EKTERLY Film-coated tablet Ref.[115832] Active ingredients: Sebetralstat

Laryngeal attacks

Following treatment of laryngeal attacks, patients should seek immediate medical attention. If laryngeal attack symptoms worsen after treatment, patients should be managed in an appropriate medical institution.

Normal C1 esterase inhibitor (nC1-INH)

There are no data available on the use of Ekterly in HAE patients with nC1-INH. Some subcategories of nC1-INH HAE may not respond to treatment due to alternative pathways that do not include plasma kallikrein activation. It is recommended to perform genetic testing, if available, according to the current HAE guidelines, and to discontinue the treatment if clinical response is not observed (see sections 4.2 and 5.1).

QT prolongation

In a clinical trial dedicated to the assessment of cardiac parameters in healthy subjects, a potential of sebetralstat to extend the QT interval was detected but only at high concentrations that are not expected to be reached with the recommended dose. There are no data available for the use of sebetralstat in patients with independent risk factors for QT prolongation such as known pre-existing QT prolongation (either acquired or congenital), electrolyte disturbances, hepatic impairment, concomitant use of drugs interacting with the metabolism of sebetralstat or concomitant use of other medicinal products known to prolong the QT interval. Caution is warranted on the risk of QT prolongation in these patients, especially in patients who have more than one risk factor (see section 5.1).

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose that is to say essentially "sodium free".

Effects of other medicinal products on sebetralstat

Sebetralstat is a substrate of CYP3A4

Itraconazole, a strong CYP3A4 inhibitor, increased the C_max of sebetralstat by 135% and the AUC by 420%. The moderate CYP3A4 inhibitor verapamil increased the C_max of sebetralstat by 76% and the AUC by 102%. Co-administration with the weak CYP3A4 inhibitor cimetidine caused no change in the exposure of sebetralstat. No dose adjustment is required when taking CYP3A4 inhibitors.

Phenytoin, a strong CYP3A4 inducer, reduced the C_max of sebetralstat by 66% and the AUC by 83%. The moderate CYP3A4 inducer efavirenz reduced the C_max of sebetralstat by 63% and the AUC by 79%. Co-administration with the weak CYP3A4 inducer modafinil caused no clinically relevant change in the exposure of sebetralstat. No dose adjustment is required when taking weak CYP3A4 inducers.

In patients taking strong or moderate CYP3A4 inducers (e.g. rifampicin, efavirenz, carbamazepine, phenytoin, phenobarbital), it is recommended that an HAE attack is treated with a dose of 900 mg (3 x 300 mg tablets).

In patients with moderate hepatic impairment who are taking a strong CYP3A4 inhibitor (e.g. erythromycin, clarithromycin, itraconazole, ketoconazole, ritonavir) a single dose of 300 mg is recommended when treating an HAE attack.

Gastric Acid Reducing Agents

No dedicated in vivo drug-drug interaction (DDI) study with gastric acid reducing agents was performed. Thus, the effect of gastric acid reducing agents on the pharmacokinetics of sebetralstat is unknown. Caution should be used when co-administering Ekterly with gastric pH modifying agents such as antacids, proton-pump inhibitors, and histamine 2 receptor antagonists.

Effects of sebetralstat on other medicinal products

No clinical DDI studies assessing the effect of sebetralstat on other medicinal products have been performed.

In vitro data suggest that sebetralstat may inhibit CYP2C9, UGT1A4 and UGT1A9, and transporters OCT2, OATP1B3, MATE1, and MATE2-K. The clinical relevance of these findings is currently unknown. Co-administration of sebetralstat with substrates of these enzymes and transporters which have a narrow therapeutic index (e.g., warfarin, mycophenolic acid, cyclosporine, tacrolimus) should be avoided unless clinically warranted given the risk of increased pharmacokinetic exposure of these co-administered drugs and thus of toxicity. If co-administration is unavoidable, close clinical monitoring is recommended where feasible.

Paediatric population

Interaction studies have only been performed in adults.

Women of childbearing potential

Women of childbearing potential must use effective contraception during treatment with Ekterly and for a period of 24 hours after the last dose.

Pregnancy

There are no data from the use of Ekterly in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Ekterly should be used during pregnancy only if the potential benefit justifies the potential risk for the fetus (e.g. for treatment of potentially life-threatening laryngeal attacks).

Breast-feeding

It is unknown whether sebetralstat or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of sebetralstat and/or its metabolites in milk (see section 5.3).

A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue/abstain from Ekterly therapy, or to discontinue breast-feeding for 24 hours after taking Ekterly, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data regarding the effects of Ekterly on human fertility. No effect on fertility was observed in animal studies (see section 5.3).

Ekterly has minor influence on the ability to drive and use machines.

Dizziness has been reported following the use of Ekterly. This symptom may also occur as a result of an attack of HAE. Patients should be advised not to drive or use machines if they feel dizzy.

Summary of the safety profile

Ekterly has been administered to a total of 411 healthy subjects and 239 hereditary angioedema patients. In clinical trials used for registration, 1945 HAE attacks have been treated with Ekterly.

The most common adverse reaction in HAE patients treated with Ekterly is headache (reported by 9.2% of patients). The reported events of headache were generally mild to moderate in severity, non-serious and resolved without any further intervention.

Tabulated list of adverse reactions

The frequency of all adverse reactions listed in the table below is defined using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000).

Table 1. Summary of adverse reactions by system organ class and frequency:

^* Includes events of abdominal pain and abdominal pain upper.

Paediatric population

In 32 adolescent patients aged 12 to <18 years old, a total of 390 HAE attacks have been treated with sebetralstat. The safety profile was similar to that observed in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.