First inhaled prostacyclin for pulmonary hypertension

February 21, 2005

Pulmonary arterial hypertension (PAH) affects roughly 50,000 people in the United States, yet only about 15,000 patients have been diagnosed and are receiving an approved treatment. The median survival time for patients left untreated following diagnosis may be as short as three years.

The Food & Drug Administration has approved the first inhaled prostacyclin for the treatment of PAH. Iloprost (Ventavis, CoTherix) inhalation solution is indicated for the treatment of PAH (World Health Organization Group I) in patients with New York Heart Association Class III or Class IV symptoms.

Iloprost is intended for inhalation administration only, via the Prodose AAD System, a nebulizer developed by Profile Therapeutics. CoTherix plans to launch iloprost in the second quarter of 2005, and CoTherix and Profile plan to launch a handheld, battery-operated nebulizer for iloprost in the fourth quarter of this year.

Iloprost is a synthetic analog of prostacyclin PGI2, said Lewis Rubin, M.D., a professor of medicine and director of the Pulmonary Hypertension Program at the University of California in San Diego. Invasive prostacyclin therapies such as epoprostenol (Flolan, GlaxoSmithKline) must be given continuously by intravenous infusion, he said. The concept behind iloprost, Rubin explained, is to deliver a longer-acting prostacyclin directly to the lung by nebulization.

Iloprost must be inhaled six to nine times per day, said Ronald DeBellis, Pharm.D., an associate professor of pharmacy practice at the Massachusetts College of Pharmacy and Health Sciences in Worcester. CoTherix is developing an extended-release formulation of iloprost, with the goal of reducing the daily number of inhalations.

The package insert contains a detailed diagram showing the proper use of the Prodose AAD system, DeBellis noted. "I think it is incredibly important for the pharmacist to teach patients how to use their nebulizer properly."

CoTherix plans to position iloprost as a complementary product to oral therapies such as bosentan (Tracleer, Actelion). DeBellis mentioned that a trial of bosentan and iloprost combined is ongoing. If an additive effect from combining these two medications is observed, it would be very helpful, he said.

The company recommends that the first inhaled dose of iloprost be 2.5 mcg. If this dose is well tolerated, dosing should be increased to 5 mcg and maintained at that dose. CoTherix advised that iloprost should be taken six to nine times per day, at intervals of not less than two hours.

The manufacturer said that each inhalation treatment requires one single-use ampule. Each ampule delivers 20 mcg/2 mL to the medication chamber of the nebulizer, and delivers a nominal dose of either 2.5 mcg or 5 mcg to the mouthpiece.

The company said caution should be exercised during iloprost therapy in those with at least Child Pugh Class B hepatic impairment. Dose adjustment is not required in those on dialysis. However, use caution in patients on dialysis, as the effect of dialysis on iloprost is unknown.

The safety and efficacy of iloprost in pediatric patients have not been established. The company warned that the direct mixing of iloprost with other medications in the nebulizer has not been evaluated.

Iloprost is fairly well tolerated, Rubin said. He mentioned that the most common adverse effects associated with iloprost administration during clinical trials included flushing of the face caused by blood vessel dilatation, increased cough, hypotension, headaches, nausea, spasm of the jaw muscles, and fainting (syncope).

"Making therapy easier to administer is critical to enhancing patient compliance and improving the management of PAH," Rubin concluded.