Sebetralstat

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.

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.

In patients taking moderate or strong CYP3A4 inducers a single dose of 900 mg is recommended when treating an HAE attack.

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%.

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

Use in patients with severe hepatic impairment (Child-Pugh C) is not recommended.

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 sebetralstat with gastric pH modifying agents such as antacids, proton-pump inhibitors, and histamine 2 receptor antagonists.

There are no data from the use of sebetralstat in pregnant women. Studies in animals have shown reproductive toxicity.

Sebetralstat 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).

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.

A risk to the suckling child cannot be excluded.

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

Women of childbearing potential

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

Fertility

There are no data regarding the effects of sebetralstat on human fertility. No effect on fertility was observed in animal studies.

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

Dizziness has been reported following the use of sebetralstat. 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

Sebetralstat 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 sebetralstat.

The most common adverse reaction in HAE patients treated with sebetralstat 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).

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.