UPTRAVI 1600mcg tablets medication leaflet

Uptravi 100 microgram film-coated tablets

Uptravi 200 microgram film-coated tablets

Uptravi 400 microgram film-coated tablets

Uptravi 600 microgram film-coated tablets

Uptravi 800 microgram film-coated tablets

Uptravi 1 000 microgram film-coated tablets

Uptravi 1 200 microgram film-coated tablets

Uptravi 1 400 microgram film-coated tablets

Uptravi 1 600 microgram film-coated tablets

Uptravi 100 microgram film-coated tablets

Each film-coated tablet contains 100 micrograms of selexipag.

Uptravi 200 microgram film-coated tablets

Each film-coated tablet contains 200 micrograms of selexipag.

Uptravi 400 microgram film-coated tablets

Each film-coated tablet contains 400 micrograms of selexipag.

Uptravi 600 microgram film-coated tablets

Each film-coated tablet contains 600 micrograms of selexipag.

Uptravi 800 microgram film-coated tablets

Each film-coated tablet contains 800 micrograms of selexipag.

Uptravi 1 000 microgram film-coated tablets

Each film-coated tablet contains 1 000 micrograms of selexipag.

Uptravi 1 200 microgram film-coated tablets

Each film-coated tablet contains 1 200 micrograms of selexipag.

Uptravi 1 400 microgram film-coated tablets

Each film-coated tablet contains 1 400 micrograms of selexipag.

Uptravi 1 600 microgram film-coated tablets

Each film-coated tablet contains 1 600 micrograms of selexipag.

For the full list of excipients, see section 6.1.

Film-coated tablet

Uptravi 100 microgram film-coated tablets

Round, 3.0 mm diameter, light-yellow, film-coated tablets, with “1” debossed on one side.

Uptravi 200 microgram film-coated tablets

Round, 7.3 mm diameter, light-yellow, film-coated tablets,with “2” debossed on one side.

Uptravi 400 microgram film-coated tablets

Round, 7.3 mm diameter, red, film-coated tablets with “4” debossed on one side.

Uptravi 600 microgram film-coated tablets

Round, 7.3 mm diameter, light-violet, film-coated tablets with “6” debossed on one side.

Uptravi 800 microgram film-coated tablets

Round, 7.3 mm diameter, green, film-coated tablets with “8” debossed on one side.

Uptravi 1 000 microgram film-coated tablets

Round, 7.3 mm diameter, orange, film-coated tablets with “10” debossed on one side.

Uptravi 1 200 microgram film-coated tablets

Round, 7.3 mm diameter, dark-violet, film-coated tablets with “12” debossed on one side.

Uptravi 1 400 microgram film-coated tablets

Round, 7.3 mm diameter, dark-yellow, film-coated tablets with “14” debossed on one side.

Uptravi 1 600 microgram film-coated tablets

Round, 7.3 mm diameter, brown, film-coated tablets with “16” debossed on one side.

Uptravi is indicated for the long-term treatment of pulmonary arterial hypertension (PAH) in adultpatients with WHO functional class (FC) II-III, either as combination therapy in patients insufficientlycontrolled with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5)inhibitor, or as monotherapy in patients who are not candidates for these therapies.

Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAHassociated with connective tissue disorders, and PAH associated with corrected simple congenitalheart disease (see section 5.1).

Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH.

Individualised dose titration

Each patient should be up-titrated to the highest individually tolerated dose, which can range from200 micrograms given twice daily to 1 600 micrograms given twice daily (individualised maintenancedose).

The recommended starting dose is 200 micrograms given twice daily, approximately 12 hours apart.

The dose is increased in increments of 200 micrograms given twice daily, usually at weekly intervals.

At the beginning of treatment and at each up-titration step it is recommended to take the first dose inthe evening. During dose titration some adverse reactions, reflecting the mode of action of selexipag(such as headache, diarrhoea, nausea and vomiting, jaw pain, myalgia, pain in extremity, arthralgia,and flushing), may occur. They are usually transient or manageable with symptomatic treatment (seesection 4.8). However, if a patient reaches a dose that cannot be tolerated, the dose should be reducedto the previous dose level.

In patients in whom up-titration was limited by reasons other than adverse reactions reflecting themode of action of selexipag, a second attempt to continue up-titration to the highest individuallytolerated dose up to a maximum dose of 1 600 micrograms twice daily may be considered.

Individualised maintenance dose

The highest tolerated dose reached during dose titration should be maintained. If the therapy over timeis less tolerated at a given dose, symptomatic treatment and/or a dose reduction to the next lower doseshould be considered.

Interruptions and discontinuations

If a dose is missed, it should be taken as soon as possible. The missed dose should not be taken if thenext scheduled dose is within approximately 6 hours.

If treatment is missed for 3 days or more, Uptravi should be restarted at a lower dose and thenup-titrated.

There is limited experience with abrupt discontinuation of selexipag in patients with PAH. Noevidence for acute rebound has been observed.

However, if the decision to withdraw Uptravi is taken, it should be done gradually while an alternativetherapy is introduced.

Dose adjustment with co-administration of moderate CYP2C8 inhibitors

When co-administered with moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox andteriflunomide), the total daily dose of Uptravi should be reduced to half by administering half of eachdose twice daily. Alternatively, a once daily dosing frequency to achieve half of the daily dose of

Uptravi may be continued in patients already well controlled on a once daily dosing regimen or maybe applied in patients for whom the appropriate dose strength(s) supporting twice daily dosing withhalf the dose is not available. If the therapy is not tolerated at a given dose, symptomatic treatmentand/or a dose reduction to the next lower dose should be considered. When co-administration of amoderate CYP2C8 inhibitor is stopped, the total daily dose of Uptravi should be increased, asapplicable. The maximum dose of 1 600 micrograms twice daily should not be exceeded (seesection 4.5).

No adjustment to the dose regimen is needed in elderly people (see section 5.2). There is limitedclinical experience in patients over the age of 75 years, therefore Uptravi should be used with cautionin this population (see section 4.4).

Uptravi should not be administered in patients with severe liver impairment (Child-Pugh class C; seesection 4.4). For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose oftreatment should be 100 micrograms twice daily and increased at weekly intervals by increments of100 micrograms twice daily until adverse reactions, reflecting the mode of action of selexipag, thatcannot be tolerated or medically managed are experienced. In these patients the maximum dose is800 micrograms given twice daily. Alternatively, a once daily dosing frequency to achieve half of thedaily dose of Uptravi may be continued in patients already well controlled on a once daily dosingregimen or may be applied in patients for whom the appropriate dose strength(s) supporting twicedaily dosing with half the dose is not available. No adjustment to the dose regimen is needed inpatients with mild hepatic impairment (Child-Pugh class A).

No adjustment to the dose regimen is needed in patients with mild or moderate renal impairment. Nochange in starting dose is required in patients with severe renal impairment (estimated glomerularfiltration rate [eGFR] < 30 mL/min/1.73 m2); dose titration should be done with caution in thesepatients (see section 4.4).

The safety and efficacy of selexipag in children aged 2 to less than 18 years have not yet beenestablished. Currently available interim data are described in sections 5.1 and 5.2, but norecommendation on a posology can be made. Administration of selexipag in the paediatric populationis not recommended.

The safety and efficacy of selexipag in children aged less than 2 years have not been studied, asanimal studies indicated an increased risk of intussusception. The clinical relevance of these findingsis unknown (see section 5.3).

Oral use.

The film-coated tablets are to be taken orally in the morning and in the evening. To improvetolerability, it is recommended to take Uptravi with food and, at the beginning of each up-titrationphase, to take the first increased dose in the evening.

The film-coated tablets are to be swallowed with water. The tablets should not be split or crushedbecause the tablet coating protects the active substance from light.

Patients who have poor vision or are blind must be instructed to get assistance from another personwhen taking Uptravi during the titration period.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Severe coronary heart disease or unstable angina.

- Myocardial infarction within the last 6 months.

- Decompensated cardiac failure if not under close medical supervision.

- Severe arrhythmias.

- Cerebrovascular events (e.g., transient ischaemic attack, stroke) within the last 3 months.

- Congenital or acquired valvular defects with clinically relevant myocardial function disordersnot related to pulmonary hypertension.

- Concomitant use of strong inhibitors of CYP2C8 (e.g., gemfibrozil; see section 4.5).

Selexipag has vasodilatory properties that may result in lowering of blood pressure. Before prescribing

Uptravi, physicians should carefully consider whether patients with certain underlying conditionscould be adversely affected by vasodilatory effects (e.g., patients on antihypertensive therapy or withresting hypotension, hypovolaemia, severe left ventricular outflow obstruction or autonomicdysfunction) (see section 4.8).

Hyperthyroidism has been observed with Uptravi. Thyroid function tests are recommended asclinically indicated in the presence of signs or symptoms of hyperthyroidism (see section 4.8).

Cases of pulmonary oedema have been reported with vasodilators (mainly prostacyclins) when used inpatients with pulmonary veno-occlusive disease. Consequently, if signs of pulmonary oedema occurwhen Uptravi is administered in patients with PAH, the possibility of pulmonary veno-occlusivedisease should be considered. If confirmed, treatment is to 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-Pughclass C), therefore treatment should not be administered in these patients. The exposure to selexipagand its active metabolite is increased in subjects with moderate hepatic impairment (Child-Pughclass B; see section 5.2). In patients with moderate hepatic impairment, the total daily dose of Uptravishould be reduced (see section 4.2).

In patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2), caution should be exercisedduring dose titration. There is no experience with Uptravi in patients undergoing dialysis (seesection 5.2), therefore Uptravi should not be used in these patients.

Women of childbearing potential should practise effective contraception while taking selexipag (seesection 4.6).

Effect of other medicinal products on selexipag

Selexipag is hydrolysed to its active metabolite by carboxylesterases (see section 5.2). Selexipag andits 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 weaksubstrate of the P-gp efflux pump. The active metabolite is a weak substrate of the breast cancerresistance protein (BCRP).

The pharmacokinetics of selexipag and its active metabolite are not affected by warfarin.

Inhibitors of CYP2C8

In the presence of 600 mg gemfibrozil, twice a day, a strong inhibitor of CYP2C8, exposure toselexipag increased approximately 2-fold, whereas exposure to the active metabolite, the majorcontributor to efficacy, increased approximately 11-fold. Concomitant administration of Uptravi withstrong 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 doseof 75 mg once a day), a moderate inhibitor of CYP2C8, had no relevant effect on the exposure toselexipag but increased the exposure to the active metabolite approximately 2.2 and 2.7-fold followingloading dose and maintenance dose, respectively. The total daily dose of Uptravi should be decreasedby reducing each dose to half when co-administered with moderate CYP2C8 inhibitors (e.g.,clopidogrel, deferasirox, teriflunomide). Alternatively, a once daily dosing frequency to achieve halfof the daily dose of Uptravi may be continued in patients already well controlled on a once dailydosing regimen or may be applied in patients for whom the appropriate dose strength(s) supportingtwice daily dosing with half the dose is not available. When co-administration of a moderate CYP2C8inhibitor is stopped increase the total daily dose of Uptravi, as applicable. The maximum dose of 1 600micrograms twice daily should not be exceeded (see section 4.2).

Inducers of CYP2C8

In the presence of 600 mg rifampicin, once a day, an inducer of CYP2C8 (and UGT enzymes), theexposure 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).

Inhibitors of 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 whenadministering these medicinal products concomitantly with Uptravi. A potential pharmacokineticinteraction with strong inhibitors of UGT1A3 and UGT2B7 cannot be excluded.

Inhibitors and inducers of CYP3A4

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

PAH-specific therapies

In the phase 3 placebo-controlled trial in patients with PAH, the use of selexipag in combination withboth an ERA and a PDE-5 inhibitor resulted in a 30% lower exposure to the active metabolite.

Transporter inhibitors (lopinavir/ritonavir)

In the presence of 400 mg/100 mg lopinavir/ritonavir twice daily, a strong OATP (OATP1B1 and

OATP1B3) and P-gp inhibitor, exposure to selexipag increased approximately 2-fold, whereas theexposure to the active metabolite of selexipag did not change. Given that the majority of thepharmacological effect is driven by the active metabolite, this effect is not clinically relevant.

Effect of selexipag on other medicinal products

Selexipag and its active metabolite do not inhibit or induce cytochrome P450 enzymes and transportproteins at clinically relevant concentrations.

Anticoagulants or inhibitors of platelet aggregation

Selexipag is an inhibitor of platelet aggregation in vitro. In the phase 3 placebo-controlled study inpatients 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-typeanticoagulants) 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 thepharmacodynamic effect of warfarin on the international normalised ratio.

Midazolam

At steady state after up-titration to 1 600 micrograms selexipag twice a day, no clinically relevantchange in exposure to midazolam, a sensitive intestinal and hepatic CYP3A4 substrate, or itsmetabolite, 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. Sinceselexipag 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 (seesection 4.4).

There are no data from the use of selexipag in pregnant women. Animal studies do not indicate director indirect harmful effects with respect to reproductive toxicity. Selexipag and its main metaboliteshowed 20- to 80-times lower prostacyclin (IP) receptor potency in vitro for animal species used inreproductive 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 (seesection 5.3).

Uptravi is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

It is unknown whether selexipag or its metabolites are excreted in human milk. In rats, selexipag or itsmetabolites 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 transientdisturbances in oestrus cycles that did not affect fertility (see section 5.3). The relevance for humans isnot known.

Uptravi has minor influence on the ability to drive and use machines. The clinical status of the patientand the adverse reaction profile of selexipag (such as headache or hypotension, see section 4.8) shouldbe 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, jawpain, myalgia, pain in extremity, arthralgia, and flushing. These reactions are more frequent during theup-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 enrolling1 156 adult patients with symptomatic PAH (GRIPHON study). The mean treatment duration was76.4 weeks (median 70.7 weeks) for patients receiving selexipag versus 71.2 weeks (median63.7 weeks) for patients on placebo. The exposure to selexipag was up to 4.2 years.

Adverse reactions obtained from the pivotal clinical GRIPHON study and post-marketing surveillanceare 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

Blood and lymphatic Anaemia*disorders Haemoglobin decreased*

Endocrine disorders Hyperthyroidism*

Thyroid-stimulating

Hormone decreased

Metabolism and Decreased appetitenutrition disorders Weight decrease

Nervous system Headache*disorders

Cardiac disorders Sinus tachycardia*

Vascular disorders Flushing* Hypotension*

Respiratory, thoracic Nasopharyngitis (of Nasal congestionand mediastinal non-infectiousdisorders origin)

Gastro-intestinal Diarrhoea* Abdominal paindisorders Vomiting* Dyspepsia*

Nausea*

Skin and subcutaneous Rashtissue disorders Urticaria

Erythema

Angioedema†

Musculoskeletal and Jaw pain*connective tissue Myalgia*disorders Arthralgia*

Pain in extremity*

General disorders and Painadministration siteconditions

* See section Description of selected adverse reactions.† Cases of angioedema have been reported in post-marketing experience with a latency that can exceed 30 days of treatment.

Pharmacological effects associated with titration and maintenance treatment

Adverse reactions associated with the mode of action of selexipag have been observed frequently, inparticular during the phase of individualised dose titration, and are tabulated below:

Prostacyclin-like associated Titration Maintenanceadverse 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 onselexipag discontinued treatment due to these adverse reactions. The approximate rate of adversereactions that were serious was 2.3% in the selexipag group and 0.5% in the placebo group. In clinicalpractice, gastro-intestinal events have been observed to respond to anti-diarrhoeal, anti-emetic, andanti-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 atregular visits compared to baseline ranged from 0.34 to 0.02 g/dL in the selexipag group comparedto 0.05 to 0.25 g/dL in the placebo group. A decrease from baseline in haemoglobin concentration tobelow 10 g/dL was reported in 8.6% of selexipag-treated patients and 5.0% of placebo-treatedpatients.

In a phase 3 placebo-controlled study in patients newly diagnosed with PAH, mean absolute changesin haemoglobin at regular visits compared to baseline ranged from 1.77 to 1.26 g/dL in the tripletherapy group (selexipag, macitentan, tadalafil) compared to 1.61 to 1.28 g/dL in the double therapygroup (placebo, macitentan and tadalafil). A decrease from baseline in haemoglobin concentration tobelow 10 g/dL was reported in 19.0% of patients in the triple therapy group and 14.5% in the doubletherapy group. Anaemia was reported with very common frequency (13.4%) in the triple therapygroup 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% ofpatients in the selexipag group, compared to no case in the placebo group (see section 4.4). Areduction (up to 0.3 MU/L from a baseline median of 2.5 MU/L) in median thyroid-stimulatinghormone was observed at most visits in the selexipag group. In the placebo group, little change inmedian values was apparent. There were no mean changes in triiodothyronine or thyroxine in eithergroup.

Increase in heart rate

In the phase 3 placebo-controlled study in patients with PAH, a transient increase in mean heart rate of3-4 bpm at 2-4 hours post-dose was observed. Electrocardiogram investigations showed sinustachycardia in 11.3% of patients in the selexipag group compared to 8.8% in the placebo group (seesection 5.1).

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

Dyspepsia

In a phase 3 placebo-controlled study in patients newly diagnosed with PAH, dyspepsia was reportedwith 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).

Of the 1 156 patients who participated in the pivotal study, 709 patients entered a long-term open-labelextension study (330 patients who continued on selexipag from the GRIPHON study and 379 patientswho received placebo in GRIPHON and crossed over to selexipag). Long-term follow up of patientstreated with selexipag for a median treatment duration of 30.5 months and for a maximum of up to103 months showed a safety profile that was similar to that observed in the pivotal clinical studydescribed above.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Isolated cases of overdose up to 3 200 micrograms were reported in adults. Mild, transient nausea wasthe only reported consequence. In the event of overdose, supportive measures must be taken asrequired. Dialysis is unlikely to be effective because selexipag and its active metabolite are highlyprotein bound.

Pharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitors excluding heparin,

ATC code: B01AC27

Selexipag is a selective IP receptor agonist distinct from prostacyclin and its analogues. Selexipag ishydrolysed by carboxylesterases to yield its active metabolite, which is approximately 37-fold morepotent than selexipag. Selexipag and the active metabolite are high-affinity IP receptor agonists with ahigh selectivity for the IP receptor versus other prostanoid receptors (EP1-EP4, DP, FP, and TP).

Selectivity against EP1, EP3, FP, and TP is important because these are well-described contractilereceptors in the gastro-intestinal tract and blood vessels. Selectivity against EP2, EP4, and DP1 isimportant because these receptors mediate immune depressive effects.

Stimulation of the IP receptor by selexipag and the active metabolite leads to vasodilatory as well asanti-proliferative and anti-fibrotic effects. Selexipag prevents cardiac and pulmonary remodelling in arat model of PAH and causes proportional decreases in pulmonary and peripheral pressures, indicatingthat peripheral vasodilation reflects pulmonary pharmacodynamic efficacy. Selexipag does not cause

IP receptor desensitisation in vitro nor tachyphylaxis in a rat model.

In a thorough QT study in healthy adult subjects, repeated doses of 800 and 1 600 micrograms ofselexipag twice daily did not show an effect on cardiac repolarisation (QTc interval) or conduction (PRand QRS intervals) and had a mild accelerating effect on heart rate (the placebo-corrected,baseline-adjusted increase in heart rate reached 6-7 bpm at 1.5 to 3 h after dosing with800 micrograms selexipag and 9-10 bpm at the same timepoints after 1 600 micrograms selexipag).

Coagulation factors

In phase 1 and 2 studies a slight decrease in plasma levels of von Willebrand factor (vWF) wasobserved with selexipag; the vWF values remained above the lower limit of the normal range.

Pulmonary haemodynamics

A phase 2 double-blind, placebo-controlled clinical study assessed haemodynamic variables after17 weeks of treatment in adult patients with PAH WHO FC II-III and concomitantly receiving ERAsand/or PDE-5 inhibitors. Patients titrating selexipag to an individually tolerated dose (200 microgramstwice daily increments up to 800 micrograms twice daily; N = 33) achieved a statistically significantmean reduction in pulmonary vascular resistance of 30.3% (95% confidence interval [CI]: 44.7%,12.2%; p = 0.0045) and an increase in cardiac index (mean treatment effect) of 0.48 L/min/m2 (95%

CI: 0.13, 0.83) compared to placebo (N = 10).

Efficacy in adult patients with PAH (GRIPHON)

The effect of selexipag on progression of PAH was demonstrated in a multi-centre, long-term(maximum duration of exposure approximately 4.2 years), double-blind, placebo-controlled,parallel-group, event-driven phase 3 study (GRIPHON) in 1 156 patients with symptomatic (WHO FC

I-IV) PAH. Patients were randomised to either placebo (N = 582) or selexipag (N = 574) twice daily.

The dose was increased at weekly intervals by increments of 200 micrograms given twice daily todetermine the individualised maintenance dose (200-1 600 micrograms twice daily).

The primary study endpoint was the time to first occurrence of a morbidity or mortality event up toend of treatment, defined as a composite of death (all causes); or hospitalisation for PAH; orprogression of PAH resulting in need for lung transplantation or balloon atrial septostomy; or initiationof parenteral prostanoid therapy or chronic oxygen therapy; or other disease-progression events(patients in WHO FC II or III at baseline) confirmed by a decrease in 6-minute walk distance(6MWD) from baseline (≥ 15%) and worsening of WHO FC or (patients in WHO FC III or IV atbaseline) confirmed by a decrease in 6MWD from baseline (≥ 15%) and need for additional

PAH-specific therapy.

All events were confirmed by an independent adjudication committee, blinded to treatment allocation.

The mean age was 48.1 years (range 18-80 years of age), with the majority of subjects being

Caucasian (65.0%) and female (79.8%). 17.9% of patients were ≥ 65 and 1.1% ≥ 75 years of age.

Approximately 1%, 46%, 53%, and 1% of patients were in WHO FC I, II, III and IV, respectively, atbaseline.

Idiopathic or heritable PAH was the most common aetiology in the study population (58%) followedby PAH due to connective tissue disorders (29%), PAH associated with simple corrected congenitalheart disease (10%), and PAH associated with other aetiologies (drugs and toxins [2%] and HIV[1%]).

At baseline, the majority of enrolled patients (80%) were being treated with a stable dose of a specifictherapy for PAH, either an ERA (15%) or a PDE-5 inhibitor (32%) or both an ERA and a PDE-5inhibitor (33%).

The overall median double-blind treatment duration was 63.7 weeks for the placebo group and70.7 weeks for the selexipag group. 23% of patients on selexipag achieved maintenance doses in therange of 200-400 micrograms, 31% achieved doses in the range of 600-1 000 micrograms, and 43%achieved doses in the range of 1 200-1 600 micrograms.

Treatment with selexipag 200-1 600 micrograms twice daily resulted in a 40% reduction (hazard ratio[HR] 0.60; 99% CI: 0.46, 0.78; one-sided log-rank p value < 0.0001) of the occurrence of morbidity ormortality events up to 7 days after last dose compared to placebo (Figure 1). The beneficial effect ofselexipag was primarily attributable to a reduction in hospitalisation for PAH and a reduction in otherdisease-progression events (Table 1).

Figure 1 Kaplan-Meier estimates of the first morbidity-mortality event

Table 1 Summary of outcome events

Patients with an

Treatment comparison: selexipag vs placeboevent

Absolute Relative risk

Endpoints & Placebo Selexipag risk reduction HRstatistics (N=582) (N=574) reduction (99% CI) (99% CI) p-value

Morbidity- 40% 0.6058.3% 41.8% 16.5% < 0.0001mortality eventa (22%; 54%) (0.46; 0.78)

Hospitalisationdue to PAHb 109 78 33% 0.675.1% 0.04(18.7%) (13.6%) (2%; 54%) (0.46; 0.98)n (%)

Diseaseb 100 38 64% 0.36progression 10.6% < 0.0001(17.2%) (6.6%) (41%; 78%) (0.22; 0.59)n (%)i.v./s.c.

Prostanoid15 11 32% 0.68initiation or 0.7% 0.53b,c (2.6%) (1.9%) (90%; 76%) (0.24; 1.90)oxygen therapyn (%)

Death up to EOTd 37 46 17% 1.17+ 7 days 1.7% 0.77(6.4%) (8.0%) (107%; 34%) (0.66; 2.07)n (%)

Death up to studyd 105 100 3% 0.97closure 0.6% 0.42(18.0%) (17.4%) (39%; 32%) (0.68; 1.39)n (%)

CI = confidence interval; EOT = end of treatment; HR = hazard ratio; i.v. = intravenous; PAH = pulmonary arterialhypertension; s.c. = subcutaneous.a % of patients with an event at 36 months = 100 × (1 - Kaplan-Meier estimate); hazard ratio estimated using Cox’sproportional hazard model; unstratified one-sided log-rank p-valueb % of patients with an event as part of the primary endpoint up to EOT + 7 days; hazard ratio estimated using Aalen

Johansen method; 2-sided p-value using Gray’s testc Includes ‘Need for lung transplantation or atrial septostomy’ (1 patient on selexipag and 2 on placebo)d % of patients with an event up to EOT + 7 days or up to study closure; hazard ratio estimated using Cox’s proportionalhazard model; unstratified one-sided log-rank p-value

The numerical increase in deaths up to end of treatment + 7 days but not up to study closure wasfurther investigated by mathematical modelling, showing that the imbalance in deaths is consistentwith the assumption of a neutral effect on PAH mortality and reduction of non-fatal events.

The observed effect of selexipag versus placebo on the primary endpoint was consistent acrossindividualised maintenance dose as shown by the hazard ratio for the three pre-defined categories(0.60 for 200-400 micrograms twice daily, 0.53 for 600-1 000 micrograms twice daily, and 0.64 for1 200-1 600 micrograms twice daily), which was consistent with the overall treatment effect (0.60).

The efficacy of selexipag on the primary endpoint was consistent across subgroups of age, sex, race,aetiology, geographical region, WHO FC, and as monotherapy or in combination with an ERA or a

PDE-5 inhibitor or triple combination with both an ERA and a PDE-5 inhibitor.

Time to PAH-related death or hospitalisation for PAH was assessed as a secondary endpoint. The riskof an event for this endpoint was reduced by 30% in patients receiving selexipag compared to placebo(HR 0.70, 99% CI: 0.50, 0.98; one-sided log-rank p = 0.0031). The percentages of patients with anevent at Month 36 were 28.9% and 41.3% in the selexipag and placebo groups, respectively, with anabsolute risk reduction of 12.4%.

The number of patients who experienced, as a first event, death due to PAH or hospitalisation for PAHup to end of treatment was 102 (17.8%) in the selexipag group and 137 (23.5%) in the placebo group.

Death due to PAH as a component of the endpoint was observed in 16 (2.8%) patients on selexipagand 14 (2.4%) on placebo. Hospitalisation for PAH was observed in 86 (15.0%) patients on selexipagand 123 (21.1%) patients on placebo. Selexipag reduced the risk of hospitalisation for PAH as a firstoutcome event compared to placebo (HR 0.67, 99% CI: 0.46, 0.98; one-sided log-rank p = 0.04).

The total number of deaths of all causes up to study closure was 100 (17.4%) for the selexipag groupand 105 (18.0%) for the placebo group (HR 0.97, 99% CI: 0.68, 1.39). The number of deaths due to

PAH up to study closure was 70 (12.2%) for the selexipag group and 83 (14.3%) for the placebogroup.

Exercise capacity was evaluated as a secondary endpoint. Median 6MWD at baseline was 376 m(range: 90-482 m) and 369 m (range: 50-515 m) in selexipag patients and placebo patients,respectively. Treatment with selexipag resulted in a placebo-corrected median effect on 6MWDmeasured at trough (i.e., approximately 12 h post-dose) of 12 m at Week 26 (99% CI: 1, 24 m;one-sided p value = 0.0027). In patients without concurrent PAH-specific therapy, theplacebo-corrected treatment effect measured at trough was 34 m (99% CI: 10, 63 m).

Quality of life was assessed in a subset of patients in the GRIPHON study using the Cambridge

Pulmonary Hypertension Outcome Review (CAMPHOR) questionnaire. There was no significanttreatment effect from baseline to Week 26.

Patients enrolled into the pivotal study (GRIPHON) were eligible to enter a long-term open-labelextension study. A total of 574 patients were treated with selexipag in the GRIPHON study; of these,330 patients continued selexipag treatment in the open-label extension study. The median follow-upduration was 4.5 years and the median exposure to selexipag was 3 years. During the follow-up, atleast one other PAH -medicinal product was added to selexipag in 28.4% of the patients. However,most of the treatment exposure (86.3%) in all of the 574 patients was accumulated without addition ofany new PAH medicinal product. Kaplan-Meier estimates of survival of these 574 patients across the

GRIPHON and the long-term extension study at 1, 2, 5 and 7 years were 92%, 85%, 71%, and 63%,respectively. Survival at 1, 2, 5, and 7 years for 273 patients of WHO FC II at baseline of the pivotalstudy were 97%, 91%, 80% and 70%, respectively, and for 294 patients of WHO FC III at baselinewere 88%, 80%, 62% and 56%, respectively. Given that additional PAH treatment was initiated in asmall proportion of patients and that there was no control group in the extension study, the survivalbenefit of selexipag cannot be confirmed from these data.

Initial triple combination treatment with selexipag, macitentan and tadalafil in newly diagnosed PAHpatients

In a double blind, placebo-controlled study, a total of 247 newly diagnosed PAH patients wererandomised to evaluate the treatment effect of initial triple (selexipag, macitentan and tadalafil)(N = 123) versus initial double (placebo, macitentan and tadalafil) (N = 124) therapy.

The primary endpoint, change from baseline in pulmonary vascular resistance (PVR) at Week 26, didnot show a statistically significant difference between the groups, while showing an improvementfrom baseline in both treatment groups (relative reduction by 54% in the initial triple therapy group vs52% in the initial double therapy group).

Over a median follow-up of 2 years, 4 (3.4%) patients in the triple therapy group and 12 (9.4%)patients in the double therapy group died.

Interim efficacy and safety in paediatric patients with PAH (SALTO)

The efficacy and safety in paediatric patients aged ≥ 2 to < 18 years with PAH was evaluated in adescriptive manner in a multi-centre, randomised, double-blind, placebo-controlled, parallel-group,phase 3 study (SALTO). A total of 138 patients were randomised 1:1 to receive either selexipag(N = 69) or placebo (N = 69) twice daily. Selexipag doses of 100, 150 or 200 micrograms wereup-titrated to 800, 1 200 or 1 600 micrograms twice daily based on the weight category and tolerability(see section 5.2). The interim analysis was performed when 92 patients reached 24 weeks of treatment.

The primary study endpoint was the time to first Clinical Events Committee (CEC) confirmed diseaseprogression up to 7 days after the last dose of study treatment. Secondary and exploratory endpointsincluded safety and tolerability, change in 6MWD, WHO FC and in N-terminal prohormone of brainnatriuretic peptide (NT-proBNP) data, echocardiography, physical activity, and quality of lifemeasurements.

Overall, median treatment duration was 50 weeks and approximately 50% of patients reached12 months of treatment. The majority of patients had idiopathic PAH (55.8%), were on backgroundcombination therapy (74.6%) and were WHO FC II (76.8%). The mean age was 11.8 years (range 3-18 years).

CEC-confirmed disease progression events were reported in 16 (23.2%) patients in the selexipaggroup and 11 (15.9%) in the placebo group.

The nature of adverse events reported was consistent with the known safety profile of selexipag(predominantly characterised by prostacyclin-like associated adverse reactions; see section 4.8) andwith the expected events in a PAH patient population including adverse events associated with PAHdisease progression. During the titration period, the adverse reaction vomiting was reported with ahigher frequency (19 [27.5%] in the selexipag group and 5 [7.2%] in the placebo group) as comparedto adults (see section 4.8). PAH disease progression was the most frequently reported serious adverseevent in 8 (11.6%) patients in the selexipag group compared to 4 (5.8%) in the placebo group. Thetotal number of deaths of all causes was 7 (10.1%) in the selexipag group and 5 (7.2%) in the placebogroup, of which 5 (7.2%) and 3 (4.3%) occurred during treatment on selexipag and placebo,respectively. All deaths, except for one, were associated with PAH.

The pharmacokinetics of selexipag and its active metabolite have been studied primarily in healthysubjects. The pharmacokinetics of selexipag and the active metabolite, both after single- andmultiple-dose administration, were dose-proportional up to a single dose of 800 micrograms andmultiple doses of up to 1 800 micrograms twice daily. After multiple-dose administration, steady stateconditions of selexipag and the active metabolite were reached within 3 days. No accumulation inplasma, either of parent compound or active metabolite, occurred after multiple-dose administration.

In healthy subjects, inter-subject variability in exposure (area under the curve over a dosing interval) atsteady state was 43% and 39% for selexipag and the active metabolite, respectively. Intra-subjectvariability in exposure was 24% and 19% for selexipag and the active metabolite, respectively.

Exposure to selexipag and the active metabolite at steady state in PAH patients and healthy subjectswas similar. The pharmacokinetics of selexipag and the active metabolite in PAH patients were notinfluenced by the severity of the disease and did not change with time.

Selexipag is rapidly absorbed and is hydrolysed by carboxylesterases to its active metabolite.

Maximum observed plasma concentrations of selexipag and its active metabolite after oraladministration are reached within 1-3 h and 3-4 h, respectively.

The absolute bioavailability of selexipag in humans is approximately 49%. This is most probably dueto a first-pass effect of selexipag, as plasma concentrations of the active metabolite are similar afterthe same oral and intravenous dose administration.

In the presence of food, the exposure to selexipag after a single dose of 400 micrograms was increasedby 10% in Caucasian subjects and decreased by 15% in Japanese subjects, whereas exposure to theactive metabolite was decreased by 27% (Caucasian subjects) and 12% (Japanese subjects). Moresubjects reported adverse events after administration in the fasted than in the fed state.

Selexipag and its active metabolite are highly bound to plasma proteins (approximately 99% in totaland to the same extent to albumin and alpha1-acid glycoprotein). The volume of distribution ofselexipag at steady state is 11.7 L.

Selexipag is hydrolysed to its active metabolite in the liver and in the intestine by carboxylesterases.

Oxidative metabolism catalysed mainly by CYP2C8 and to a smaller extent by CYP3A4 leads to theformation of hydroxylated and dealkylated products. UGT1A3 and UGT2B7 are involved in theglucuronidation of the active metabolite. Except for the active metabolite, none of the circulatingmetabolites in human plasma exceed 3% of the total drug-related material. Both in healthy subjectsand PAH patients, after oral administration, exposure at steady state to the active metabolite isapproximately 3- to 4-fold higher than to the parent compound.

Elimination of selexipag is predominantly via metabolism with a mean terminal half-life of 0.8-2.5 h.

The active metabolite has a half-life of 6.2-13.5 h. The total body clearance of selexipag is 17.9 L/h.

Excretion in healthy subjects was complete 5 days after administration and occurred primarily viafaeces (accounting for 93% of the administered dose) compared to 12% in urine.

No clinically relevant effects of sex, race, age, or body weight on the pharmacokinetics of selexipagand its active metabolite have been observed in healthy subjects or PAH patients.

The pharmacokinetics of selexipag in paediatric patients aged ≥ 2 to < 18 years with PAH was studiedin the open-label, single-arm, phase 2 study (AC-065A203 [N = 62]) and in SALTO [N = 36] [seesection 5.1]).

Paediatric patients were administered selexipag at a starting dose of 100 micrograms twice daily (bodyweight ≥ 9 kg and < 25 kg), 150 micrograms twice daily (body weight ≥ 25 kg and < 50 kg) and200 micrograms twice daily (body weight ≥ 50 kg). The dose was up-titrated to the highestindividually tolerated dose up to a maximum of 800 micrograms twice daily (body weight ≥ 9 kg and< 25 kg), 1 200 micrograms twice daily (body weight ≥ 25 kg and < 50 kg), and 1 600 microgramstwice daily (body weight ≥ 50 kg). The applied body weight adjusted dosing regimen resulted in acombined exposure of selexipag and its active metabolite comparable to that observed in adultpatients.

A 1.4- to 1.7-fold increase in exposure (maximum plasma concentration and area under the plasmaconcentration-time curve) to selexipag and its active metabolite was observed in subjects with severerenal impairment (eGFR < 30 mL/min/1.73 m2).

In subjects with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment,exposure to selexipag was 2- and 4-fold higher, respectively, when compared to healthy subjects.

Exposure to the active metabolite remained almost unchanged in subjects with mild hepaticimpairment and was doubled in subjects with moderate hepatic impairment. Only two subjects withsevere (Child-Pugh class C) hepatic impairment were dosed with selexipag. Exposure to selexipag andits active metabolite in these two subjects was similar to that in subjects with moderate (Child-Pughclass B) hepatic impairment.

Based on modelling and simulation data from a study in subjects with hepatic impairment, theexposure to selexipag at steady state in subjects with moderate hepatic impairment (Child-Pughclass B) after a once-daily regimen is predicted to be approximately 2-fold higher than that in healthysubjects during a twice-daily regimen. The exposure to the active metabolite at steady state in thesepatients during a once-daily regimen is predicted to be similar to that in healthy subjects during atwice-daily regimen. Subjects with severe hepatic impairment (Child-Pugh class C) showed similarpredicted exposure at steady state as subjects with moderate hepatic impairment during a once-dailyregimen.

In the repeated-dose toxicity studies in rodents, strong blood pressure decrease as a result ofexaggerated pharmacology induced transient clinical signs and reduced food consumption andbody-weight gain. In adult and juvenile dogs, intestine and bone/bone marrow were identified as themain target organs after treatment with selexipag. A delay in the closure of the femoral and/or tibialepiphyseal growth plate was observed in juvenile dogs. A no-observed-adverse-effect level was notestablished. In juvenile dogs, intussusception due to prostacyclin-related effects on intestinal motilitywas observed sporadically. Safety margins adapted for IP receptor potency for the active metabolitewere 2-fold (based on total exposure) in relation to human therapeutic exposure. The finding did notoccur in mouse or rat toxicity studies. Because of the species-specific sensitivity of dogs to developintussusception, this finding is considered not relevant for adult humans.

Increased bone ossification and related changes in the bone marrow in dog studies are considered to bedue to the activation of EP4 receptors in dogs. As human EP4 receptors are not activated by selexipagor its active metabolite, this effect is species-specific and, therefore, not relevant to humans.

Selexipag and the active metabolite are not genotoxic on the basis of the overall evidence of conductedgenotoxicity studies.

In the 2-year carcinogenicity studies, selexipag caused an increased incidence of thyroid adenomas inmice and Leydig cell adenomas in rats. The mechanisms are rodent-specific. Tortuosity of retinalarterioles was noted after 2 years of treatment only in rats. Mechanistically, the effect is considered tobe induced by life-long vasodilation and subsequent changes in ocular haemodynamics. Additionalhistopathological findings of selexipag were observed only at exposures sufficiently in excess of themaximum human exposure, indicating little relevance to humans.

In a fertility study performed in rats, a prolongation of oestrus cycles resulting in increases in daysuntil copulation was observed at exposures 173-fold above therapeutic exposures (based on totalexposures), the no-observed-effect level being 30-fold above therapeutic exposures. Otherwise,fertility parameters were not affected.

Selexipag was not teratogenic in rats and rabbits (exposure margins above therapeutic exposure of13-fold for selexipag and 43-fold for the active metabolite, based on total exposure). Safety marginsfor potential IP receptor-related effects on reproduction were 20 for fertility and 5 and 1 (based on freeexposure) for embryo-foetal development in rats and rabbits, respectively, when adapted fordifferences in receptor potency. In the rat pre-/post-natal development study, selexipag induced noeffects on maternal and pup reproductive function.

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Blister: 4 years.

Unopened bottle: 18 months. After the first opening of the bottle: 3 months or until the expiry date(whichever occurs first).

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Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/15/1083/001

EU/1/15/1083/002

EU/1/15/1083/003

EU/1/15/1083/004

EU/1/15/1083/005

EU/1/15/1083/006

EU/1/15/1083/007

EU/1/15/1083/008

EU/1/15/1083/009

EU/1/15/1083/010

EU/1/15/1083/011

EU/1/15/1083/012

EU/1/15/1083/013

Date of first authorisation: 12 May 2016

Date of latest renewal: 14 December 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.