By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The U.S. Food and Drug Administration (FDA) has approved iloprost for the treatment of severe frostbite to reduce the risk of amputation of fingers or toes. Iloprost, a synthetic analog of prostaglandin, initially was approved in 2004 for the treatment of pulmonary arterial hypertension. For that indication, it was given a priority review, accelerated approval, breakthrough therapy, and orphan drug designations.1 Iloprost for the frostbite indication is distributed by Eicos Sciences as Aurlumyn.
INDICATIONS
Iloprost is indicated for the treatment of severe frostbite in adults to reduce the risk of digit amputations.2 Effectiveness was established in young, healthy adults who experienced frostbite at high altitudes.
DOSAGE
The initial dose is an intravenous (IV) infusion at 0.5 ng/kg/minute and titrate in 0.5 ng/kg/min increments based on tolerability at intervals of 30 minutes to a maximum of 2 ng/kg/minute.2 The drug is administered as a continuous infusion for six hours each day up to a maximum of eight consecutive days. The dose should be reduced for patients with moderate or severe hepatic impairment or renal impairment (estimated glomerular filtration rate < 30 mL/min). Iloprost is available as 100 mg/mL in single-dose vials.
POTENTIAL ADVANTAGES
Iloprost is the first FDA approved treatment for frostbites to reduce the risk of digit amputations.
POTENTIAL DISADVANTAGES
Iloprost can cause symptomatic hypotension.2 Common adverse reactions include headache, flushing, palpitations/tachycardia, nausea, vomiting, dizziness, and hypotension.2
COMMENTS
The efficacy of iloprost was based on an open-label, randomized controlled trial in study participants with severe frostbite (n = 47).2,3 Severe frostbite was defined as having at least one digit (finger or toe) with frostbite stage 3 (lesion extending just past the proximal phalanx) or stage 4 (lesion extending proximal to the metacarpal or metatarsal joint). Subjects were young (mean age 33.1 years) with no notable medical or surgical history and frostbite occurring at high altitude (> 2,000 m). Seventy percent had frostbite of the feet, 62% the hands, and 32% had involvement of both feet and hands. After mountain rescue subjects were treated with rapid rewarming of the frostbite areas, 250 mg of aspirin and 400 mg of IV buflomedil (an alpha-adrenergic blocker not available in the United States). Then they were randomized to three groups: buflomedil (400 mg for one hour per day), iloprost (0.5 ng to 2 ng per kg/min for six hours/day), or iloprost plus recombinant tissue plasminogen (rtPA) (on day 1 only). All groups received aspirin 250 mg daily and duration of treatment was eight days. The efficacy endpoint was a bone scan using technetium 99m scintigraphy performed seven days after initial clinical presentation. The scan was correlated with final amputation requirement. Iloprost had the best outcome with 16 participants (142 digits) with frostbite and no predicted risk of amputation. Buflomedil had 15 participants with 106 digits with frostbite and 42 (39.6%) digits with predicted risk. Iloprost and recombinant tissue plasminogen activator (rtPA) had 16 participants with 159 digits with frostbite and 5 (3.1%) digits with predicted risk. Most patients had follow-up data and the need for amputation was consistent with the bone scan finding.1
CLINICAL IMPLICATIONS
Frostbite is a cold environment injury that occurs when tissues are exposed to temperatures below the freezing point (i.e., intracellular and extracellular ice crystal formation).4 This commonly affects upper and lower limbs and digits. Iloprost is a synthetic prostaglandin I2 that inhibits platelet aggregation and promotes vasodilation. Data on its effectiveness are limited to largely retrospective case analysis of young, healthy males engaging in high altitude or cold weather activities.4 Iloprost appears to be an effective treatment. The Wilderness Society frostbite guidelines (2019) suggest that iloprost should be considered first-line therapy for grade 3 and 4 frostbite < 72 hours after injury when tPA is contraindicated and in austere environments where tPA infusion is considered risky or evacuation to a treatment facility will be delayed.5 Expedition physicians should consider adding iloprost to their medical armamentarium.5 Cost for Aurlumyn was not available at the time of this review.
REFERENCES
- U.S. Food and Drug Administration. FDA news release. FDA approves first medication to treat severe frostbite. https://www.fda.gov/news-events/press-announcements/fda-approves-first-medication-treat-severe-frostbite
- Aurlumyn Prescribing Information. Eicos Sciences. February 2004. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217933s000lbl.pdf
- Cauchy E, Cheguillaume B, Chetaille E. A controlled trial of a prostacyclin and rt-PA in the treatment of severe frostbite. N Engl J Med 2011;364:189-190.
- Gauthier J, Morris-Janzen D, Poole A. Iloprost for the treatment of frostbite: A scoping review. Int J Circumpolar Health 2023;82:2189552.
- McIntosh SE, Freer L, Grissom CK, et al. Wilderness Medical Society clinical practice guidelines for the prevention and treatment of frostbite: 2019 update. https://journals.sagepub.com/doi/full/10.1016/j.wem.2019.05.002
