Selexipag

Registered South African indications:

• Pulmonary arterial hypertension (PAH, WHO Group I) 

Contraindications
South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Coadministration with strong CYP2C8 inhibitors (e.g. gemfibrozil)

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its 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
• Coadministration with strong CYP2C8 inhibitors (e.g. gemfibrozil)

Cautions
South African manufacturer recommendations

• Pregnancy
• Women of childbearing potential
• Breastfeeding
• Severe renal impairment (eGFR<30ml/min/1.73m²)
• Moderate to severe (Child-Pugh class B and C) hepatic impairment
• Mannitol intolerance (See additional prescribing points)
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy
• Women of childbearing potential
• Breastfeeding
• Severe renal impairment (eGFR<30ml/min/1.73m²)
• Moderate to severe hepatic impairment (Child-Pugh class B and C)
• Elderly (>75 years)
• Patients on antihypertensive therapy or with resting hypotension
• Pre-existing hypovolaemia, severe left ventricular outflow obstruction or autonomic dysfunction
• Pre-existing pulmonary veno-occlusive disease
• Underlying conditions that could be adversely affected by vasodilatory effects
  - Hypovolaemia
  - Severe left ventricular outflow obstruction
  - Autonomic dysfunction
  - Resting hypotension
  - Coadministration with antihypertensive therapy
• Coadministration with strong uridine glucuronyl transferases UGT1A3 and UGT2B7 inhibitors
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: tab

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Pulmonary arterial hypertension (PAH, WHO Group I) (Additional agent(s) may be required)
- Long-term treatment in patients with WHO functional class (FC) II-IV to delay disease progression. Disease progression events included: death, hospitalisation for PAH, initiation of prostanoids, or other disease progression events (decrease of 6-minute walk distance [6MWD] associated with either worsened PAH symptoms or need for additional PAH specific treatment)

• Oral (tab): Initial: 200μg, 12hrly; Titrate in increments of 200μg, 12hrly at weekly intervals; Max: 3200μg/24hrs (as 1600μg, 12hrly)

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Effective in combination with an endothelin receptor antagonist (ERA) or a phosphodiesterase-5 (PDE-5) inhibitor, or in triple combination with an ERA and a PDE-5 inhibitor, or as monotherapy

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The goal is to reach the individually appropriate dose for each patient (the individualised maintenance dose)

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While a maximum with acceptable tolerability is being determined, it is recommended not to discontinue treatment in the event of mild to moderate pharmacological side effects since they are usually transient or manageable with symptomatic treatment 

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If a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous dose level

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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 or a dose reduction to the next lower dose should be considered

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Interruptions and discontinuation: See additional prescribing points

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Method of administration: See additional prescribing points

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Dosage adjustment with coadministration of moderate CYP2C8 inhibitors: When coadministered with moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox and teriflunomide), reduce the dosing of selexipag to once daily. Revert back to twice-daily dosing frequency of selexipag when coadministration of moderate CYP2C8 inhibitor is stopped

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International manufacturer recommendations

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

Pulmonary arterial hypertension (PAH) in patients with WHO functional class (FC) II–III (Additional agent(s) may be required)
- Long-term treatment 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

• Oral (tab): Initial: 200μg, 12hrly; Titrate in increments of 200μg, 12hrly at weekly intervals; Max: 3200μg/24hrs (as 1600μg, 12hrly)

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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

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At the beginning of treatment and at each up-titration step it is recommended to take the first dose in the evening

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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

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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

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Dose adjustment with coadministration of moderate CYP2C8 inhibitors: When coadministered with moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox and teriflunomide), reduce the dosing of selexipag to once daily. 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. Revert to twice-daily dosing frequency of selexipag when coadministration of moderate CYP2C8 inhibitor is stopped

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Interruptions and discontinuation: See additional prescribing points

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Method of administration: See additional prescribing points

Not established for use in children below 18 years

Pregnancy
South African manufacturer recommendations

• Caution
• Safety and/or efficacy in pregnancy has not been established. There are limited data on the use of selexipag in pregnant women
• Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity
• Women of childbearing potential should practice effective contraception while taking selexipag

International manufacturer recommendations

• Caution; not recommended
• 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 20-80 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
• Selexipag is not recommended during pregnancy and in women of childbearing potential not using contraception
• Women of childbearing potential should practise effective contraception while taking selexipag

Breastfeeding
South African manufacturer recommendations

• Caution; not recommended 
• It is unknown whether selexipag or its metabolites are excreted in human milk. In rats, selexipag or its metabolites are excreted in the milk
• Breastfeeding is not recommended during treatment with selexipag

International manufacturer recommendations

• Caution; not recommended 
• It is unknown whether selexipag or its metabolites are excreted in human milk. In rats, selexipag or its metabolites are excreted in milk
• A risk to the nursing child cannot be excluded. Selexipag should not be used during breastfeeding

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. The relevance for humans is not known

Renal Impairment 
South African manufacturer recommendations

• Mild or moderate (eGFR>30ml/min/1.73m²): No dose adjustment recommended 
• Severe (eGFR<30ml/min/1.73m²): Caution; no dose adjustment recommended 
  No change in starting dose is required, caution should be exercised during dose titration
  There is no experience with selexipag in patients undergoing dialysis

International manufacturer recommendations

• Mild or moderate (eGFR>30ml/min/1.73m²): No dose adjustment recommended 
• Severe (eGFR<30ml/min/1.73m²): Caution; no dose adjustment recommended 
  No change in starting dose is required, caution should be exercised during dose titration

Hepatic Impairment
South African manufacturer recommendations

• Mild (Child-Pugh class A): No dose adjustment recommended 
• Moderate (Child-Pugh class B): Caution; dose adjustment recommended 
  A once-daily regimen is recommended due to the increased exposure to selexipag and its active metabolite
• Severe (Child-Pugh class C): Caution; no information available 

International manufacturer recommendations 

• Mild (Child-Pugh class A): No dose adjustment recommended 
• Moderate (Child-Pugh class B): Caution; dose adjustment recommended 
  Oral (tab): Initial: 200μg, dly; Titrate in increments of 200μg, dly at weekly intervals until adverse reactions, reflecting the mode of action of selexipag, that cannot be tolerated or medically managed are experienced
• Severe (Child-Pugh class C): Caution; not recommended 

Elderly 
South African manufacturer recommendations

• No dose adjustment recommended 

International manufacturer recommendations 

• ≥65 years: No dose adjustment recommended 
• >75 years: Caution; no dose adjustment recommended 
  There is limited clinical experience

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache

Cardiovascular Disorders 

• Flushing
• Hypotension
• Sinus tachycardia
• Flushing

Respiratory Disorders 

• Nasopharyngitis (of noninfectious origin)
• Nasal congestion

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Abdominal pain

Endocrine and Metabolic Disorders 

• Hyperthyroidism
• Decreased appetite
• Thyroid-stimulating
• Decreased hormone 
• Decreased weight

Musculoskeletal Disorders

• Jaw pain
• Myalgia
• Arthralgia
• Pain in extremity

Skin and Subcutaneous Tissue Disorders

• Rash
• Urticaria
• Erythema

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Decreased haemoglobin 

Others

• Pain

• Strong CYP2C8 inhibitors
• Gemfibrozil
• Moderate CYP2C8 inhibitors
• Clopidogrel
• Deferasirox 
• Teriflunomide
• CYP2C8 inducers
• UDP-glucuronosyltransferase (UGT) enzymes inducers
• Rifampicin
• Carbamazepine
• Phenytoin
• Diuretics
• Antihypertensive agents
• Vasodilators
• Pulmonary arterial hypertension (PAH)-specific therapies (See additional prescribing points)
• Endothelin receptor antagonist (ERA)
• Phosphodiesterase type 5 (PDE-5) inhibitor

• Hepatic function

Specific cases may require

• Thyroid function 

Additional observations

• Signs of
  - Pulmonary oedema and improvements in pulmonary function
  - Exercise tolerance
  - Quality of life

Method of administration
South African manufacturer recommendations

• The film-coated tablets are to be taken orally in the morning and in the evening. Selexipag may be taken with or without food. Tolerability may be improved when taken with food. The tablets should not be split, crushed or chewed, and are to be swallowed with water

International manufacturer recommendations

• 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

Interruptions and discontinuations
South African manufacturer recommendations

• If a dose of medication is missed, it should be taken as soon as possible. The missed dose should not be taken if the time for the next scheduled dose is within 6 hours. If treatment is missed for 3 days or more, selexipag should be re-started at a lower dose and then titrated

International manufacturer recommendations

• 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

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

Mannitol intolerance (South African manufacturer recommendations)

• Selexipag contains mannitol that may have a laxative effect or cause diarrhoea. Patients with the rare hereditary condition of mannitol intolerance should not take selexipag

The vasculo-protective effects of prostacyclin (PGI₂) are mediated by the prostacyclin receptor (IP receptor). Decreased expression of IP receptors and decreased synthesis of prostacyclin contribute to the pathophysiology of pulmonary arterial hypertension. Selexipag is an oral, selective, IP receptor agonist, and is structurally and pharmacologically distinct from prostacyclin and its analogs. Selexipag is hydrolysed by carboxylesterases to yield its active metabolite, which is approximately 37-fold more potent than selexipag. Selexipag and the active metabolite are high affinity IP receptor agonists with a high 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 contractile receptors in gastro-intestinal tract and blood vessels. Selectivity against EP₂, EP₄ and DP₁ is important because these receptors mediate immune depressive effects. Stimulation of the IP receptor by selexipag and the active metabolite leads to vasodilatory as well as anti-proliferative and anti-fibrotic effects. Selexipag improves haemodynamic variables and prevents cardiac and pulmonary remodeling in a rat model of PAH. In these PAH rats, pulmonary and peripheral vasodilation in response to selexipag correlate, indicating that peripheral vasodilation reflects pulmonary pharmacodynamic efficacy. Selexipag does not cause IP receptor desensitization in vitro nor tachyphylaxis in a rat model. PAH patients have variable degrees of IP receptor expression. Differences in maintenance dose of selexipag between individuals may be related to differences in IP receptor expression levels.

Tablet 200μg

• Uptravi (Janssen Pharmaceutica) originator

Tablet 400μg

• Uptravi (Janssen Pharmaceutica) originator

Tablet 600μg

• Uptravi (Janssen Pharmaceutica) originator

Tablet 800μg

• Uptravi (Janssen Pharmaceutica) originator

Tablet 1000μg

• Uptravi (Janssen Pharmaceutica) originator

Tablet 1200μg

• Uptravi (Janssen Pharmaceutica) originator

Tablet 1400μg

• Uptravi (Janssen Pharmaceutica) originator

Tablet 1600μg

• Uptravi (Janssen Pharmaceutica) originator