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    / Janssen


    Active Ingredient
    Selexipag 200, 400, 600, 800, 1000, 1200, 1400, 1600 mcg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Film Coated Tablets

    60 X 200 mcg

    partial basket chart 22481

    Film Coated Tablets

    140 X 200 mcg

    partial basket chart 22333

    Film Coated Tablets

    60 X 400 mcg

    partial basket chart 22558

    Film Coated Tablets

    60 X 600 mcg

    partial basket chart 22559

    Film Coated Tablets

    60 X 800 mcg

    partial basket chart 22561

    Film Coated Tablets

    60 X 1000 mcg

    partial basket chart 22743

    Film Coated Tablets

    60 X 1200 mcg

    partial basket chart 22780

    Film Coated Tablets

    60 X 1400 mcg

    partial basket chart 22882

    Film Coated Tablets

    60 X 1600 mcg

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    Related information


    Dosage

    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. 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, Selexipag 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 Selexipag is taken, it should be done gradually while an alternative therapy is introduced.
    Elderly (≥ 65 years): No adjustment to the dose regimen is needed in elderly people. There is limited clinical experience in patients over the age of 75 years; therefore Selexipag should be used with caution in this population.
    Hepatic impairment: Selexipag should not be administered in patients with severe liver impairment (Child Pugh class C). For patients with moderate hepatic impairment (Child Pugh class B), the starting dose of Selexipag should be 200 micrograms once daily, and increased at weekly intervals by increments of 200 micrograms given once daily until adverse reactions, reflecting the mode of action of selexipag, that cannot be tolerated or medically managed are experienced. 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.
    Paediatric population (< 18 years): The safety and efficacy of Selexipag in children aged 0 to less than 18 years have not yet been established. No data are available. Administration of selexipag in the paediatric population is not recommended. Animal studies indicated an increased risk of intussusception, but the clinical relevance of these findings is unknown.
    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 Selexipag with food and, at the beginning of each up titration phase, to take the first increased dose in the evening. The tablets should not be split, crushed or chewed, and are to be swallowed with water. Patients who have poor vision or are blind must be instructed to get assistance from another person when taking Selexipag during the titration period.


    Indications

    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.


    Contra-Indications

    Hypersensitivity to the active substance or to any of the excipients. 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.


    Special Precautions

    Hypotension: Selexipag has vasodilatory properties that may result in lowering of blood pressure. Before prescribing Selexipag, 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: Hyperthyroidism has been observed with Selexipag. Thyroid function tests are recommended as clinically indicated in the presence of signs or symptoms of hyperthyroidism.
    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 Selexipag is administered in patients with PAH, the possibility of pulmonary veno‑occlusive disease should be considered. If confirmed, treatment with Selexipag should be discontinued.
    Elderly (≥ 65 years): There is limited clinical experience with selexipag in patients over the age of 75 years, therefore Selexipag should be used with caution in this population.
    Hepatic impairment: There is no clinical experience with selexipag in patients with severe liver impairment (Child‑Pugh class C), therefore Selexipag 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) In patients with moderate hepatic impairment, Selexipag should be dosed once daily.
    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 Selexipag in patients undergoing dialysis, therefore Selexipag should not be used in these patients.
    Women of childbearing potential: Women of childbearing potential should practise effective contraception while taking selexipag.
    See prescribing information for full details.


    Side Effects

    Anaemia, haemoglobin decreased, hyperthyroidism, thyroid-stimulating hormone decreased, decreased appetite, weight decrease, headache, flushing, hypotension, Nasopharyngitis (of non-infectious origin), nasal congestion, diarrhoea, vomiting, Nausea, abdominal pain, rash, urticaria, erythema, jaw pain, myalgia, arthralgia, Pain in extremity.
    See prescribing information for full details.


    Drug interactions

    Effect of other medicinal products on Selexipag: Selexipag is hydrolysed to its active metabolite by hepatic carboxylesterase 1.  Selexipag and its active metabolite both undergo oxidative metabolism by CYP2C8 and 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 or inducers of CYP2C8, UGT1A3, and UGT2B7: The effect of inhibitors of CYP2C8 (gemfibrozil), inhibitors of UGT1A3 and UGT2B7 (valproic acid, probenecid, and fluconazole), inducers of CYP2C8 (rifampicin, rifapentine), or inducers of UGT1A3, and UGT2B7 (rifampicin) on the exposure to selexipag and its active metabolite has not been studied. Caution is required when administering these medicinal products concomitantly with Selexipag. A potential pharmacokinetic interaction with strong inhibitors or inducers of these enzymes cannot be excluded.
    Inhibitors and inducers of CYP3A4: 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.
    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 400/100 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 cytochrome P450 enzymes at clinically relevant concentrations. Selexipag and its active metabolite do not inhibit transport proteins. Selexipag and its active metabolite are not expected to induce cytochrome P450 enzymes in the liver and kidney at clinically relevant concentrations. In vitro data indicate that selexipag could be an inducer of both CYP3A4 and CYP2C9 in the intestine.
    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.
    Hormonal contraceptives: Specific drug‑drug interaction studies with hormonal contraceptives have not been conducted. Since selexipag did not affect the exposure to the CYP3A4 substrate R‑warfarin or to the CYP2C9 substrate S‑warfarin, reduced efficacy of hormonal contraceptives is not expected.


    Pregnancy and Lactation

    Pregnancy: There are no data from the use of selexipag in pregnant women.
    Lactation: It is unknown whether selexipag or its metabolites are excreted in human milkSelexipag should not be used during breast‑feeding.
    See prescribing information for full details.


    Overdose

    Isolated cases of overdose up to 3,200 micrograms were reported. 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.


    Important notes

    Lactose: no content of lactose.


    Manufacturer
    Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
    Licence holder
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