Ekterly (sebetralstat)

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Administer sebetralstat orally at the earliest recognition of an acute HAE attack. A second dose may be administered >=3 hours after the first dose if response is inadequate, or if symptoms worsen or recur.

Store tablets at 20-25oC (excursions permitted to 15-30oC).

No dosing information is available for this tab.

Sebetralstat is primary metabolized by CYP3A4, and to a lesser extent, CYP2C8.

In vitro studies indicate that sebetralstat is a substrate of CYP3A4 and CYP2C8; sebetralstat is not a substrate of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, or CYP2E1. In vitro, sebetralstat inhibits CYP2C9 and CYP3A4; sebetralstat does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C19, or CYP2D6.

In vitro studies indicate that sebetralstat is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); sebetralstat is not a substrate of organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, or multidrug and toxin extrusion (MATE) 1. In vitro, sebetralstat inhibits BCRP, OATP1B1, OATP1B3, OAT3, OCT2, MATE1, MATE 2-K; sebetralstat does not inhibit P-gp or OAT1.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Sebetralstat/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inducers may accelerate the metabolism of sebetralstat by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of sebetralstat and strong CYP3A4 inducers may result in decreased levels and effectiveness of sebetralstat.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of sebetralstat states that the concurrent use of strong CYP3A4 inducers should be avoided.(1)

DISCUSSION: Sebetralstat maximum concentration (Cmax) decreased by 66% and area-under-curve (AUC) decreased by 83% following concomitant administration with phenytoin (a strong CYP3A4 inducer) 100 mg three times daily for 15 days.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's Wort.(2)

Sebetralstat/Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of sebetralstat.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels and effects of sebetralstat including QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: Child-Pugh class B or C hepatic impairment may increase the risk for increased exposure to sebetralstat. Sebetralstat should be avoided in patients with severe hepatic impairment (Child-Pugh class C).(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of sebetralstat states that concomitant use with strong CYP3A4 inhibitors should be avoided.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Concomitant use of sebetralstat with itraconazole (200 mg once daily for 6 days), a strong CYP3A4 inhibitor, increased sebetralstat maximum concentration (Cmax) and area-under-curve (AUC) by 2.4-fold and 5.2-fold, respectively.(1) In a study in healthy subjects, 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). The increase in the QTc interval was concentration dependent.(1) Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, relacorilant, telaprevir, tipranavir, troleandomycin, and tucatinib.(3-4)

Sebetralstat/Strong Cyp3a4 Inhibitors That Prolong Qt

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong QT may inhibit the metabolism of sebetralstat and result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased levels and effects of sebetralstat including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: Child-Pugh class B or C hepatic impairment may increase the risk for increased exposure to sebetralstat. Sebetralstat should be avoided in patients with severe hepatic impairment (Child-Pugh class C).(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of sebetralstat states that concomitant use with strong CYP3A4 inhibitors should be avoided.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Concomitant use of sebetralstat with itraconazole (200 mg once daily for 6 days), a strong CYP3A4 inhibitor, increased sebetralstat maximum concentration (Cmax) and area-under-curve (AUC) by 2.4-fold and 5.2-fold, respectively.(1) In a study in healthy subjects, 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). The increase in the QTc interval was concentration dependent.(1) Strong CYP3A4 inhibitors that prolong the QT interval linked to this monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir-ritonavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(3,4)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Sebetralstat/Moderate Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Moderate CYP3A4 inducers may accelerate the metabolism of sebetralstat by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of sebetralstat and a moderate CYP3A4 inducer may result in decreased levels and effectiveness of sebetralstat.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of sebetralstat states that the concurrent use of moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: Sebetralstat maximum concentration (Cmax) decreased by 63% and area-under-curve (AUC) decreased by 79% following concomitant administration with efavirenz (a moderate CYP3A4 inducer) 600 mg once daily for 14 days. Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Sebetralstat/Moderate Cyp3a4 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of sebetralstat.(1)

CLINICAL EFFECTS: Concurrent use of CYP3A4 inhibitors may increase the levels and effects of sebetralstat including QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: Child-Pugh class B or C hepatic impairment may increase the risk for increased exposure to sebetralstat. Sebetralstat should be avoided in patients with severe hepatic impairment (Child-Pugh class C).(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of sebetralstat states when used concomitantly with moderate CYP3A4 inhibitors, reduce the dose of sebetralstat to one dose of 300 mg (one tablet) orally at the earliest recognition of a hereditary angioedema 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.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Concomitant use of sebetralstat with verapamil (240 mg once daily for 6 days), a moderate CYP3A4 inhibitor, increased sebetralstat maximum concentration (Cmax) and area-under-curve (AUC) by 1.8-fold and 2-fold, respectively.(1) In a study in healthy subjects, 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). The increase in the QTc interval was concentration dependent.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, rilzabrutinib, schisandra, tofisopam, treosulfan, verapamil, voxelotor.(3-4)

Sebetralstat/Moderate Cyp3a4 Inhibitors That Prolong Qt

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 that prolong QT may inhibit the metabolism of sebetralstat and result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in increased levels and effects of sebetralstat including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes.(1)

PREDISPOSING FACTORS: Child-Pugh class B or C hepatic impairment may increase the risk for increased exposure to sebetralstat. Sebetralstat should be avoided in patients with severe hepatic impairment (Child-Pugh class C).(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of sebetralstat states when used concomitantly with moderate CYP3A4 inhibitors, reduce the dose of sebetralstat to one dose of 300 mg (one tablet) orally at the earliest recognition of a hereditary angioedema 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.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Concomitant use of sebetralstat with verapamil (240 mg once daily for 6 days), a moderate CYP3A4 inhibitor, increased sebetralstat maximum concentration (Cmax) and area-under-curve (AUC) by 1.8-fold and 2-fold, respectively.(1) In a study in healthy subjects, 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). The increase in the QTc interval was concentration dependent.(1) Moderate CYP3A4 inhibitors that prolong QT include: crizotinib, dronedarone, erythromycin, fluconazole, lefamulin, and nilotinib.(3-4)

*None.

There are no contraindication contraindications for this drug.

• Child-pugh class B hepatic impairment
• Disease of liver

There are no moderate contraindications for this drug.

The most common adverse reaction (incidence >=2%) reported with sebetralstat in clinical studies was headache.

There are no severe adverse reactions for this drug.

Less Frequent

• Headache disorder

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The safety and efficacy of sebetralstat for the treatment of acute attacks of HAE have been established in pediatric patients >=12 years of age. Use of sebetralstat in this population is supported by data from a double-blind, randomized, placebo-controlled, 3-way crossover trial (KONFIDENT) that included 13 pediatric patients 12 to <18 years of age. No significant pharmacokinetic differences were observed based on body weight or age. Results of the subgroup analysis in this population were consistent with results for adults >=18 years of age. The safety and efficacy of sebetralstat have not been established in pediatric patients <12 years of age.

Data are insufficient in humans to inform drug-related risks with sebetralstat use in pregnancy. In animal studies, no fetal harm was observed following oral administration of sebetralstat to pregnant rats and rabbits at dose exposures 15 and 11 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of <=1200 mg. At 60 times the MRHD, an increase in embryofetal loss and malformation was observed in rats.

It is not known whether sebetralstat is distributed into human milk. Effects of the drug on breastfed infants or milk production are also not known. In animals, after dosing with radiolabeled sebetralstat, radioactivity is present in milk; sebetralstat and/or its metabolites have also been observed in animal milk. Therefore, it is likely that drug is present in human milk.

The manufacturer makes no specific dosage recommendations for geriatric patients (>=65 years of age).

Experience in patients >=65 years of age is insufficient to determine whether they respond differently to sebetralstat than younger patients.