Sebetralstat (Monograph)

Brand name: Ekterly
Drug class: Kallikrein Inhibitors

Introduction

Sebetralstat is a plasma kallikrein inhibitor.¹

Uses for Sebetralstat

Sebetralstat has the following uses:

Sebetralstat is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adult and pediatric patients 12 years of age and older. ¹

Sebetralstat Dosage and Administration

General

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

Tablets: 300 mg ¹

Dosage

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

Adults and Pediatric Patients ≥12 Years of Age

• Recommended Dosage: one dose of 600 mg (2 tablets) taken orally at the earliest recognition of an HAE attack.¹ A second dose of 600 mg (2 tablets) may be taken 3 hours after the first dose if response is inadequate, or if symptoms worsen or recur.¹ Maximum recommended dosage is 1,200 mg in any 24-hour period.¹

• See full prescribing information for dosage modifications for sebetralstat when used concomitantly with cytochrome P-450 (CYP) 3A4 inhibitors and inducers.¹

• See full prescribing information for recommended dosage for patients with hepatic impairment.¹

Cautions for Sebetralstat

Contraindications

None.¹

Warnings/Precautions

Specific Populations

Pregnancy

There are no available data on sebetralstat in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.¹ In animal reproduction studies, oral administration of sebetralstat to pregnant rats and rabbits during organogenesis produced no evidence of fetal harm with dose exposures up to approximately 15 and 11 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of up to 1,200 mg (based on AUC).¹ Sebetralstat produced an increase in embryofetal losses and fetal malformations in rats at an exposure that was 60 times the MRHD.¹

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.¹ All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.¹ In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.¹

Lactation

There are no data on the presence of sebetralstat or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production.¹ Radioactivity is present in animal milk after dosing with radiolabeled sebetralstat.¹ When a drug is present in animal milk, it is likely that the drug will be present in human milk.¹ Data in rats have shown excretion of sebetralstat and/or its metabolites in milk.¹ The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sebetralstat and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.¹

Pediatric Use

The safety and effectiveness of sebetralstat for treatment of acute attacks of hereditary angioedema (HAE) have been established in pediatric patients 12 years of age and older.¹ Use of sebetralstat for this indication is supported by evidence from an adequate and well-controlled study (KONFIDENT) in adults and pediatric patients 12 years of age and older with additional population pharmacokinetic (PK) analysis from adults and pediatric patients 12 years of age and older, which showed no clinically significant differences in PK based on body weight or age.¹ Results of the subgroup analysis for pediatric patients 12 years of age and older were consistent with study results for adult patients.¹

The safety and effectiveness of sebetralstat in pediatric patients <12 years of age have not been established.¹

Geriatric Use

Clinical studies of sebetralstat did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.¹

Hepatic Impairment

No dose adjustment of sebetralstat is recommended for patients with mild hepatic impairment (Child-Pugh Class A).¹ For patients with moderate hepatic impairment (Child-Pugh Class B), the recommended dose of sebetralstat is one dose of 300 mg (one tablet) orally at the earliest recognition of an HAE attack.¹ A second dose of 300 mg (one tablet) may be taken at least 3 hours after the first dose if response is inadequate, or if symptoms worsen or recur.¹ Avoid use of sebetralstat in patients with severe hepatic impairment (Child-Pugh Class C).¹

Common Adverse Effects

The most common adverse reaction (incidence ≥2%) is headache.¹

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:

• Strong and Moderate CYP3A4 Inhibitors: Avoid use with strong CYP3A4 inhibitors.¹ In patients taking moderate CYP3A4 inhibitors, take one dose of 300 mg.¹ A second dose of 300 mg may be taken at least 3 hours after the first dose if response is inadequate, or if symptoms worsen or recur.¹

• CYP3A4 Inducers: Avoid use with moderate or strong CYP3A4 inducers.¹

Actions

Mechanism of Action

Sebetralstat is a competitive, reversible inhibitor of plasma kallikrein.¹ Plasma kallikrein is a serine protease that cleaves high molecular weight kininogen (HK), releasing bradykinin which increases vascular permeability through activation of bradykinin receptors causing edema.¹ Sebetralstat inhibits the cleavage of HK and reduces production of bradykinin, thereby treating the clinical symptoms of an acute, episodic attack of HAE.¹ Sebetralstat also inhibits the positive feedback mechanism of the kallikrein kinin system by plasma kallikrein, thereby reducing factor XIIa and additional plasma kallikrein generation.¹

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Patient Information).¹

• Advise patients not to use sebetralstat with strong CYP3A4 inhibitors.¹ When used concomitantly with moderate CYP3A4 inhibitors, advise patients to reduce dose to one tablet of 300 mg (total dose 300 mg) at the earliest recognition of an HAE attack.¹ A second dose of 300 mg (one tablet) may be taken at least 3 hours after the first dose if response is inadequate, or if symptoms worsen or recur.¹

• Advise patients with severe hepatic impairment to avoid use of sebetralstat.¹ In patients with moderate hepatic impairment, advise patients to take one tablet of 300 mg (total dose 300 mg) at the earliest recognition of an HAE attack.¹ A second dose of 300 mg (one tablet) may be taken at least 3 hours after the first dose if response is inadequate, or if symptoms worsen or recur.¹

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.

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