SELEXIPAG
Clinical safety rating
cautionComprehensive clinical and safety monograph for SELEXIPAG (SELEXIPAG).
Selective agonist of the prostacyclin (IP) receptor, causing vasodilation and inhibition of platelet aggregation via increased cAMP levels.
| Metabolism | Primarily metabolized by CYP2C8 and CYP3A4; minor contribution from UGT1A3, UGT2B7, and CYP2C9. |
| Excretion | Primarily hepatic metabolism (approximately 97% of dose) via CYP2C8 and CYP3A4; biliary/fecal excretion of metabolites accounts for ~77% of total clearance; renal excretion <1% as unchanged drug. |
| Half-life | Terminal elimination half-life is approximately 6–8 hours following intravenous administration; with oral administration, the effective half-life is ~6–9 hours due to enterohepatic recirculation; clinical context: dosing every 6 hours is required to maintain therapeutic plasma concentrations. |
| Protein binding | Approximately 99% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution at steady state is approximately 1.7 L/kg (range 1.1–2.5 L/kg), indicating extensive extravascular distribution. |
| Bioavailability | Oral bioavailability is approximately 90% under fed conditions; absorption is delayed and reduced by high-fat meals, but overall systemic exposure is increased by ~30% compared to fasting. |
| Onset of Action | For oral tablets, onset of clinical effect (reduction in pulmonary vascular resistance) typically occurs within 1–2 hours; for intravenous infusion, onset is within 15–30 minutes. |
| Duration of Action | Duration of hemodynamic effect is approximately 6–8 hours after an oral dose, consistent with dosing interval; clinical effects on exercise capacity and symptoms are sustained with chronic dosing. |
| Molecular Weight | 496.6 |
Oral, starting dose 200 mcg twice daily, titrated in increments of 200 mcg twice daily at weekly intervals as tolerated to a maximum of 1600 mcg twice daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not studied in severe renal impairment (eGFR <15 mL/min/1.73 m²) or on dialysis; use with caution. |
| Liver impairment | Contraindicated in Child-Pugh class C. For Child-Pugh class A or B, reduce starting dose to 200 mcg once daily and titrate cautiously; monitor closely. |
| Pediatric use | Not approved for pediatric use; safety and efficacy not established. |
| Geriatric use | No specific dose adjustment recommended; initiate at 200 mcg twice daily and titrate based on tolerability, considering increased sensitivity and comorbidities. |
| 1st trimester | Animal studies have shown teratogenic effects; human data limited. Use only if benefit outweighs risk. |
| 2nd trimester | May cause fetal harm based on animal data. Avoid unless no alternative. |
| 3rd trimester | May cause fetal harm; consider risk-benefit. Use only if clearly needed. |
Clinical note
Comprehensive clinical and safety monograph for SELEXIPAG (SELEXIPAG).
| Placental transfer | Selexipag and its active metabolite are predicted to cross the placenta based on molecular weight (<500 Da) and animal studies showing transfer. |
| Breastfeeding | No human data on excretion in breast milk. Animal studies show presence in milk. Due to potential for serious adverse reactions, breastfeeding is not recommended during therapy and for at least 2 weeks after last dose. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Selexipag is contraindicated in pregnancy. Animal studies show increased post-implantation loss and reduced fetal weights. No adequate human data; based on its mechanism (IP receptor agonist), risk of fetal harm cannot be excluded, particularly in the first trimester. |
| Fetal Monitoring | Pregnancy status should be verified before starting selexipag. Women of childbearing potential must use effective contraception. Monitor for pulmonary arterial hypertension worsening; no specific fetal monitoring recommended beyond standard obstetric care. |
| Fertility Effects | No human data on fertility. In animal studies, no effects on male or female fertility were observed at exposures up to 5 times the human exposure. However, due to limited data, effect on human fertility cannot be excluded. |
■ FDA Black Box Warning
Not recommended for use in patients with severe hepatic impairment (Child-Pugh class C).
| Serious Effects |
Hypersensitivity to selexipag or any excipientConcomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil)Severe hepatic impairment (Child-Pugh class C)
| Precautions | Elderly patients may have increased exposure., Patients with hepatic impairment: dose adjustment required for moderate impairment; avoid in severe impairment., Concomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil) increases selexipag exposure by 11-fold; reduce dose., Concomitant use with strong CYP3A4 inducers (e.g., rifampin) reduces exposure; monitor efficacy., May cause headache, diarrhea, jaw pain, flushing, and nausea. |
| Food/Dietary | Take with food to improve tolerance. Avoid grapefruit and grapefruit juice as they may increase selexipag plasma concentrations. No other significant food interactions known. |
| Clinical Pearls | Selexipag is a prostacyclin receptor (IP receptor) agonist used for pulmonary arterial hypertension (PAH). It is a prodrug that requires hepatic carboxylesterase 1 (CES1) activation. Monitor for signs of pulmonary edema suggestive of pulmonary veno-occlusive disease. Concurrent use with strong CYP2C8 inhibitors (e.g., gemfibrozil) increases exposure and is contraindicated. Dose adjustment needed in moderate hepatic impairment (Child-Pugh B). Thyroid abnormalities and bleeding risk are potential concerns. |
| Patient Advice | Take selexipag exactly as prescribed, typically twice daily with food to reduce gastrointestinal side effects. · Do not crush or chew tablets; swallow whole. · Common side effects include headache, diarrhea, nausea, jaw pain, and muscle aches; report persistent or severe symptoms. · Avoid grapefruit juice as it may increase drug levels. · Inform your doctor if you experience signs of bleeding (unusual bruising, nosebleeds) or thyroid issues (fatigue, weight changes). · Do not stop abruptly without medical advice; sudden discontinuation may worsen PAH. · If you are taking gemfibrozil or other CYP2C8 inhibitors, discuss with your doctor as combination is contraindicated. · Women of childbearing potential should use effective contraception; discuss pregnancy planning with your doctor. |
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