Iloprost

Iloprost
Names
Trade namesVentavis, Ilomedine, others
IUPAC name
  • 5-{(E)-(1S,5S,6R,7R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-inyl]-bicyclo[3.3.0]octan-3-ylidene}pentanoic acid
Clinical data
Drug classProstacyclin[1]
Main usespulmonary arterial hypertension (PAH), Raynaud's phenomenon, chronic limb ischemia, frost bite[1][2][3]
Side effectsHeadache, flushing, bleeding, chest pain, nausea, cough, swelling[4]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Routes of
use		Inhaled; Intravenous
External links
AHFS/Drugs.comMonograph
MedlinePlusa612032
Legal
License data
Legal status
  • US: ℞-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetics
BioavailabilityUnclear
Metabolismβ-oxidation
Elimination half-life20–30 minutes
Chemical and physical data
FormulaC22H32O4
Molar mass360.494 g·mol−1
3D model (JSmol)
SMILES
  • CC#CCC(C)[C@@H](/C=C/[C@H]1[C@@H](C[C@H]2[C@@H]1C/C(=C/CCCC(=O)O)/C2)O)O
InChI
  • InChI=1S/C22H32O4/c1-3-4-7-15(2)20(23)11-10-18-19-13-16(8-5-6-9-22(25)26)12-17(19)14-21(18)24/h8,10-11,15,17-21,23-24H,5-7,9,12-14H2,1-2H3,(H,25,26)/b11-10+,16-8+/t15?,17-,18+,19-,20+,21+/m0/s1 ☒N
  • Key:HIFJCPQKFCZDDL-ACWOEMLNSA-N ☒N

Iloprost, sold under the brand name Ventavis among others, is a medication used to treat pulmonary arterial hypertension (PAH), Raynaud's phenomenon, and chronic limb ischemia.[1][2] It may also be used for frostbite.[3] It may be used by breathing in or injection into a vein.[2]

Common side effects of the inhaled form include headache, flushing, bleeding, chest pain, nausea, cough, and swelling.[4] Other side effects may include low blood pressure and low platelets.[2] Safety in pregnancy is unclear, but benefits may justify its use.[5] It is a manufactured form of prostacyclin which results in blood vessels to dilate.[1][4]

Iloprost was approved for medical use in Europe in 2003 and the United States in 2004.[4][1] It is available as a generic medication.[2] In the United Kingdom 50 micrograms for injection cost the NHS about £60 while 10 micrograms to inhale costs about £10 as of 2021.[2] In the United States this amount of the inhaled form is about 140 USD per dose.[6]

Medical uses

Inhaled

In the U.S., iloprost is inhaled specifically using the I-Neb AAD or Prodose AAD delivery systems. In Europe iloprost has been approved for use with two compressed air nebulizers with AAD delivery systems (Halolite and Prodose) as well as with two ultrasonic nebulizers Ventaneb and I-Neb.

Ventavis is supplied in 1 mL single-use glass ampules containing either 10 μg/mL or 20 μg/mL. The 20 μg/mL concentration is intended for patients who are maintained at the 5 μg dose and who have repeatedly experienced extended treatment times which could result in incomplete dosing. Transitioning patients to the 20 μg/mL concentration using the I-neb AAD System will decrease treatment times to help maintain patient compliance.[7]

The approved dosing regimen for iloprost is 6 to 9 times daily (no more than every 2 hours) during waking hours, according to individual need and tolerability. The significant clinical effects observed in the pivotal study of patients with PAH were achieved with a median dose of 30 μg per day (range: 12.5 to 45 μg delivered at the mouthpiece), corresponding to 6 daily inhalations of 5 μg. The majority of patients (> 80%) in the pivotal study used this median dose or a higher dose with an excellent treatment compliance after 12 weeks.

The first inhaled dose of iloprost should be 2.5 μg (as delivered at the mouthpiece). If this dose is well tolerated, dosing should be increased to 5 μg and maintained at that dose. Any patient who cannot tolerate the 5 μg dose should be maintained at 2.5 μg.

Each inhalation treatment requires one entire single-use ampule. Each single-use ampule delivers a concentration of 10 μg/mL to the medication chamber of either the I-Neb AAD or Prodose AAD System, and delivers a nominal dose of either 2.5 μg or 5.0 μg to the mouthpiece. After each inhalation session, any solution remaining in the medication chamber should be discarded. Use of the remaining solution, even if the reservoir is "topped off" with fresh medication, will result in unpredictable dosing. Patients should follow the manufacturer's instructions for cleaning the I-Neb AAD or Prodose AAD System components after each dose administration.

Complete information regarding use of iloprost in specific populations (e.g. nursing mothers, pediatrics, patients with hepatic or renal impairment), drug interactions, and overdosage can be found in full prescribing information.

Intravenous

Vial and box of IV iloprost

Iloprost is also available in an intravenous form in some regions of the world.[8] It has been used for frostbite.[9] The intravenous form; however, is not available in the United States as of 2022.[9]

It is usually given diluted, via a peripheral vein or central venous catheter. The diluted iloprost should be delivered by an accurate rate delivery system such as a syringe driver. Doses vary with individuals as side effects are better tolerated by some than others. The duration of the treatment is typically 3 days. This is usually repeated every 8 to 12 weeks.[10]

By gradual injection it may be used at a dose of 0.5–2 nanograms/kg/minute.[2]

Contraindications

Unstable angina; within 6 months of myocardial infarction; decompensated cardiac failure (unless under close medical supervision); severe arrhythmias; congenital or acquired heart-valve defects; within 3 months of cerebrovascular events; pulmonary veno-occlusive disease; conditions which increase risk of bleeding.

Side effects

Common side effects due to inhaled iloprost included: vasodilation (flushing, 27%), cough (39%), headache (30%), flu syndrome (14%), nausea (13%), neck spasms (12%), hypotension (11%), insomnia (8%), and fainting (syncope) (8%); other serious adverse events reported with the use of Ventavis included congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, swelling of the limbs (especially around the ankles and feet), and kidney failure.

Serious side effects with the use of inhaled iloprost include congestive heart failure, chest pain, supraventricular tachycardia, shortness of breath, peripheral edema, and kidney failure.

  • Iloprost is intended for inhalation administration only via the I-Neb AAD or Prodose AAD Systems, pulmonary drug delivery devices. It has not been studied with any other nebulizers.
  • Vital signs should be monitored while initiating inhaled iloprost therapy. Dose adjustments or a change in therapy should be considered if exertional syncope occurs. Inhaled iloprost should not be initiated in patients with systolic blood pressure lower than 85 mm Hg. Iloprost should be stopped immediately if signs of pulmonary edema occur. This may be a sign of pulmonary venous hypertension. Iloprost has not been evaluated in patients with chronic obstructive pulmonary disease (COPD), severe asthma, or with acute pulmonary infections.
  • Should signs of pulmonary edema occur when inhaled iloprost is administered in patients with pulmonary hypertension, the treatment should be stopped immediately. This may be a sign of pulmonary venous hypertension.

Pharmacology

Iloprost is a synthetic analogue of prostacyclin PGI2. Iloprost dilates systemic and pulmonary arterial vascular beds. It also affects platelet aggregation but the relevance of this effect to the treatment of pulmonary hypertension is unknown. The two diastereoisomers of iloprost differ in their potency in dilating blood vessels, with the 4S isomer substantially more potent than the 4R isomer. While Iloprost is an analog of PGI2 that activates PGI2's receptor, the Prostacyclin receptor, to stimulate vasodilation, it has little selectivity in that it binds to and activates all four receptors for prostaglandin E2 viz., Prostaglandin EP1 receptor, Prostaglandin EP2 receptor, Prostaglandin EP3 receptor, and Prostaglandin EP4 receptor.[11] Activation of the EP2 and EP4 receptors cause vasodilation but activation of the EP3 receptor causes vasoconstriction.

References

  1. 1 2 3 4 5 "Iloprost Monograph for Professionals". Drugs.com. Archived from the original on 27 April 2021. Retrieved 25 November 2021.
  2. 1 2 3 4 5 6 7 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 200. ISBN 978-0857114105.
  3. 1 2 Kaller, M (October 2017). "BET 2: Treatment of frostbite with iloprost". Emergency medicine journal : EMJ. 34 (10): 689–690. doi:10.1136/emermed-2017-207129.2. PMID 28963381.
  4. 1 2 3 4 "Ventavis". Archived from the original on 12 November 2020. Retrieved 25 November 2021.
  5. ↑ "Iloprost (Ventavis) Use During Pregnancy". Drugs.com. Archived from the original on 30 November 2020. Retrieved 25 November 2021.
  6. ↑ "Ventavis Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 20 April 2021. Retrieved 25 November 2021.
  7. ↑ Ventavis Prescribing Information 2009 http://www.pahpathways.com/pdfs/ventavis_prescribing_info.pdf%5B%5D
  8. ↑ "BIJSLUITER: INFORMATIE VOOR DE GEBRUIK(ST)ER" (PDF). Retrieved 2009-02-05. (in Dutch)
  9. 1 2 Sheridan, RL; Goverman, JM; Walker, TG (9 June 2022). "Diagnosis and Treatment of Frostbite". The New England journal of medicine. 386 (23): 2213–2220. doi:10.1056/NEJMra1800868. PMID 35675178.
  10. ↑ "Iloprost Information" (PDF). Archived from the original (PDF) on 2016-04-06. Retrieved 2009-02-05.
  11. ↑ Moreno JJ (2017). "Eicosanoid receptors: Targets for the treatment of disrupted intestinal epithelial homeostasis". European Journal of Pharmacology. 796: 7–19. doi:10.1016/j.ejphar.2016.12.004. PMID 27940058. S2CID 1513449.
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