Berotralstat (Monograph)

Brand name: Orladeyo
Drug class: Kallikrein Inhibitors
Chemical name: 2-[3-(aminomethyl)phenyl]-N-[5-[(R)-(3-cyanophenyl)-(cyclopropylmethylamino)methyl]-2-fluorophenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide;dihydrochloride
Molecular formula: C₃₀H₂₆F₄N₆O•2HCl
CAS number: 1809010-52-3

Medically reviewed by Drugs.com on Jan 31, 2022. Written by ASHP.

Introduction

Berotralstat dihydrochloride is a plasma kallikrein inhibitor.

Uses for Berotralstat

Berotralstat has the following uses:

Berotralstat is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years and older.

Berotralstat has the following limitations of use:

Berotralstat should not be used for treatment of acute HAE attacks.

Berotralstat Dosage and Administration

General

Berotralstat dihydrochloride is available in the following dosage form(s) and strength(s):

Capsules: 110 mg (of berotralstat) and 150 mg (of berotralstat)

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Pediatric Patients

Dosage and Administration

Recommended dosage in pediatric patients 12 years of age and older: One capsule (150 mg) taken orally once daily with food.

Dosage adjustment is or may be necessary in the following patients; see full prescribing information:

Patients with moderate or severe hepatic impairment.
Patients receiving concomitant therapy with P-gp or BCRP inhibitors.
Patients with persistent GI reactions.

Adults

Dosage and Administration

Recommended dosage: One capsule (150 mg) taken orally once daily with food.

Dosage adjustment is or may be necessary in the following patients; see full prescribing information:

Patients with moderate or severe hepatic impairment.
Patients receiving concomitant therapy with P-gp or BCRP inhibitors.
Patients with persistent GI reactions.

Cautions for Berotralstat

Contraindications

None.

Warnings/Precautions

Risk Of QT Prolongation With Higher Than Recommended Dosages

Berotralstat should not be used for treatment of acute attacks of HAE. Use of additional doses or doses higher than 150 mg once daily to treat an acute attack of HAE is not recommended due to the risk of QT prolongation. An increase in QT was observed at dosages higher than the recommended 150 mg once daily dosage and was concentration dependent.

Specific Populations

Pregnancy

Risk Summary: There are insufficient data in pregnant women available to inform drug-related risks with berotralstat use in pregnancy. Based on animal reproduction studies, no evidence of structural alterations was observed when berotralstat was 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 (MRHDD) in adults on an AUC basis.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Animal Data: In animal reproduction studies, oral administration of berotralstat to pregnant rats and rabbits during the period of organogenesis did not cause fetal structural alterations. The berotralstat dose in rats and rabbits was up to approximately 10 and 2 times, respectively, the MRHDD in adults (on an AUC basis at maternal doses of 75 and 100 mg/kg/day, respectively). In a pre- and postnatal development study in rats, oral administration of berotralstat to pregnant rats during the period of organogenesis and until delivery at doses up to 45 mg/kg/day (approximately 2 times of the MRHDD on a mg/m² basis) did not cause fetal structural alterations either. Berotralstat concentrations in the fetal blood were approximately 5-11% of the maternal blood.

Lactation

Risk Summary: There are no data on the presence of berotralstat in human milk, its effects on the breastfed infant, or its effects on milk production. However, when a drug is present in animal milk, it is likely that the drug will be present in human milk. Low levels of berotralstat were detected in the plasma of rat pups when dams were dosed with the drug orally during the lactation period. The berotralstat concentration in the pup plasma was approximately 2% of the maternal plasma.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for berotralstat and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

Animal Data: In the pre- and post-natal development study in rats, berotralstat was administered to dams during the pregnancy and lactation periods at doses up to 45 mg/kg/day (approximately 2 times of the MRHDD on a mg/m² basis). Berotralstat was detected in the plasma of pups during the lactation period. The berotralstat concentration in the pup plasma was approximately 2% of the maternal plasma. Both dams and pups at 45 mg/kg/day showed statistically significant decreases in body weight gain (p < 0.05). No treatment-related effects were observed at 25 mg/kg/day (approximately equal to the MRHDD on a mg/m² basis).

Pediatric Use

The safety and effectiveness of berotralstat for prophylaxis to prevent attacks of hereditary angioedema have been established in pediatric patients aged 12 and older. Use of berotralstat in this population is supported by evidence from an adequate and well-controlled study (Trial 1) that included adults and a total of 6 adolescent patients aged 12 to <18 years of age. The safety profile and attack rate on study were similar to those observed in adults. An additional 10 adolescent patients aged 12 to <18 years were enrolled in the open-label study (Trial 2).

The safety and effectiveness of berotralstat in pediatric patients <12 years of age have not been established.

Geriatric Use

The safety and effectiveness of berotralstat were evaluated in a subgroup of patients (N=9) aged ≥65 years in Trial 1. Results of the subgroup analysis by age were consistent with overall study results. The safety profile from an additional 5 elderly patients aged ≥65 years enrolled in the open-label, long-term safety study (Trial 2) was consistent with data from Trial 1.

Renal Impairment

No dosage adjustment of berotralstat is recommended for patients with mild, moderate, or severe renal impairment.

Berotralstat has not been studied in patients with end-stage renal disease (Cl_cr<15 mL/min or eGFR <15 mL/min/1.73 m² or patients requiring hemodialysis), and, therefore is not recommended for use in these patient populations.

Hepatic Impairment

No dosage adjustment of berotralstat is recommended for patients with mild hepatic impairment (Child-Pugh Class A).

In patients with moderate or severe hepatic impairment (Child-Pugh B or C), the recommended dose of berotralstat is 110 mg once daily with food.

Common Adverse Effects

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

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

P-gp or BCRP inhibitors: Reduce berotralstat dosage when co-administered.

P-gp inducers: Avoid use with berotralstat.

CYP2D6, CYP3A4 or P-gp substrates: Appropriately monitor or dose titrate narrow therapeutic index drugs that are predominantly metabolized by CYP2D6, CYP3A4 or are P-gp substrates when co-administered with berotralstat.

Actions

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.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Inform patients of the risks and benefits of berotralstat before prescribing or administering to the patient.

Drug Interactions

Advise patients that berotralstat may interact with other drugs. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products.

Not for Acute Treatment of HAE Attacks

Advise patients to take their usual rescue medication to treat an acute attack of HAE. Inform patients that the safety and effectiveness of berotralstat have not been established as an acute treatment for HAE attacks. Advise patients that they should not take daily doses higher than 150 mg once daily or additional doses of berotralstat to treat an acute attack of HAE due to risk of QT prolongation.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.