDay

Treatment duration

  • The following regimens also apply to HCV/HIV-1 coinfection
  • Genotype 1
    • Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A): 12 weeks; may consider 8 weeks in treatment-naïve patients without cirrhosis who have pretreatment HCV RNA <6 million IU/mL

    • Treatment-experienced (ie, those who have failed a peginterferon alfa + ribavirin based regimen with or without an HCV protease inhibitor) without cirrhosis: 12 weeks

    • Treatment-experienced with compensated cirrhosis (Child-Pugh A): 24 weeks; may also consider adding daily weight-based ribavirin

    • Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C), including those who have undergone liver transplantation: 12 weeks in combination with ribavirin

  • Genotypes 1 or 4
    • Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A), including those who have undergone liver transplantation: 12 weeks in combination with ribavirin
  • Genotypes 4, 5, or 6
    • Treatment-naïve and treatment-experienced, without cirrhosis or with compensated cirrhosis (Child-Pugh A): 12 weeks

Ribavirin dosing

  • <47 kg: 15 mg/kg/day PO (divided dose AM and PM)
  • 47-49 kg: 600 mg/day PO (ie, 200 mg AM, 400 mg PM)
  • 50-65 kg: 800 mg/day PO (ie, 400 mg AM, 400 mg PM)
  • 66-80 kg: 1000 mg/day PO (ie, 400 mg AM, 600 mg PM)
  • >80 kg: 1200 mg/day PO (ie, 600 mg AM, 600 mg PM)

Dosage Modifications

Renal impairment

  • Mild or moderate: No dosage adjustment required
  • Severe (eGFR <30 mL/min/1.73 m²) or ESRD: No dosage recommendation can be given owing to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite

Dosing Considerations

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HCV direct acting antivirals (DDAs)

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Interactions

Interaction Checker

and ledipasvir/sofosbuvir

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10%

            Asthenia (31-36%)

            Fatigue (4-18%)

            Headache (13-29%)

            Cough (5-11%)

            1-10%

            Nausea (6-9%)

            Diarrhea (3-7%)

            Dizziness (1-5%)

            Dyspnea (3-9%)

            Insomnia (3-6%)

            Increased bilirubin >1.5 x ULN (<1 to 3%)

            Increased lipase >3 x ULN (<1 to 3%)

            Myalgia (4-9%)

            Irritability (7-8%)

            Frequency Not Defined

            Asymptomatic creatine kinase elevation, Grades 3/4

            Postmarketing Reports

            Bradycardia in patients taking amiodarone who initiate ledipasvir/sofosbuvir therapy

            Skin rash, sometimes with blisters or angioedema-like swelling

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            Warnings

            Black Box Warnings

            Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HCV direct acting antivirals (DDAs)

            HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with DDAs 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

            Contraindications

            If coadministered with ribavirin, the contraindications to ribavirin also apply to this combination regimen

            Cautions

            Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV DDAs, and who were not receiving HBV antiviral therapy; HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level (see Black Box Warnings and Dosing Considerations)

            Do not use with other products that contain sofosbuvir (Sovaldi, Epclusa); duplicate therapy and increased risk for adverse effects

            Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with sofosbuvir in combination with an investigational agent (daclatasvir, an investigational NS5A inhibitor) or simeprevir; coadministration is not recommended, if no alternative exists, inpatient cardiac monitoring is recommended for the first 48 hr and then daily home monitoring for at least the first 2 weeks

            Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to starting ledipasvir/sofosbuvir therapy should undergo cardiac monitoring; patients who develop signs or symptoms of bradycardia, including near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems should seek medical evaluation immediately

            Ledipasvir and sofosbuvir are substrates of P-gp and BCRP; coadministration with P-gp inducers (eg, rifampin, St. John’s wort) is not recommended; may significantly decrease ledipasvir and sofosbuvir plasma concentrations and reduce therapeutic effect

            Ledipasvir is an inhibitor of P-gp and BCRP; may increase intestinal absorption of coadministered substrates for these transporters

            Coadministration of ledipasvir with acid-reducing agents may decrease ledipasvir solubility, resulting in decreased serum concentrations

            If coadministered with ribavirin, the warnings and precautions for ribavirin also apply to this combination regimen

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            Pregnancy & Lactation

            Pregnancy

            If the drug combination is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant; refer to ribavirin prescribing information for more information on ribavirin-associated risks of use during pregnancy

            No adequate human data are available to establish whether or not the drug combination poses a risk to pregnancy outcomes; in animal reproduction studies, no evidence of adverse developmental outcomes was observed with the drug combination ledipasvir or sofosbuvir at exposures greater than those in humans at the recommended human dose (RHD)

            Lactation

            It is not known whether ledipasvir or sofosbuvir, the drug combination, or their metabolites are present in human breast milk, affect human milk production or have effects on the breastfed infant.

            The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for the drug combination and any potential adverse effects on the breastfed child from the drug combination or from the underlying maternal condition

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Ledipasvir: Inhibits HCV NS5A protein, which is required for viral replication; resistance selection in cell culture and cross-resistance studies indicate ledipasvir targets NS5A as its mode of action

            Sofosbuvir: Nucleotide prodrug that undergoes metabolism to the active uridine analog triphosphate, an inhibitor of HCV NS5B RNA-dependent polymerase; its inhibition, in turn, suppresses viral replication

            Absorption

            Peak plasma concentration

            • ledipasvir: 4-4.5 hr
            • sofosbuvir: 0.8-1 hr
            • GS-331007: 3.5-4 hr

            Peak plasma level

            • ledipasvir: 323 ng/mL
            • sofosbuvir: 618 ng/mL
            • GS-331007: 707 ng/mL

            AUC

            • ledipasvir: 7,290 ng•hr/mL
            • sofosbuvir: 1,320 ng•hr/mL
            • GS-331007: 12,000 ng•hr/mL

            Distribution

            Protein bound

            • ledipasvir: >99.8%
            • sofosbuvir: 61-65%
            • GS-331007: minimal

            Metabolism

            ledipasvir: No detectable metabolism

            sofosbuvir: Extensively metabolized in liver to form the pharmacologically active nucleoside analog triphosphate GS-461203; dephosphorylation results in formation of GS331007 (accounts for <90% of total systemic exposure of sofosbuvir)

            Elimination

            Half-life, terminal

            • ledipasvir: 47 hr
            • sofosbuvir: 0.5 hr
            • GS-331007: 27 hr

            Excretion

            • ledipasvir: >98% feces (mostly unchanged); <1% urine
            • GS-331007: 14% feces; 80% urine; 2.5% expired air
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            Administration

            Oral Preparation (Oral Pellets)

            Do not chew pellets

            If pellets are administered with food, sprinkle on ≥1 spoonfuls of nonacidic soft food (eg, pudding, chocolate syrup, mashed potato, ice cream) at or below room temperature

            Take pellets within 30 min of gently mixing with food and swallow entire contents without chewing to avoid a bitter aftertaste

            Oral Administration

            Take with or without food

            Storage

            Tablets and oral pellets: Store <30ºC; dispense in original bottle

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.