UPTRAVI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for UPTRAVI (UPTRAVI).
Uptravi (selexipag) is a prostacyclin receptor (IP receptor) agonist. Selexipag and its active metabolite, ACT-333679, selectively bind to the IP receptor, leading to vasodilation, inhibition of platelet aggregation, and antiproliferative effects on smooth muscle cells.
| Metabolism | Selexipag is hydrolyzed by carboxylesterases (mainly CES1 and CES2) to its active metabolite, ACT-333679. Both are further metabolized by CYP3A4 and CYP2C8. ACT-333679 is also a substrate for UGT1A3 and UGT2B7. |
| Excretion | Primarily hepatic metabolism; renal excretion of unchanged drug is <1%. Fecal excretion accounts for approximately 70% of total elimination, mainly as metabolites. Biliary excretion contributes to fecal elimination. |
| Half-life | Terminal elimination half-life is approximately 7–9 hours in healthy subjects, but prolonged in patients with hepatic impairment (Child-Pugh class A: ~11 hours; class B: ~16 hours). Steady-state is reached within 2–4 days of twice-daily dosing. |
| Protein binding | 99% bound to plasma proteins, primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Approximately 0.3 L/kg in healthy subjects, indicating distribution primarily within the vascular space and well-perfused tissues. |
| Bioavailability | Oral bioavailability is approximately 50–60% due to first-pass metabolism. Food does not significantly affect absorption. |
| Onset of Action | Bioavailability is rapid; peak plasma concentration occurs at 0.5–1.5 hours post-oral dose. Clinical effect on pulmonary vascular resistance is measurable within the first week of therapy, though maximal hemodynamic improvement may take several months. |
| Duration of Action | Twice-daily dosing maintains therapeutic plasma concentrations throughout the dosing interval. The drug's effect on exercise capacity and hemodynamics is sustained with continuous therapy; duration of individual dose effect is approximately 8–12 hours. |
| Molecular Weight | 498.61 |
Initial dose 200 mcg orally twice daily, titrated in increments of 200 mcg twice daily at weekly intervals to a maximum of 1600 mcg twice daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR ≥15 mL/min/1.73 m²). Not studied in severe renal impairment (eGFR <15 mL/min/1.73 m²) or on dialysis; use caution. |
| Liver impairment | Mild hepatic impairment (Child-Pugh A): No dose adjustment. Moderate hepatic impairment (Child-Pugh B): Initial dose 200 mcg once daily, titrate cautiously. Severe hepatic impairment (Child-Pugh C): Not recommended. |
| Pediatric use | Not indicated for pediatric patients; safety and efficacy not established in patients <18 years. |
| Geriatric use | No specific dose adjustment recommended; elderly patients may have increased sensitivity, monitor closely. |
| 1st trimester | Data in pregnant women are insufficient to inform a drug-associated risk; animal studies have shown reproductive toxicity. Use only if potential benefit justifies risk to fetus. |
| 2nd trimester | Same as T1; avoid unless clearly needed. |
| 3rd trimester | Same as T1; avoid unless clearly needed. May cause fetal harm. |
Clinical note
Comprehensive clinical and safety monograph for UPTRAVI (UPTRAVI).
| Placental transfer | Seletipag is expected to cross the placenta due to its molecular weight (<500 Da). Animal studies confirm placental transfer. |
| Breastfeeding | No data on presence in human milk, effects on breastfed infant, or milk production. Because of potential for serious adverse reactions, breastfeeding is not recommended during treatment. |
■ FDA Black Box Warning
None.
| Serious Effects |
Concomitant use with strong inhibitors of CYP2C8 (e.g., gemfibrozil)Known hypersensitivity to selexipag or any excipient
| Precautions | Pulmonary edema may occur; consider the possibility of pulmonary veno-occlusive disease (PVOD) if symptoms develop, Hepatic impairment: Avoid use in severe hepatic impairment (Child-Pugh Class C), Concomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil) increases exposure; reduce dose or consider alternative, Concomitant use with strong CYP3A4 inducers (e.g., rifampin) may reduce efficacy; monitor for loss of effect |
| Food/Dietary | Avoid grapefruit juice as it may increase systemic exposure to UPTRAVI. Take with or without food, but consistent timing with meals is recommended to maintain stable drug levels. |
Loading safety data…
| Lactation Rating |
| L4 (Possibly Hazardous) |
| Teratogenic Risk | In animal studies, UPTRAVI (selexipag) and its active metabolite showed developmental toxicity including reduced fetal weights and increased skeletal variations at maternal toxic doses. No adequate and well-controlled studies in pregnant women. Risk cannot be ruled out. First trimester: potential teratogenicity based on animal data. Second and third trimesters: may cause fetal harm due to pharmacological action (IP receptor agonist) potentially affecting uterine blood flow. |
| Fetal Monitoring | Monitor maternal blood pressure and heart rate during pregnancy. Fetal monitoring includes ultrasound for growth restriction and amniotic fluid volume assessment. No specific monitoring guidelines; clinical judgment recommended. |
| Fertility Effects | In animal studies, no effects on fertility were observed at clinically relevant exposures. No human data available. Potential for impairment of fertility in females due to pharmacological effects is unknown. |
| Clinical Pearls | Titrate to maximum tolerated dose up to 1600 mg twice daily. Monitor for signs of pulmonary edema (PPH with veno-occlusive disease). Co-administration with strong CYP2C8 inhibitors (e.g., gemfibrozil) reduces UPTRAVI clearance; decrease dose by 50% during co-administration. Avoid abrupt discontinuation; taper if possible. May cause orthostatic hypotension; assess blood pressure regularly. UPTRAVI is a prodrug of the active metabolite ACT-333679, a selective prostacyclin receptor (IP receptor) agonist. |
| Patient Advice | Take exactly as prescribed; do not crush or split tablets. · Do not stop taking this medication suddenly; consult your doctor if you need to discontinue. · Avoid grapefruit juice as it may increase drug exposure. · Report any severe headaches, jaw pain, or flushing to your healthcare provider. · Use caution when driving or operating machinery until you know how this medication affects you. · Store at room temperature away from moisture and heat. |