Usage
Selexipag is prescribed for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) in adults to delay disease progression and reduce the risk of hospitalization for PAH. Its pharmacological classification is a prostacyclin receptor agonist, specifically a selective non-prostanoid IP prostacyclin receptor agonist. Selexipag’s mechanism of action involves vasodilation of the pulmonary arteries by selectively activating IP prostacyclin receptors. This leads to a decrease in pulmonary vascular resistance and improved blood flow through the lungs.
Alternate Names
Selexipag is also known by the brand name Uptravi®.
How It Works
Pharmacodynamics: Selexipag is a prodrug that is rapidly hydrolyzed to its active metabolite, ACT-333679, which is 37 times more potent than selexipag itself. Both selexipag and ACT-333679 are selective agonists for the IP prostacyclin receptor. This activation leads to vasodilation of the pulmonary arteries, reducing pulmonary vascular resistance and improving cardiac output. It does not bind to other prostacyclin receptors.
Pharmacokinetics: Selexipag is administered orally and is rapidly absorbed, reaching maximum plasma concentrations within 2.5 hours. ACT-333679 reaches peak plasma levels at approximately 4 hours. Food can reduce exposure to ACT-333679 by up to 27%. Selexipag’s half-life is between 0.7–2.3 hours, while ACT-333679 has a half-life of 9.4–14.22 hours. Selexipag and ACT-333679 are primarily metabolized by CYP2C8 and uridine 5’-diphospho-glucuronosyltransferases (UGTs) 1A3 and 2B7. Elimination pathways include renal (about 28%) and hepatic (about 72%).
Mode of Action: Selexipag’s primary mode of action is through the selective binding and activation of IP prostacyclin receptors on the smooth muscle cells of the pulmonary arteries. This leads to an increase in intracellular cyclic adenosine monophosphate (cAMP), causing smooth muscle relaxation and vasodilation.
Dosage
Standard Dosage
Adults:
Initial dose: 200 mcg twice daily, taken orally approximately 12 hours apart.
Maintenance dose: Increase the dose in 200 mcg increments twice daily at weekly intervals, as tolerated, up to a maximum of 1600 mcg twice daily. The maintenance dose is the highest tolerated dose. Take the initial dose at each new dosage level in the evening.
Children:
The safety and efficacy of selexipag in children have not been established.
Special Cases:
- Elderly Patients: No dosage adjustments are required based on age.
- Patients with Renal Impairment: No dosage adjustments are necessary for patients with an estimated glomerular filtration rate (eGFR) greater than 15 mL/min/1.73 m². Dose adjustments have not been studied for patients with severe renal impairment or undergoing dialysis.
- Patients with Hepatic Dysfunction:
- Mild impairment (Child-Pugh Class A): No dosage adjustment.
- Moderate impairment (Child-Pugh Class B): Initial dose of 200 mcg once daily; increase by 200 mcg increments once daily at weekly intervals as tolerated, up to a maximum dose of 1600 mcg once daily.
- Severe impairment (Child-Pugh Class C): Selexipag is contraindicated.
- Patients with Comorbid Conditions: Caution is advised in patients with pulmonary veno-occlusive disease (PVOD). Discontinue selexipag if PVOD is confirmed.
Clinical Use Cases
Selexipag is indicated for chronic PAH management and does not have specific dosage recommendations for acute clinical situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. For patients temporarily unable to take oral medication, an intravenous formulation with specific conversion guidelines exists (please consult additional references).
Dosage Adjustments
Co-administration with moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox, teriflunomide): reduce the dosing frequency to once daily. Co-administration with strong CYP2C8 inducers (e.g., rifampin): increase the selexipag dose up to two times the normal dose. Reduce therapy dose back down when rifampin is stopped.
Side Effects
Common Side Effects:
Headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, flushing.
Rare but Serious Side Effects:
Pulmonary edema (especially in patients with underlying PVOD), hypotension, anemia.
Long-Term Effects:
No specific long-term adverse effects have been identified beyond those listed above.
Adverse Drug Reactions (ADR):
Angioedema, hypersensitivity reactions.
Contraindications
- Concomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil).
- Severe hepatic impairment (Child-Pugh class C).
- Hypersensitivity to selexipag or any of its components.
Drug Interactions
- Strong CYP2C8 inhibitors: Significantly increase selexipag exposure.
- Moderate CYP2C8 inhibitors: Increase selexipag exposure.
- Strong CYP2C8 inducers: Decrease selexipag exposure.
- UGT1A3 and 2B7 inhibitors: Potential for increased selexipag exposure.
- Anticoagulants (e.g., warfarin): Selexipag does not appear to significantly affect warfarin’s pharmacodynamic effect.
Pregnancy and Breastfeeding
Pregnancy Safety Category: Data on use in pregnant women are limited. Animal studies did not show evidence of developmental toxicity. However, due to the potential for serious adverse reactions in infants from breast milk exposure, discontinue nursing or discontinue selexipag during breastfeeding.
Drug Profile Summary
- Mechanism of Action: Selective IP prostacyclin receptor agonist, leading to vasodilation of pulmonary arteries.
- Side Effects: Headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, flushing. Rarely: pulmonary edema, hypotension, anemia.
- Contraindications: Strong CYP2C8 inhibitors, severe hepatic impairment, hypersensitivity.
- Drug Interactions: CYP2C8 inhibitors and inducers, UGT1A3 and 2B7 inhibitors.
- Pregnancy & Breastfeeding: Limited human data; not recommended during breastfeeding.
- Dosage: Adults: Starting dose 200 mcg BID, titrate up to 1600 mcg BID as tolerated. Moderate hepatic impairment: Starting dose 200 mcg QD, titrate up to 1600 mcg QD as tolerated.
- Monitoring Parameters: Blood pressure, heart rate, signs of pulmonary edema, liver function tests.
Popular Combinations
Selexipag can be used in combination with endothelin receptor antagonists (ERAs) and phosphodiesterase-5 (PDE-5) inhibitors. This combination therapy targets multiple pathways involved in PAH pathogenesis.
Precautions
- General Precautions: Assess for underlying hepatic impairment, potential drug interactions. Monitor for signs of pulmonary edema, especially in patients with suspected PVOD.
- Specific Populations: Pregnant women: use with caution. Breastfeeding mothers: not recommended. Children: Safety and efficacy not established. Elderly: Close monitoring is recommended.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Selexipag?
A: The initial dose is 200 mcg twice daily. Titrate upwards in 200 mcg increments at weekly intervals based on tolerability, to a maximum of 1600 mcg twice daily.
Q2: How should Selexipag be administered?
A: Selexipag is administered orally as a tablet, ideally with food to improve tolerability. Tablets should be swallowed whole, not crushed or chewed.
Q3: What are the common side effects of Selexipag?
A: Common side effects include headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in the extremities, and flushing. These are often transient or manageable with symptomatic treatment.
Q4: What are the contraindications for using Selexipag?
A: Selexipag is contraindicated in patients with concomitant use of strong CYP2C8 inhibitors, severe hepatic impairment, and hypersensitivity to selexipag or any of its components.
Q5: How does Selexipag interact with other drugs?
A: Selexipag’s metabolism is primarily mediated by CYP2C8. Therefore, co-administration with CYP2C8 inhibitors or inducers can alter selexipag’s plasma concentrations. It’s important to review a patient’s medication list for potential drug interactions before starting selexipag.
Q6: Can Selexipag be used during pregnancy and breastfeeding?
A: There are limited data on the use of selexipag in pregnant women. It is not recommended during breastfeeding due to potential exposure to the infant through breast milk.
Q7: What should be monitored in patients taking Selexipag?
A: Blood pressure, heart rate, and signs or symptoms suggestive of pulmonary edema should be monitored. Additionally, monitor liver function tests, especially in patients with pre-existing liver disease.
Q8: How does selexipag compare to other PAH treatments?
A: Selexipag offers the advantage of oral administration, which can improve patient compliance compared to intravenous or inhaled prostacyclin therapies. It has demonstrated efficacy in delaying disease progression and reducing hospitalization risk in PAH patients.
Q9: What should I do if a patient misses a dose of selexipag?
A: If a dose is missed, the patient should take the missed dose as soon as they remember, unless it is close to the time for the next dose. Do not double the dose to catch up.
A: Yes, an intravenous formulation exists for patients temporarily unable to take the oral form. Consult the relevant references for specific conversion guidelines from the oral to the intravenous dosage.
