sofosbuvir/velpatasvir (Rx)

Brand and Other Names:Epclusa
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

sofosbuvir/velpatasvir

tablet

  • 400mg/100mg

Chronic Hepatitis C

Indicated for chronic hepatitis C virus (HCV) infection in adults with HCV genotypes 1, 2, 3, 4, 5, and 6 without cirrhosis or with compensated cirrhosis; or with decompensated cirrhosis for use in combination with ribavirin

1 tablet (400 mg sofosbuvir/100 mg velpatasvir) PO qDay

Treatment duration for treatment-naïve and treatment-experienced liver transplant recipients

  • Without cirrhosis or with compensated cirrhosis (Child-Pugh A): Sofosbuvir/velpatasvir for 12 weeks
  • With decompensated cirrhosis (Child-Pugh B or C): Sofosbuvir/velpatasvir plus ribavirin for 12 weeks
  • Weight-based ribavirin dose
    • <75 kg: 1000 mg/day PO divided BID
    • ≥75 kg: 1200 mg/day PO divided BID
    • Modify ribavirin starting dose and on-treatment dosage based on hemoglobin and creatinine clearance

Dosage Modifications

Refer to ribavirin prescribing information for dosage modifications

Renal impairment

  • Any degree of renal impairment, including patients requiring dialysis: No dosage adjustment required

Hepatic impairment

  • Mild, moderate, or severe (Child-Pugh A, B, or C): No dosage adjustment required

Dosing Considerations

  • Test for evidence of current or prior hepatitis B virus (HBV) infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment

Dosage Forms & Strengths

sofosbuvir/velpatasvir

tablet

  • 200mg/50mg
  • 400mg/100mg

Chronic Hepatitis C

Indicated for chronic hepatitis C virus (HCV) infection in adults and children (≥6 years) or weighing at least 17 kg with HCV genotypes 1, 2, 3, 4, 5, and 6 without cirrhosis or with compensated cirrhosis; or with decompensated cirrhosis for use in combination with ribavirin

<6 years or <17 kg: Safety and efficacy not established

≥6 years or ≥17 kg

  • 17 to <30 kg: 1 tablet (200 mg sofosbuvir/50 mg velpatasvir) PO qDay
  • ≥30 kg: 1 tablet (400 mg sofosbuvir/100 mg velpatasvir) PO qDay OR 2 tablets (200 mg sofosbuvir/50 mg velpatasvir) PO qDay; total daily dose is 400 mg sofosbuvir/100 mg velpatasvir
  • Treatment duration for treatment-naïve and treatment-experienced liver transplant recipients
    • Without cirrhosis or with compensated cirrhosis (Child-Pugh A): Sofosbuvir/velpatasvir for 12 weeks
    • With decompensated cirrhosis (Child-Pugh B or C): Sofosbuvir/velpatasvir plus ribavirin for 12 weeks
  • Weight-based ribavirin dose
    • <47 kg: 15 mg/kg/day PO (divided dose AM and PM)
    • 47-49 kg: 600 mg/day PO (1 x 200 mg AM, 2 x 200 mg PM)
    • 50-65 kg: 800 mg/day PO (2 x 200 mg AM, 2 x 200 mg PM)
    • 66-80 kg: 1000 mg/day PO (2 x 200 mg AM, 3 x 200 mg PM)
    • >80 kg: 1200 mg/day PO (3 x 200 mg AM, 3 x 200 mg PM)
    • Modify ribavirin starting dose and on-treatment dosage based on hemoglobin and creatinine clearance

Dosage Modifications

Refer to ribavirin prescribing information for dosage modifications

  • Renal impairment

    • No data available in children and adolescents with renal impairment
  • Hepatic impairment

    • Mild, moderate, or severe (Child-Pugh A, B, or C): No dosage adjustment required
    • Monitor liver function (including direct bilirubin), as clinically indicated for patients with decompensated cirrhosis receiving treatment with ribavirin

Dosing Considerations

Test for evidence of current or prior hepatitis B virus (HBV) infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment

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Interactions

Interaction Checker

and sofosbuvir/velpatasvir

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            Adverse Effects

            >10%

            Without cirrhosis or with compensated cirrhosis

            • Headache (22%)
            • Fatigue (15%)

            With decompensated cirrhosis

            • Fatigue (32%)
            • Anemia (26%)
            • Hemoglobin <10 g/dL (23%)
            • Nausea (15%)
            • Headache 11%)
            • Insomnia (11%)

            1-10%

            Without cirrhosis or with compensated cirrhosis

            • Nausea (9%)
            • Asthenia (5%)
            • Insomnia (5%)
            • Lipase increase >3 x ULN (3%)
            • Rash (2%)
            • Depression (1%)
            • Increased creatinine kinase ≥10 x ULN (1%)

            With decompensated cirrhosis

            • Diarrhea (10%)
            • Hemoglobin <3.5 g/dL (7%)
            • Rash (5%)
            • Increased creatinine kinase ≥10 x ULN (2%)

            Postmarketing Reports

            Cardiac disorders: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiated treatment with sofosbuvir in combination with another HCV direct-acting antiviral

            Skin and subcutaneous tissue disorders: Angioedema

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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

            Sofosbuvir/velpatasvir plus ribavirin combination regimen is contraindicated in patients for whom ribavirin is contraindicated

            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)

            If administered with ribavirin, warnings and precautions for ribavirin apply to this combination; see ribavirin prescribing information

            Bradycardia

            • Coadministration with amiodarone is not recommended
            • Serious symptomatic bradycardia may occur if sofosbuvir is coadministered with amiodarone in combination with another direct-acting antiviral (eg, daclatasvir, simeprevir)
            • Bradycardia has generally occurred within hours to days, but reports have been observed up to 2 weeks after initiating HCV treatment
            • Patients also taking beta blockers, or those with underlying cardiac comorbidities, and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone
            • If no alternative exists for amiodarone, inpatient cardiac monitoring is recommended for the first 48 hr and then daily home monitoring for at least the first 2 weeks
            • Because of amiodarone’s long half-life, patients discontinuing amiodarone just prior to starting therapy should also undergo similar cardiac monitoring

            Drug interaction overview

            • Drugs affecting sofosbuvir/velpatasvir
              • Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 (the predominant circulating metabolite of sofosbuvir) is not
              • In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed
              • Drugs that are potent P-gp inducers and/or moderate-to-potent inducers of CYP2B6, CYP2C8, or CYP3A4 (eg, rifampin, carbamazepine, St. John’s wort) may significantly decrease sofosbuvir and/or velpatasvir plasma concentrations, leading to potentially reduced therapeutic effect; avoid coadministration
            • Drugs that increase gastric pH
              • Coadministration with drugs that increase gastric pH are expected to decrease velpatasvir serum concentration
              • See the Administration section for how long is needed between sofosbuvir/velpatasvir doses and drugs that increase gastric pH
            • Sofosbuvir/velpatasvir effect on other drugs
              • Velpatasvir inhibits drug transporters P-gp, BCRP, OATP1B1, OATP1B3, and OATP2B1
              • Coadministration with drugs that are substrates of these transporters may increase the exposure of such drugs
              • Frequent monitoring of relevant laboratory parameters (eg, International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with a narrow therapeutic index (eg, certain immunosuppressants) recommended to ensure safe and effective use; dose adjustments of concomitant medications may be necessary
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            Pregnancy

            Pregnancy

            Contraindicated if administered with ribavirin in pregnant women and in men whose female partners are pregnant

            There are no adequate data available to establish pregnancy risk for sofosbuvir or velpatasvir

            Lactation

            Unknown if sofosbuvir, velpatasvir, or their metabolites are distributed in human breast milk

            Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

            If regimen includes ribavirin, refer to ribavirin prescribing information

            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

            Sofosbuvir: Inhibitor of HCV NS5B RNA-dependent polymerase; its inhibition, in turn, suppresses viral replication

            Velpatasvir: Pangenotypic HCV NS5A inhibitor; the NS5A protein is required for viral replication

            Absorption

            Velpatasvir solubility decreases as gastric pH increases; practically insoluble (<0.1 mg/mL) at pH >5

            Peak concentration time

            • Sofosbuvir: 0.5-1 hr
            • Velpatasvir: 3 hr

            Peak plasma concentration

            • Sofosbuvir: 567 ng/mL
            • Velpatasvir: 259 ng/mL

            AUC

            • Sofosbuvir: 1268 ng·hr/mL
            • Velpatasvir: 2980 ng·hr/mL

            Distribution

            Protein bound

            • Sofosbuvir: 61-65%
            • Velpatasvir: >99.5%

            Metabolism

            Sofosbuvir

            • Liver metabolism by cathepsin A, CES1, and HINT1
            • Substrate of P-gp transporter and breast cancer resistance protein (substrate for sofosbuvir but not metabolite GS-331007)

            Velpatasvir

            • Substrate of P-gp transporter, CYP2B6, 2C8, and 3A4

            Elimination

            Half-life

            • Sofosbuvir: 0.5 hr; GS-33107 25 hr (active metabolite)
            • Velpatasvir: 15 hr

            Excretion

            • Major route of elimination
              • Sofosbuvir: Metabolism
              • GS-33107: Glomerular filtration and active tubular secretion
              • Velpatasvir: Biliary excretion as parent compound (77%)
            • Urine
              • Sofosbuvir: 80%
              • Velpatasvir: 14%
            • Feces
              • Sofosbuvir: 0.4%
              • Velpatasvir: 94%
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            Administration

            Oral Administration

            Take regularly at about the same time each day

            May take with or without food

            If coadministered with ribavirin, take with food

            Use with drugs that increase gastric pH

            • Coadministration with drugs that increase gastric pH are expected to decrease velpatasvir serum concentration
            • Antacids: Separate administration of sofosbuvir/velpatasvir by at least 4 hr
            • H2-antagonists: May be administered simultaneously with or 12 hr apart from sofosbuvir/velpatasvir at a dose that does not exceed doses comparable to famotidine 40 mg BID
            • PPIs: Coadministration with omeprazole or other PPIs is not recommended; if considered medically necessary, give sofosbuvir/velpatasvir with food 4 hr before omeprazole 20 mg; use with other PPIs has not been studied

            Storage

            Store below 30°C (86 ºF)

            Dispense only in original container

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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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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.