Sebetralstat
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anum Ijaz M.B.B.S., M.D.[2]
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Overview
Sebetralstat is a plasma kallikrein inhibitor that is FDA approved for the treatment of acute attacks of hereditary angioedema (HAE) in adult and pediatric patients aged 12 years and older.. Common adverse reactions include headache(incidence ≥2%)..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
FDA-labeled Indications
- EKTERLY® is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adult and pediatric patients aged 12 years and older.
Recommended Dosage
- The recommended dosage of EKTERLY is one dose of 600 mg (two tablets) orally at the earliest recognition of an acute HAE attack.
- A second dose of 600 mg (two tablets) may be taken at least 3 hours after the first dose if response is inadequate, or if symptoms worsen or recur.
- Maximum recommended dosage is 1,200 mg (four tablets) in any 24-hour period.
Dosage Modifications for CYP3A4 Inhibitors and Inducers
Refer to the table below for dosage modification of EKTERLY when used concomitantly with CYP3A4 inhibitors and inducers.
Add Dosage modification table 1.
Recommended Dosage in Patients with Hepatic Impairment
Refer to the table below for recommended dosage of EKTERLY in patients with hepatic impairment.
Dosage Forms and Strengths
Tablets: 300 mg, yellow, oval, biconvex, film-coated tablets debossed with tablet logo one side and “300” on the other side.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sebetralstat in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sebetralstat in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
FDA-labeled Indications
- EKTERLY® is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adult and pediatric patients aged 12 years and older.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sebetralstat in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sebetralstat in pediatric patients.
Contraindications
None.
Warnings
There is limited information regarding Sebetralstat Warnings' in the drug label.
Adverse Reactions
Clinical Trials Experience
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of EKTERLY is based on data from a double-blind, randomized, placebo-controlled, three-way, crossover clinical trial (KONFIDENT).
- In KONFIDENT, a total of 110 patients aged 12 years and older with HAE treated 264 attacks. In the safety population, 93 patients received EKTERLY 600 mg, 86 patients received EKTERLY 300 mg, and 83 patients received placebo.
- While EKTERLY 300 mg was included in KONFIDENT, the safety data is based on the recommended dosage of EKTERLY 600 mg.
Add adverse reactions table
Postmarketing Experience
There is limited information regarding Sebetralstat Postmarketing Experience in the drug label.
Drug Interactions
Effect of Other Drugs on EKTERLY
Strong CYP3A4 Inhibitors
- Avoid use of EKTERLY with strong CYP3A4 inhibitors.
- Sebetralstat is a substrate of CYP3A4. Concomitant use of sebetralstat with a strong CYP3A4 inhibitor increases sebetralstat exposure, which may increase the risk of sebetralstat adverse reactions.
Moderate and Weak CYP3A4 Inhibitors
- Reduce dose of EKTERLY to one dose of 300 mg (one tablet) orally at the earliest recognition of an HAE attack when used concomitantly with moderate CYP3A4 inhibitors. 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.
- Sebetralstat is a substrate of CYP3A4. Concomitant use of sebetralstat with a moderate CYP3A4 inhibitor increases sebetralstat exposure, which may increase the risk of sebetralstat adverse reactions.
- No dose modification is recommended when EKTERLY is used concomitantly with a weak CYP3A4 inhibitor
Strong and Moderate CYP3A4 Inducers
- Use of EKTERLY with strong or moderate CYP3A4 inducers is not recommended.
Sebetralstat is a substrate of CYP3A4.
- Concomitant use of sebetralstat with a strong or moderate CYP3A4 inducer decreases sebetralstat exposure, which may decrease efficacy.
Weak CYP3A4 Inducers No dose modification is recommended when EKTERLY is used concomitantly with weak CYP3A4 inducers.
Use in Specific Populations
Pregnancy
Risk Summary
- There are no available data on EKTERLY in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.
- 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 (on an area under the curve [AUC] basis).
- Sebetralstat produced an increase in embryofetal losses and fetal malformations in rats at an exposure that was 60 times the MRHD (see Data).
- The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
- All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.
Data
Animal Data
- In an embryofetal development study with pregnant rats dosed by the oral route during the period of organogenesis from gestation days 6 to 17, sebetralstat caused a dose-related increase in the incidence of external and visceral malformations, described as cleft palates and ventricular septal defects and an increase in embryofetal losses (early and late fetal deaths, mean number of live fetuses, and post-implantation loss at an exposure that was 60 times the MRHD (on an AUC basis with a maternal dose of 600 mg/kg/day)).
- Maternal toxicity, as evidenced by decreased body weight gains, was observed at exposures 60 times the MRHD (on an AUC basis with a maternal oral dose of 600 mg/kg/day).
- No fetal or maternal toxicities were observed at exposures up to 15 times the MRHD (on an AUC basis with a maternal oral dose of 300 mg/kg/day).
- In an embryofetal development study with pregnant rabbits dosed by the oral route during the period of organogenesis from gestation days 6 to 18, maternal toxicity was evidenced by a decrease in body weight gain at an exposure that was 11 times the MRHD (on an AUC basis with a maternal dose of 300 mg/kg/day).
- No adverse effects on maternal toxicity were observed at an exposure that was 2 times the MRHD (on an AUC basis with a maternal dose of 100 mg/kg/day).
- No adverse effects on fetal toxicity were observed at an exposure that was 11 times the MRHD (on an AUC basis with a maternal oral dose of 300 mg/kg/day).
- In a prenatal and postnatal development study with pregnant rats dosed by the oral route during the periods of gestation and lactation from gestation day 6 to lactation day 20, sebetralstat had no effects on the growth and development of offspring at an exposure that was 40 times the MRHD (on an AUC basis with a maternal oral dose of 450 mg/kg/day).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sebetralstat in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Sebetralstat during labor and delivery.
Nursing Mothers
Risk Summary
- 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.
- Radioactivity is present in animal milk after dosing with radiolabeled sebetralstat. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Data in the rat have shown excretion of sebetralstat and/or its metabolites in milk (see Data).
- The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EKTERLY and any potential adverse effects on the breastfed child from EKTERLY or from the underlying maternal condition.
Data
Animal Data
- In a single dose placental transfer and milk secretion study in lactating rats dosed with radiolabeled sebetralstat by the oral route, total radioactivity was detected in fetal plasma at 1 hour post dose.
- Similar concentrations of total radioactivity were observed in the milk and plasma of lactating females, with the maximum radioactive concentration observed at 1 hour post dose that returned to background levels by 24 hours post dose.
- The concentration of total radioactivity in animal milk does not necessarily predict the concentration of drug in human milk.
Pediatric Use
- The safety and effectiveness of EKTERLY for treatment of acute attacks of hereditary angioedema (HAE) have been established in pediatric patients aged 12 years and older.
- Use of EKTERLY for this indication is supported by evidence from an adequate and well-controlled study (KONFIDENT) in adults and pediatric patients aged 12 years and older with additional population pharmacokinetic (PK) analysis from adults and pediatric patients aged 12 years and older, which showed no clinically significant differences in PK based on body weight or age.
- Results of the subgroup analysis for pediatric patients aged 12 years and older were consistent with study results for adult patients.
- The safety and effectiveness of EKTERLY in pediatric patients aged <12 years of age have not been established.
Geriatic Use
- Clinical studies of EKTERLY did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.
Gender
There is no FDA guidance on the use of Sebetralstat with respect to specific gender populations.
Race
There is no FDA guidance on the use of Sebetralstat with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Sebetralstat in patients with renal impairment.
Hepatic Impairment
- No dose adjustment of EKTERLY is recommended for patients with mild hepatic impairment (Child-Pugh Class A).
- For patients with moderate hepatic impairment (Child-Pugh Class B), the recommended dose of EKTERLY is one dose of 300 mg (one tablet) orally at the earliest recognition of an HAE attack.
- 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.
- Avoid use of EKTERLY in patients with severe hepatic impairment (Child-Pugh Class C)
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sebetralstat in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Sebetralstat in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Sebetralstat Administration in the drug label.
Monitoring
There is limited information regarding Sebetralstat Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Sebetralstat and IV administrations.
Overdosage
Consider contacting the poison control help line (1-800-222-1222) or medical toxicologist for overdose management recommendations.
Pharmacology
There is limited information regarding Sebetralstat Pharmacology in the drug label.
Mechanism of Action
- Sebetralstat is a competitive, reversible inhibitor of plasma kallikrein.
- 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.
- Sebetralstat inhibits the cleavage of HK and reduces production of bradykinin, thereby treating the clinical symptoms of an acute, episodic attack of HAE.
- Sebetralstat also inhibits the positive feedback mechanism of the kallikrein kinin system by plasma kallikrein, thereby reducing factor XIIa and additional plasma kallikrein generation.
Structure
The active ingredient of EKTERLY is sebetralstat, a plasma kallikrein inhibitor. The chemical name of sebetralstat is N-[(3-fluoro-4-methoxypyridin-2-yl) methyl]-3-(methoxymethyl)-1-({4-[(2-oxo-1,2-dihydropyridin-1-yl) methyl]phenyl}methyl)-1H-pyrazole-4-carboxamide. The chemical structure of sebetralstat is:
Add structure image
Pharmacodynamics
- Concentration-dependent inhibition of plasma kallikrein, measured as a reduction from baseline of specific enzyme activity, was observed in exploratory assays.
- Following administration of a single oral dose of 600 mg sebetralstat to healthy subjects, greater than 90% mean inhibition of plasma kallikrein activity was observed beginning at 30 minutes after dosing and maintained through about 6 hours post-dose.
Cardiac Electrophysiology
- The largest mean increase in QTc interval was 10.4 msec (upper confidence interval = 15.3 msec) after administration of sebetralstat (2.5 times the maximum recommended dose) in healthy subjects.
- The increase in the QTc interval was concentration dependent.
Pharmacokinetics
- Following a single oral dose of 600 mg sebetralstat in subjects with HAE, the geometric mean (CV%) Cmax is 6,080 ng/mL (40%) and AUC0-inf is 17,600 ng•h/mL (36%).
- Following administration of a second oral dose of 600 mg sebetralstat 3 hours after the first dose, Cmax increases 10% and AUC0-inf increases 90% when compared to those observed following a single dose.
- No clinically relevant differences in sebetralstat pharmacokinetics were observed between healthy subjects and patients with HAE.
- Absorption
After a single oral dose of 600 mg sebetralstat, the median time to peak plasma concentration is approximately 1 hour.
- Effect of Food
No clinically relevant differences in sebetralstat pharmacokinetics were observed following administration of a high-fat meal (900-1,000 calories in total – 500-600, 250 and 150 calories from fat, carbohydrate and protein respectively).
- Distribution
The estimated typical apparent volume of distribution (Vz/F) for sebetralstat is 70.1 L (95% CI: 64.8, 75.4). Sebetralstat plasma protein binding is 77% in vitro.
- Elimination
Following administration of a single oral dose of 600 mg sebetralstat, the mean (SD) elimination half-life of sebetralstat ranged from 5.3 (2.3) to 8.9 (5.1) hours. The estimated typical apparent clearance (CL/F) is 30.7 L/h (95% CI: 29.1, 32.2).
- Metabolism
Sebetralstat is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8.
- Excretion
Following administration of a single oral dose of 600 mg radiolabeled sebetralstat to healthy male subjects, approximately 63% of the dose was recovered in feces (12.5% as unchanged sebetralstat) and 32% in urine (8.7% as unchanged sebetralstat).
- Specific Populations
No clinically relevant differences in the pharmacokinetics of sebetralstat were observed based on body weight (45-135 kg), age (19-68 years), sex, race (71% White, 17% Black, 11% Asian), and mild renal impairment (eGFR 60-89 mL/min/1.73 m2). The effect of moderate and severe renal impairment (eGFR <60 mL/min/1.73 m2) on sebetralstat pharmacokinetics is unknown.
- Patients with Hepatic Impairment
The pharmacokinetics of sebetralstat were evaluated in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment following administration of a single 600 mg dose. In subjects with mild hepatic impairment Cmax was increased by 7% and AUC increased by 16% compared to subjects with normal hepatic function. In subjects with moderate hepatic impairment Cmax was increased by 63% and AUC was increased by 100% compared to subjects with normal hepatic function. The effect of severe hepatic impairment (Child-Pugh Class C) on sebetralstat pharmacokinetics is unknown
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
- A 6-month carcinogenicity study in rasH2-Tg transgenic mice was conducted to assess the carcinogenic potential of sebetralstat.
- Sebetralstat demonstrated no tumorigenic potential in a study with male and female mice that received oral doses up to 200 mg/kg/day and 300 mg/kg/day, respectively.
Mutagenesis
- Sebetralstat was not mutagenic or clastogenic in the following assays: in vitro bacterial reverse mutation (Ames) test, in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and in vivo rat micronucleus assay.
Impairment of Fertility
- Fertility and reproductive performance were unaffected in male or female rats that received sebetralstat by the oral route at dose levels up to 600 mg/kg/day (approximately 38 times the MRHD in adults on an AUC basis).
Clinical Studies
- The efficacy of EKTERLY for the treatment of acute attacks of hereditary angioedema (HAE) in adult and pediatric patients aged 12 years and older was evaluated in a double-blind, randomized, placebo-controlled, multicenter crossover clinical trial (KONFIDENT [NCT05259917]).
- KONFIDENT employed a 3-way, complete crossover design comparing EKTERLY 600 mg and EKTERLY 300 mg to placebo.
- If needed (as determined by the patient) a second dose could be administered after 3 hours. Patients were required to treat an eligible HAE attack prior to crossover to the next treatment period.
- Severe laryngeal attacks were not treated in KONFIDENT. The duration of trial participation was approximately 25 weeks.
- Although evaluated in KONFIDENT, EKTERLY 300 mg is not a recommended dose for treatment of acute HAE attacks.
- A total of 110 patients were randomized and experienced at least one HAE attack. Of the 264 treated HAE attacks, 142 (54%) had peripheral symptoms only, 85 (32%) had abdominal symptoms only, 27 (10%) had abdominal and peripheral symptoms, 8 (3%) had mild to moderate laryngeal symptoms, and 2 (1%) had missing attack location.
- The primary endpoint for KONFIDENT was the ‘time to beginning of symptom relief’ defined as at least “a little better” at two consecutive time points within 12 hours of first dose administration, assessed using a seven-point scale Patient Reported Global Impression of Change (PGI-C) ranging from “much worse” to “much better”.
- As shown in Figure 1, there was a statistically significant faster time to the beginning of symptom relief for EKTERLY 600 mg compared to placebo. A total of 71 out of 93 (76%) patients administered EKTERLY 600 mg and 41 out of 84 (49%) patients administered placebo achieved the primary endpoint. The median time to beginning of symptom relief within 12 hours of first dose was 2.0 hours (95% CI: 1.5, 2.8) in patients administered EKTERLY 600 mg.
Add figures 1,2,3
- Less than 50% of placebo patients reached beginning of symptom relief within 12 hours; therefore, the median time could not be estimated.
- Patients who did not achieve the endpoint, received alternate on-demand therapy, or lacked at least 2 consecutive post-baseline assessments were right-censored at 12 hours.
Secondary Endpoints
- The first key secondary endpoint was the ‘time to first incidence of reduction in severity’ at two consecutive time points within 12 hours of first dose administration, assessed using a five-point scale Patient Global Impression of Severity (PGI-S) ranging from “none” to “severe”.
- The ‘time to first incidence of reduction in severity’ (Figure 2) was statistically significantly faster for EKTERLY 600 mg compared to placebo.
- A total of 49 out of 93 (53%) patients administered EKTERLY 600 mg and 26 out of 84 (31%) patients administered placebo achieved reduction in severity within 12 hours. The median time to achieve this endpoint was 9.1 hours (95% CI: 3.8, not reached) in patients administered EKTERLY 600 mg.
- Less than 50% of placebo patients reached beginning of reduction in severity within 12 hours; therefore, the median time could not be estimated.
- Patients who did not achieve the endpoint, received alternate on-demand therapy, or lacked at least 2 consecutive post-baseline assessments were right-censored at 12 hours.
- The second key secondary endpoint was ‘time to attack resolution’ defined as PGI-S of “none” within 24 hours of first dose administration.
- The ‘time to attack resolution’ (Figure 3) was statistically significantly faster for EKTERLY 600 mg compared to placebo. A total of 46 out of 93 (49%) patients administered EKTERLY 600 mg and 23 out of 84 (27%) patients administered placebo achieved attack resolution within 24 hours.
- Less than 50% of EKTERLY 600 mg and placebo patients had attack resolution within 24 hours; therefore, the median time could not be estimated.
- Patients who did not achieve the endpoint, received alternate on-demand therapy, or lacked post-baseline assessments were right-censored at 24 hours.
Other Endpoints
- The time to beginning of at least “better” at two consecutive time points on the PGI-C within 12 hours of the first dose administration was assessed.
- A total of 54 out of 93 (58%) patients administered EKTERLY 600 mg and 21 out of 84 (25%) patients administered placebo achieved this endpoint. The median time was 4.6 hours (95% CI: 3.3, 9.5) in patients administered EKTERLY 600 mg.
How Supplied
EKTERLY (sebetralstat) tablets: 300 mg, yellow, oval, biconvex, film-coated tablets debossed with tab logo on one side and “300” on the other side.
EKTERLY is supplied as
Carton of 4, containing four child-resistant blister cards. Each child- resistant blister card contains 1 x 300 mg tablet (NDC 82928-300-04). Carton of 4, containing two child-resistant blister cards. Each child-resistant blister card contains 2 x 300 mg tablets (NDC 82928-300-05).
Storage
Each carton contains a tamper evident seal. Do not use if tamper evident seal is broken or missing. Store at 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C and 30°C (59°F to 86°F).
Images
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Patient Counseling Information
Advise patients to read the FDA-approved patient labeling (Patient Information).
Dosage Modification for Strong and Moderate CYP3A4 Inhibitors
- Advise patients not to use EKTERLY with strong CYP3A4 inhibitors.
- 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.
- 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.
Recommended Dosage in Patients with Hepatic Impairment
- Advise patients with severe hepatic impairment to avoid use of EKTERLY.
- In patients with moderate hepatic impairment, advise patients to take one tablet of 300 mg (total dose 300 mg) at earliest recognition of an HAE attack.
- 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.
Precautions with Alcohol
Alcohol-Sebetralstat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
EKTERLY (ek-TURR-lee)
Look-Alike Drug Names
There is limited information regarding Sebetralstat Look-Alike Drug Names in the drug label.
Price
References
The contents of this FDA label are provided by the National Library of Medicine.