Selexipag

Selexipag is hydrolysed to its active metabolite by carboxylesterases. Selexipag and its active metabolite both undergo oxidative metabolism mainly by CYP2C8 and to a smaller extent by CYP3A4.

Concomitant administration of selexipag with clopidogrel (loading dose of 300 mg or maintenance dose of 75 mg once a day), a moderate inhibitor of CYP2C8, had no relevant effect on the exposure to selexipag but increased the exposure to the active metabolite approximately 2.2 and 2.7-fold following loading dose and maintenance dose, respectively. Dosing frequency of selexipag should be reduced to once daily when co-administered with moderate CYP2C8 inhibitors (e.g. clopidogrel, deferasirox, teriflunomide). Dosing frequency of selexipag should be reverted to twice daily when co-administration of moderate CYP2C8 inhibitor is stopped.

Selexipag is hydrolysed to its active metabolite by carboxylesterases. Selexipag and its active metabolite both undergo oxidative metabolism mainly by CYP2C8 and to a smaller extent by CYP3A4.

In the presence of 600 mg rifampicin, once a day, an inducer of CYP2C8 (and UGT enzymes), the exposure to selexipag did not change, whereas exposure to the active metabolite was reduced by half. Dose adjustment of selexipag may be required with concomitant administration of inducers of CYP2C8 (e.g. rifampicin, carbamazepine, phenytoin).

Selexipag and its active metabolite are substrates of OATP1B1 and OATP1B3. Selexipag is a weak substrate of the P-gp efflux pump.

In the presence of 400/100 mg lopinavir/ritonavir twice daily, a strong OATP (OATP1B1 and OATP1B3) and P-gp inhibitor, exposure to selexipag increased approximately 2-fold, whereas the exposure to the active metabolite of selexipag did not change. Given that the majority of the pharmacological effect is driven by the active metabolite, this effect is not clinically relevant.

Selexipag is hydrolysed to its active metabolite by carboxylesterases. Selexipag and its active metabolite both undergo oxidative metabolism mainly by CYP2C8 and to a smaller extent by CYP3A4.

In the presence of 400/100 mg lopinavir/ritonavir twice daily, a strong CYP3A4 inhibitor, exposure to selexipag increased approximately 2-fold, whereas the exposure to the active metabolite of selexipag did not change. Given the 37-fold higher potency of the active metabolite, this effect is not clinically relevant. Since a strong inhibitor of CYP3A4 did not affect the pharmacokinetics of the active metabolite, indicating that the CYP3A4 pathway is not important in the elimination of the active metabolite, no effect of inducers of CYP3A4 on the pharmacokinetics of the active metabolite is expected.

For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose of Uptravi should be 200 micrograms once daily, and increased at weekly intervals by increments of 200 micrograms given once daily until adverse reactions, reflecting the mode of action of selexipag, that cannot be tolerated or medically managed are experienced.

Selexipag should not be administered in patients with severe liver impairment (Child-Pugh class C).

The glucuronidation of the active metabolite of selexipag is catalysed by UGT1A3 and UGT2B7.

The effect of strong inhibitors of UGT1A3 and UGT2B7 (valproic acid, probenecid, and fluconazole) on the exposure to selexipag and its active metabolite has not been studied. Caution is required when administering these medicinal products concomitantly with selexipag. A potential pharmacokinetic interaction with strong inhibitors of UGT1A3 and UGT2B7 cannot be excluded.

Selexipag has vasodilatory properties that may result in lowering of blood pressure. Before prescribing selexipag, physicians should carefully consider whether patients with certain underlying conditions could be adversely affected by vasodilatory effects (e.g. patients on antihypertensive therapy or with resting hypotension, hypovolaemia, severe left ventricular outflow obstruction or autonomic dysfunction).

Hyperthyroidism has been observed with selexipag. Thyroid function tests are recommended as clinically indicated in the presence of signs or symptoms of hyperthyroidism.

Cases of pulmonary oedema have been reported with vasodilators (mainly prostacyclins) when used in patients with pulmonary veno-occlusive disease. Consequently, if signs of pulmonary oedema occur when selexipag is administered in patients with PAH, the possibility of pulmonary veno-occlusive disease should be considered. If confirmed, treatment with selexipag should be discontinued.

There are no data from the use of selexipag in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Selexipag and its main metabolite showed 20- to 80-times lower prostacyclin (IP) receptor potency in vitro for animal species used in reproductive toxicity testing compared to humans. Therefore, safety margins for potential IP receptor-mediated effects on reproduction are accordingly lower than for non-IP-related effects.

Selexipag is not recommended during pregnancy and in women of childbearing potential not using contraception.

It is unknown whether selexipag or its metabolites are excreted in human milk. In rats, selexipag or its metabolites are excreted in milk. A risk to the suckling child cannot be excluded. Selexipag should not be used during breast-feeding.

Women of childbearing potential

Women of childbearing potential should practise effective contraception while taking selexipag.

Fertility

There are no clinical data available. In rat studies, selexipag at high doses caused transient disturbances in oestrus cycles that did not affect fertility. The relevance for humans is not known.

Selexipag has minor influence on the ability to drive and use machines. The clinical status of the patient and the adverse reaction profile of selexipag (such as headache or hypotension) should be kept in mind when considering the patient’s ability to drive and use machines.