Iloprost (Monograph)

Brand name: Ventavis
Drug class: Vasodilating Agents
VA class: HS875
Chemical name: (E)-(3aS,4R,5R,6aS)-hexahydro-5-hydroxy-4-[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-ynyl]-Δ2(1H),Δ-pentalenevaleric acid
Molecular formula: C₂₂H₃₂O₄
CAS number: 73873-87-7

Medically reviewed by Drugs.com on Jul 25, 2022. Written by ASHP.

Introduction

Vasodilator and platelet-aggregation inhibitor; a synthetic prostacyclin (PGI₂) analog.

Uses for Iloprost

Pulmonary Arterial Hypertension (PAH)

Management of PAH (WHO group 1 pulmonary hypertension) to improve a composite end point consisting of exercise tolerance, symptoms (NYHA/WHO functional class), and lack of clinical deterioration; has been designated an orphan drug by FDA for this use.

Efficacy established principally in patients with NYHA/WHO functional class III or IV PAH (idiopathic, heritable, or associated with connective tissue diseases).

Recommended as one of several treatment options for management of PAH in patients with NYHA/WHO functional class III or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy failed.

Individualize choice of PAH therapy; consider factors such as disease severity, route of administration, potential adverse effects, costs of treatment, clinician experience, and patient preference.

In patients with inadequate response to initial monotherapy, may consider combination therapy with an endothelin-receptor antagonist, phosphodiesterase (PDE) type 5 inhibitor, or soluble guanylate cyclase stimulator (added sequentially). Such combination therapy may provide additive and/or synergistic benefits by targeting different pathophysiologic pathways of the disease.

Iloprost Dosage and Administration

General

Restricted Distribution

• Iloprost and nebulizers available only through specialty pharmacies. Contact manufacturer at 866-228-3546 for specific information.

Administration

Oral Inhalation

For oral inhalation only. Do not ingest orally.

Administer using the I-neb AAD system ultrasonic nebulizer.

Each treatment session generally lasts 4–10 minutes. May interrupt treatment session for ≤10 minutes with no effect on dose administered. 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.

Patients should have immediate access to a back-up system in the event of equipment malfunction.

Patients should be trained in proper administration (including dosing frequency), manipulation of glass iloprost ampuls, and nebulizer operation/maintenance.

Do not admix iloprost with other orally inhaled drugs. Do not use nebulizer to administer any other drugs.

Do not allow solution to come in contact with the eyes or skin.

I-neb AAD System

Commercially available in 1-mL single-use ampuls containing 10 or 20 mcg/mL of iloprost.

The 20-mcg/ mL concentration is intended for patients who are receiving maintenance therapy with the 5-mcg dose and repeatedly experience long treatment times, which could occur if patient's inspiratory effort is insufficient to deliver full dose within approximately 10 minutes. Incomplete dosing could occur if patient discontinued inhalation session prematurely due to long treatment time. Transition to the 20-mcg/mL concentration will decrease time to deliver full treatment dose and help maintain compliance.

Use the manufacturer-supplied pipette to transfer the entire contents of one single-use ampul to the nebulizer drug chamber immediately prior to each inhalation session.

The 10-mcg/mL ampul delivers a dose of either 2.5 or 5 mcg to the mouthpiece, depending on the drug chamber selected by the clinician. Use the drug chamber with the red latch and the color-matched control disc to deliver a 2.5-mcg dose. Use the drug chamber with the purple latch and the color-matched control disc to deliver a 5-mcg dose.

The 20-mcg/mL ampul delivers a dose of 5 mcg; use the drug chamber with the gold latch and color-matched control disc to deliver this dose.

After each inhalation session, discard any remaining drug solution and clean the nebulizer. Review manufacturer’s information to ensure proper methods for cleaning, operation, and maintenance of the nebulizer.

Dosage

Monitor vital signs, especially BP, closely during initiation of iloprost. Do not initiate in patients with SBP <85 mm Hg.

Adults

PAH

Oral Inhalation

Initially, 2.5 mcg (as delivered at the mouthpiece of the nebulizer); if tolerated, increase the next dose (≥2 hours after initial dose) to 5 mcg and maintain dosage at that level.

Administer 6–9 times daily at minimum intervals of 2 hours while awake according to clinical response. Duration of acute benefits may be <2 hours.

Prescribing Limits

Adults

PAH

Oral Inhalation

Maximum dosage evaluated: 45 mcg daily (5 mcg 9 times daily).

Special Populations

Hepatic Impairment

Consider increasing dosing interval (e.g., to 3–4 hours between doses depending on patient's response at the end of each dosing interval) in patients with moderate to severe hepatic impairment (Child-Pugh class B or C). (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment not required in patients with renal impairment who do not require dialysis. (See Renal Impairment under Cautions.)

Geriatric Patients

Titrate dosage carefully. (See Geriatric Use under Cautions.)

Cautions for Iloprost

Contraindications

• No known contraindications.

Warnings/Precautions

Administration Precautions

For oral inhalation use only using the I-neb AAD system nebulizer.

Do not take inhalation solution orally or allow it to come in contact with skin or eyes.

Hypotensive Effects

Monitor vital signs during initiation of iloprost therapy. Take precautions to avoid additional decreases in BP in patients with low SBP.

Do not initiate in patients with SBP <85 mm Hg.

Be alert for the presence of underlying conditions or concomitant drugs that predispose to syncope. (See Specific Drugs under Interactions.)

In patients who develop exertional syncope during iloprost therapy, consider the need for adjustment of iloprost dosage or initiation of alternative therapy.

Risk of Pulmonary Edema

If signs of pulmonary edema occur, stop iloprost immediately, as these manifestations may indicate the presence of pulmonary venous hypertension.

Other Pulmonary Effects

Risk of bronchospasm; may be more severe or frequent in patients with history of hyperreactive airways.

Safety and efficacy not established in patients with COPD, severe asthma, or acute pulmonary infections.

Specific Populations

Pregnancy

Category C.

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in patients <18 years of age.

Geriatric Use

Studies did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Elimination of iloprost is reduced and/or systemic exposure is increased after oral or IV administration in patients with impaired hepatic function. Orally inhaled iloprost has not been evaluated in patients with hepatic impairment.

Renal Impairment

Systemic exposure is increased after IV administration in patients with severe renal impairment requiring intermittent dialysis. Orally inhaled iloprost has not been evaluated in patients with renal impairment, including those undergoing dialysis. (See Special Populations under Pharmacokinetics and see Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Cough, headache, vasodilation (flushing), influenza-like syndrome, nausea, trismus, hypotension, insomnia, syncope, vomiting, palpitations, back pain, increased alkaline phosphatase, increased γ-glutamyl transferase (γ-glutamyl transpeptidase, GGT, GGTP), muscle cramps, hemoptysis, tongue pain, pneumonia.

Interactions for Iloprost

Minimally metabolized by CYP isoenzymes. Does not inhibit CYP enzyme system. Pharmacokinetic interaction unlikely with drugs metabolized by CYP isoenzymes.

In clinical trials, iloprost was used concomitantly with anticoagulants, diuretics, cardiac glycosides, calcium-channel blocking agents, analgesics, antipyretics, NSAIAs, corticosteroids, and other drugs.

Specific Drugs

Iloprost Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability not determined.

Distribution

Extent

Generally not detectable in plasma 0.5–1 hour after inhalation.

Plasma Protein Binding

60% (mainly albumin).

Elimination

Metabolism

Undergoes β-oxidation of the carboxyl side chain. Main metabolite (tetranor-iloprost; pharmacologically inactive) found in urine in free and conjugated form. CYP isoenzymes play minor role in metabolism of iloprost.

Elimination Route

Following oral and IV administration, 81% of radiolabeled dose recovered in urine (68%) and feces (12%) within 14 hours.

Half-life

20–30 minutes.

Special Populations

In patients with hepatic impairment, elimination reduced and/or systemic exposure increased after oral or IV administration.

In patients with severe renal impairment, systemic exposure increased after IV administration in individuals requiring dialysis; AUC not substantially increased after IV administration in those not requiring dialysis.

Stability

Storage

Oral Inhalation

Inhalation Solution

20–25°C (may be exposed to 15–30°C).

Actions

• Pharmacologic actions (e.g., direct vasodilation of pulmonary and systemic arterial vascular beds, inhibition of platelet aggregation) similar to those of epoprostenol.

• Longer half-life and duration of pulmonary vasodilatory effect than epoprostenol; unlike epoprostenol, is stable in solution at neutral pH and at room temperature; therefore, can be administered by repeated oral inhalation rather than continuous IV infusion.

• Oral inhalation results in alveolar drug deposition and possibly greater selectivity for pulmonary vasculature.

• 4S isomer substantially more potent than 4R isomer.

Advice to Patients

• Importance of providing patient a copy of the manufacturer’s patient information and a copy of the user guide for the I-neb AAD system.

• Importance of patients receiving adequate training in the proper administration of iloprost (including dosing frequency), manipulation of ampuls of the drug, and operation and maintenance of the nebulizer.

• Importance of advising patients to use iloprost only as prescribed with the I-neb AAD system, in accordance with the manufacturer’s instructions.

• Importance of not changing the microprocessor disc or drug chamber in the nebulizer without consulting clinician.

• Importance of not mixing iloprost with other drugs and of not administering other drugs via the I-neb AAD system.

• Importance of having immediate access to a back-up I-neb AAD system in order to avoid potential interruptions in drug therapy secondary to equipment malfunction.

• Advise patients that the interval between inhalation sessions should be ≥2 hours and that the duration of acute benefits may be <2 hours.

• Advise patients that they may experience dizziness, lightheadedness, or fainting due to decreased BP; caution them to rise slowly after sitting or lying down.

• Advise patients to avoid driving or operating machinery if they experience dizziness or fainting and to consult their clinician about dosage adjustment if fainting persists or worsens.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and dietary and herbal supplements, as well as any concomitant illnesses (e.g., liver or kidney disease).

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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.

Available only through specialty pharmacies. (See Restricted Distribution under Dosage and Administration.)

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