4.1. Therapeutic indications

Ekterly is indicated for the treatment of hereditary angioedema (HAE) attacks in adult and adolescents aged 12 years and older.

4.2. Posology and method of administration

Posology

The recommended dose of Ekterly is 300 mg administered at the earliest recognition of an attack. An additional dose may be taken if needed.

Special populations

Elderly population

No dose adjustment is required for patients above 65 years of age (see section 5.2).

Renal impairment

No dose adjustment is required for patients with renal impairment.

Hepatic impairment

No dose adjustment of Ekterly is required for patients with mild or moderate hepatic impairment (Child-Pugh A or B). Use of Ekterly in patients with severe hepatic impairment (Child-Pugh C) is not recommended.

Paediatric population

The safety and efficacy of sebetralstat in children under 12 years of age have not been established.

No data are available.

Patients taking strong CYP3A4 inhibitors

In patients who are taking a strong CYP3A4 inhibitor a single dose of 300 mg is recommended when treating an HAE attack.

Patients taking strong or moderate CYP3A4 inducers

In patients who are taking strong or moderate CYP3A4 inducers a single dose of 900 mg (3 x 300 mg tablets) is recommended when treating an HAE attack.

Method of administration

For oral use. The film-coated tablets can be taken with or without food (see section 5.2).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Laryngeal attacks: Following treatment of laryngeal attacks with Ekterly, advise patients to seek immediate medical attention.

Excipients

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

Sebetralstat is an in vitro inhibitor of MATE1, MATE2-K and OCT2 and co-administration may raise exposure to substrates of these transporters such as metformin. Clinicians should consider monitoring blood lactate and renal function in patients who carry a higher risk for lactic acidosis.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on sebetralstat

Sebetralstat is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Quinidine, a P-gp inhibitor, increased the maximum concentration (Cmax) of sebetralstat by 18% and the AUC of sebetralstat by 14%. Sebetralstat exposure may be increased with concomitant administration of P-gp inhibitors, however no dose adjustment is required.

Eltrombopag, a BCRP inhibitor, increased the Cmax of sebetralstat by 12%, however the AUC of sebetralstat remained unchanged. Sebetralstat peak levels may be increased with concomitant administration of BCRP inhibitors, however no dose adjustment is required.

Sebetralstat is a substrate of CYP3A4.

Itraconazole, a strong CYP3A4 inhibitor, increased the Cmax of sebetralstat by 135% and the AUC by 420%. The moderate CYP3A4 inhibitor verapamil increased the Cmax of sebetralstat by 76% and the AUC by 102%. Co-administration with the weak CYP3A4 inhibitor cimetidine caused no increase in the Cmax or AUC of sebetralstat. In patients who are taking a strong CYP3A4 inhibitor a single dose of 300 mg is recommended when treating an HAE attack. No dose adjustment is required when taking weak or moderate CYP3A4 inhibitors.

Phenytoin, a strong CYP3A4 inducer, reduced the Cmax of sebetralstat by 66% and the AUC by 83%. The moderate CYP3A4 inducer efavirenz reduced the Cmax of sebetralstat by 63% and the AUC by 79%. Co-administration with the weak CYP3A4 modafinil reduced the Cmax of sebetralstat by 11% and the AUC by 21%. In patients taking strong or moderate CYP3A4 inducers, it is recommended that an HAE attack is treated with a single dose of 900 mg (3 x 300 mg tablets). No dose adjustment is required when taking weak CYP3A4 inducers.

Effects of sebetralstat on other medicinal products

In vitro studies indicate that sebetralstat inhibits CYPs 2C9 and 3A4, and the transporters BCRP, OATP1B1, OATP1B3, OAT3, OCT2, MATE1 and MATE2-K. Clinical interaction data are not available. The potential for interaction should be considered when sebetralstat is administered to patients taking substrates of these enzymes and transporters, particularly narrow therapeutic index substrates. If possible, substrates of these drugs and transporters, should not be taken at the same time of the day as sebetralstat is used to treat an HAE attack to minimise the potential for an interaction (see section 5.2).

In vitro studies indicate that sebetralstat inhibits UGTs 1A4 and 1A9. Clinical interaction data are not available (see section 5.2).

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of Ekterly in pregnant women.

Studies in pregnant rats indicate that daily sebetralstat administration was associated with embryofoetal harm at exposures higher than clinical exposures. A study in rabbits had equivocal results (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Ekterly during pregnancy and in women of childbearing potential not using effective, medically appropriate contraception.

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 newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Ekterly therapy 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).

4.7. Effects on ability to drive and use machines

Fatigue 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 experience fatigue.

4.8. Undesirable effects

Summary of the safety profile

Ekterly has been administered to a total of 411 healthy subjects and 239 hereditary angioedema patients. In clinical studies used for registration, 1,945 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

System organ class

Adverse Reaction

Frequency

Nervous system disorders

Headache

Common

Gastrointestinal disorders

Dyspepsia

Common

Nausea

Uncommon

Abdominal pain

Uncommon

General disorders and administration site conditions

Fatigue

Uncommon

Musculoskeletal and connective tissue disorders

Back pain

Uncommon

Vascular disorders

Hot flush

Uncommon

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No case of overdose has been reported in clinical trials.