brincidofovir (Rx)

Brand and Other Names:Tembexa
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 100mg

oral suspension

  • 10mg/mL

Smallpox

Indicated for treatment of human smallpox disease caused by variola virus in adult and pediatric patients, including neonates

≥48 kg (tablet or oral suspension): 200 mg PO qWeek x 2 doses (on Days 1 and 8)

<48 kg (oral suspension): 4 mg/kg PO qWeek x 2 doses (on Days 1 and 8)

Dosage Modifications

Renal or hepatic impairment

  • No dosage adjustment required with any degree of impairment

Dosing Considerations

Limitations of use

  • Not indicated for treatment of diseases other than human smallpox disease
  • Effectiveness for the treatment of smallpox disease has not been determined in humans because adequate and well-controlled field trials have not been feasible, and inducing smallpox disease in humans to study the drug’s efficacy is not ethical (animal trial rule)
  • Efficacy may be reduced in immunocompromised patients based on studies in immune-deficient animals

Laboratory testing

  • Perform hepatic laboratory testing before initiating and during treatment, as clinically appropriate
  • Perform pregnancy testing before initiating in females of childbearing potential to inform risk

Dosage Forms & Strengths

tablet

  • 100mg

oral suspension

  • 10mg/mL

Smallpox

Indicated for treatment of human smallpox disease caused by variola virus in adult and pediatric patients, including neonates

≥48 kg (tablet or oral suspension): 200 mg PO qWeek x 2 doses (on Days 1 and 8)

10-48 kg (oral suspension): 4 mg/kg PO qWeek x 2 doses (on Days 1 and 8)

<10 kg (oral suspension): 6 mg/kg PO qWeek x 2 doses (on Days 1 and 8)

Dosage Modifications

Renal or hepatic impairment

  • No dosage adjustment required with any degree of impairment

Dosing Considerations

Limitations of use

  • Not indicated for treatment of diseases other than human smallpox disease
  • Effectiveness for the treatment of smallpox disease has not been determined in humans because adequate and well-controlled field trials have not been feasible, and inducing smallpox disease in humans to study the drug’s efficacy is not ethical (animal trial rule)
  • Efficacy may be reduced in immunocompromised patients based on studies in immune-deficient animals

Laboratory testing

  • Perform hepatic laboratory testing before initiating and during treatment, as clinically appropriate
  • Perform pregnancy testing before initiating in females of childbearing potential to inform risk
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Interactions

Interaction Checker

and brincidofovir

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            1-10%

            Diarrhea (8%)

            Nausea (5%)

            Vomiting (4%)

            Serum creatinine elevated (>1.5-3x ULN) (4%)

            Abdominal pain (3%)

            ALT elevated (>3 to 20x ULN) (2-3%)

            Total bilirubin elevated (>1.5 to 10x ULN) (1-3%)

            AST elevated (>3 to 20x ULN) (1-2%)

            <2%

            • General and administration site: Peripheral edema
            • Metabolism and nutrition: Decreased appetite
            • Musculoskeletal and connective tissue: Muscular weakness
            • Nervous system: Dysgeusia
            • Skin and subcutaneous tissue: Rash (ie, rash, maculopapular rash, pruritic rash)
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            Warnings

            Black Box Warnings

            Increased incidence of mortality observed in brincidofovir-treated individuals compared with placebo-treated individuals in a 24-week clinical trial when evaluated in another disease

            Contraindications

            None

            Cautions

            Increased mortality if used for longer duration

            • Not indicated for use in diseases other than human smallpox
            • Increased mortality observed in a randomized, placebo-controlled phase 3 trial when evaluated for another disease (CMV infection)
            • Increased risk in mortality is possible if used for a duration longer than at the recommended dosage on Days 1 and 8

            Elevated hepatic transaminases and bilirubin

            • Elevations in ALT, AST, and total bilirubin observed
            • Perform hepatic laboratory testing in all patients before starting and during treatment, as clinically appropriate
            • Monitor patients who develop abnormal test results for development of severe hepatic injury
            • Consider discontinuing if ALT levels remain persistently >10x ULN
            • Do not give second dose if ALT elevation accompanied by clinical signs and symptoms of liver inflammation or increasing direct bilirubin, alkaline phosphatase, or INR

            Diarrhea and GI adverse effects

            • Diarrhea common during treatment
            • Other GI effects include nausea, vomiting, and abdominal pain
            • Monitor for dehydration, and if necessary, do not give the second dose

            Embryofetal toxicity, carcinogenicity, and male infertility

            • Based on findings from animal reproduction studies, may cause fetal harm when administered to pregnant females
            • Considered a potential human carcinogen; mammary adenocarcinomas and squamous cell carcinomas occurred in rats at systemic exposures less than the expected human exposure based on the recommended dose
            • Based on testicular toxicity in animal studies, may irreversibly impair fertility in males of reproductive potential

            Drug interaction overview

            • Cidofovir
              • Do not coadminister with IV cidofovir
              • Brincidofovir, a lipid-linked derivative of cidofovir, is intracellularly converted to cidofovir
            • OATP 1B1 and 1B3 inhibitors
              • If possible, consider alternant medications that are not OATP1B1 or 1B3 inhibitors
              • If concomitant use is necessary, increase monitoring for adverse reactions associated with brincidofovir (elevations in transaminases and bilirubin, diarrhea, or other GI adverse events) and postpone dosing of OATP1B1 or 1B3 inhibitors for at least 3 hr after brincidofovir administration
            • Vaccines
              • No vaccine-drug interaction studies have been performed in humans; clinical impacts unknown
              • Animal studies suggest coadministration of brincidofovir at the same time as live smallpox vaccine (vaccinia virus) may reduce the immune response to the vaccine
              • Brincidofovir may reduce immune response to replication-defective smallpox vaccine (modified vaccinia virus Ankara)
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            Pregnancy & Lactation

            Pregnancy

            Based on findings from animal reproduction studies, may cause fetal harm when administered to pregnant females

            Perform pregnancy testing in individuals of childbearing potential before initiating

            Animal studies

            • Administration to pregnant rats and rabbits during organogenesis resulted in embryotoxicity and structural malformations
            • These effects occurred in animals at systemic exposures less than the expected human exposure based on the recommended dose

            Contraception

            • Females of childbearing potential: Use effective contraception during treatment and for at least 2 months after the last dose
            • Males: Advise sexually active individuals with partners of childbearing potential to use condoms during treatment and for at least 4 months after last dose

            Male infertility

            • Based on testicular toxicity in animal studies, may irreversibly impair fertility in males of reproductive potential

            Lactation

            • Breastfeeding is not recommended in patients with smallpox
            • Data are not available on the presence in human milk, effects on breastfed infants, or on milk production
            • Brincidofovir is present in animal milk

            Animal studies

            • When administered to lactating rats (4 mg/kg/day or 15 mg/kg twice weekly), brincidofovir was detected in milk, but not in the plasma of 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

            Prodrug; brincidofovir effectively penetrates cells via its lipid conjugate, releasing the nucleotide analog cidofovir, which then acts to inhibit viral replication

            Cidofovir diphosphate selectively inhibits orthopoxvirus DNA polymerase-mediated viral DNA synthesis; incorporation of cidofovir into the growing viral DNA chain results in reductions in the rate of viral DNA synthesis

            Absorption

            Bioavailability: 16.8% (oral suspension); 13.4% (tablet)

            Peak plasma time: 3 hr (brincidofovir); 47 hr (cidofovir diphosphate)

            Peak plasma concentration: 480 ng/mL (brincidofovir); 9.7 pg/106 cells (cidofovir diphosphate)

            AUC: 3400 ng⋅hr/mL(brincidofovir); 1200 pg⋅hr/106 cells (cidofovir diphosphate)

            Effect of food

            • AUC decreased by 31%
            • Peak plasma concentration decreased by 49%

            Distribution

            Protein bound: >99.9%

            Vd: 1230 L

            Blood/plasma ratio: 0.48-0.61

            Metabolism

            Brincidofovir is a prodrug that is converted intracellularly to cidofovir, which is subsequently phosphorylated to cidofovir diphosphate, the active antiviral moiety, following oral administration

            Metabolic pathways: Hydrolysis, CYP4F2

            Elimination

            Half-life: 19.3 hr (brincidofovir); 113 hr (cidofovir diphosphate)

            Clearance: 44.1 L/hr

            Excretion: 51% (as metabolites) in urine; 40% (as metabolites) in feces

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            Administration

            Preparation

            Suspected carcinogen: Avoid direct contact with broken or crushed tablets or oral suspension; if contact with skin or mucous membranes occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with water

            Oral Administration

            Tablets

            • May take on an empty stomach or with a low-fat meal (~400 calories, with ~25% of calories from fat)
            • Swallow tablets whole; do not crush or divide

            Suspension

            • Take on an empty stomach
            • Shake oral suspension before use
            • Use an appropriate oral dosing syringe to correctly measure the total prescribed dose
            • Discard unused portion after completion of 2 prescribed doses
            • Administration via enteral tube
              • Draw up prescribed dose with calibrated catheter-tip syringe, and use this syringe to administer dose via the enteral tube
              • Refill catheter-tip syringe with 3 mL of water, shake, and administer the contents via the enteral tube
              • Flush with water before and after enteral administration

            Storage

            Store at 20-25ºC (68-77ºF); excursions permitted from 15-30ºC (59-86ºF)

            Do not freeze

            Handling

            • Avoid direct contact with oral suspension
            • If contact with skin or mucous membranes occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with water
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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            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.