Treprostinil

Treprostinil is a prostacyclin analogue with a longer half-life than epoprostenol, given by continuous subcutaneous or intravenous infusion, by inhalation, or orally as extended-release tablets, for pulmonary arterial hypertension (group 1). The inhaled form is also used for pulmonary hypertension from interstitial lung disease (group 3). Start only in a PAH centre.

Classification. Prostacyclin analogue (prostanoid), vasodilator, antiplatelet.

Mechanism. Stimulates prostacyclin receptors, raising cyclic AMP, with vasodilatation and inhibition of platelet aggregation.

Pharmacokinetics. Subcutaneous bioavailability about 100%. Oral bioavailability about 17%. Half-life 4 hours (subcutaneous or intravenous). Metabolised by CYP2C8 and excreted in urine and faeces.

Specialist, PAH, subcutaneous or intravenous infusion. Start 1.25 ng/kg/minute (0.625 ng/kg/minute if not tolerated, or in mild to moderate liver impairment). Increase by up to 1.25 ng/kg/minute each week for the first 4 weeks, then up to 2.5 ng/kg/minute each week. Most patients need 20 to 80 ng/kg/minute. Doses are adjusted to symptoms and adverse effects.

Specialist, PAH and group 3 pulmonary hypertension with interstitial lung disease, inhaled. Start 3 breaths (18 micrograms) four times daily. Increase by 3 breaths at each session at intervals of at least 1 week, to a target of 9 breaths (54 micrograms) four times daily. Maximum 12 breaths (72 micrograms) four times daily.

Specialist, PAH, oral extended-release. Start 0.125 mg three times daily or 0.25 mg twice daily, with food. Increase by 0.25 mg twice daily or 0.125 mg three times daily every 3 to 4 days as tolerated. The maximum is set by tolerance. In mild to moderate liver impairment, start 0.125 mg twice daily.

Alternative. Subcutaneous treprostinil avoids a central line, an option when epoprostenol is impractical.

Emergency. Not used for acute decompensation outside specialist care.

Loading. No loading dose.

Contraindications. Hypersensitivity. Oral extended-release treprostinil is not advised in severe liver impairment.

Serious adverse effects. Rebound pulmonary hypertension if stopped suddenly, bloodstream infection (intravenous), hypotension, bleeding, thrombocytopenia (rare).

Common adverse effects. Infusion site pain and reaction (very common subcutaneously), headache, diarrhoea, nausea, jaw pain, flushing, cough with inhaled use.

Interactions. CYP2C8 inhibitors (gemfibrozil) raise exposure. CYP2C8 inducers (rifampicin) lower exposure by about 20%. Antihypertensives and diuretics add hypotension. Anticoagulants and antiplatelets raise bleeding risk.

Common prescribing errors. Abrupt interruption. Mixing doses or units between routes. Dosing by actual rather than ideal body weight in obesity when programming the pump.

Special groups.

• Pregnancy: avoid unless needed; limited data. Breastfeeding: no data.

• Older adults: start at the lower end of the range.

• Kidney impairment: no adjustment. Liver impairment: reduce the starting dose.

• East Africa: subcutaneous treprostinil is the most practical parenteral option where central line care is unavailable. Supply and cost are the limiting factors.

Formulations. Injection 20 mg/20 mL (1 mg/mL), 50 mg/20 mL, 100 mg/20 mL, 200 mg/20 mL; inhalation solution 0.6 mg/mL and inhalation powder capsules; extended-release tablets 0.125, 0.25, 1 and 2.5 mg.

Administration. Subcutaneous: undiluted by a small infusion pump through a catheter, with the site changed every 3 days. Intravenous: diluted in sterile water or sodium chloride 0.9% through a central line. Inhaled: by a dedicated device. Oral: swallow whole with food.

Baseline. Blood pressure, right heart catheter results, functional class, 6 minute walk distance, NT-proBNP, liver function.

Monitoring. Infusion site, blood pressure, adverse effects at each titration step, clinical review every 3 to 6 months.

Stop and reduce rules. Reduce the dose or slow the titration for hypotension or intolerable adverse effects. Do not stop suddenly; wean slowly under specialist care. Therapeutic drug monitoring is not used.

Referral and escalation. Manage in a PAH centre. Refer for infusion interruption, worsening functional class or sepsis.