Pre-marketing experiences

Pre-marketing safety data on Ventavis were obtained from 215 patients with pulmonary arterial hypertension receiving iloprost in two 12-week clinical trials and two long-term extensions. Patients received inhaled Ventavis for periods of from 1 day to more than 3 years. The median number of weeks of exposure was 15 weeks. Forty patients completed 12 months of open-label treatment with iloprost.

The following table shows adverse events reported by at least 4 iloprost patients and reported at least 3% more frequently for iloprost patients than placebo patients in the 12- week placebo-controlled study.

Table 3: Adverse Events in Phase 3 Clinical Trial

Pre-marketing serious adverse events reported with the use of inhaled iloprost and not shown in Table 3 include congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, peripheral edema, and kidney failure.

In a small clinical trial (the STEP trial, see Clinical Trials), safety trends in patients receiving concomitant bosentan and iloprost were consistent with those observed in the larger experience of the Phase 3 study in patients receiving only iloprost.

Adverse events with higher doses

In a study in healthy volunteers (n=160), inhaled doses of iloprost solution were given every 2 hours, beginning with 5 mcg and increasing up to 20 mcg for a total of 6 dose inhalations (total cumulative dose of 70 mcg) or up to the highest dose tolerated in a subgroup of 40 volunteers. There were 13 subjects (32%) who failed to reach the highest scheduled dose (20 mcg). Five were unable to increase the dose because of (mild to moderate) transient chest pain/discomfort/tightness, usually accompanied by headache, nausea, and dizziness. The remaining 8 subjects discontinued for other reasons.

Postmarketing Experience

The following adverse reactions have been identified during the postapproval use of Ventavis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cases of epistaxis and gingival bleeding have been reported within one month of starting iloprost treatment.

In studies in normal volunteers, there was no pharmacodynamic interaction between intravenous iloprost and either nifedipine, diltiazem, or captopril. However, iloprost has the potential to increase the hypotensive effect of vasodilators and antihypertensive agents. Since iloprost inhibits platelet function, there is a potential for increased risk of bleeding, particularly in patients maintained on anticoagulants. During clinical trials, iloprost was used concurrently with anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, analgesics, antipyretics, nonsteroidal anti-inflammatories, corticosteroids, and other medications. Intravenous infusion of iloprost had no effect on the pharmacokinetics of digoxin. Acetylsalicylic acid did not alter the clearance (pharmacokinetics) of iloprost. Although clinical studies have not been conducted, in vitro studies of iloprost indicate that no relevant inhibition of cytochrome P450 drug metabolism would be expected.

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