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Stability of Treprostinil With Diluents and Medications

Aimee Doran


Erick Borg

K. Rollins

Ken Phares

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Conference: 2018 PHA International PH Conference & Scientific Sessions

Release Date: 07.28.2018

Presentation Type: Abstracts

File Download: Conference 2018_1010

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2018 International PH Conference and Scientific SeAbstract presented at the 2018 International PH Conference and Scientific Sessions in Orlando, Fla., June 28-July 1, 2018.

Background

Parenteral treprostinil (TRE) is indicated for the treatment of pulmonary arterial hypertension (PAH) to diminish symptoms associated with exercise. Pivotal studies with subcutaneous TRE included 470 patients with New York Heart Association functional class II (11%), III (81%), or IV (7%) PAH, with a mean age of 45 (range: 9 to 75) years. A number of studies have evaluated the effects of parenteral TRE on functional status, hemodynamics, and survival in pediatric patients with pulmonary vascular disease. The safety and efficacy of intravenous (IV) TRE in neonates with persistent pulmonary hypertension is currently being evaluated in a randomized, placebo-controlled, Phase II study (NCT02261883). Lack of data demonstrating stability of TRE with diluents and IV medications commonly used in the adult, pediatric, and neonatal PAH inpatient populations complicates the ability of health care teams to make decisions. These high-risk populations may have central line access issues or caloric needs, necessitating co-administration of IV medications and use of dextrose solutions. The purpose of this study was to evaluate the chemical and physical stability of TRE over time, when diluted in 5/10% dextrose in water (D5/D10W), and when individually combined in normal saline (NS) with IV inotropes and other medications commonly used in the critical care setting.

Methods

TRE was diluted to three concentrations (0.00025, 0.004, and 0.13 mg/mL) with D5/D10W and stored at 25°C/60% relative humidity. Samples were evaluated for stability at 24 and 54 hours (hr). TRE (0.4 mg/mL) was combined with heparin (20 units/mL) in NS and stored at ambient conditions (20 to 23°C). Samples were evaluated for stability at 24 and 52 hr. TRE was individually combined with eleven IV medications at lower and/or higher concentrations in NS and stored at ambient conditions. Samples were evaluated for stability at 18 and 24 hr. Physical stability was evaluated by visual assessment for appearance of precipitation or color change. Chemical stability was evaluated by assay comparison to initial medication concentration(s) using high-performance liquid chromatography.

Results

• Three concentrations of TRE (0.00025, 0.004, and 0.13mg/mL) diluted in D5W or D10W were chemically and physically stable to 54 hr. • TRE (0.4 mg/mL) with heparin (20 units/mL) was chemically and physically stable to 52 hr in NS. • Lower-concentration TRE (0.4mg/mL) was chemically and physically stable to 24 hr in NS with: dexmedetomidine (4 µg/mL), dobutamine (1 mg/mL), fentanyl (10 µg/mL), furosemide (1.5 mg/mL), midazolam (0.1 mg/mL), milrinone (0.2 mg/mL), morphine (5 mg/mL), norepinephrine (16 µg/mL), and vasopressin (2 units/mL). • Higher-concentration TRE (1 mg/mL) was chemically and physically stable to 24 hr in NS with: dexmedetomidine (4 µg/mL), dobutamine (8 mg/mL), fentanyl (50 µg/mL), furosemide (10 mg/mL), midazolam (5 mg/mL), milrinone (1 mg/mL), morphine (5 mg/mL), and norepinephrine (80 µg/mL). • Lower-concentration TRE (0.4 mg/mL) with dopamine (1.6 mg/mL) was chemically and physically stable to 18 hr in NS. Higher-concentration TRE (1 mg/mL) with dopamine (40 mg/mL) was not physically or chemically stable. • TRE (0.4 and 1 mg/mL) and epinephrine (8 and 90 µg/mL) stability was inconclusive due to epinephrine standard degradation.

Conclusions

TRE was chemically and physically stable to 52 hr at 25°C/60% relative humidity when diluted in D5W or D10W. TRE and eleven IV medications were chemically and physically stable to various time points at ambient conditions when combined in NS. The compatibility of TRE with epinephrine warrants further evaluation, due to inconclusive results from the reference standard.