Overview
11 DESCRIPTION ORLADEYO (berotralstat) is a plasma kallikrein inhibitor. Berotralstat is presented as the dihydrochloride salt with the chemical name 1-[3-(aminomethyl)phenyl]- N -(5-{( R )-(3-cyanophenyl)[(cyclopropylmethyl)amino]methyl}-2-fluorophenyl)-3-(trifluoromethyl)-1 H -pyrazole-5-carboxamide dihydrochloride.
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Berotralstat is a plasma kallikrein inhibitor that 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 (cHMWK) and bradykinin, a potent vasodilator that increases vascular permeability resulting in swelling and pain associated with HAE. In patients with HAE due to C1-inhibitor (C1-INH) 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. Berotralstat decreases plasma kallikrein activity to control excess bradykinin generation in patients with HAE. 12.
Indications
- 1 INDICATIONS AND USAGE ORLADEYO ® is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adults and pediatric patients 2 years of age and older. ORLADEYO is a plasma kallikrein inhibitor indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adults and pediatric patients 2 years and older. ( 1 ) Limitations of Use : ORLADEYO should not be used for treatment of acute HAE attacks. ( 1 ) Limitations of Use : The safety and effectiveness of ORLADEYO for the treatment of acute HAE attacks have not been established.
Common Doses
- 150 mg
- 72 mg
- 15 mL
- 96 mg
Dosage
2 DOSAGE AND ADMINISTRATION Recommended dosage in adult and pediatric patients aged 12 years and older: 150 mg capsule orally once daily with food. ( 2.1 ) Recommended dosage in pediatric patients aged 2 to less than 12 years is based on body weight as follows ( 2.2 , 2.5 ): Weight Recommended Dosage (oral pellets) Administration Instructions 12 kg to less than 24 kg 72 mg once daily Pour directly in mouth and swallow immediately with non-acidic liquid, or, Sprinkle over 1 tablespoon (15 mL) of non-acidic soft food and consume immediately.
Contraindications
- 4 CONTRAINDICATIONS None. None. ( 4 )
Side Effects
- 6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in the labeling: QTc Interval Prolongation [see Warnings and Precautions (5.1) ] . Most common adverse reactions (≥10%) are abdominal pain, vomiting, diarrhea, back pain, and gastroesophageal reflux disease. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BioCryst Pharmaceuticals, Inc. at 1-833-633-2279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.
Interactions
- 7 DRUG INTERACTIONS P-gp inducers: Avoid use with ORLADEYO. ( 7.1 ) CYP2D6, CYP3A4 or P-gp Substrates: When used concomitantly with ORLADEYO, closely monitor or modify the dosage of the substrates where minimal increases in concentration may lead to serious adverse reactions. ( 7.2 , 12.3 ) 7.1 Effect of Other Drugs on ORLADEYO P-gp Inducers Berotralstat is a substrate of P-gp and BCRP. P-gp inducers may decrease berotralstat plasma concentration, leading to reduced efficacy of ORLADEYO. Avoid concomitant use of P-gp inducers with ORLADEYO. 7.