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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:
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The molecular formula is C26H26FN5O4 and molecular weight is 491.5. Sebetralstat is a white to off-white crystalline powder. It is slightly soluble in ethanol, acetone and isopropanol, and practically insoluble in water.
EKTERLY is supplied as 300 mg film-coated tablets for oral administration. Each tablet contains the active ingredient sebetralstat. The inactive ingredients include croscarmellose sodium, glycerol mono and dicaprylocaprate, guar gum/guar galactomannan, hypromellose, iron oxide black, iron oxide yellow, macrogol polyvinyl alcohol graft copolymer, magnesium stearate, maltodextrin, medium chain triglycerides, microcrystalline cellulose, polyvinyl alcohol, povidone, talc and titanium dioxide.
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) [see Clinical Studies (14)]. 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.
Table 3 displays adverse reaction(s) with an incidence of ≥2% in the EKTERLY 600 mg treated patients and more common than placebo.
Table 3: Adverse Reaction(s) with EKTERLY with Incidence ≥2% and More Common than Placebo in Patients with Hereditary Angioedema (KONFIDENT)
|
Adverse Reaction |
EKTERLY 600 mg |
Placebo |
|
n (%) |
n (%) |
|
|
Headache |
3 (3.2) |
1 (1.2) |
|
aOne (1) patient assigned to administer placebo actually received EKTERLY 600 mg. Safety results are presented by actual treatment received. |
||
Avoid use of EKTERLY with strong CYP3A4 inhibitors [see Clinical Pharmacology (12.3)].
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.
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 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 [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
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.
Sebetralstat is a substrate of CYP3A4. Concomitant use of sebetralstat with a strong or moderate CYP3A4 inducer decreases sebetralstat exposure, which may decrease efficacy.
No dose modification is recommended when EKTERLY is used concomitantly with weak CYP3A4 inducers [see Clinical Pharmacology (12.3)].
Included as part of the PRECAUTIONS section.
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.
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.
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).
Consider contacting the poison control help line (1-800-222-1222) or medical toxicologist for overdose management recommendations.
No information provided.
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.
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.
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.
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.
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).
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.
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).
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 [see Use in Specific Populations (8.6)].
Clinical Studies and Model-Informed Approaches
Strong CYP3A4 Inhibitors: Sebetralstat Cmax increased 2.4-fold and AUC0-inf increased 5.2-fold following concomitant administration with itraconazole (a strong CYP3A4 inhibitor) 200 mg once daily for 6 days [see Drug Interactions (7.1)].
Moderate CYP3A4 Inhibitors: Sebetralstat Cmax increased 1.8-fold and AUC0-inf increased 2-fold following concomitant administration with verapamil (a moderate CYP3A4 inhibitor) 240 mg once daily for 6 days [see Drug Interactions (7.1)].
Strong CYP3A4 Inducers: Sebetralstat Cmax decreased by 66% and AUC0-inf decreased by 83% following concomitant administration with phenytoin (a strong CYP3A4 inducer) 100 mg three times daily for 15 days [see Drug Interactions (7.1)].
Moderate CYP3A4 Inducers: Sebetralstat Cmax decreased by 63% and AUC0-inf decreased by 79% following concomitant administration with efavirenz (a moderate CYP3A4 inducer) 600 mg once daily for 14 days [see Drug Interactions (7.1)].
Acid-Reducing Agents: Sebetralstat Cmax is estimated to decrease by up to 56% and AUC0-inf is estimated to decrease by up to 30% at pH 6 relative to pH 0.5.
Other Drugs: No clinically significant differences in sebetralstat pharmacokinetics were observed when administered concomitantly with quinidine (P-gp inhibitor), eltrombopag (BCRP inhibitor), cimetidine (evaluated as a weak CYP3A4 inhibitor), or modafinil (weak CYP3A4 inducer).
In Vitro Studies
CYP450 Enzymes: Sebetralstat is a substrate of CYP3A4 and CYP2C8, and is not a substrate of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, or CYP2E1. Sebetralstat is an inhibitor of CYP2C9 and CYP3A4. Sebetralstat did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C19, or CYP2D6.
Transporter Systems: Sebetralstat is a substrate of P-gp and BCRP, and is not a substrate of OATP1B1, OATP1B3, OAT1, OAT3, OCT2, or MATE1. Sebetralstat is an inhibitor of BCRP, OATP1B1, OATP1B3, OAT3, OCT2, MATE1, MATE2-K, and BSEP. Sebetralstat did not inhibit P-gp or OAT1.
Advise patients to read the FDA-approved patient labeling (Patient Information).
Advise patients not to use EKTERLY with strong CYP3A4 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. 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 [see Dosage and Administration (2.2), Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
For more information, visit www.EKTERLY.com
EKTERLY® is a registered trademark of KalVista Pharmaceuticals Limited.
Distributed by:
KalVista Pharmaceuticals, Inc.
55 Cambridge Parkway Suite 901E
Cambridge, MA 02142
