Physicochemical stability of Pemetrexed Accord 25 mg/mL in punctured original vials and after dilution with 0.9% sodium chloride solution in non-PVC bottles

Author byline as per print journal: Irene Krämer, PhD; Frank Erdnuess, PhD; Judith Thiesen, PhD

Abstract:
In this study, the physicochemical stability of Pemetrexed Accord 25 mg/mL concentrate and its diluted infusion solutions was examined under various storage conditions. Pemetrexed Accord 25 mg/mL remained physicochemically stable for 28 days when stored protected from light in the punctured original vials either at 2°C–8°C or at 20°C–25°C. After dilution with 0.9% sodium chloride solution to nominal concentrations of 2.5 mg/mL, 9 mg/mL, and 12.5 mg/mL, pemetrexed infusion solutions were shown to be physicochemical stable for 35 days under the same storage conditions. These results enable cost-effective use of Pemetrexed Accord 25 mg/mL residues in original vials and preparation of diluted pemetrexed infusion solutions in advance by pharmacy-based cytotoxic units.

Submitted: 29 February 2024; Revised: 15 April 2024; Accepted: 26 April 2024; Published online first: 6 May 2024

Introduction

Pemetrexed is an antineoplastic antifolate agent, approved alone or in combination with cisplatin for the treatment of non-small lung cancer and malignant pleural mesothelioma [1]. Pemetrexed Accord 25 mg/mL contains pemetrexed as disodium hemipentahydrate and must be diluted with 0.9% sodium chloride solution prior to infusion. The physicochemical in-use stability of diluted pemetrexed infusion solutions is maintained for 72 hours at 20°C–25°C, whereas any unused portion in the punctured vial must be discarded [1]. Pemetrexed concentrates in punctured vials, as well as diluted solutions of pemetrexed disodium brand products formulated with different excipients, are known to be physicochemically stable for up to 31 days when stored refrigerated [2, 3].

Study objectives

The aim of this study was to determine the physicochemical stability of Pemetrexed Accord 25 mg/mL concentrate in punctured original vials and after dilution with 0.9% sodium chloride solution in non-PVC bottles to nominal pemetrexed concentrations 2.5 mg/mL, 9 mg/mL, and 12.5 mg/mL under different storage conditions for a period of 28 days and 35 days, respectively.

Methods

Vials of Pemetrexed Accord 25 mg/mL (batch number P2103500) were punctured four times on four consecutive days using a sterile needle. Diluted pemetrexed solutions 2.5 mg/mL, 9 mg/mL, and 12.5 mg/mL were prepared by adding the appropriate amount of Pemetrexed Accord 25 mg/mL (batch number P2105269) to 0.9% sodium chloride solution in Baxter non-PVC bottles. The test solutions were stored protected from light at 2°C– 8°C or at 20°C– 25°C for 28 days (concentrate) and 35 days (diluted solutions). Samples of the test solutions were taken and analysed initially (Day 0) and at predetermined time points. Physical stability was assessed by pH measurements, visual inspections for changes in colour, clarity, and the presence of particulate matter, osmolality (diluted solutions only), and particle counting of sub-visible particles. Chemical stability was assessed via high-performance liquid chromatography (HPLC) assay with acceptance criteria of 95%–105% of the label claim (concentrate) and initial concentration ± 5% (diluted solutions)) [4].

Results

Pemetrexed Accord 25 mg/mL concentrate in punctured vials, as well as diluted pemetrexed infusion solutions, were shown to be physicochemically stable for 28 days and 35 days, respectively. Neither concentration (2.5 mg/mL, 9 mg/mL, 12.5 mg/mL, 25 mg/mL) nor storage temperature (2°C–8°C, 20°C–25°C) had an influence on physicochemical stability. The HPLC assays revealed only slight variations in pemetrexed concentrations at different time points, which were considered to be related to the assay variability, see Table 1.

Table 1

Conclusion

Residues of Pemetrexed Accord 25 mg/mL in punctured vials can be used cost-effectively for 28 days after first opening. Diluted Pemetrexed Accord infusion solutions, ranging from 2.5 mg/mL to 12.5 mg/mL, can be prepared in advance by pharmacy-based cytotoxic units in non-PVC bottles and used over a period of 35 days, preferably stored refrigerated.

Analysis was performed and documented by an accredited external laboratory. Results were carefully checked for plausibility and cautiously interpreted.

Funding sources

This study was funded by Accord Healthcare.

Competing interests: The authors Irene Krämer, Frank Erdnuess, and Judith Thiesen have no competing interests to declare.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Professor Irene Krämer, PhD
Frank Erdnuess, PhD
Judith Thiesen, PhD

Department of Pharmacy, University Medical Center of the Johannes Gutenberg University Mainz, 1 Langenbeckstraße, DE-55131 Mainz, Germany

References
1. Accord Healthcare. Summary of product characteristics for Pemetrexed Accord 25 mg/mL concentrate for solution for infusion. Available from: https://www.accord-healthcare.com/ie/system/files/ema-spc-25mg-ml-h-4072-en-var21.pdf
2. Zhang Y, Trissel LA. Physical and chemical stability of pemetrexed solutions in plastic syringes. Ann Pharmacother. 2005;39(12):2026-8.
3. Rondelot G, Serrurier C, Vigneron J, Zenier H. Stability of pemetrexed 25 mg/ml in a glass vial and 5 mg/ml stored in a PVC container after storage for one month at 2-8 °C. Eur J Hosp Pharm Sci. 2007;13(1):14-6.
4. Accord Healthcare Limited/Intas Pharmaceuticals Limited. Data for HPLC assay and acceptance criteria on file; 26-07-21 and 22-03-22.

Author for correspondence: Judith Thiesen, PhD, Department of Pharmacy, University Medical Center of the Johannes Gutenberg University Mainz, 1 Langenbeckstraße, DE-55131 Mainz, Germany

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