Treprostinil

SCOPE — this is the page's PRIMARY route and indication: continuous subcutaneous/intravenous treprostinil infusion for pulmonary arterial hypertension. The page also names Tyvaso (inhaled) and Orenitram (oral); NEITHER inhaled nor oral treprostinil appears anywhere in either fetched label. The page's second stated indication, digital ulcers in systemic sclerosis, is likewise absent from both labels — the UK SPC dosing is for pulmonary hypertension only ('The treatment should be initiated and monitored only by clinicians experienced in the treatment of pulmonary hypertension'). || §4.2 VERBATIM, initiation: 'Treatment should be initiated under close medical supervision in a medical setting able to provide intensive care. The recommended initial infusion rate is 1.25 ng/kg/min. If this initial dose is poorly tolerated, the infusion rate should be reduced to 0.625 ng/kg/min.' || §4.2 VERBATIM, titration: 'The infusion rate should be increased under medical supervision in increments of 1.25 ng/kg/min per week for the first four weeks of treatment and then 2.5 ng/kg/min per week. The dose should be adjusted on an individual basis and under medical supervision in order to achieve a maintenance dose at which symptoms improve and which is tolerated by the patient. Efficacy in the main 12 week trials was only maintained if the dose was increased on average 3-4 times per month.' || §4.2 VERBATIM, doses actually reached (these are MEANS, not ceilings): 'During follow-up phases of clinical trials the mean doses reached after 12 months were 26 ng/kg/min, after 24 months were 36 ng/kg/min, and after 48 months were 42 ng/kg/min.' || NO MAXIMUM DOSE IS STATED, so maxDose is deliberately left empty. The SPC sets no ceiling — the dose 'should be adjusted on an individual basis'. Two figures in the fetched text must NOT be mistaken for a treprostinil maximum: (a) 'epoprostenol treatment can be initiated at a maximum dose of 2 ng/kg/min' is a ceiling for a DIFFERENT drug during transition off treprostinil; (b) the infusion-rate tables are described as covering 'doses of up to 42.5 ng/kg/min', which is the range the table spans, not a licensed maximum — and Tables 1 and 2 themselves were not retrieved in the fetched text. || OBESITY, §4.2 VERBATIM: 'For patients with obesity (weighing ≥ 30% more than ideal body weight) initial dose and following dose increments should be based on ideal body weight.' §4.4 adds: 'Obese patients (BMI greater than 30 kg/m2) clear treprostinil more slowly.' The US label §2.5 likewise specifies 0.625 ng/kg/min 'ideal body weight' in hepatic insufficiency. || DO NOT STOP ABRUPTLY, §4.2 VERBATIM: 'Abrupt withdrawal or sudden marked reductions in the dose of treprostinil may cause a rebound in pulmonary arterial hypertension. It is therefore recommended that interruption of treprostinil therapy is avoided and that the infusion is re-started as soon as possible after an abrupt accidental dose reduction or interruption... In most cases, after an interruption of a few hours, restarting of treprostinil infusion can be done using the same dose rate; interruptions for longer periods may require the dose of treprostinil to be re-titrated.' || INFUSION RATE FORMULA, §4.2 VERBATIM: rate (ml/h) = D (ng/kg/min) x W (kg) x [0.00006 / treprostinil concentration (mg/ml)], where D is the prescribed dose in ng/kg/min and W the body weight in kg; 'Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng'. 'Treprostinil exists at concentrations of 1, 2.5, 5 and 10 mg/ml' (US §3: 20-mL vials containing 20, 50, 100 or 200 mg treprostinil = 1, 2.5, 5 or 10 mg/mL). Worked SPC examples: a 60 kg patient at 1.25 ng/kg/min using the 1 mg/ml strength; a 65 kg patient at 40 ng/kg/min using the 5 mg/ml strength; a 60 kg patient at 5 ng/kg/min with a 1 ml/h rate and 50 ml reservoir gives a diluted concentration of 0.018 mg/ml (0.9 ml of 1 mg/ml treprostinil made up to 50 ml); a 75 kg patient at 30 ng/kg/min with a 2 ml/h rate and 100 ml reservoir gives 0.0675 mg/ml (2.7 ml of 2.5 mg/ml treprostinil made up to 100 ml). ⚠️ 'Flushing the infusion line whilst connected to the patient may lead to accidental overdose.' || SUBCUTANEOUS route, §4.2: administered undiluted via subcutaneous catheter using an ambulatory pump adjustable in increments of about 0.002 ml/h, accurate to within ±6%; 'During use, a single reservoir (syringe) of undiluted Treprostinil can be administered up to 72 hours at 37°C.' || INTRAVENOUS route, §4.2: diluted with Sterile Water for Injection or 0.9% w/v Sodium Chloride Injection, given via a surgically placed indwelling central venous catheter (or temporarily via a peripheral cannula — 'Use of a peripheral infusion for more than a few hours may be associated with an increased risk of thrombophlebitis'); pump adjustable in increments of about 0.05 ml/h with typical flow rates between 0.4 and 2 ml/h; 'The maximum duration of use of diluted Treprostinil should be no more than 24 hours'; 'a 0.2 micron filter must be placed between the infusion tubing and the catheter hub, and replaced every 24 hours at the time of changing the infusion reservoir'; split-septum closed hub device replaced every 7 days; sterile gauze dressing replaced every two days or a transparent semi-permeable dressing at least every seven days; 'topical antibiotic ointments or creams should not be applied'. || IMPLANTABLE IV PUMP, §4.2: 'The initial dose with the implantable pump is the same that the stable dose administered with external infusion pumps at the time of transition. The implantable pump is not devised for initial dose adjustment.' Reserved for selected patients already stabilised on treprostinil who are intolerant of, unsuitable for or refuse the subcutaneous or external intravenous route. || TRANSITION TO EPOPROSTENOL, §4.2 VERBATIM: 'Treprostinil infusions should first be decreased slowly by 2.5 ng/kg/min. After at least 1 hour at the new treprostinil dose, epoprostenol treatment can be initiated at a maximum dose of 2 ng/kg/min. The treprostinil dose should then be decreased at subsequent intervals of at least 2 hours, and at the same time the epoprostenol dose is gradually increased after maintaining the initial dose for at least one hour.' || ELDERLY, §4.2: clinical studies did not include sufficient numbers of patients aged 65 and over; 'In a population pharmacokinetic (PK) analysis, plasma clearance of treprostinil was reduced by 20%'; dose selection should be cautious. || US CROSS-CHECK AGREES: §2.2 'The infusion rate is initiated at 1.25 ng/kg/min. If this initial dose cannot be tolerated because of systemic effects, reduce the infusion rate to 0.625 ng/kg/min'; §2.4 gives the same 1.25 then 2.5 ng/kg/min weekly increments and adds 'Dosage adjustments may be undertaken more often if tolerated.' || DRUG INTERACTIONS affecting dose, §4.4: a CYP2C8 inhibitor (e.g. gemfibrozil) may increase treprostinil exposure and 'Treprostinil dose reduction should be considered'; a CYP2C8 inducer (e.g. rifampicin) may decrease exposure and 'Treprostinil dose increase should be considered.'

NO PAEDIATRIC DOSE EXISTS IN EITHER FETCHED LABEL — dosePerKg is deliberately null and the weight calculator is left unset. UK SPC §4.2 VERBATIM: 'Children and adolescents — There are few data in patients less than 18 years of age. Available clinical studies do not establish whether the efficacy and safety of the recommended posology scheme for adults can be extrapolated to children and adolescents.' US §8.4 VERBATIM: 'Safety and effectiveness in pediatric patients have not been established. Clinical studies of treprostinil injection did not include sufficient numbers of patients aged ≤16 years to determine whether they respond differently from older patients.' Note that the ADULT dose is itself weight-based (ng/kg/min) but it is an adult-derived rate; it is not extrapolated to children here. Seek specialist paediatric pulmonary hypertension advice.