Jane S. Ricciuti, RPh, MS

Disclosures

September 20, 2002

In This Article

Cardiovascular Agents

Remodulin
(treprostinil sodium) Injection

Manufacturer: United Therapeutics

Drug Approval Classification: Original New Drug Application (Approval Date: 5/21/02)

Indication: Remodulin is indicated as a continuous subcutaneous infusion for the treatment of pulmonary arterial hypertension in patients with New York Heart Association (NYHA) Class II-IV symptoms to diminish symptoms associated with exercise.

Dosing: Remodulin is administered by continuous subcutaneous infusion. The infusion rate is initiated at 1.25 ng/kg/min. If this initial dose cannot be tolerated, the infusion rate should be reduced to 0.625 ng/kg/min. The infusion rate should be increased in increments of no more than 1.25 ng/kg/min per week for the first 4 weeks and then no more than 2.5 ng/kg/min per week for the remaining duration of infusion, depending on clinical response. There is little experience with doses > 40 ng/kg/min. Abrupt cessation of infusion should be avoided.

Clinical Summary: Two pivotal trials that were submitted with Remodulin's New Drug Application were 12-week international multicenter, double-blind, randomized, parallel placebo-controlled comparisons of the safety and efficacy of subcutaneous treprostinil sodium plus conventional therapy to conventional therapy in patients with pulmonary hypertension. In both trials, a total of 470 patients with pulmonary hypertension of diverse etiology were randomized.

The change in 6-minute walking distance was the primary end point to demonstrate exercise capacity. The median change from baseline was 10 meters for Remodulin-treated patients vs 0 meters for the placebo group. Other end points demonstrated improvement in dyspnea score, fatigue, and signs and symptoms of pulmonary hypertension.

Adverse Effects: Adverse effects reported with Remodulin included infusion- site pain (85%) and infusion-site reaction (83%). Other, less common adverse events included headache (27%), diarrhea (25%), nausea (22%), rash (14%), jaw pain (13%), vasodilatation (11%), dizziness (9%), edema (9%), pruritus (8%), and hypotension (4%).

Pharmacokinetics: There are 3 relevant pharmacodynamic effects for Remodulin:

Inhibition of platelet activation,

  • Vasorelaxation, and

  • Inhibition of smooth muscle cell proliferation.

  • Remodulin is metabolized in the liver with < 4% excreted unchanged in the urine. Five metabolites (of unknown activity) are formed. The metabolic pathways used have not been identified. Remodulin is rapidly cleared, with a half-life of 2-4 hours. The primary route of elimination is urine (79%). There appears to be no significant inhibition of P450 isozymes. Hepatic impairment significantly increased both the Cmax and the AUC.

    Remodulin (treprostinil) Labeling

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