Uptravi Adverse Reactions

The most commonly reported adverse drug reactions related to the pharmacological effects of UPTRAVI are headache, diarrhoea, nausea and vomiting, jaw pain, myalgia, pain in extremity, flushing, and arthralgia. These reactions are more frequent during the dose 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 1156 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.
Table 2 presents adverse events over the entire treatment period in the Phase 3 study. (See Table 2.)

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Table 3 presents adverse drug reactions occurring in selexipag-treated subjects at an incidence < 3% and with a placebo-corrected difference ≥ 1% (during treatment and up to 7 days after treatment discontinuation). Adverse reactions are listed by system organ class and frequency category, using the convention: common (≥ 1/100 and < 1/10). Frequency determination does not account for other factors including varying study duration, pre-existing conditions, and baseline patient characteristics. (See Table 3.)

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Description of selected adverse reactions: Pharmacological effects associated with titration and maintenance treatment: Adverse reactions associated with the pharmacological action of selexipag have been observed frequently, in particular during the phase of individualised dose titration (Table 4). These effects are usually transient or manageable with symptomatic treatment. (See Table 4.)

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Increase in heart rate: 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. ECG investigations showed sinus tachycardia in 11.3% of patients in the selexipag group compared to 8.8% in the placebo group.
Eye disorders: Eye disorders in the selexipag and placebo groups occurred in 11.0% and 7.8%, respectively (mostly eye pain at 1.6% vs. 0.3%) and retinal disorders in 3.5% vs. 1.9%. Tortuosity and dilation of retinal arterioles were seen in rats after 2 years of treatment with very high doses (more than 25-fold above human exposure).
Malignancies: Malignancies occurred in 1.9% (n=11) in the selexipag group and 0.7% (n=4) in the placebo group, mainly due to cutaneous malignancies and blood and lymphatic system malignancies (see Pharmacology: Toxicology: Preclinical Safety Data: Genotoxicity and Carcinogenicity under Actions).
Laboratory abnormalities: Haemoglobin/Anaemia: In a Phase 3 placebo-controlled study in patients with PAH, mean absolute changes in haemoglobin at regular visits compared to baseline ranged from -3.4 to -0.2 g/L in the selexipag group compared to -0.5 to 2.5 g/L in the placebo group. A decrease from baseline in haemoglobin concentration to below 100 g/L was reported in 8.6% of patients treated with selexipag and 5.0% of placebo-treated patients. Median haemoglobin concentrations decreased over the first 3 months of treatment and stabilised thereafter.
Adverse events of anaemia were more frequent in selexipag patients who were taking concomitant treatment for PAH: ERA monotherapy: 14.9% and 9.2% with Selexipag and placebo respectively; PDE5i monotherapy: 11.1% and 5.4%; ERA and PDE5i: 11.2% and 10.7%. The incidence of anaemia AEs in patients who received no concomitant PAH specific therapies were 4.5% in the selexipag group and 6.7% in the placebo group.
Thyroid function tests: In a Phase 3 placebo-controlled study in patients with PAH, a reduction in median thyroid-stimulating hormone (TSH) (up to -0.3 MU/L from a baseline median of 2.5 MU/L) 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.
Combination treatment of selexipag with macitentan and tadalafil in newly diagnosed PAH patients: Safety of triple combination treatment (selexipag, macitentan and tadalafil) versus double combination (macitentan, tadalafil and placebo) in newly diagnosed PAH patients was evaluated in the double-blind, placebo-controlled TRITON clinical study. The median duration of exposure to selexipag/ placebo was 90 weeks.
The adverse reactions that occurred in at least 10% of patients in triple therapy group and ≥ 5% more commonly on selexipag, macitentan and tadalafil than on placebo, macitentan, and tadalafil are shown in Table 4. Adverse reactions are listed by system organ class and frequency category is defined using the convention: very common (≥ 10%). (See Table 5.)

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Postmarketing data: In addition to the adverse reactions reported during clinical studies and listed above, the following adverse reactions have been reported during postmarketing experience (Table 6). Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. (See Table 6.)

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Reporting suspected adverse effects: Reporting suspected adverse reactions after registration 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 to the National Centre for Adverse Drug Reactions Monitoring.