AURLUMYN

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION Initiate intravenous infusion at 0.5 ng/kg/minute and titrate in 0.5 ng/kg/minute increments based on tolerability at intervals of 30 minutes to a maximum of 2 ng/kg/minute ( 2.1 ). Administer as continuous infusion for 6 hours each day up to a maximum of 8 consecutive days ( 2.1 ). 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 ( 2.3 ). 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 ( 2.4 ). See Full Prescribing Information for instructions on preparation and administration ( 2.2 ). 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 Preparation: Use aseptic technique to prepare AURLUMYN. Inspect the vial for particulate matter prior to administration. Do not use if the solution is discolored or cloudy or if foreign particles are present. Dilution: AURLUMYN should only be diluted using 0.9% Sodium Chloride Injection, USP. Do not dilute or mix AURLUMYN with any other parenteral medications or solutions prior to or during administration. Withdraw 1 mL (100 mcg) of AURLUMYN solution from the vial and transfer into 100 mL of 0.9% Sodium Chloride Injection, USP polyvinyl chloride (PVC) infusion bag to make a final concentration of 1 mcg/mL (1,000 ng/mL). AURLUMYN can be added to commercially available infusion bags labeled to contain 100 mL of 0.9% Sodium Chloride Injection, USP. Gently mix the intravenous bag by slowly inverting the bag. Do not shake. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if visibly opaque particles, discoloration, or foreign particles are observed. Immediately use diluted AURLUMYN infusion solution. If not used immediately, the diluted solution can be stored at room temperature (20°C to 25°C [68°F to 77°F]) for up to 4 hours. Administration Administer AURLUMYN as an intravenous infusion through a peripheral line or peripherally inserted central catheter using an infusion pump. Use an infusion set with an in-line 0.22- or 0.2-micron filter. Once diluted, AURLUMYN should be administered with an infusion pump that can support the minimum and maximum flow rates. The infusion pump used to administer AURLUMYN should: (1) be able to deliver rates 0.1 to 99.9 mL per hour, (2) adjust infusions rates with increments of 0.1 mL per hour, (3) be accurate to within 5% of programmed rate, and (4) be positive pressure-driven (continuous or pulsatile). The reservoir and infusion line set should be made of polyvinyl chloride. Infusion rates may be calculated using the following formula: Infusion Rate (mL/hr) = [Dose (ng/kg/min) × Weight (kg) × 60 min/hr] Final Concentration (1,000 ng/mL) Avoid inadvertent administration of a bolus of the drug. Do not flush the catheter without withdrawing residual drug from the catheter system. Discard any unused portion. 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.

4 CONTRAINDICATIONS None. None ( 4 ).

5 WARNINGS AND PRECAUTIONS 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.

6 ADVERSE REACTIONS 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.

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).