FDA approved Orenitram (treprostinil) for Pulmonary Arterial HypertensionFDA approved new pill Orenitram to treat pulmonary arterial hypertension

Treprostinil is a prostacyclin mimetic. Its pharmacological effects include direct vasodilation of pulmonary and systemic arterial vascular beds, and inhibition of platelet aggregation. The exact mechanism of action in PAH is not fully characterized.

Orenitram is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to delay disease progression and to improve exercise capacity. The studies that established effectiveness included predominately patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (66%) or PAH associated with connective tissue disease (26%).

- Administer with food. Swallow tablets whole; do not crush, split, or chew. - Starting dose: 0.125 mg TID (approximately 8 hours apart) or 0.25 mg BID (approximately 12 hours apart). - Titrate by 0.125 mg TID or 0.25 or 0.5 mg BID, not more frequently than every 3 to 4 days as tolerated. Increase to highest tolerated dose. Maximum daily dose is 120 mg. - If dose increments are not tolerated, consider slower titration or decrease dose in increments of 0.125 mg TID or 0.25 mg BID. Avoid abrupt discontinuation. - Transitioning from subcutaneous or intravenous treprostinil: Decrease Remodulin dose while simultaneously increasing Orenitram dose. Remodulin can be reduced up to 30 ng/kg/min per day and Orenitram increased up to 6 mg per day (2 mg TID) if tolerated. Estimated target total daily Orenitram dose (mg) = 0.0072 × Remodulin dose (ng/kg/min) × weight (kg). - Hepatic impairment: Mild (Child Pugh A): start at 0.125 mg BID, increment by 0.125 mg BID not more frequently than every 3-4 days. Avoid use in moderate impairment (Child Pugh B). Contraindicated in severe impairment (Child Pugh C). - CYP2C8 inhibitors: When co-administered with strong CYP2C8 inhibitors (e.g., gemfibrozil), initial dose is 0.125 mg BID with increments of 0.125 mg BID not more frequently than every 3-4 days. - Missed doses: If a dose is missed, take as soon as possible with food. If two or more doses are missed, restart at a lower dose and re-titrate. For planned short-term interruption, consider temporary parenteral treprostinil infusion. To calculate parenteral dose: Remodulin (ng/kg/min) = 139 × Orenitram total daily dose (mg) / weight (kg). When discontinuing, reduce dose in steps of 0.5 to 1 mg per day.

Four multicenter, randomized, double-blind, placebo-controlled studies compared Orenitram to placebo in a total of 349 (Study 1), 350 (Study 2), 310 (Study 3), and 690 (Study 4) patients with PAH. Study 1 was a 12-week study in patients not receiving background PAH therapy; primary endpoint was placebo-corrected change in six-minute walk distance (6MWD) from baseline to Week 12. The primary analysis population consisted of 228 patients who had access to the 0.25 mg tablet at randomization. Patients were titrated to a maximum of 12 mg BID. Detailed efficacy results for all studies are not fully presented in the label.

- Contraindicated in patients with severe hepatic impairment (Child Pugh Class C) due to increases in systemic exposure. - Avoid use in moderate hepatic impairment (Child Pugh Class B). - Avoid abrupt discontinuation; taper dose to prevent worsening of PAH symptoms. - Use with caution in patients with hepatic impairment; dose adjustments required for mild impairment. - Concomitant use with strong CYP2C8 inhibitors requires dose