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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for UPTRAVI (UPTRAVI).
| Breastfeeding | No data on presence in human milk, effects on breastfed infant, or milk production. M/P ratio is unknown. The active metabolite is potentially excreted in animal milk. Due to potential for serious adverse reactions, breastfeeding is not recommended during treatment and for at least 2 days after final dose. |
| 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. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Severe hepatic impairment (Child-Pugh Class C)","Concomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil)"]
| 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"] |
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| 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. |