1.1 Frostbite

AURLUMYN is indicated for the treatment of severe frostbite in adults to reduce the risk of digit amputations. Effectiveness was established in young, healthy adults who suffered frostbite at high altitudes.

2.1 Recommended Dosage

Monitor vital signs prior to the start of the infusion and with every dose increase.

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

Start the 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 according to tolerability up to 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 AURLUMYN 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 infusion is stopped at any point for a dose-limiting adverse event, 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.

2.2 Preparation and Administration

2.3 Use in Patients with Hepatic Impairment

Patients with moderate or severe hepatic impairment (Child-Pugh Class B or C): Initiate dosage at 0.25 ng/kg/minute for 30 minutes then continue titration in 0.5 ng/kg/minutes increments every 30 minutes according to tolerability to a maximum dose of 2 ng/kg/minute [see Use in Specific Populations ( 8.6)] .

2.4 Use in Patients with Renal Impairment

Patients with renal impairment with eGFR less than 30 mL/min: Initiate and titrate dosing per recommended dosage. If patient cannot tolerate the starting dose of 0.5 ng/kg/minute the dose can be lowered to 0.25 ng/kg/minute. The effect of dialysis on iloprost exposure 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.

5.1 Hypotension

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

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse events reported with the use of intravenous iloprost in patients with frostbite from the published literature include headache, flushing, palpitations/tachycardia, nausea, vomiting, dizziness, and hypotension.

Pre-marketing safety data on AURLUMYN were obtained from 116 patients with Systemic Sclerosis receiving iloprost in 2 multicenter, double-blind, randomized, placebo-controlled studies in patients with Systemic Sclerosis experiencing symptomatic digital ischemic episodes (Raynaud's Phenomenon). Patients received intravenous AURLUMYN administered as a continuous infusion over 6 hours each day for 5 consecutive days and the dose was adjusted according to individual tolerability within the range of 0.5 to 2.0 ng /kg /min. The observed safety profile in these patients was similar to that observed with IV iloprost.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and efficacy in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of iloprost did not include sufficient numbers of subjects aged 65 years 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.

8.6 Hepatic Impairment

In an intravenous 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 [see Dosage and Administration ( 2.3)].

8.7 Renal Impairment

In a study of intravenous infusion of iloprost on a dialysis-free day in adults with kidney failure receiving intermittent hemodialysis treatment (n = 7), the mean AUC 0-4hwas 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 AUC 0-4hwas 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 [see Dosage and Administration ( 2.4)].

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.

12.1 Mechanism of Action

Iloprost is a synthetic analog of prostacyclin PGI 2. Iloprost is a vasodilator and inhibits platelet aggregation.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Iloprost was not mutagenic in bacterial and mammalian cells in the presence or absence of extrinsic metabolic activation. Iloprost did not cause chromosomal aberrations in vitro in human lymphocytes and was not clastogenic in vivoin NMRI/SPF mice. There was no evidence of a tumorigenic effect of iloprost clathrate (13% iloprost by weight) in Sprague-Dawley rats dosed orally for up to 8 months at doses of up to 125 mg/kg/day (C maxof 45 ng/mL serum, 556 times the C maxat maximum recommended human dose), followed by 16 months at 100 mg/kg/day , or in Crl:CD-1 ®(ICR)BR albino mice dosed orally for up to 24 months at doses of up to 125 mg/kg/day (C maxof 156 ng/mL serum, 1926 times the Cmax at maximum recommended human dose). The recommended clinical dosage regimen for iloprost (2 ng/kg/min) affords a serum C maxof 0.081 ng/mL. Fertility of males or females was not impaired in Han-Wistar rats at intravenous doses up to 1 mg/kg/day, 225 times the maximum recommended daily dose of Iloprost on a mg/m 2basis.

14.1 Frostbite

The efficacy of intravenous (IV) iloprost for the treatment of severe frostbite to reduce the risk of digit amputations is derived from a published open-label, randomized controlled trial that enrolled patients with severe frostbite (Cauchy et al, 2011; Cheguillaume, 2011) 1. 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).

The trial randomized 47 patients at a single site between 1996 and 2008. At enrollment, all eligible patients (n=47) were treated with rapid rewarming of areas with frostbite, aspirin 250 mg IV, and buflomedil 400 mg IV and then randomized to Groups A, B or C. All patients continued to receive aspirin 250 mg IV daily up to 8 days. In addition, Group A (n=15) received buflomedil 400 mg IV for up to 8 days, Group B (n=16) received iloprost IV for 6 hours daily for up to 8 days, and Group C (n=16) received recombinant tissue plasminogen activator IV on Day 1 and iloprost IV for 6 hours daily for up to 8 days.

The mean age of the study population was 33 years (range: 18-55 years), 94% were men, 96% sustained frostbite during sports activities, 6% had history of smoking, and none had diabetes. At randomization, 70% of the patients had frostbite involving the feet, 62% had frostbite involving the hands, and 32% had frostbite involving both feet and hands.

The primary endpoint was the presence of an anomaly (absence of uptake) in the bone phase of technetium 99m scan performed 7 days after initial clinical presentation of frostbite (BS2 bone scintigraphy anomaly) in at least one finger/toe affected by severe frostbite. The BS2 bone scintigraphy anomaly is expected to predict risk of amputation.

On day 7, the presence of BS2 bone scintigraphy anomaly was observed in 60% (9/15), 0% (0/16) and 19% (3/16) of the patients in Groups A, B, and C, respectively. Compared to Group A, the presence of bone scintigraphy anomaly was significantly lower in Group B (p < 0.001) and Group C (p<0.03), favoring iloprost.

Additional follow-up data confirming amputation were obtained for 40/47 patients, which was concordant with the bone scintigraphy results.

1

Cauchy, E., et al. (2011). A controlled trial of a prostacyclin and rt-PA in the treatment of severe frostbite. N Engl J Med 364, 189-190; Cheguillaume, B. (2011). Controlled trial of iloprost and iloprost and rt-PA in the treatment of severe frostbite. Grenoble School of Medicine Thesis. HAL, https://dumas.ccsd.cnrs.fr/dumas-00618697.

Unopened vials of AURLUMYN are stable until the date indicated on the package when stored at 20°C to 25°C (68°F to 77°F), with excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

The unopened vial should be kept in the carton and not exposed to direct sunlight. Do not freeze.