selexipag

Actions and spectrum: 

selexipag is a selective prostacyclin receptor agonist with vasodilatory and anti-proliferative effects. It acts on the prostacyclin receptor (IP receptor) to increase the production of cyclic adenosine monophosphate (cAMP) in vascular smooth muscle cells.

This leads to vasodilation, inhibition of platelet aggregation, and suppression of smooth muscle cell proliferation. selexipag is primarily used for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and delay disease progression. It has a broad spectrum of action, targeting multiple components involved in PAH pathophysiology. 

DRUG INTERACTION

Contraindicated  

Serious Use Alternative  

Monitor Closely  

Minor  

Frequency defined 

1-10% 

Anemia (8%) 

Decreased hemoglobin (8.6%) 

Decreased appetite (6%)  

>10% 

Diarrhea (42%) 

Nausea (33%) 

Pain in extremities (17%) 

Flushing (12%) 

Rash (11%) 

Headache (65%) 

Jaw pain (26%) 

Vomiting (18%) 

Myalgia (16%) 

Arthralgia (11%)  

Frequency not defined 

Vascular disorders: hypotension 

Reduced TSH (till −0.3 MU/L from the baseline of about 2.5 MU/L) 

Black Box Warning: 

selexipag has a black box warning regarding the risk of embryo-fetal toxicity. selexipag is contraindicated in pregnancy and not to be used in pregnant and lactating women. It is essential for women of childbearing potential to use effective contraception while taking selexipag. 

Contraindication/Caution: 

Contraindication: 

• Hypersensitivity: It is not used in patients with allergic or hypersensitivity to selexipag or any of its components. 
• Pregnancy: selexipag is contraindicated in pregnancy due to the risk of embryo-fetal toxicity and serious birth defects. 
• Severe hepatic impairment: It is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C) due to the increased exposure to selexipag. 
• Use with strong CYP2C8 inhibitors: Concurrent use of selexipag with strong inhibitors of CYP2C8, such as gemfibrozil, is contraindicated due to the potential for significant drug interactions and increased selexipag exposure. 
• Pulmonary hypertension with idiopathic interstitial pneumonias: selexipag is contraindicated in patients with PH-IIP, as it has not been studied in this patient population and may worsen the underlying lung disease.

Caution: 

• Hypotension: selexipag may cause a decrease in blood pressure. Caution should be exercised when using selexipag in patients with conditions predisposing them to hypotension or in those taking antihypertensive medications. 
• Hepatic impairment: selexipag should be used under caution in patients with the mild or moderate hepatic impairment (Child-Pugh Class A or B) as the exposure to selexipag and its active metabolite may be increased. 
• Renal impairment: dose adjustment is not necessary for selexipag in patients with renal impairment. However, it should be used in caution with renal impairment or end stage renal disease as there is limited data available in these populations. 
• Bleeding risk: selexipag may increase the risk of bleeding, particularly in patients with bleeding or those receiving concomitant anticoagulant therapy. Caution should be exercised when using selexipag in these patients. 
• Pulmonary effects: selexipag may cause pulmonary adverse reactions, including cough and bronchitis. It should be used under caution in patients with underlying lung disease. 
• Drug interactions: selexipag is metabolized by CYP2C8 and may interact with drugs that induce or inhibit this enzyme. Caution should be exercised when co-administering selexipag with drugs such as strong inducers or inhibitors of CYP2C8.

Comorbidities: 

• Cardiovascular disease: Patients with underlying cardiovascular conditions such as CHF, coronary artery disease, or arrhythmias may require careful monitoring when using selexipag. 
• Hepatic impairment: selexipag is metabolized in the liver, so patients with hepatic impairment may require dose adjustments or close monitoring due to potential changes in drug metabolism. 
• Renal impairment: While selexipag does not require dose adjustment in patients with renal impairment. 
• Bleeding disorders: selexipag carries a risk of bleeding, so it should be used in caution patients with bleeding disorders or on anticoagulant therapy. 
• Pulmonary disease: selexipag is primarily used to treat PAH but underlying pulmonary diseases such as chronic obstructive pulmonary disease (COPD) or asthma may influence the response to treatment and require close monitoring. 

Pregnancy consideration: N/A 

Lactation: N/A  

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.   
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology: 

selexipag is a selective prostacyclin receptor agonist that acts as a vasodilator and inhibits the platelet aggregation. It is specifically designed to target the prostacyclin receptor (IP receptor) found on vascular smooth muscle cells and platelets. 

Upon administration, selexipag is rapidly converted into its active metabolite, ACT-333679, through hydrolysis by carboxylesterases. ACT-333679 then binds to the IP receptor, activating the cyclic adenosine monophosphate (cAMP) pathway, leading to vasodilation and systemic arterial vascular beds. 

The vasodilatory effects of selexipag are primarily exerted on the pulmonary vasculature, reducing pulmonary vascular resistance, and improving exercise capacity in patients with pulmonary arterial hypertension (PAH). It also inhibits platelet aggregation, thereby reducing the risk of thrombosis.  

Pharmacodynamics: 

The pharmacodynamics of selexipag involve its selective activation of the prostacyclin (IP) receptor. By binding to this receptor, selexipag and its active metabolite, ACT-333679, stimulate the production of cyclic adenosine monophosphate (cAMP) in vascular smooth muscle cells and platelets. 

The activation of the IP receptor and subsequent increase in cAMP levels lead to various effects, including vasodilation of pulmonary and systemic arterial vascular beds, inhibition of platelet aggregation, and suppression of smooth muscle cell proliferation.  

Pharmacokinetics: 

Absorption 

selexipag is administered orally and is rapidly absorbed from the gastrointestinal tract. It undergoes first-pass metabolism in the liver, primarily by the action of cytochrome P450 enzymes, before reaching systemic circulation. The absolute bioavailability of selexipag is low, estimated to be around 15%. 

Distribution 

selexipag is highly bound to plasma proteins, particularly albumin. It has a large volume of distribution, indicating extensive tissue distribution. The drug crosses the blood-brain barrier poorly. 

Metabolism 

selexipag is metabolized primarily by cytochrome P450 enzymes, CYP2C8 and to a lesser extent CYP3A4. It is metabolized to its active metabolite, ACT-333679, which exhibits pharmacological activity like selexipag. The active metabolite undergoes further metabolism before being eliminated. 

Elimination and excretion 

The elimination of selexipag and its metabolites occurs through the feces, with minimal renal excretion. The drug has a long elimination half-life, estimated to be 7-9 hours for selexipag and 9-11 hours for ACT-333679. 

Administration: 

selexipag is available in tablet form for oral administration. The recommended starting dose of selexipag is typically 200 micrograms (mcg) twice daily. The dose is gradually increased based on the individual patient’s tolerability and response.

The dose titration is done in increments of 200 mcg, with the target maintenance dose ranging from 1,600 mcg to 2,000 mcg twice daily. It is important to take selexipag with food to minimize the potential for stomach-related side effects. The tablets should be administered whole and not crushed, chewed, or divided. 

Patient information leaflet 

Generic Name: selexipag 

Pronounced: [ se-LEX-i-pag ] 

Why do we use selexipag? 

selexipag is primarily used to treat pulmonary arterial hypertension. It is characterized with high blood pressure in the arteries, leading to shortness of breath, fatigue, and chest pain. selexipag helps to dilate and relax the blood vessels in the lungs, reducing the workload on the heart and improving exercise capacity in patients with PAH. 

selexipag is specifically indicated for the long-term treatment of PAH in patients who are not candidates for other forms of PAH therapy or who have not responded adequately to other PAH treatments. It can be used as a monotherapy or as a combination with other PAH medications.