Iloprost is a

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...

used to treat pulmonary arterial hypertension (PAH),

scleroderma Scleroderma is a group of autoimmune diseases that may result in changes to the skin, blood vessels, muscles, and internal organs. The disease can be either localized to the skin or involve other organs, as well. Symptoms may include areas ...

Raynaud's phenomenon Raynaud syndrome, also known as Raynaud's phenomenon, eponymously named after the physician Auguste Gabriel Maurice Raynaud, who first described it in his doctoral thesis in 1862, is a medical condition in which the spasm of small arteries cau ...

and other diseases in which the blood vessels are constricted and blood cannot flow to the tissues. This damages the tissues and causes high blood pressure. There is ongoing research into using it as a

frostbite Frostbite is a skin injury that occurs when exposed to extreme low temperatures, causing the freezing of the skin or other tissues, commonly affecting the fingers, toes, nose, ears, cheeks and chin areas. Most often, frostbite occurs in the ha ...

treatment. Iloprost works by opening (dilating) the blood vessels to allow the blood to flow through again. It was developed by the

pharmaceutical company The pharmaceutical industry discovers, develops, produces, and markets drugs or pharmaceutical drugs for use as medications to be administered to patients (or self-administered), with the aim to cure them, vaccinate them, or alleviate sympto ...

Schering AG and is marketed by

Bayer Schering Pharma AG Bayer AG (, commonly pronounced ; ) is a German multinational pharmaceutical and biotechnology company and one of the largest pharmaceutical companies in the world. Headquartered in Leverkusen, Bayer's areas of business include pharmaceutica ...

in Europe and Actelion Pharmaceuticals in the USA. Iloprost is given via inhalation, and a therapeautic benefit of the drug is that a very low dose is required because of the deposition in the lung. Iloprost has few systemic side effects for that reason.

Clinical pharmacology

Iloprost is a synthetic analogue of

prostacyclin Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator. When used as a drug, it is also known as epoprosten ...

PGI₂. Iloprost dilates systemic and pulmonary arterial

vascular The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away f ...

beds. It also affects

platelet Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby i ...

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 4''S'' isomer substantially more potent than the 4''R'' 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 E2 receptor 2, also known as EP2, is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER2: it is one of four identified EP receptors, the others being EP1, EP3, and EP4, which bind with and mediate c ...

, prostaglandin EP3 receptor, and

prostaglandin EP4 receptor Prostaglandin E2 receptor 4 (EP4) is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the PTGER4 gene in humans; it is one of four identified EP receptors, the others being EP1, EP2, and EP3, all of which bind with and mediate cell ...

. Activation of the EP2 and EP4 receptors cause vasodilation but activation of the EP3 receptor causes vasoconstriction.

Dosage and administration

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. 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

Iloprost is also available in an intravenous form, developed and marketed by Schering AG under the trade name Ilomedine. (in Dutch) IV iloprost is usually administered 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 patients than others. The duration of the treatment is typically 3 days. This is usually repeated every 8 to 12 weeks.

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.

Common side effects

* In clinical studies, common adverse reactions due to inhaled iloprost included:

vasodilation Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstrictio ...

(flushing, 27%), cough (39%), headache (30%), flu syndrome (14%), nausea (13%), neck spasms (12%),

hypotension Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dia ...

(11%), insomnia (8%), and

fainting Syncope, commonly known as fainting, or passing out, is a loss of consciousness and muscle strength characterized by a fast onset, short duration, and spontaneous recovery. It is caused by a decrease in blood flow to the brain, typically from ...

(syncope) (8%); other serious adverse events reported with the use of Ventavis included

congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...

, chest pain, supraventricular

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ( ...

dyspnea Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...

, swelling of the limbs (especially around the ankles and feet), and

kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

. Serious adverse events reported with the use of inhaled iloprost include

, chest pain, supraventricular tachycardia,

shortness of breath Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...

peripheral edema Peripheral edema is edema (accumulation of fluid causing swelling) in tissues perfused by the peripheral vascular system, usually in the lower limbs. In the most dependent parts of the body (those hanging distally), it may be called dependent ede ...

, and kidney failure.

Warnings

* Iloprost as Ventavis 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 Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce ...

(COPD), severe

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...

, 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.

References

* Ventavis Package inser
prescribing information
available in PDF format. * * ATS 2005. The International Conference of the American Thoracic Society. 20–25 May 2005. San Diego, CA. *

External links

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