Jane S. Ricciuti, RPh, MS

Disclosures

February 07, 2005

In This Article

Pulmonary Agents

Manufacturer: CoTherix, Inc.

Drug Approval Classification: Original New Drug Application (Approval Date: 12/29/04)

Indication: Ventavis (iloprost) inhalation solution is indicated for the treatment of PAH (WHO Group I) in patients with New York Heart Association (NYHA) class III or IV symptoms. In controlled trials, it improved a composite endpoint consisting of exercise tolerance, symptoms (NYHA class), and lack of deterioration. Iloprost has not been adequately studied with concomitant use of other approved therapies for PAH.

Dosing: Iloprost is intended to be inhaled using the Prodose AAD System, a pulmonary drug delivery device. The first inhaled dose should be 2.5 mcg (as delivered at the mouthpiece). If this dose is well tolerated, dosing should be increased to 5 mcg and maintained at that dose. Iloprost should be taken 6 to 9 times per day (no more than every 2 hours) during waking hours, according to individual need and tolerability. The maximum daily dose evaluated in clinical studies was 45 mcg (5 mcg 9 times per day).

Clinical Summary: Iloprost is a synthetic analogue of prostacyclin PGI2. Iloprost dilates systemic and pulmonary arterial vascular beds. It also affects platelet aggregation, but the relevance of this effect to the treatment of pulmonary hypertension is unknown.

A randomized, double-blind, multicenter, placebo-controlled trial was conducted in 203 adult patients with NYHA class III or IV PAH or pulmonary hypertension related to chronic thromboembolic disease (WHO Group IV; 28%). Patients received 2.5 or 5.0 mcg of iloprost by repeated inhalations 6 to 9 times per day during waking hours. The mean age of the entire study population was 52 years, and 68% of the patients were female.

The primary efficacy endpoint was clinical response at 12 weeks, a composite endpoint defined by:

  • improvement in exercise capacity (6-minute walk test) by at least 10% vs baseline evaluated 30 minutes after dosing,

  • improvement by at least 1 NYHA class vs baseline, and

  • no death or deterioration of pulmonary hypertension.

The response rate for the primary efficacy endpoint among PAH patients was 19% for the iloprost group, compared with 4% for the placebo group ( P = .0033). All 3 components of the composite endpoint favored iloprost. The absolute change in 6-minute walk distance measured 30 minutes after inhalation among patients with PAH was greater in the iloprost group than in the placebo group at all time points. At Week 12, the placebo-corrected difference was 40 meters ( P < .01). When walk distance was measured immediately prior to inhalation, the improvement over placebo was approximately 60% of the effect seen at 30 minutes after inhalation.

Adverse Effects: Serious adverse events reported with the use of inhaled iloprost include congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, peripheral edema, and kidney failure.

Most common adverse events in the phase 3 clinical trial:

  • Increased cough: iloprost (39) and placebo (26)

  • Headache: iloprost (30) and placebo (20

  • Vasodilation: iloprost (27) and placebo (9)

Pharmacokinetics: Clearance in normal subjects was approximately 20 mL/min/kg. Iloprost is metabolized principally via beta-oxidation of the carboxyl side chain. In vitro studies reveal that cytochrome P450-dependent metabolism plays only a minor role in the biotransformation of iloprost.

Reference

Ventavis (iloprost) Inhalation Solution Labeling

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