Adverse reactions : תופעות לוואי

4.8 Undesirable effects
Summary of the safety profile
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.

Tabulated list of adverse reactions

Adverse reactions obtained from the pivotal clinical study are tabulated below. The adverse reactions are ranked by frequency within each system organ class (SOC) and , presented in order of decreasing seriousness. Frequencies are defined as 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).



System organ class           Very common               Common                         Uncommon (≥ 1/10)                  (≥ 1/100 to < 1/10)            (≥ 1/1,000 to < 1/100) Blood and lymphatic                                    Anaemia* disorders                                              Haemoglobin decreased* Endocrine disorders                                    Hyperthyroidism* Thyroid-stimulating
Hormone decreased
Metabolism and                                         Decreased appetite nutrition disorders                                    Weight decrease Nervous system               Headache* disorders
Cardiac disorders                                                                     Sinus tachycardia* Vascular disorders           Flushing*                 Hypotension*
Respiratory, thoracic        Nasopharyngitis (of       Nasal congestion and mediastinal              non-infectious disorders                    origin)
Gastro-intestinal            Diarrhoea*                Abdominal pain disorders                    Vomiting *                Dyspepsia*
Nausea*
Skin and subcutaneous                                  Rash tissue disorders                                       Urticaria
Erythema
Musculoskeletal and          Jaw pain* connective tissue            Myalgia* disorders                    Arthralgia*
Pain in extremity*
General disorders and                                  Pain administration site conditions
* See section Description of selected adverse reactions.

Description of selected adverse reactions
Pharmacological effects associated with titration and maintenance treatment 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                     Titration                           Maintenance adverse reactions                        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).

Haemoglobin decrease
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 newly diagnosed with PAH, mean absolute changes in haemoglobin at regular visits compared to baseline ranged from −1.77 to −1.26 g/dL in the triple therapy group (selexipag, macitentan, tadalafil) compared to −1.61 to −1.28 g/dL in the double therapy group (placebo, macitentan and tadalafil). A decrease from baseline in haemoglobin concentration to below 10 g/dL was reported in 19.0% of patients in the triple therapy group and 14.5% in the double therapy group. Anaemia was reported with very common frequency (13.4%) in the triple therapy group compared to common frequency (8.3%) in the double therapy group.

Thyroid function tests
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.

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. 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).

Hypotension
In the Phase 3 placebo-controlled study in patients with PAH, hypotension was reported for 5.8% of patients in the selexipag group compared to 3.8% in the placebo group. Mean absolute changes in systolic blood pressure at regular visits compared to baseline ranged from −2.0 to −1.5 mmHg in the selexipag group compared to −1.3 to 0.0 mmHg in the placebo group and in diastolic blood pressure ranged from −1.6 to −0.1 mmHg in the selexipag group compared to −1.1 to 0.3 mmHg in the placebo group. Systolic blood pressure decrease below 90 mmHg was recorded for 9.7% of patients in the selexipag group compared 6.7% in the placebo group.

Dyspepsia
In a phase 3 placebo-controlled study in patients newly diagnosed with PAH, dyspepsia was reported with very common frequency (16.8%) in patients receiving triple therapy (selexipag, 

macitentan, tadalafil) compared to common frequency (8.3%) in patients receiving double therapy (placebo, macitentan and tadalafil).

Long-term safety
Of the 1,156 patients who participated in the pivotal study, 709 patients entered a long-term open- label extension study (330 patients who continued on selexipag from the GRIPHON study and 379 patients who received placebo in GRIPHON and crossed over to selexipag). Long-term follow up of patients treated with selexipag for a median treatment duration of 30.5 months and for a maximum of up to 103 months showed a safety profile that was similar to that observed in the pivotal clinical study described above.

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form at the following link: https://sideeffects.health.gov.il/