4.1. Therapeutic indications

Uptravi is indicated for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients with WHO functional class (FC) II–III, either as combination therapy in patients insufficiently controlled 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, PAH associated with connective tissue disorders, and PAH associated with corrected simple congenital heart disease (see section 5.1).

4.2. Posology and method of administration

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

Posology

Individualised dose titration

Each patient should be up‑titrated to the highest individually tolerated dose, which can range from 200 micrograms given twice daily to 1 600 micrograms given twice daily (individualised maintenance dose).

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 in the 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 (see section 4.8). However, if a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous dose level.

In patients in whom up‑titration was limited by reasons other than adverse reactions reflecting the mode of action of selexipag, a second attempt to continue up‑titration to the highest individually tolerated 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 time is less tolerated at a given dose, symptomatic treatment and/or a dose reduction to the next lower dose should 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 the next 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 then up‑titrated.

There is limited experience with abrupt discontinuation of selexipag in patients with PAH. No evidence for acute rebound has been observed.

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

Dose adjustment with co-administration of moderate CYP2C8 inhibitors

When co-administered with moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox and teriflunomide), the total daily dose of Uptravi should be reduced to half by administering half of each dose 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 may be applied in patients for whom the appropriate dose strength(s) supporting twice daily dosing with half the dose is not available. If the therapy is not tolerated at a given dose, symptomatic treatment and/or a dose reduction to the next lower dose should be considered. When co‑administration of a moderate CYP2C8 inhibitor is stopped, the total daily dose of Uptravi should be increased, as applicable. The maximum dose of 1 600 micrograms twice daily should not be exceeded (see section 4.5).

Special populations

Elderly (≥ 65 years)

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

Hepatic impairment

Uptravi should not be administered in patients with severe liver impairment (Child‑Pugh class C; see section 4.4). For patients with moderate hepatic impairment (Child‑Pugh class B), the starting dose of treatment should be 100 micrograms twice daily and increased at weekly intervals by increments of 100 micrograms twice daily until adverse reactions, reflecting the mode of action of selexipag, that cannot be tolerated or medically managed are experienced. In these patients the maximum dose is 800 micrograms given 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 may be applied in patients for whom the appropriate dose strength(s) supporting twice daily dosing with half the dose is not available. No adjustment to the dose regimen is needed in patients with mild hepatic impairment (Child‑Pugh class A).

Renal impairment

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

Paediatric population

The safety and efficacy of selexipag in children aged 2 to less than 18 years have not yet been established. Currently available interim data are described in sections 5.1 and 5.2, but no recommendation on a posology can be made. Administration of selexipag in the paediatric population is not recommended.

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

Method of administration

Oral use.

The film‑coated tablets are to be taken orally in the morning and in the evening. To improve tolerability, it is recommended to take Uptravi with food and, at the beginning of each up‑titration phase, 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 crushed because 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 person when taking Uptravi during the titration period.

4.3. Contraindications

• 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 disorders not related to pulmonary hypertension.

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

4.4. Special warnings and precautions for use

Hypotension

Selexipag 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) (see section 4.8).

Hyperthyroidism

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

Pulmonary veno‑occlusive disease

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 is to be discontinued.

Elderly (≥ 65 years)

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).

Hepatic impairment

There is no clinical experience with selexipag in patients with severe liver impairment (Child‑Pugh class C), therefore treatment 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, the total daily dose of Uptravi should be reduced (see section 4.2).

Renal impairment

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

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

4.5. Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on 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.

Inhibitors of CYP2C8

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. The total daily dose of Uptravi should be decreased by 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 half of the daily dose of Uptravi may be continued in patients already well controlled on a once daily dosing regimen or may be applied in patients for whom the appropriate dose strength(s) supporting twice daily dosing with half the dose is not available. When co-administration of a moderate CYP2C8 inhibitor is stopped increase the total daily dose of Uptravi, as applicable. The maximum dose of 1 600 micrograms 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), 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).

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 when administering these medicinal products concomitantly with Uptravi. A potential pharmacokinetic interaction 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 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.

PAH‑specific therapies

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.

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 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.

Effect of selexipag on other medicinal products

Selexipag and its active metabolite do not inhibit or induce cytochrome P450 enzymes and transport proteins 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 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.

Midazolam

At steady state after up-titration to 1 600 micrograms 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.

Hormonal contraceptives

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.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should practise effective contraception while taking selexipag (see section 4.4).

Pregnancy

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.

Breast-feeding

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.

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 (see section 5.3). The relevance for humans is not known.

4.7. Effects on ability to drive and use machines

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, see section 4.8) should be kept in mind when considering the patient's ability to drive and use machines.

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 adult patients with symptomatic PAH (GRIPHON study). 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 GRIPHON study and post-marketing surveillance 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

Blood and lymphatic disorders

Anaemia*

Haemoglobin decreased*

Endocrine disorders

Hyperthyroidism*

Thyroid-stimulating Hormone decreased

Metabolism and nutrition disorders

Decreased appetite

Weight decrease

Nervous system disorders

Headache*

Cardiac disorders

Sinus tachycardia*

Vascular disorders

Flushing*

Hypotension*

Respiratory, thoracic and mediastinal disorders

Nasopharyngitis (of non-infectious origin)

Nasal congestion

Gastro‑intestinal disorders

Diarrhoea*

Vomiting*

Nausea*

Abdominal pain

Dyspepsia*

Skin and subcutaneous tissue disorders

Rash

Urticaria

Erythema

Angioedema†

Musculoskeletal and connective tissue disorders

Jaw pain*

Myalgia*

Arthralgia*

Pain in extremity*

General disorders and administration site conditions

Pain

* 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

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 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).

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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