Berotralstat (Monograph)

Brand name: Orladeyo
Drug class: Kallikrein Inhibitors

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

Plasma kallikrein inhibitor.

Uses for Berotralstat

Hereditary Angioedema

Prevention of angioedema attacks in adults and pediatric patients ≥12 years of age with hereditary angioedema (HAE). Designated an orphan drug by FDA for this use.

Guidelines generally support berotralstat among other options as a first-line treatment for prevention of HAE attacks.

Not indicated for treatment of acute HAE attacks.

Berotralstat Dosage and Administration

Administration

Oral Administration

Administer orally once daily with food.

Commercially available as oral capsules containing 110 mg or 150 mg of berotralstat.

Dosage

Pediatric Patients

Prophlyaxis of HAE Attacks

Oral

Pediatric patients ≥12 years of age: 150 mg once daily with food.

Adults

Prophylaxis of HAE Attacks

Oral

150 mg once daily with food.

Dosage Modification for Concomitant Use with P-glycoprotein or Breast Cancer Resistance Protein Inhibitors

In patients receiving concomitant chronic therapy with P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) inhibitors (e.g., cyclosporine), reduce dosage to 110 mg once daily with food.

Dosage Modification for GI Reactions

In patients who experience persistent GI reactions, consider a reduced dosage of 110 mg once daily with food.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): No dosage adjustment required.

Moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment: Recommended dosage is 110 mg orally once daily with food.

Renal Impairment

Mild, moderate, or severe renal impairment: No dosage adjustment required.

End-stage renal disease (Cl_cr <15 mL/minute or eGFR <15 mL/minute per 1.73 m² or on hemodialysis): Use not recommended (not studied).

Geriatric Use

No specific dosage recommendations at this time.

Cautions for Berotralstat

Contraindications

None.

Warnings/Precautions

QT Prolongation

Do not use for treatment of acute attacks of HAE. QT prolongation (concentration dependent) observed at dosages higher than the recommended 150 mg once daily. Use of additional doses or doses higher than 150 mg once daily not recommended due to risk of QT prolongation.

Specific Populations

Pregnancy

Insufficient data in humans to inform drug-related risks with berotralstat use in pregnancy.

No evidence of structural alterations when berotralstat administered orally to pregnant rats and rabbits during organogenesis at doses up to approximately 10 and 2 times, respectively, the maximum recommended human daily dose.

Lactation

Unknown whether distributed into human milk. Effects on breast-fed infants or on milk production unknown.

Low levels of berotralstat detected in plasma of rat pups following administration of oral berotralstat to dams during lactation.

Consider developmental and health benefits of breast-feeding along with the mother's clinical need for berotralstat and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and effectiveness established for HAE prophylaxis in pediatric patients ≥12 years of age. Safety profile and attack rates were similar between pediatric patients 12 to <18 years of age and adults.

Safety and effectiveness not established in pediatric patients <12 years of age.

Geriatric Use

Safety and effectiveness evaluated in geriatric patients ≥65 years of age. Results of subgroup analysis by age consistent with overall study results.

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Berotralstat pharmacokinetics unchanged; no dosage adjustment required.

Moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment: Increased concentrations; reduced dosage of 110 mg orally once daily recommended.

Renal Impairment

Mild, moderate, or severe renal impairment: No clinically important differences observed; no dosage adjustment required.

End-stage renal disease (Cl_cr <15 mL/minute or eGFR <15 mL/minute per 1.73 m² or on hemodialysis): Use not recommended (not studied).

Common Adverse Effects

Most common adverse reactions (≥10%): abdominal pain, vomiting, diarrhea, back pain, gastroesophageal reflux disease.

Drug Interactions

Moderate inhibitor of CYP2D6 and CYP3A4; weak inhibitor of CYP2C9 and CYP2C19.

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate.

P-gp inhibitor.

The following drug interactions are based on studies of berotralstat, or are predicted to occur with use of berotralstat.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP2D6 or CYP3A4 substrates: Appropriately monitor or dose-titrate narrow therapeutic index drugs that are predominantly metabolized by CYP2D6 (e.g., thioridazine, pimozide) or CYP3A4 (e.g., cyclosporine, fentanyl), when used concomitantly with berotralstat.

Drugs Affecting or Affected by P-glycoprotein Transport and Breast Cancer Resistance Protein

P-gp inducers: Concomitant use of berotralstat and P-gp inducers (e.g., rifampin, St. John's wort) not recommended (reduced berotralstat plasma concentrations and efficacy).

P-gp or BCRP inhibitors: In patients with chronic use of P-gp or BCRP inhibitors (e.g., cyclosporine), reduced dosage of berotralstat 110 mg once daily recommended.

P-gp substrates: If berotralstat used concomitantly with P-gp substrates (e.g., digoxin), appropriately monitor and dose titrate the P-gp substrate.

Specific Drugs

Berotralstat Pharmacokinetics

Absorption

Bioavailability

Median time to peak plasma concentration is 5 hours (range, 1–8 hours) following oral administration with food.

Food

No differences in peak plasma concentration and AUC observed following administration with a high-fat meal; however, median time to peak concentration was delayed by 3 hours, from 2 hours (fasted state) to 5 hours (fed state).

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

Approximately 99% bound to plasma proteins.

Elimination

Metabolism

Metabolized by CYP2D6 and CYP3A4 with low turnover in vitro.

Elimination Route

Following a single dose of oral radiolabeled berotralstat 300 mg, 79% of dose excreted in feces; approximately 9% eliminated in urine (3.4% as unchanged drug).

Half-life

Approximately 93 hours (range, 39–152 hours).

Special Populations

Pediatric patients: Exposure at steady state following oral administration of berotralstat (150 mg once daily) approximately 20% higher in pediatric patients 12 to <18 years of age compared to adults; not considered clinically important.

Geriatric patients: Pharmacokinetic analyses that included patients ≥65 years of age indicate age does not have a clinically important impact on systemic exposure of berotralstat.

Mild hepatic impairment: Berotralstat pharmacokinetics unchanged compared to individuals with normal hepatic function.

Moderate hepatic impairment: Berotralstat peak plasma concentrations and AUC increased by 77 and 78%, respectively. Median half-life increased by 37%.

Severe hepatic impairment: Berotralstat peak plasma concentrations increased by 27%, AUC decreased by 5%, and median half-life increased by 22%. Percent of unbound berotralstat increased 2-fold compared to healthy individuals.

Severe renal impairment (Clcr <30 mL/minute): No clinically important differences compared to individuals with normal renal function (Clcr >90 mL/minute); peak drug concentrations and AUC increased by 47 and 14%, respectively.

End-stage renal disease (Clcr <15 mL/minute or eGFR <15 mL/minute/1.73 m² or on hemodialysis): Pharmacokinetics not studied.

Body weight, gender, race: No clinically important impact on systemic exposure of berotralstat.

Stability

Storage

Oral

Capsules

20–25°C (excursions permitted between 15–30°C).

Actions

• Plasma kallikrein inhibitor that binds to plasma kallikrein and inhibits its proteolytic activity.

• Decreases plasma kallikrein activity to control excess bradykinin generation in patients with HAE. By inhibiting kallikrein, high-molecular-weight-kininogen is not cleaved, which reduces release of bradykinin, a potent vasodilator that promotes swelling and pain associated with HAE.

• In patients with HAE due to C1-inhibitor deficiency or dysfunction, normal regulation of plasma kallikrein activity not present, which leads to uncontrolled increases in plasma kallikrein activity and bradykinin release, resulting in angioedema attacks.

Advice to Patients

• Inform patients to take berotralstat with food.

• Inform patients that berotralstat should not be used as an acute treatment for hereditary angioedema (HAE) attacks. Advise patients to take their usual rescue medication to treat an acute attack of HAE.

• Advise patients to not take berotralstat doses higher than 150 mg once daily or additional doses due to risk of QT prolongation.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products (e.g., St. John’s wort), as well as any concomitant illnesses.

• Advise patients of other precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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