Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
Uptravi has vasodilatory properties that may result in lowering of blood pressure. Before prescribing Uptravi, 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 Uptravi. 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 Uptravi is administered in patients with PAH, the possibility of pulmonary veno-occlusive disease should be considered. If confirmed, treatment with Uptravi should be discontinued.
There is limited clinical experience with selexipag in patients over the age of 75 years, therefore Uptravi should be used with caution in this population (see section 4.2).
There is no clinical experience with selexipag in patients with severe liver impairment (Child-Pugh class C), therefore Uptravi should not be administered in these patients. The exposure to selexipag and its active metabolite is increased in subjects with moderate hepatic impairment (Child-Pugh class B; see section 5.2). In patients with moderate hepatic impairment, Uptravi should be dosed once daily (see section 4.2).
In patients with severe renal impairment (eGFR <30 mL/min/1.73 m²), caution should be exercised during dose titration. There is no experience with Uptravi in patients undergoing dialysis (see section 5.2), therefore Uptravi should not be used in these patients.
Women of childbearing potential should practise effective contraception while taking selexipag.
Selexipag is hydrolysed to its active metabolite by carboxylesterases (see section 5.2). Selexipag and its active metabolite both undergo oxidative metabolism mainly by CYP2C8 and to a smaller extent by CYP3A4. The glucuronidation of the active metabolite is catalysed by UGT1A3 and UGT2B7. Selexipag and its active metabolite are substrates of OATP1B1 and OATP1B3. Selexipag is a weak substrate of the P-gp efflux pump. The active metabolite is a weak substrate of the breast cancer resistance protein (BCRP).
The pharmacokinetics of selexipag and its active metabolite are not affected by warfarin.
In the presence of 600 mg gemfibrozil, twice a day, a strong inhibitor of CYP2C8, exposure to selexipag increased approximately 2-fold, whereas exposure to the active metabolite, the major contributor to efficacy, increased approximately 11-fold. Concomitant administration of Uptravi with strong inhibitors of CYP2C8 (e.g. gemfibrozil) is contraindicated (see section 4.3).
Concomitant administration of Uptravi 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 Uptravi should be reduced to once daily when co-administered with moderate CYP2C8 inhibitors (e.g. clopidogrel, deferasirox, teriflunomide). Dosing frequency of Uptravi should be reverted to twice daily when co-administration of moderate CYP2C8 inhibitor is stopped (see section 4.2).
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).
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 Uptravi. A potential pharmacokinetic interaction with strong inhibitors of UGT1A3 and UGT2B7 cannot be excluded.
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.
In the Phase 3 placebo-controlled trial in patients with PAH, the use of selexipag in combination with both an ERA and a PDE-5 inhibitor resulted in a 30% lower exposure to the active metabolite.
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 and its active metabolite do not inhibit or induce cytochrome P450 enzymes and transport proteins at clinically relevant concentrations.
Selexipag is an inhibitor of platelet aggregation in vitro. In the Phase 3 placebo-controlled study in patients with PAH, no increased risk of bleeding was detected with selexipag compared to placebo, including when selexipag was administered with anticoagulants (such as heparin, coumarin-type anticoagulants) or inhibitors of platelet aggregation. In a study in healthy subjects, selexipag (400 micrograms twice daily) did not alter the exposure to S-warfarin (CYP2C9 substrate) or R-warfarin (CYP3A4 substrate) after a single dose of 20 mg warfarin. Selexipag did not influence the pharmacodynamic effect of warfarin on the international normalised ratio.
At steady state after up-titration to 1,600 μg selexipag twice a day, no clinically relevant change in exposure to midazolam, a sensitive intestinal and hepatic CYP3A4 substrate, or its metabolite, 1-hydroxymidazolam, was observed. Concomitant administration of selexipag with CYP3A4 substrates does not require dose adjustment.
Specific drug-drug interaction studies with hormonal contraceptives have not been conducted. Since selexipag did not affect the exposure to the CYP3A4 substrates midazolam and R-warfarin or to the CYP2C9 substrate S-warfarin, reduced efficacy of hormonal contraceptives is not expected.
Women of childbearing potential should practise effective contraception while taking selexipag.
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 (see section 5.3).
Uptravi 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 (see section 5.3). A risk to the suckling child cannot be excluded. Uptravi should not be used during breast-feeding.
There are no clinical data available. In rat studies, selexipag at high doses caused transient disturbances in oestrus cycles that did not affect fertility (see section 5.3). The relevance for humans is not known.
Uptravi 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.
The most commonly reported adverse reactions are headache, diarrhoea, nausea and vomiting, jaw pain, myalgia, pain in extremity, arthralgia, and flushing. These reactions are more frequent during the up-titration phase. The majority of these reactions are of mild to moderate intensity.
The safety of selexipag has been evaluated in a long-term, Phase 3 placebo-controlled study enrolling 1,156 patients with symptomatic PAH. The mean treatment duration was 76.4 weeks (median 70.7 weeks) for patients receiving selexipag versus 71.2 weeks (median 63.7 weeks) for patients on placebo. The exposure to selexipag was up to 4.2 years.
Adverse reactions obtained from the pivotal clinical study are tabulated below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Common: Anaemia, Haemoglobin decreased
Common: Hyperthyroidism, Thyroid-stimulating, Hormone decreased (see section 4.4)
Common: Decreased appetite, Weight decrease
Very common: Headache*
Uncommon: Sinus tachycardia
Very common: Flushing*
Common: Hypotension (see section 4.4)
Very common: Nasopharyngitis (of non-infectious origin)
Common: Nasal congestion
Very common: Diarrhoea*, Vomiting*, Nausea*
Common: Abdominal pain
Common: Rash, Urticaria, Erythema
Very common: Jaw pain*, Myalgia*, Arthralgia*, Pain in extremity*
Common: Pain
* See section Description of selected adverse reactions.
Adverse reactions associated with the mode of action of selexipag have been observed frequently, in particular during the phase of individualised dose titration, and are tabulated below:
| Prostacyclin-like associated adverse reactions | Titration | Maintenance | ||
|---|---|---|---|---|
| Selexipag | Placebo | Selexipag | Placebo | |
| Headache | 64% | 28% | 40% | 20% |
| Diarrhoea | 36% | 12% | 30% | 13% |
| Nausea | 29% | 13% | 20% | 10% |
| Pain in jaw | 26% | 4% | 21% | 4% |
| Myalgia | 15% | 5% | 9% | 3% |
| Pain in extremity | 14% | 5% | 13% | 6% |
| Vomiting | 14% | 4% | 8% | 6% |
| Flushing | 11% | 4% | 10% | 3% |
| Arthralgia | 7% | 5% | 9% | 5% |
These effects are usually transient or manageable with symptomatic treatment. 7.5% of patients on selexipag discontinued treatment due to these adverse reactions. The approximate rate of adverse reactions that were serious was 2.3% in the selexipag group and 0.5% in the placebo group. In clinical practice, gastro-intestinal events have been observed to respond to anti-diarrhoeal, anti-emetic, and anti-nauseant medicinal products and/or medicinal products for functional gastro-intestinal disorders. Pain-associated events have frequently been treated with analgesics (such as paracetamol).
In a Phase 3 placebo-controlled study in patients with PAH, mean absolute changes in haemoglobin at regular visits compared to baseline ranged from −0.34 to −0.02 g/dL in the selexipag group compared to −0.05 to 0.25 g/dL in the placebo group. A decrease from baseline in haemoglobin concentration to below 10 g/dL was reported in 8.6% of selexipag-treated patients and 5.0% of placebo-treated patients.
In a Phase 3 placebo-controlled study in patients with PAH, hyperthyroidism was reported for 1.6% of patients in the selexipag group, compared to no case in the placebo group (see section 4.4). A reduction (up to −0.3 MU/L from a baseline median of 2.5 MU/L) in median thyroid-stimulating hormone was observed at most visits in the selexipag group. In the placebo group, little change in median values was apparent. There were no mean changes in triiodothyronine or thyroxine in either group.
In the Phase 3 placebo-controlled study in patients with PAH, a transient increase in mean heart rate of 3–4 bpm at 2–4 hours post-dose was observed. Electrocardiogram investigations showed sinus tachycardia in 11.3% of patients in the selexipag group compared to 8.8% in the placebo group (see section 5.1).
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.
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