Introduction
Berotralstat (brand name: Orladeyo) is an oral, once-daily plasma kallikrein inhibitor approved for the prevention of hereditary angioedema (HAE) attacks in patients 12 years and older. It represents the first oral prophylactic treatment option for HAE, offering an alternative to injectable and intravenous therapies.
Mechanism of Action
Berotralstat works by selectively inhibiting plasma kallikrein, a serine protease that plays a central role in the pathogenesis of hereditary angioedema. In HAE, deficient or dysfunctional C1 esterase inhibitor leads to uncontrolled plasma kallikrein activity, resulting in excessive bradykinin production. Bradykinin causes vasodilation and increased vascular permeability, leading to HAE attacks. By inhibiting plasma kallikrein, berotralstat reduces bradykinin generation, thereby preventing angioedema attacks.
Indications
Berotralstat is indicated for:
- Prophylaxis to prevent attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years and older
Dosage and Administration
Standard dosing: 150 mg orally once daily with food Administration:- Take with a meal or snack
- Swallow capsule whole; do not crush, chew, or open
- If a dose is missed, take as soon as possible on the same day
- Do not take two doses on the same day to make up for a missed dose
- Hepatic impairment: Not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C)
- Renal impairment: No dosage adjustment necessary for mild to moderate impairment; use with caution in severe impairment
- Pediatrics: Safety and effectiveness established in patients 12 years and older
- Geriatrics: No dosage adjustment required
Pharmacokinetics
Absorption: Median Tmax approximately 2 hours; high-fat meal increases exposure by approximately 40% Distribution: Volume of distribution ~200 L; protein binding >99% Metabolism: Primarily via CYP3A4; minor contributions from CYP2D6 and CYP2C19 Elimination: Half-life ~60 hours; fecal excretion (87%), renal excretion (<1%) Steady-state: Achieved within 7 days of once-daily dosingContraindications
- Hypersensitivity to berotralstat or any component of the formulation
- Concomitant use with strong CYP3A4 inhibitors
- Moderate or severe hepatic impairment (Child-Pugh B or C)
Warnings and Precautions
Cardiac Effects: May cause QT interval prolongation. Avoid use in patients with congenital long QT syndrome, congestive heart failure, or bradyarrhythmias. Consider ECG monitoring in patients with conditions that increase risk of QT prolongation. Hepatic Impairment: Not recommended in moderate or severe hepatic impairment due to increased exposure. Drug Interactions: Serious interactions possible with strong CYP3A4 inhibitors and inducers. Pregnancy: Limited data available; use only if potential benefit justifies potential risk. Pediatric Use: Safety and effectiveness established in patients ≥12 years.Drug Interactions
Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir): Contraindicated - may significantly increase berotralstat exposure Strong CYP3A4 inducers (e.g., rifampin, carbamazepine): May decrease berotralstat efficacy Moderate CYP3A4 inhibitors (e.g., fluconazole, diltiazem): Use with caution; consider monitoring QT-prolonging drugs: Additive effects possible; monitor ECG if co-administeredAdverse Effects
Most common adverse reactions (≥10%):- Abdominal pain (15%)
- Vomiting (13%)
- Headache (11%)
- Diarrhea (11%)
- Back pain (10%)
- Gastroesophageal reflux disease (10%)
- QT prolongation
- Liver transaminase elevations
Monitoring Parameters
- Frequency and severity of HAE attacks
- ECG monitoring in patients at risk for QT prolongation
- Liver function tests at baseline and periodically during treatment
- Adverse effects, particularly gastrointestinal symptoms
- Efficacy assessment through patient-reported outcomes
Patient Education
- Take berotralstat exactly as prescribed, once daily with food
- Do not stop taking without consulting your healthcare provider
- Report any new or worsening symptoms, especially abdominal pain, vomiting, or heart palpitations
- Inform all healthcare providers about all medications you are taking
- Keep a record of HAE attacks to discuss with your healthcare provider
- Store at room temperature (20-25°C) in original container
- Seek immediate medical attention for severe HAE attacks
References
1. Banerji A, Busse P, Shennak M, et al. Inhibition of plasma kallikrein for hereditary angioedema. N Engl J Med. 2020;382(16):1516-1525. 2. Orladeyo [package insert]. Durham, NC: BioCryst Pharmaceuticals, Inc.; 2020. 3. Longhurst HJ, Busse P, Baker J, et al. Efficacy and safety of berotralstat for hereditary angioedema: a systematic review and meta-analysis. J Allergy Clin Immunol Pract. 2022;10(1):274-283. 4. Riedl MA, Lumry WR, Busse P, et al. Berotralstat for long-term prophylaxis of hereditary angioedema: interim analysis of the APeX-S study. Clin Exp Allergy. 2021;51(10):1357-1369. 5. US Food and Drug Administration. Orladeyo (berotralstat) prescribing information. December 2020.