ledipasvir/sofosbuvir (Rx)

Brand and Other Names:Harvoni
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

ledipasvir/sofosbuvir

tablet

  • 90mg/400mg
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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
    • Treatment-experienced 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
  • Note:
    • 8 weeks can be considered in treatment-naïve patients without cirrhosis who have pretreatment HCV RNA <6 million IU/mL
    • Treatment –experienced patients include those who have failed a peginterferon alfa + ribavirin based regimen with or without an HCV protease inhibitor
    • Ledipasvir/sofosbuvir + ribavirin for 12 weeks can be considered in treatment-experienced genotype 1 patients with cirrhosis who are eligible for ribavirin; see ribavirin dosage recommendations below
    • In patients with decompensated cirrhosis, the starting dosage of ribavirin is 600 mg and can be titrated up to 1000 mg for patients <75 kg and 1200 mg for those ≥75 kg in two divided doses with food; if starting dosage of ribavirin is not well tolerated, reduce dosage as clinically indicated based on hemoglobin levels
    • Ribavirin dosage recommendations: The daily dosage of ribavirin is weight-based (1000 mg for patients <75 kg and 1200 mg for those ≥75 kg) administered orally in two divided doses with food
    • For further information on ribavirin dosing and dosage modifications, refer to the ribavirin prescribing information
  • 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

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

  • 90mg/400mg
more...

Hepatitis C Virus Infection

Indicated for pediatric patients aged ≥12 yr or weighing at least 35 kg with hepatitis C virus (HCV) genotype 1, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis

<12 years or <35 kg: Safety and efficacy not established

≥12 years or weight ≥35 kg: 1 tablet (90mg/400mg) 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
    • Treatment-experienced without cirrhosis: 12 weeks
    • Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A): 24 weeks
  • Genotypes 4, 5, or 6
    • Treatment-naïve and treatment experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A): 12 weeks

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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     activity indicator 
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    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 Category: B

            Lactation: Unknown if distributed in human breast milk

            Ledipasvir was detected in the plasma of suckling rats, likely due to the presence of ledipasvir in milk; had no clear effects on the nursing pups

            The predominant circulating metabolite of sofosbuvir (GS-331007) was the primary component observed in the milk of lactating rats, without effect on nursing pups

            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 Administration

            May take with or without food

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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.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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