Iloprost, a synthetic analog of prostacyclin (PGI2), is a vasodilator and platelet-aggregation inhibitor.1, 4, 8, 13
Pulmonary Arterial Hypertension
Iloprost is used in the management of pulmonary arterial hypertension (PAH; World Health Organization [WHO] group 1 pulmonary hypertension) to improve a composite end point consisting of exercise tolerance, symptoms (based on New York Heart Association [NYHA]/WHO functional class), and lack of clinical deterioration.1, 4, 13, 16 Clinical studies establishing efficacy of the drug were conducted principally in patients with NYHA/WHO functional class III or IV PAH (idiopathic, heritable, or associated with connective tissue diseases).1, 4, 13, 16 Iloprost has been designated an orphan drug by FDA for use in the treatment of PAH.9
Efficacy of iloprost in the treatment of PAH has been established in a 12-week randomized, double-blind, multicenter, placebo-controlled trial in adults with certain forms of severe (NYHA functional class III or IV) pulmonary hypertension, including PAH (WHO group I pulmonary hypertension; 72% of patients, including 53% with idiopathic disease, 17% with PAH associated with connective tissue disease, and 2% with PAH associated with use of anorexigenic agents) and pulmonary hypertension secondary to chronic thromboembolic disease (WHO group 4 pulmonary hypertension; 28% of patients).1, 4, 7 Patients received orally inhaled iloprost (2.5 or 5 mcg 6-9 times daily during waking hours) titrated according to clinical response or placebo in addition to standard therapy (e.g., anticoagulants, cardiac glycosides, diuretics, and/or vasodilators [e.g., calcium-channel blocking agents] but not prostacyclin [epoprostenol], other prostacyclin analogs [e.g., treprostinil], or endothelin receptor antagonists [e.g., bosentan]).1, 4 Clinical response was evaluated using a composite clinical end point that consisted of improved exercise capacity (10% or greater increase in the distance walked in 6 minutes), symptomatic improvement by at least one NYHA class, and the absence of clinical deterioration (assessed using predefined criteria) or death.1, 4 Clinical deterioration was defined as the occurrence of 2 or more of the following end points: refractory systolic blood pressure of less than 85 mm Hg; worsening of right heart failure with cardiac edema, ascites, or pleural effusion despite adequate therapy; rapidly progressive cardiogenic hepatic failure (e.g., increases in serum AST or ALT to 100 U/L or greater, total bilirubin concentration of 5 mg/dL or greater); rapidly progressive cardiogenic renal failure (e.g., decrease of estimated creatinine clearance to 50% or less of baseline); decrease in 6-minute walking distance by 30% or more; new long-term need for IV catecholamines or diuretics; cardiac index of 1.3 L/minute per m2 or less; central venous pressure of 22 mm Hg or greater despite adequate diuretic therapy; and mixed venous oxygen saturation of 45% or less despite supplemental oxygen therapy.1, 4
The composite end point was achieved in 17 or 5% of patients receiving iloprost (median dosage: 30 mcg daily; range: 12.5-45 mcg daily) or placebo, respectively.1, 4 In the subgroup of patients with PAH, iloprost was associated with clinical improvement (composite end point achieved by 19 or 4% of patients with PAH receiving iloprost or placebo, respectively); however, there was inadequate evidence of clinical improvement with iloprost therapy in the subgroup of patients with pulmonary hypertension secondary to chronic thromboembolic disease.1 Among patients with PAH, when the 6-minute walking distance was measured 30 minutes after an inhalation session, the absolute change from baseline was greater in those receiving iloprost than in those receiving placebo.1, 4 When the test was performed immediately prior to an inhalation session, the improvement observed with iloprost relative to placebo was about 60% of that observed postinhalation.1, 4 Patients with pulmonary hypertension receiving iloprost experienced improvements in hemodynamic parameters (i.e., pulmonary vascular resistance, mean pulmonary arterial pressure, cardiac output, mixed venous oxygen saturation) compared with baseline; these improvements were greater when measured approximately 15 minutes after an inhalation session than when measured at least 2 hours after a previous inhalation session.1 However, the relationship between changes in hemodynamic parameters and clinical effects has not been determined.1
In a controlled clinical trial in a limited number of patients with PAH, the addition of orally inhaled iloprost (up to 5 mcg 6-9 times daily) to a stable regimen of oral bosentan (125 mg twice daily for at least 16 weeks) was tolerated; the safety profile of the combined regimen appeared to be consistent with that observed in other studies with iloprost alone.1, 18 However, results from randomized controlled trials evaluating efficacy of the addition of iloprost to bosentan are conflicting.18, 19
The efficacy of prostacyclin analogues was indirectly compared in a meta-analysis of 14 placebo-controlled studies that evaluated treprostinil (7 studies), epoprostenol (3 studies), iloprost (2 studies), and beraprost (2 studies).20 Among the 4 prostanoids, epoprostenol demonstrated improvement in functional class compared to the other regimens and treatment withdrawal was more likely with beraprost compared to iloprost.20
Current expert consensus guidelines recommend that all adult patients with symptomatic (World Health Organization [WHO] or New York Heart Association [NYHA] functional classification [FC] II-IV) pulmonary arterial hypertension (PAH) be treated with PAH-targeted medications (e.g., prostacyclin derivative [e.g., epoprostenol, treprostinil, iloprost], PDE type 5 inhibitor [i.e. sildenafil, tadalafil], endothelin receptor antagonist [e.g., ambrisentan, bosentan, macitentan], or a soluble guanylate cyclase stimulator [e.g., riociguat]) to reduce symptoms, improve functional capacity, and to delay progression of PAH, hospitalization, and death.700 Selection of drug therapy should be based on disease severity (WHO/NYHA class), risk of further short-term deterioration, comorbid illnesses, concomitant medications, expected tolerance of known side effects, route of administration (i.e., oral, parenteral, inhaled), costs of therapy, and patient preferences.700 In addition, patients with PAH should receive supportive care (e.g., oxygen, diuretics, anticoagulants).700
For treatment-naive PAH patients with WHO/NYHA FC II or III symptoms who are not candidates for, or who have failed calcium-channel blocking agent therapy, these experts recommend initial combination therapy with ambrisentan and tadalafil, but give this a weak recommendation based on moderate quality evidence; monotherapy with an endothelin-receptor antagonist (e.g., ambrisentan, bosentan, macitentan), phosphodiesterase type 5 inhibitor (e.g., sildenafil, tadalafil), or soluble guanylate cyclase stimulator (e.g., riociguat) can be initiated in patients who are intolerant to or unwilling to take combination treatment.700 Initial treatment with continuous IV epoprostenol, IV treprostinil, or subcutaneous treprostinil is recommended in patients with WHO/NYHA FC III who have evidence of rapid disease progression or poor prognosis; an inhaled or oral prostanoid is recommended in patients who are unwilling and not able to manage parenteral prostanoids.700 In patients with WHO FC III PAH who have evidence of disease progression and/or poor clinical prognosis despite treatment with one or two classes of oral agents, consideration should be given to the addition of a parenteral or inhaled prostanoid (e.g., IV epoprostenol, IV treprostinil, inhaled treprostinil, inhaled iloprost).700 For treatment-naive patients with WHO FC IV PAH who are unable or unwilling to manage parenteral prostanoid therapy, treatment with an inhaled prostanoid in combination with an oral phosphodiesterase type 5 inhibitor and an endothelin-receptor antagonist is recommended.700
Iloprost is administered by oral inhalation via the I-neb® AAD® nebulizer.1, 14 Each treatment session generally lasts 4-10 minutes.1 May interrupt treatment session for ≤10 minutes with no effect on dose administered.1 If interruption exceeds 10 minutes, system resets itself and patient should discard remaining solution in the nebulizer drug chamber and wait ≥2 hours for the next dose.1 To avoid potential interruptions in drug delivery secondary to equipment malfunction, patients should have immediate access to a back-up I-neb® AAD® system.1
Commercially available iloprost inhalation solution is available in 2 concentrations, either 10 or 20 mcg/mL in 1-mL single-use ampuls.1 The 20-mcg/mL concentration of iloprost is intended for patients who are receiving maintenance therapy with the 5-mcg dose and have repeatedly experienced long treatment times,1 which could occur if the patient's inspiratory effort is insufficient to allow delivery of the full dose within approximately 10 minutes; transition to the 20-mcg/mL concentration will decrease the time required to deliver the full treatment dose and help maintain compliance.1
Transfer the entire contents of one single-use 1-mL ampul containing 10 or 20 mcg of iloprost to the drug chamber of the nebulizer using the pipette supplied by the manufacturer immediately before each inhalation session.1 The 1-mL ampul containing 10 mcg/mL of iloprost will deliver a dose of either 2.5 or 5 mcg of the drug to the mouthpiece of the I-neb® AAD® system depending on the drug chamber selected by the clinician.1 Use the drug chamber with the red latch and the color-matched control disc to deliver a dose of 2.5 mcg to the mouthpiece.1 Use the drug chamber with the purple latch and the color-matched control disc to deliver a dose of 5 mcg to the mouthpiece.1 The 1-mL ampul containing 20 mcg/mL of iloprost will deliver a dose of 5 mcg of drug to the mouthpiece of the I-neb® AAD® system; use the drug chamber with the gold latch and color-matched control disc to deliver this dose.1 One single-use ampul is required for each inhalation session.1
Iloprost should not be admixed with other orally inhaled drugs, nor should other drugs be administered via the I-neb® AAD® system.1
After each inhalation session, discard any drug solution remaining in the drug chamber of the I-neb® AAD® system and clean the nebulizer in accordance with the manufacturer's instructions.1, 6 Do not allow solution to come in contact with the eyes or skin.1 Consult the manufacturer's labeling for proper methods of administration and associated precautions;1 ensure patients are trained in proper administration techniques (including dosing frequency), manipulation of glass ampuls of iloprost, and operation and maintenance of the nebulizer.1, 6
Store at 20-25°C (excursions permitted between 15-30°C).1
Pulmonary Arterial Hypertension
For the management of pulmonary arterial hypertension (PAH) in adults, the recommended initial dose of iloprost is 2.5 mcg (as delivered at the mouthpiece of the I-neb® AAD® system).1 If this initial dose is tolerated, the next scheduled dose (at least 2 hours after the initial dose) should be increased to 5 mcg and dosage should be maintained at that level.1 Iloprost should be administered 6-9 times daily at minimum intervals of 2 hours during waking hours according to clinical response.1 The maximum dosage of iloprost evaluated in clinical studies was 45 mcg daily (5 mcg 9 times daily).1
Advise patients that the interval between inhalation sessions should be at least 2 hours and that the duration of acute benefits may be less than 2 hours.1
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1 The effect of dialysis on elimination of iloprost has not been determined.1
Initial dosage in geriatric patients should be selected with caution (usually at the low end of the dosage range) and titrated carefully because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1
Monitor vital signs during initiation of iloprost therapy.1 Do not initiate the drug in patients with systolic blood pressure less than 85 mm Hg.1
Evaluate patients for the presence of underlying conditions or concomitant drugs that may predispose to syncope.1 In patients who develop exertional syncope during iloprost therapy, consider the need for adjustment of iloprost dosage or initiation of alternative therapy.1
If signs of pulmonary edema occur, stop iloprost, as this may indicate the presence of pulmonary venous hypertension.1
Bronchospasm can occur with iloprost inhalation; such effects were more frequent and severe in patients with a history of hyperreactive airways.1 Safety and efficacy of iloprost have not been established in patients with chronic obstructive pulmonary disease (COPD), severe asthma, or acute pulmonary infections.1
A drug-associated risk of adverse maternal or fetal outcomes has not been demonstrated in limited case reports and case series of iloprost.1 Available animal data are conflicting.1 Untreated pulmonary arterial hypertension (PAH) in pregnancy increases the risk for maternal heart failure, stroke and death, miscarriage, preterm delivery, low birthweight infants, and stillbirth.1
Iloprost is distributed into milk in rats; it is not known whether the drug is distributed into human milk.1 When a drug is present in animal milk, it is likely the drug will be present in human milk.1 Because of the potential for severe adverse effects in nursing infants, advise women not to breastfeed during treatment.1
Safety and efficacy of iloprost have not been established in pediatric patients.1, 11
Clinical studies of iloprost did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.1 In general, dosage should be titrated carefully in geriatric patients.1 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly should be considered.1
Elimination of iloprost is reduced and/or systemic exposure is increased (without affecting half-life) after oral or IV administration in patients with impaired hepatic function.1, 11 Safety and efficacy of orally inhaled iloprost have not been established in patients with hepatic impairment.1
Exposure to iloprost was substantially increased after IV administration in patients with end-stage renal impairment requiring intermittent dialysis compared with that in patients with renal failure not requiring dialysis or in healthy individuals.1 Safety and efficacy of orally inhaled iloprost have not been established in patients with renal impairment, including those undergoing dialysis.1, 11
Adverse effects reported at least 3% more frequently with iloprost than with placebo include vasodilation (flushing), cough, headache, trismus, insomnia, nausea, hypotension, vomiting, increased alkaline phosphatase, flu syndrome, back pain, tongue pain, palpitations, syncope, increased γ-glutamyl transferase (GGT), muscle cramps, hemoptysis, and pneumonia.1
Iloprost is metabolized principally via β-oxidation of the carboxyl side chain.1 Its metabolite, tetranor-iloprost, is considered to be inactive.1 Metabolism via cytochrome P-450 (CYP) isoenzymes is minor.1
During clinical trials, iloprost was used concomitantly with anticoagulants, diuretics, cardiac glycosides, calcium-channel blocking agents, analgesics, antipyretics, nonsteroidal anti-inflammatory agents, corticosteroids, and other drugs.1
Potential pharmacologic interaction (increased risk of bleeding due to inhibition of platelet function by iloprost).1, 11
Potential pharmacologic interaction (additive hypotensive effect).1, 11
Pharmacokinetics of iloprost were not affected by concomitant aspirin.1
No increase in adverse effects observed in patients receiving inhaled iloprost and oral bosentan.1
Calcium-channel Blocking Agents
No pharmacodynamic interaction observed in healthy individuals receiving IV iloprost and diltiazem or nifedipine.1
No pharmacodynamic interaction observed in healthy individuals receiving IV iloprost and captopril.1
No pharmacokinetic interaction observed in patients receiving IV iloprost and digoxin.1, 11 Pharmacokinetic interaction unlikely.1, 5, 11
Potential pharmacologic interaction (additive hypotensive effect).1, 11
Iloprost, a synthetic analog of prostacyclin, has pharmacologic actions (e.g., vasodilation of pulmonary and systemic arterial vascular beds, inhibition of platelet aggregation) similar to those of epoprostenol.1, 5, 8, 10, 11, 12, 13 Unlike epoprostenol, iloprost is chemically stable in solution at neutral pH and at room temperature, and iloprost has a longer half-life (20-30 minutes) and duration of pulmonary vasodilatory effect than epoprostenol; therefore, iloprost may be administered by repeated oral inhalation rather than continuous IV infusion, as is required for epoprostenol.1, 4, 5, 8, 10, 11, 12, 13 Oral inhalation of iloprost results in alveolar drug deposition and possibly greater selectivity for the pulmonary vasculature, potentially resulting in fewer adverse systemic effects (e.g., systemic hypotension).5, 8, 10, 11, 12, 13, 16
Based on results of in vitro studies, iloprost does not appear to inhibit cytochrome P-450 (CYP) isoenzymes, and CYP isoenzymes play only a minor role in the metabolism of iloprost.1 Iloprost is metabolized principally via β-oxidation of the carboxyl side chain and is eliminated principally in urine as tetranor-iloprost and its conjugates.1, 5 Following oral or IV administration of radiolabeled iloprost in healthy individuals, about 68 and 12% of the total radioactivity was recovered in urine and feces, respectively, over 14 hours.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Iloprost oral inhalation solution (Ventavis®) and the I-neb® Adaptive Aerosol Delivery [AAD®] system are available only through specialty pharmacies ([Web]).41
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral Inhalation | Solution, for nebulization | 10 mcg/mL (10 mcg) | Ventavis® (available with I-neb® AAD® system) | |
20 mcg/mL (20 mcg) | Ventavis® (available with I-neb® AAD® system) | Actelion |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions May 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Actelion. Ventavis® (iloprost) inhalation solution prescribing information. Titusville, NK; 2022 Mar.
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18. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006 1;174(11):1257-63.
19. Hoeper MM, Leuchte H, Halank M, et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2006;28(4):691-4.
20. Zhang H, Li X, Huang J, Li H, Su Z, Wang J. Comparative Efficacy and Safety of Prostacyclin Analogs for Pulmonary Arterial Hypertension: A Network Meta-Analysis. Medicine (Baltimore). 2016;95(4):e2575.
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25. Zhu B, Wang L, Sun L et al. Combination therapy improves exercise capacity and reduces risk of clinical worsening in patients with pulmonary arterial hypertension: a meta-analysis. J Cardiovasc Pharmacol . 2012; 60:342-6. [PubMed 22691882]
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42. Actelion, South San Francisco, CA: Personal communication.
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