Introduction
Orladeyo (berotralstat) is an oral, once-daily plasma kallikrein inhibitor approved for the prevention of hereditary angioedema (HAE) attacks in patients 12 years and older. Developed by BioCryst Pharmaceuticals, it represents the first oral prophylactic treatment option for this rare genetic disorder characterized by recurrent, unpredictable episodes of swelling.
Mechanism of Action
Orladeyo works as a potent, selective inhibitor of plasma kallikrein. In HAE, a deficiency or dysfunction of C1 esterase inhibitor leads to uncontrolled plasma kallikrein activity, resulting in excessive generation of bradykinin. Bradykinin is a potent vasodilator that increases vascular permeability, causing HAE attacks. By inhibiting plasma kallikrein, berotralstat reduces bradykinin production, thereby preventing the swelling episodes characteristic of HAE.
Indications
Orladeyo is indicated for:
- Prophylaxis to prevent attacks of hereditary angioedema in patients 12 years and older
- Not indicated for the treatment of acute HAE attacks
Dosage and Administration
Standard dosing: 150 mg orally once daily with food Administration:- Take with a meal to enhance absorption
- Swallow capsule whole; do not crush, chew, or open
- If a dose is missed, take as soon as possible on the same day
- Hepatic impairment: Use not recommended in patients with moderate or severe hepatic impairment
- Renal impairment: No dosage adjustment necessary
- Pediatric: Safety and efficacy established in patients 12 years and older
- Geriatric: No dosage adjustment necessary
Pharmacokinetics
Absorption: Peak plasma concentrations achieved within 2-4 hours; high-fat meal increases exposure by approximately 40% Distribution: Volume of distribution ~172 L; plasma protein binding >99% Metabolism: Primarily via CYP3A4; minor contributions from CYP2D6 and CYP2C19 Elimination: Half-life ~25 hours; fecal excretion is the major route of elimination (85%) Steady-state: Achieved within 5 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
QTc Prolongation: Dose-related QTc prolongation observed; avoid use in patients with congenital long QT syndrome or with other drugs that prolong QT interval Hepatic Toxicity: Transaminase elevations reported; monitor liver enzymes at baseline and during treatment Drug Interactions: Potential for significant interactions with CYP3A4 inhibitors and inducers Pregnancy: Limited data available; use only if potential benefit justifies potential risk Lactation: No data on presence in human milk; consider developmental and health benefits of breastfeedingDrug Interactions
Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): Contraindicated due to increased berotralstat exposure and QTc prolongation risk Moderate CYP3A4 inhibitors (e.g., fluconazole, diltiazem): May increase berotralstat exposure; monitor for adverse effects CYP3A4 inducers (e.g., rifampin, carbamazepine): May decrease berotralstat efficacy QTc-prolonging drugs: Concomitant use may increase risk of cardiac arrhythmiasAdverse Effects
Most common adverse reactions (≥10%):- Abdominal pain (16%)
- Vomiting (13%)
- Diarrhea (12%)
- Back pain (11%)
- Gastroesophageal reflux disease (11%)
- QTc prolongation
- Hepatic transaminase elevations
Monitoring Parameters
- Liver function tests at baseline, periodically during treatment, and as clinically indicated
- ECG monitoring at baseline and during treatment in patients with cardiac risk factors
- Frequency and severity of HAE attacks
- Adverse effects, particularly gastrointestinal symptoms
- Pregnancy testing in women of childbearing potential as clinically indicated
Patient Education
- Take Orladeyo once daily with food at approximately the same time each day
- Do not use for treatment of acute HAE attacks; ensure availability of acute treatment medications
- Report any cardiac symptoms (palpitations, dizziness, syncope) immediately
- Inform healthcare providers of all medications being taken, including over-the-counter products
- Notify your physician if you experience persistent gastrointestinal symptoms
- Do not stop taking Orladeyo without consulting your healthcare provider
- Store at room temperature (20-25°C) in original container
References
1. FDA Prescribing Information: Orladeyo (berotralstat) capsules. December 2020. 2. Longhurst HJ, et al. Inhibition of plasma kallikrein for hereditary angioedema. N Engl J Med. 2020;382(16):1516-1525. 3. Riedl MA, et al. Safety and efficacy of berotralstat for hereditary angioedema: long-term results from the APeX-S study. J Allergy Clin Immunol Pract. 2021;9(6):2305-2314. 4. Banerji A, et al. Effect of berotralstat on hereditary angioedema attack frequency: APeX-2 randomized controlled trial. J Allergy Clin Immunol Pract. 2021;9(6):2295-2304. 5. ClinicalTrials.gov: Study of BCX7353 as Preventative Treatment for HAE Attacks (APeX-2). NCT03485911.