indication

For use as a continuous subcutaneous infusion or intravenous infusion (for those not able to tolerate a subcutaneous infusion) for the treatment of pulmonary arterial hypertension in patients with NYHA Class II-IV symptoms to diminish symptoms associated with exercise.

pharmacology

Pulmonary arterial hypertension (PAH) is a disease in which blood pressure is abnormally high in the arteries between the heart and lungs. PAH is characterized by symptoms of shortness of breath during physical exertion. The condition can ultimately lead to heart failure. Treprostinil is a potent oral antiplatelet agent. The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation. In animals, the vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume. Other studies have shown that treprostinil causes a dose-related negative inotropic and lusitropic effect. No major effects on cardiac conduction have been observed.

mechanism of action

The major pharmacological actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation. In addition to treprostinil's direct vasodilatory effects, it also inhibits inflammatory cytokine. As a synthetic analogue of prostacyclin, it binds to the prostacyclin receptor, which subsequently induces the aforementioned downstream effects.

toxicity

Symptoms of overdose are extensions of its dose-limiting pharmacologic effects and include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Most events were self-limiting and resolved with reduction or withholding of treprostinil.

biotransformation

Substantially metabolized by the liver, but the precise enzymes responsible are unknown. Five metabolites have been described (HU1 through HU5) however, the biological activity and metabolic fate of these are unknown. The chemical structure of HU1 is unknown. The metabolite HU5 is the glucuronide conjugate of treprostinil. The other metabolites are formed by oxidation of the 3-hydroxyoctyl side chain (HU2) and subsequent additional oxidation (HU3) or dehydration (HU4). Study results of in vitro human hepatic cytochrome P450 demonstrates that treprostinil does not inhibit CYP-1A2, 2C9, 2C19, 2D6, 2E1, or 3A. Whether treprostinil induces these enzymes has not been studied.

absorption

Relatively rapid and complete after subcutaneous infusion, with an absolute bioavailability approximately 100%. In patients with mild (n=4) or moderate (n=5) hepatic insufficiency and portopulmonary hypertension following a subcutaneous dose of 10 ng per kg of body weight per min for 150 mins the AUC 0-∞ was increased 3-fold and 5-fold respectively.

half life

Terminal elimination half-life is approximately 2 to 4 hours. Plasma half-life is 34 and 85 minutes for intravenous and subcutaneous infusion of the drug, respectively.

drug interactions

Abciximab: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Abciximab. Monitor for increased bleeding during concomitant thearpy.

Acebutolol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Acenocoumarol: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the anticoagulant, Acenocoumarol. Monitor for increased bleeding during concomitant thearpy.

Acetazolamide: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Acetylsalicylic acid: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Acetylsalicylic acid. Monitor for increased bleeding during concomitant thearpy.

Aliskiren: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Amiloride: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Aminosalicylic Acid: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the salicylate, Aminosalicylic acid. Monitor for increased bleeding during concomitant thearpy.

Amlodipine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Amyl Nitrite: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Anagrelide: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Anagrelide. Monitor for increased bleeding during concomitant thearpy.

Apraclonidine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Argatroban: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the anticoagulant, Argatroban. Monitor for increased bleeding during concomitant thearpy.

Atenolol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Benazepril: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Bendroflumethiazide: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Betaxolol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Bisoprolol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Bivalirudin: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the anticoagulant, Bivalirudin. Monitor for increased bleeding during concomitant thearpy.

Brimonidine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Bumetanide: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Candesartan: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Captopril: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Carteolol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Carvedilol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Celecoxib: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Celecoxib. Monitor for increased bleeding during concomitant thearpy.

Chlorothiazide: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Chlorthalidone: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Cilazapril: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Cilostazol: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Cilostazol. Monitor for increased bleeding during concomitant thearpy.

Citalopram: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Citalopram. Monitor for increased bleeding during concomitant thearpy.

Clonidine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Clopidogrel: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Clopidogrel. Monitor for increased bleeding during concomitant thearpy.

Cyclandelate: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Dexmedetomidine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Dichlorphenamide: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Diclofenac: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Diclofenac. Monitor for increased bleeding during concomitant thearpy.

Diflunisal: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Diflunisal. Monitor for increased bleeding during concomitant thearpy.

Diltiazem: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Dipyridamole: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Dipyridamole. Monitor for increased bleeding during concomitant thearpy. Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Doxazosin: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Drospirenone: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Drotrecogin alfa: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the anticoagulant, Drotrecogin alfa. Monitor for increased bleeding during concomitant thearpy.

Enalapril: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Enoxaparin: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the anticoagulant, Exoxaparin. Monitor for increased bleeding during concomitant thearpy.

Eplerenone: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Eprosartan: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Eptifibatide: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Eptifibatide. Monitor for increased bleeding during concomitant thearpy.

Escitalopram: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Escitalopram. Monitor for increased bleeding during concomitant thearpy.

Esmolol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Ethacrynic acid: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Etodolac: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Etodolac. Monitor for increased bleeding during concomitant thearpy.

Felodipine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Fenoprofen: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Fenoprofen. Monitor for increased bleeding during concomitant thearpy.

Fluoxetine: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Fluoxetine. Monitor for increased bleeding during concomitant thearpy.

Flurbiprofen: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Flurbiprofen. Monitor for increased bleeding during concomitant thearpy.

Fluvoxamine: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Fluvoxamine. Monitor for increased bleeding during concomitant thearpy.

Fosinopril: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Furosemide: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Guanabenz: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Guanfacine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Heparin: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the anticoagulant, Heparin. Monitor for increased bleeding during concomitant thearpy.

Hydralazine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Hydrochlorothiazide: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Hydroflumethiazide: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Ibuprofen: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Ibuprofen. Monitor for increased bleeding during concomitant thearpy.

Indapamide: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Indomethacin: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Indomethacin. Monitor for increased bleeding during concomitant thearpy.

Irbesartan: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Isosorbide Dinitrate: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Isosorbide Mononitrate: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Isradipine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Ketoprofen: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Ketoprofen. Monitor for increased bleeding during concomitant thearpy.

Ketorolac: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Ketorolac. Monitor for increased bleeding during concomitant thearpy.

Labetalol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Lepirudin: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the anticoagulant, Lepirudin. Monitor for increased bleeding during concomitant thearpy.

Levobunolol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Lisinopril: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Losartan: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Lumiracoxib: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Lumiracoxib. Monitor for increased bleeding during concomitant thearpy.

Mannitol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Meclofenamic acid: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Meclofenamate. Monitor for increased bleeding during concomitant thearpy.

Mefenamic acid: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Mefenamic acid. Monitor for increased bleeding during concomitant thearpy.

Meloxicam: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Meloxicam. Monitor for increased bleeding during concomitant thearpy.

Methazolamide: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Methyclothiazide: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Metipranolol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Metolazone: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Metoprolol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Minoxidil: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Moexipril: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Nabumetone: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Nabumetone. Monitor for increased bleeding during concomitant thearpy.

Nadolol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Naproxen: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Naproxen. Monitor for increased bleeding during concomitant thearpy.

Nebivolol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Nesiritide: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Nicardipine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Nifedipine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Nimodipine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Nisoldipine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Nitrendipine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Nitroglycerin: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Nitroprusside: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Olmesartan: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Oxaprozin: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Oxaprozin. Monitor for increased bleeding during concomitant thearpy.

Oxprenolol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Papaverine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Paroxetine: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Paroxetine. Monitor for increased bleeding during concomitant thearpy.

Penbutolol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Perindopril: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Phenoxybenzamine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Phentolamine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Pindolol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Piroxicam: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Piroxicam. Monitor for increased bleeding during concomitant thearpy.

Polythiazide: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Prazosin: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Quinapril: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Ramipril: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Reserpine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Rivaroxaban: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the anticoagulant, Rivaroxaban. Monitor for increased bleeding during concomitant thearpy.

Salsalate: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the salicylate, Salsalate. Monitor for increased bleeding during concomitant thearpy.

Sertraline: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Sertraline. Monitor for increased bleeding during concomitant thearpy.

Sotalol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Spironolactone: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Sulindac: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Sulindac. Monitor for increased bleeding during concomitant thearpy.

Telmisartan: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Terazosin: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Tiaprofenic acid: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Tiaprofenic acid. Monitor for increased bleeding during concomitant thearpy.

Ticlopidine: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Ticlopidine. Monitor for increased bleeding during concomitant thearpy.

Timolol: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Tirofiban: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Tirofiban. Monitor for increased bleeding during concomitant thearpy.

Tizanidine: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Tolazoline: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Tolmetin: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Tolmetin. Monitor for increased bleeding during concomitant thearpy.

Torasemide: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Trandolapril: The prostacyclin analogue, Treprostinil, may increase the hypotensive effect of Trandolapril.

Triamterene: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Trichlormethiazide: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Urea: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Valsartan: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Verapamil: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Warfarin: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the anticoagulant, Warfarin. Monitor for increased bleeding during concomitant thearpy.