berotralstat (Rx)

Brand and Other Names:Orladeyo
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 110mg
  • 150mg

Hereditary Angioedema

Indicated for prevention of hereditary angioedema (HAE) attacks

150 mg PO qDay

Dosage Modifications

Renal impairment

  • Mild-severe (CrCl >15 mL/min): No dosage adjustment necessary
  • End-stage renal disease (CrCl <15 mL/min or eGFR <15 mL/min/1.73 m2): Not recommended; not studied

Hepatic impairment

  • Mild (Child-Pugh A): No dosage adjustment necessary
  • Moderate or severe (Child-Pugh B or C): Reduce to 110 mg PO qDay

P-gp or BCRP inhibitors

  • Long-term administration of P-gp or BCRP inhibitors (eg, cyclosporine): Reduce berotralstat to 110 mg PO qDay

Persistent gastrointestinal (GI) reactions

  • Consider reducing to 110 mg PO qDay

Dosing Considerations

Limitations of use

  • Safety and efficacy not established for acute HAE attacks; do not use for treatment
  • Additional doses or doses >150 mg/day are not recommended owing to potential for QT prolongation

Dosage Forms & Strengths

capsule

  • 110mg
  • 150mg

Hereditary Angioedema

Indicated for prevention of hereditary angioedema (HAE) attacks in adults and adolescents aged 12 years and older

<12 years: Safety and efficacy not established

≥12 years

  • 150 mg PO qDay

Dosage Modifications

Renal impairment

  • Mild-severe (CrCl >15 mL/min): No dosage adjustment necessary
  • End-stage renal disease (CrCl <15 mL/min or eGFR <15 mL/min/1.73 m2): Not recommended; not studied

Hepatic impairment

  • Mild (Child-Pugh A): No dosage adjustment necessary
  • Moderate or severe (Child-Pugh B or C): Reduce to 110 mg PO qDay

P-gp or BCRP inhibitors

  • Long-term administration of P-gp or BCRP inhibitors (eg, cyclosporine): Reduce berotralstat to 110 mg PO qDay

Persistent gastrointestinal (GI) reactions

  • Reduce dose to 110 mg PO qDay

Dosing Considerations

Limitations of use

Safety and efficacy not established for acute HAE attacks; should not use for treatment

Additional doses or doses >150 mg/day are not recommended owing to potential for QT prolongation

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Interactions

Interaction Checker

and berotralstat

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Abdominal pain (10-23%)

            Vomiting (10-15%)

            Diarrhea (10-15%)

            1-10%

            Gastroesophageal reflux disease (5-10%)

            Back pain (2-10%)

            Headache (9%)

            Fatigue (6%)

            Flatulence (6%)

            Frequency Not Defined

            In Trial 1, single patient discontinued treatment after a single 150-mg dose due to asymptomatic elevated ALT >8x ULN and AST >3x ULN and total bilirubin was normal

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            Warnings

            Contraindications

            None

            Cautions

            QT prolongation may occur at dosages >150 mg/day; additional doses or doses >150 mg/day are not recommended

            Drug interaction overview

            • Berotralstat is a P-gp and BCRP substrate, a P-gp inhibitor, a moderate CYP2D6 inhibitor, and weak CYP2D6 and CYP2C19 inhibitor
            • P-gp or BCRP inhibitors
              • Reduce berotralstat dose when coadministered
              • Cyclosporine, a P-gp and BCRP inhibitor, increased berotralstat peak plasma concentration by 25%, AUC(0-last) by 55%, and AUC(0-inf) by 69%
            • P-gp inducers
              • Avoid coadministration
              • P-gp inducers (eg, rifampin, St. John’s wort) may decrease berotralstat plasma concentration and efficacy
            • CYP2D6 or CYP3A4
              • Monitor or titrate substrate dose when coadministered with narrow therapeutic index drugs that are CYP2D6 or CYP3A substrates
              • Berotralstat moderately inhibits CYP2D6 or CYP3A4 at recommended dose (ie, 150 mg)
            • P-gp substrates
              • Monitoring or dose titration is recommended for P-gp substrates (eg, digoxin)
              • Berotralstat inhibits P-gp at higher than recommended dose (ie, 300 mg)
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            Pregnancy & Lactation

            Pregnancy

            Insufficient data available regarding use in pregnant females to inform drug-associated risks

            Animal data

            • No structural alterations observed when orally administered to pregnant rats and rabbits during organogenesis at doses up to ~10 and 2x, respectively, the maximum recommended human daily dose in adults based on AUC

            Lactation

            There are no data on drug presence in human milk, effects on breastfed infants, or effects on milk production

            Low levels of berotralstat detected in plasma of rat pups when oral administered to dams during lactation period; berotralstat concentration in pup plasma was ~2% of maternal plasma

            When drug is present in animal milk, it is likely the drug will be present in human milk

            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

            Kallikrein inhibitor; binds to plasma kallikrein and inhibits its proteolytic activity

            Plasma kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK and bradykinin, a potent vasodilator that increases vascular permeability resulting in swelling and pain associated with HAE

            In patients with HAE caused by C1-inhibitor deficiency or dysfunction, normal regulation of plasma kallikrein activity is not present, which leads to uncontrolled increases in plasma kallikrein activity and results in angioedema attacks

            Absorption

            Peak plasma time: 5 hr

            Peak plasma concentration at steady-state

            • 110 mg/day: 97.8 ng/mL
            • 150 mg/day: 158 ng/mL

            AUC at steady-state

            • 110 mg/day: 1,600 ng⋅hr/mL
            • 150 mg/day: 2,770 ng⋅hr/mL

            Steady-state

            • Reached at days 6-12
            • Exposure at steady state is ~5x that after a single dose

            Effect of food

            • No differences of peak plasma concentration and AUC with high-fat meal
            • Median peak plasma time was delayed by 3 hr

            Distribution

            Protein bound: ~99%

            Blood-to-plasma ratio: ~0.92

            Metabolism

            Metabolized by CYP2D6 and CYP3A4

            Elimination

            Half-life: ~93 hr

            Excretion: Urine (~9% [3.4% unchanged]); feces (79%)

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            Administration

            Oral Administration

            Administer with food

            Storage

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

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            Formulary

            FormularyPatient Discounts

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            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.