Iloprost (Frostbite) (Monograph)

Drug class: Vasodilating Agents, Miscellaneous

Introduction

Iloprost is a synthetic analog of prostacyclin PGI₂.

Uses for Iloprost (Frostbite)

Iloprost has the following uses:

Iloprost injection is used IV for the treatment of severe frostbite in adults to reduce the risk of digit amputations.

Effectiveness of the drug was established in young, healthy adults who suffered frostbite at high altitudes.

Iloprost (Frostbite) Dosage and Administration

General

Iloprost is available in the following dosage form(s) and strength(s):

Injection: 100 mcg per mL in a single-dose vial

Dosage

Adults

Dosage and Administration

• Administer as a continuous IV infusion over 6 hours each day for up to a maximum of 8 consecutive days.

• Dilute the commercially available injection concentrate with 0.9% sodium chloride injection only prior to administration. See Full Prescribing Information for instructions on preparing the infusion.

• Start initial infusion on day 1 at a rate of 0.5 ng/kg/minute and increase in increments of 0.5 ng/kg/minute every 30 minutes based on tolerability up to a maximum of 2 ng/kg/minute. Dosage is based on actual patient body weight (kg). Repeat dose titration steps on day 2 and day 3. From day 4 onward, start the infusion at the highest tolerated dose from the previous day, and adjust the rate as needed, based on tolerability.

• Adverse reactions such as headache, flushing, jaw pain, myalgia, nausea, and vomiting may be dose-limiting. If dose-limiting adverse reactions occur that cannot be tolerated by the patient, then decrease the dose in a stepwise manner by 0.5 ng/kg/min every 30 minutes, until a tolerated dose is reached. If a dose-limiting adverse reaction occurs during administration of iloprost at the starting dose, the infusion should be discontinued, and re-initiation of the infusion can be attempted after the event has resolved or been treated. If the infusion is stopped at any point for a dose-limiting adverse event, the infusion can be reinitiated at a previously tolerated dose/infusion rate once the event has resolved. The maximum tolerated dose should be maintained for the remaining 6-hour daily infusion.

• Patients with moderate or severe hepatic impairment (Child-Pugh Class B or C): initiate infusion at 0.25 ng/kg/minute and titrate as described above.

• Patients with renal impairment with eGFR less than 30 mL/min: initiate infusion at 0.5 ng/kg/minute and titrate as described above. If the patient cannot tolerate the starting dose of 0.5 ng/kg/minute, the dose can be decreased to 0.25 ng/kg/minute.

Cautions for Iloprost (Frostbite)

Contraindications

None.

Warnings/Precautions

Hypotension

Iloprost is a systemic vasodilator and may cause symptomatic hypotension. Correct hypotension prior to administration of iloprost. Monitor vital signs while administering the drug. Consider temporary discontinuation of concomitant vasodilator or other antihypertensive medications while administering iloprost to reduce potential additive hypotensive effects. Consider down-titration or discontinuation of iloprost if hypotension persists despite discontinuation of other antihypertensives and fluid resuscitation.

Specific Populations

Pregnancy

There are no available data with iloprost injection during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are limited published cases of inhaled iloprost use during pregnancy, primarily during the second and third trimesters, that have not identified a drug-associated risk of adverse maternal or fetal outcomes. In animal reproductive studies, administration of continuous IV iloprost to pregnant Han-Wistar rats during organogenesis at doses 2-times the maximum recommended human dose on a mg/m² basis resulted in adverse developmental outcomes. However, there were no adverse developmental outcomes with oral or IV administration of iloprost to pregnant Sprague-Dawley rats, rabbits, and monkeys at doses 1111-, 1061-, and 12-times, respectively, the maximum recommended human dose by Cmax.

The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Lactation

There are no data on the presence of iloprost in human milk, the effects on the breastfed infant, or the effects on milk production. Iloprost is present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions, advise women not to breastfeed during treatment with iloprost.

Pediatric Use

Safety and efficacy in pediatric patients have not been established.

Geriatric Use

Clinical studies of iloprost did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently than younger subjects. Other reported clinical experience with iloprost has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

In an IV iloprost study in patients with liver cirrhosis, the mean clearance in Child-Pugh Class B subjects (n = 5) was approximately 10 mL/min/kg (half that of healthy subjects based on a cross study comparison). In patients with moderate or severe hepatic impairment (Child-Pugh Class B or C), use a lower starting dose of 0.25 ng/kg/minute.

Renal Impairment

In a study of IV infusion of iloprost on a dialysis-free day in adults with kidney failure receiving intermittent hemodialysis treatment (n = 7), the mean AUC0-4h was 230 pg*h/mL compared to 54 pg*h/mL in patients with kidney failure (n = 8) not requiring intermittent dialysis. The half-life was similar in both groups. The mean AUC0-4h was 48 pg*h/mL in normal subjects in a different study. In patients with renal impairment with eGFR less than 30 mL/min, the dose can be lowered to 0.25 ng/kg/minute if the patient cannot tolerate the starting dose of 0.5 ng/kg/minute.

The effect of dialysis on the clearance of iloprost has not been evaluated. For patients requiring intermittent hemodialysis, consider iloprost administration after the end of hemodialysis. Alternatively, hemodialysis can be started at least one hour after the end of iloprost infusion.

Common Adverse Effects

Most common adverse events of iloprost include headache, flushing, palpitations/tachycardia, nausea, vomiting, dizziness, and hypotension.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

IV infusion of iloprost had no effect on the pharmacokinetics of digoxin. Acetylsalicylic acid did not alter the clearance (pharmacokinetics) of iloprost.

Actions

Mechanism of Action

Iloprost is a synthetic analog of prostacyclin PGI₂. The drug is a vasodilator and inhibits platelet aggregation.

Advice to Patients

• Advise patients that they may have a fall in blood pressure with iloprost, so they may become dizzy during drug administration. They should stand up slowly when they get out of a chair or bed.

Additional Information

AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer'slabeling be consulted for more detailed information on usual uses,dosage and administration, cautions, precautions, contraindications,potential drug interactions, laboratory test interferences, and acutetoxicity.

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.

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