Treprostinil

Treatment should be initiated under close medical supervision in a medical setting able to provide intensive care, and initiated and monitored only by clinicians experienced in the treatment of pulmonary hypertension. Efficacy in the main 12-week trials was only maintained if the dose was increased on average 3-4 times per month. During follow-up phases of clinical trials the mean doses reached were 26 ng/kg/min after 12 months, 36 ng/kg/min after 24 months and 42 ng/kg/min after 48 months (no maximum dose is stated in the SPC). Dose-dependent adverse effects (flushing, headache, hypotension, nausea, vomiting, diarrhoea) may resolve as treatment continues, but if they persist or become intolerable the infusion rate may be reduced. OBESITY: for patients weighing >=30% more than ideal body weight, the initial dose and subsequent dose increments should be based on IDEAL body weight. Abrupt withdrawal or sudden marked dose reductions may cause rebound pulmonary arterial hypertension — avoid interruption and restart as soon as possible after an accidental reduction or interruption; after an interruption of a few hours, restarting can usually be done at the same dose rate, while longer interruptions may require re-titration. HEPATIC IMPAIRMENT: exposure increases by 260% to 510% in mild to moderate impairment (Child-Pugh A and B) and clearance falls by up to 80% — decrease the initial dose to 0.625 ng/kg/min and make incremental increases cautiously. Elderly: clinical studies did not include sufficient patients aged 65 and over; plasma clearance was reduced by 20% in a population PK analysis, so dose selection should be cautious. Children and adolescents: there are few data in patients less than 18 years of age and available clinical studies do not establish whether the adult posology can be extrapolated to children and adolescents. Subcutaneous infusion rate (mL/h) = D (ng/kg/min) x W (kg) x [0.00006 / treprostinil concentration (mg/mL)], where 0.00006 = 60 min/hour x 0.000001 mg/ng; treprostinil exists at concentrations of 1, 2.5, 5 and 10 mg/mL. A single undiluted subcutaneous reservoir may be used for up to 72 hours at 37 degrees C; diluted intravenous treprostinil must be used for no more than 24 hours, with a 0.2 micron in-line filter replaced every 24 hours at each reservoir change. Transition to intravenous epoprostenol (under strict medical supervision): decrease treprostinil slowly by 2.5 ng/kg/min; after at least 1 hour at the new treprostinil dose, start epoprostenol at a maximum dose of 2 ng/kg/min; then decrease treprostinil at intervals of at least 2 hours while gradually increasing epoprostenol, maintaining each initial dose for at least one hour. Section 4.5 was not fetched from the SPC; the CYP2C8 interaction below is taken from section 7 of the US treprostinil injection label in this bundle.