Iloprost

AURLUMYN is a prostacyclin mimetic 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 ( 1.1 ).

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.

Injection: 100 mcg per mL iloprost as a clear and colorless solution in a single-dose vial. Injection: 100 mcg per mL in a single dose vial ( 3 ).

None. None ( 4 ).

AURLUMYN may cause symptomatic hypotension. Monitor vital signs while initiating AURLUMYN. Correct hypotension prior to administration of AURLUMYN ( 5.1 ).

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.

Most common adverse events include headache, flushing, palpitations/tachycardia, nausea, vomiting, dizziness, and hypotension (6.1). To report SUSPECTED ADVERSE REACTIONS, contact BTG International, Inc. at 1-877-377-3748 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

Lactation: Advise not to breastfeed ( 8.2 ).

8.1 Pregnancy Risk Summary There are no available data with AURLUMYN 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 intravenous iloprost to pregnant Han-Wistar rats during organogenesis at doses 2-times the maximum recommended human dose on a mg/m 2 basis resulted in adverse developmental outcomes. However, there were no adverse developmental outcomes with oral or intravenous 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 ( see Data ). 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. Data Animal Data In developmental toxicity studies in pregnant Han-Wistar rats, continuous intravenous administration of iloprost at a dosage of 0.01 mg/kg daily (2 times the maximum recommended human dose on a mg/m 2 basis, serum levels not available) led to shortened digits of the thoracic extremity in fetuses and pups. In similar studies in pregnant Sprague-Dawley rats that received iloprost clathrate (13% iloprost by weight) orally at dosages of up to 50 mg/kg/day (C max of 90 ng/mL), in pregnant rabbits at intravenous dosages of up to 0.5 mg/kg/day (C max of 86 ng/mL), and in pregnant monkeys at dosages of up to 0.04 mg/kg/day (serum levels of 1 ng/mL), at 1111-, 1062- and 12-times, respectively, the maximum recommended human dose by Cmax, no such digital anomalies or other gross-structural abnormalities were observed in the fetuses/pups. However, in gravid Sprague-Dawley rats, iloprost clathrate (13% iloprost) significantly increased the number of non-viable fetuses at a maternally toxic oral dosage of 250 mg/kg/day (729 times the maximum recommended human dose on a mg/m 2 basis) and in Han-Wistar rats was found to be embryolethal in 15 of 44 litters at an intravenous dosage of 1 mg/kg/day (225 times the maximum recommended human dose on a mg/m 2 basis).

8.2 Lactation Risk Summary 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 ( see Data ). 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 [see Warnings and Precautions ( 5 ) and Adverse Reactions ( 6 )] . Data In studies with Han-Wistar rats, higher mortality was observed in pups of lactating dams receiving iloprost intravenously at 1 mg/kg daily (at 225 times the maximum recommended human dose on a mg/m 2 basis). In Sprague-Dawley rats, higher mortality was also observed in nursing pups at a maternally toxic oral dose of 250 mg/kg/day of iloprost clathrate (13% iloprost by weight) (729 times the maximum recommended human dose on a mg/m 2 basis). In rats, a passage of low levels of iloprost or metabolites into the milk was observed (less than 1% of iloprost dose given intravenously). No disturbance of post-natal development and reproductive performance was seen in animals exposed during 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 0-4h 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 AUC 0-4h 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 [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.

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