Iloprost

Class: Vasodilating Agents, Miscellaneous
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
Brands: Ventavis

Introduction

Vasodilator and platelet-aggregation inhibitor; a synthetic prostacyclin (PGI₂) analog.^{1 3 4 8 13}

Uses for Iloprost

Pulmonary Arterial Hypertension

Treatment of pulmonary arterial hypertension (PAH; WHO group 1 pulmonary hypertension) in patients with NYHA class III or IV symptoms;^{1 3 4 13 15 16} designated an orphan drug by FDA for this use.⁹

Efficacy based principally on composite assessment of exercise tolerance and NHYA class symptoms in the absence of clinical deterioration.^{1 4}

Additional studies needed to fully elucidate long-term safety and efficacy of iloprost alone or in conjunction with other therapies in the management of PAH.^{8 10 11 12 13}

Iloprost Dosage and Administration

General

• 
  

  Drug and nebulizers available through restricted distribution program; not available through community pharmacies.³ Contact manufacturer at 877-483-6828 for specific information.³

  
  

Administration

Oral Inhalation

For oral inhalation only.^{1 2} Do not ingest orally.¹

Administer using the Prodose AAD system jet nebulizer or the I-neb AAD system ultrasonic nebulizer.^{1 2 3 6 14} Safety and efficacy of administering iloprost via nebulizers other than the Prodose AAD or I-neb AAD system have not been established.¹

Each treatment session generally lasts 4–10 minutes.² May interrupt treatment session for ≤10 minutes with no effect on dose administered.² 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.²

Patients should have immediate access to a back-up system in the event of equipment malfunction.¹

Patients should be trained in proper administration (including dosing frequency), manipulation of glass iloprost ampuls, and nebulizer operation/maintenance.^{1 2 6}

Do not admix iloprost with other orally inhaled drugs.¹ Do not use nebulizer to administer any other drugs.²

Do not allow solution to come in contact with the eyes or skin.¹

Prodose AAD System

Use only the 20-mcg (2-mL) ampul of iloprost.^{1 2}

Use the manufacturer-supplied pipette to transfer the entire contents of one 20-mcg single-use ampul to the nebulizer drug chamber immediately prior to each inhalation session.^{1 2 6} The dose delivered to the mouthpiece (2.5 or 5 mcg) is determined by the microprocesser disc selected by the clinician.^{2 6 17}

After each inhalation session, discard any remaining drug solution and clean the nebulizer.^{1 2} Review manufacturer’s information to ensure proper methods for cleaning, operation, and maintenance of the nebulizer.^{1 6}

I-neb AAD System

May use either the 10-mcg (1-mL) ampul or the 20-mcg (2-mL) ampul of iloprost.¹

Use the manufacturer-supplied pipette to transfer the entire contents of one 10- or 20-mcg single-use ampul to the nebulizer drug chamber immediately prior to each inhalation session.^{1 2} Both ampuls deliver a dose of either 2.5 or 5 mcg to the mouthpiece, 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 2.5-mcg dose.² Use the drug chamber with the purple latch and the color-matched control disc to deliver a 5-mcg dose.²

After each inhalation session, discard any remaining drug solution and clean the nebulizer.^{1 2} Review manufacturer’s information to ensure proper methods for cleaning, operation, and maintenance of the nebulizer.¹

Dosage

Monitor vital signs, especially BP, closely during initiation of iloprost.^{1 3} Do not initiate in patients with SBP <85 mm Hg.^{1 3}

Adults

Pulmonary Arterial Hypertension

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.¹

Administer 6–9 times daily at minimum intervals of 2 hours while awake according to clinical response.¹ Duration of acute benefits may be <2 hours.¹

Prescribing Limits

Adults

Pulmonary Arterial Hypertension

Oral Inhalation

Maximum dosage evaluated: 45 mcg daily (5 mcg 9 times daily).¹

Special Populations

Hepatic Impairment

No specific dosage recommendations.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment not required in patients with renal impairment who do not require dialysis.¹ Caution advised in patients who require dialysis.¹ (See Renal Impairment under Cautions.)

Geriatric Patients

Titrate dosage carefully.¹ (See Geriatric Use under Cautions.)

Cautions for Iloprost

Contraindications

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  No known contraindications.^{1 3}

  
  

Warnings/Precautions

Warnings

Hypotensive Effects

Monitor vital signs during initiation of iloprost therapy.^{1 3} Take precautions to avoid additional decreases in BP in patients with low SBP.^{1 3}

Do not initiate in patients with SBP <85 mm Hg.^{1 3}

Be alert for the presence of underlying conditions or concomitant drugs that predispose to syncope.¹ (See Specific Drugs under Interactions.)

In patients who develop exertional syncope during iloprost therapy, consider the need for dosage adjustment of iloprost or initiation of alternative therapy.¹

Risk of Pulmonary Edema

If signs of pulmonary edema occur, stop iloprost immediately, as these manifestations may indicate the presence of pulmonary venous hypertension.¹

General Precautions

Other Pulmonary Disorders

Safety and efficacy not established in patients with COPD, severe asthma, or acute pulmonary infections.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether iloprost is distributed into milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 2 11}

Geriatric Use

Studies did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹ Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹ (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use caution in patients with moderate or severe (Child-Pugh class B or C) hepatic impairment.^{1 11}

Elimination of iloprost is reduced and/or systemic exposure is increased after oral or IV administration in patients with impaired hepatic function.^{1 11} Orally inhaled iloprost has not been evaluated in patients with hepatic impairment.^{1 11}

Renal Impairment

Systemic exposure is increased after IV administration in patients with severe renal impairment requiring intermittent dialysis.^{1 11} Orally inhaled iloprost has not been evaluated in patients with renal impairment, including those undergoing dialysis.^{1 11} Use caution in patients with severe renal impairment undergoing dialysis.¹ (See Special Populations under Pharmacokinetics and see Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Cough,^{1 4} headache,^{1 4} vasodilation (flushing),^{1 4} influenza-like syndrome,^{1 4} nausea,^{1 4} trismus,^{1 4} hypotension,^{1 4} insomnia,¹ syncope,^{1 4} vomiting,¹ palpitations,¹ back pain,¹ abnormal laboratory test,¹ increased alkaline phosphatase,¹ increased γ-glutamyl transferase (γ-glutamyl transpeptidase, GGT, GGTP),¹ muscle cramps,¹ hemoptysis,¹ tongue pain,¹ pneumonia.^{1 4}

Interactions for Iloprost

Minimally metabolized by CYP isoenzymes.¹ Does not inhibit CYP enzyme system.¹ Pharmacokinetic interaction unlikely with drugs metabolized by CYP isoenzymes.¹

In clinical trials, iloprost was used concomitantly with anticoagulants, diuretics, cardiac glycosides, calcium-channel blocking agents, analgesics, antipyretics, NSAIAs, corticosteroids, and other drugs.¹

Specific Drugs

Drug	Interaction
Anticoagulants	Increased bleeding risk1 11
Antihypertensive agents	Additive hypotensive effect1 11
Apirin	Pharmacokinetics of iloprost not affected by aspirin1
Bosentan	No increase in adverse effects observed with concomitant therapy1
Calcium-channel blocking agents	No pharmacodynamic interaction observed with diltiazem or nifedipine administered concomitantly with IV iloprost1 3
Captopril	No pharmacodynamic interaction observed in healthy individuals receiving IV iloprost and captopril1
Digoxin	No pharmacokinetic interaction observed in patients receiving IV iloprost and digoxin; pharmacokinetic interaction unlikely1 3 5 11
Vasodilating agents	Additive hypotensive effect1 11

Iloprost Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability has not been determined.¹

Distribution

Extent

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

Plasma Protein Binding

60% (mainly albumin).¹

Elimination

Metabolism

Undergoes β-oxidation of the carboxyl side chain.^{1 5} Main metabolite (tetranor-iloprost; pharmacologically inactive) found in urine in free and conjugated form.^{1 5} CYP isoenzymes play minor role in metabolism of iloprost.¹

Elimination Route

Following oral and IV administration, 81% of radiolabeled dose is recovered in urine (68%) and feces (12%) within 14 hours.¹

Half-life

20–30 minutes.¹

Special Populations

In patients with hepatic impairment, elimination is reduced and/or systemic exposure is increased after oral or IV administration.^{1 11}

In patients with severe renal impairment, systemic exposure is increased after IV administration in individuals requiring dialysis; AUC not substantially increased after IV administration in those not requiring dialysis.¹

Stability

Storage

Oral Inhalation

Inhalation Solution

20–25°C (may be exposed to 15–30°C).¹

ActionsActions

• 
  

  Pharmacologic actions (e.g., direct vasodilation of pulmonary and systemic arterial vascular beds, inhibition of platelet aggregation) similar to those of epoprostenol.^{1 3 5 8 10 11 12 13}

  
  


• 
  

  Has a longer half-life and duration of pulmonary vasodilatory effect than epoprostenol and, 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.^{1 4 5 8 10 11 12 13}

  
  


• 
  

  Oral inhalation results in alveolar drug deposition and possibly greater selectivity for pulmonary vasculature.^{5 8 10 11 12 13 16}

  
  


• 
  

  4S isomer is substantially more potent than the 4R isomer.¹

  
  

Advice to Patients

• 
  

  Importance of providing patient a copy of the manufacturer’s patient information and a copy of the user guide for the Prodose AAD system or the I-neb AAD system.^{1 2 3 6}

  
  


• 
  

  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.^{1 2 6}

  
  


• 
  

  Importance of advising patients to use iloprost only as prescribed with the Prodose AAD system or the I-neb AAD system, in accordance with the manufacturer’s instructions.^{1 2}

  
  


• 
  

  Importance of not changing the microprocessor disc or drug chamber in the nebulizer without consulting their clinician.^{1 2}

  
  


• 
  

  Importance of not mixing iloprost with other drugs and of not administering other drugs via the Prodose AAD or I-neb AAD system.^{1 2}

  
  


• 
  

  Importance of having immediate access to a back-up Prodose AAD or I-neb AAD system in order to avoid potential interruptions in drug therapy secondary to equipment malfunction.¹

  
  


• 
  

  Advise patients that the interval between inhalation sessions should be ≥2 hours and that the duration of acute benefits may be <2 hours.¹

  
  


• 
  

  Advise patients that they may experience dizziness, lightheadedness, or fainting due to decreased BP; caution them to rise slowly after sitting or lying down.^{1 2 3}

  
  


• 
  

  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.^{1 2 3}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 2}

  
  


• 
  

  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).^{1 2}

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Distribution of iloprost is restricted.³ (See General under Dosage and Administration.)

Iloprost

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral Inhalation Only	Solution, for nebulization	10 mcg/mL (10 mcg, 20 mcg)	Ventavis (with alcohol; preservative-free, available with Prodose AAD or I-neb AAD system)	CoTherix

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions May 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. CoTherix, Inc. Ventavis (iloprost) inhalation solution prescribing information. South San Francisco, CA; 2005 Oct.

2. CoTherix, Inc. Ventavis (iloprost) inhalation solution patient information. South San Francisco, CA; 2005 Sep.

3. CoTherix, Inc., South San Francisco, CA: Personal communication.

4. Olschewski H, Simonneau G, Galie N et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002; 347:322-9. [IDIS 484396] [PubMed 12151469]

5. Goldsmith DR, Wagstaff AJ. Inhaled iloprost in primary pulmonary hypertension. Drugs. 2004; 64:763-75. [PubMed 15025551]

6. Respironics New Jersey, Inc. Prodose AAD System user guide. Cedar Grove, NJ; 2004 Nov.

7. Simonneau G, Galie N, Rubin LJ et al . Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004; 43:5S-12S. [PubMed 15194173]

8. Badesch DB, McLaughlin VV, Delcroix M, et al. Prostanoid therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2004; 43:56S-61S. [IDIS 521449] [PubMed 15194179]

9. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97 414). Rockville, MD. From FDA website. Accessed 2005 Aug 10.

10. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004; 351:1425-36. [IDIS 521321] [PubMed 15459304]

11. Baker SE, Hockman RH. Inhaled iloprost in pulmonary arterial hypertension. Ann Pharmacother. 2005; 39:1265-74. [IDIS 535380] [PubMed 15976392]

12. Olschewski H, Rose F, Schermuly R et al. Prostacyclin and its analogues in the treatment of pulmonary hypertension. Pharmacol Ther. 2004; 102:139-53. [PubMed 15163595]

13. Hoeper MM. Drug treatment of pulmonary arterial hypertension: current and future agents. Drugs. 2005; 65:1337-54. [PubMed 15977967]

14. Profile Therapeutics plc. Prodose AAD System premarket notification. West Sussex, United Kingdom. From FDA website. Accessed 2005 Aug 30.

15. Rich S, Rubin LJ, Abenhaim L et al. Executive summary from the World Health Organization world symposium on primary pulmonary hypertension 1998. World Health Organization publication. Evian, France: 1998 Sep 6-10.

16. Paramothayan NS, Lasserson TJ, Wells AU et al. Prostacyclin for pulmonary hypertension in adults. Cochrane Database Syst Rev. 2005; 2:CD002994.pub2. [PubMed 15846646]

17. Respironics, Inc. I-neb AAD System premarket notification. Murrysville, PA. From FDA website. Accessed 2005 Oct 31.

18. McLaughlin VV, Oudiz R, Frost A et al. A randomized double-blind, placebo-controlled study of iloprost inahalation as add-on therapy to bosentan in pulmonary arterial hypertension (PAH).Chest.2005; 128(Suppl 4):S160.Abstract.

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