VENTAVIS

contains iloprost, a synthetic analog of prostacyclin PGI 2.

The chemical name for iloprost is (5 E )-[3a S,4 R,5 R,6a S )-5-hydroxy-4-[(1 E )-(3 S,4 RS )-3-hydroxy-4-methyloct-1-en-6-ynyl]-hexahydropentalen-2(1 H )-ylidene]pentanoic acid.

Iloprost consists of a mixture of the 4R and 4S diastereoisomers at a ratio of approximately 53:47.

Iloprost is an oily substance, which is soluble in methanol, ethanol, ethyl acetate, acetone, and pH 7 buffer, sparingly soluble in buffer pH 9, and very slightly soluble in distilled water, buffer pH 3, and buffer pH 5.

The molecular formula of iloprost is

C 22 H 32 O and its molecular weight is 360.49.

The structural formula is shown below

AURLUMYN (iloprost) injection is a clear, colorless, sterile solution formulated for intravenous use.

AURLUMYN is supplied in single-use glass vials containing 1-mL per vial.

Each mL of the solution contains 100 mcg (0.1 mg) of iloprost as the active ingredient and the following inactive ingredients: 8.1 mg ethanol, 9 mg sodium chloride, and 0.242 mg tromethamine.

Hydrochloric acid and sodium hydroxide is added to adjust pH to 8.3.

The solution contains no preservatives.

It is used to treat high pulmonary pressure, reduce symptoms and improve patient ability to exercise.

Tell your doctor before you use the treatment if you suffer from liver, kidney, heart, low blood pressure, asthma, colds with cough or chronic pulmonary blockage.

The treatment may affect your emotions and thinking.

Use the treatment during pregnancy and breastfeeding only after consulting your doctor to discuss the benefits and the damage that it may cause.

Avoiding the arrival of the medicine to the eye, mouth, or skin, avoid standing up immediately after waking up, because it may cause the rotor, especially in pregnant women and children.

Mechanism of Action Iloprost is a synthetic analog of prostacyclin PGI 2.

Iloprost is a vasodilator and inhibits platelet aggregation. 12.3 Pharmacokinetics General Iloprost administered intravenously has linear pharmacokinetics over the dose range of to 3 ng/kg/min. The half-life of iloprost is to 30 minutes.

Following intravenous infusion, the apparent steady-state volume of distribution was 0.7 to 0.8 L/kg in healthy subjects.

Iloprost is approximately 60% protein-bound, mainly to albumin, and this ratio is concentration-independent in the range of to 3000 pg/mL.

Metabolism and Excretion In vitro studies reveal that cytochrome P450-dependent metabolism plays only a minor role in the biotransformation of iloprost.

Iloprost is metabolized principally via β-oxidation of the carboxyl side chain.

The main metabolite is tetranor-iloprost, which is found in the urine in free and conjugated form.

In animal experiments, tetranor-iloprost was pharmacologically inactive.

Clearance in normal subjects was approximately 20 mL/min/kg. A mass-balance study using intravenously and orally administered [ 3 H]-iloprost in healthy subjects (n = 8) showed recovery of 81% of total radioactivity over 14 hours post-dose, with 68% and 12% recoveries in urine and feces, respectively.

Intravenous infusion of iloprost had no effect on the pharmacokinetics of digoxin.

Acetylsalicylic acid did not alter the clearance (pharmacokinetics) of iloprost.

The prostate is a factory prostacecline, operating by opening blood vessels in the lung.

Do you have questions on this subject? Ask Sina, artificial intelligence to answer all your medical questions.

Write your question here, Sina is preparing the answer for you.

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

To report SUSPECTED ADVERSE

REACTIONS, contact BTG International, Inc.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.

Cases of overdose of intravenous iloprost have not been reported.

Hypotension, vomiting, and diarrhea are likely.

A specific antidote is not known.

Interruption of the infusion session, monitoring, and symptomatic measures are recommended.

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.

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

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.

Information for instructions on preparation and administration. 2.1 Recommended Dosage Monitor vital signs prior to the start of the infusion and with every dose increase.

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 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 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.

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.

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: be able to deliver rates 0.1 to 99.9 mL per hour, adjust infusions rates with increments of 0.1 mL per hour, be accurate to within 5% of programmed rate, and 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. 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.

(iloprost) injection is a clear, colorless sterile solution supplied as 100 mcg per mL single-dose glass vial per carton (NDC 50633-340-01).

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) .

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

Do not freeze.

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) .

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

Do not freeze.

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.

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 to 4% and 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 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).

Safety and efficacy in pediatric patients have not been established.

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.