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Physical compatibility of calcium gluconate and magnesium sulfate injections
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xaliplatin, a potent alkylating agent, is widely used for the treatment of gastrointestinal cancers despite its associated adverse effects including sensorial peripheral neuropathy (SPN).1 Oxalate ions are toxic metabolites of oxaliplatin. They appear to be the root cause of oxaliplatinrelated SPN by chelating physiologically relevant divalent ions. A proposed antidote to oxaliplatin-related SPN is the coadministration of calcium gluconate and magnesium sulfate solutions.2 Several clinical studies have discussed the simultaneous i.v. administration of 1 g of each salt in an often nonspecified vehicle.3,4 Considering the low solubility of calcium sulfate, the precipitation of this salt is a serious concern when calcium gluconate and magnesium sulfate are mixed. We conducted an in vitro study to evaluate the compatibility of admixtures of calcium gluconate and magnesium sulfate in polyvinyl chloride (PVC) bags of 0.9% sodium chloride injection and 5% dextrose injection. Samples were aseptically prepared by adding 10 mL of 10% calcium gluconate injectiona and 2 mL of 50% magnesium sulfate injectionb to 100- and 250mL PVC bags containing 5% dextrose injectionc,d and 0.9% sodium chloride injectione,f using polypropylene syringes.g All containers were stored protected from light at 24.5–25.5 °C and 4.5–5.5 °C.h Control samples were similarly prepared using no added drug salt, calcium gluconate only, or magnesium sulfate only. Admixtures were evaluated after one hour, three days, and seven days for evidence of visible precipitation and change in turbidity using a nephelometer.i The presence of particulate matter after seven days was investigated in accordance with the methods stated in chapter 788 of the United States Pharmacopeia.5 Duplicate preparations were evaluated using these methods.
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Compatibility was defined as the absence of visible precipitation, no change in turbidity exceeding 0.5 nephelmoteric turbidity unit (NTU),6 no more than 12 particles larger than 10 mm per milliliter, and no more than 2 particles larger than 25 mm per milliliter.5 No visible sign of precipitation and no change in turbidity exceeding 0.5 NTU were observed for any of the tested samples. Similarly, the microscopic evaluation of all the samples stored for seven days complied with the USP chapter 788 specifications for particulate matter in injections. a Calcium gluconate, USP, 10%, 0.232 mmol/mL, 10-mL vials, lot 407316, Pharmaceutical Partners of Canada, Richmond Hill, Ontario. b Magnesium sulfate injection, USP, 50%, 2 mmol/mL, 10-mL vials, lot 157820, Sandoz Canada, Boucherville, Quebec. c Dextrose 5% injection, USP, in polyvinyl chloride (PVC) containers, 100-mL bags, lot W9I17C0, and 250-mL bags, lot W0D06C2, Baxter Canada, Mississauga, Ontario. d Dextrose 5% injection, USP, in PVC containers, 250-mL bags, lot W0D06C2, Baxter Canada. e Sodium chloride 0.9% injection in PVC containers, 100-mL bags, lot W0A25C0, Baxter Canada. f Sodium chloride 0.9% injection in PVC containers, 250-mL bags, lot W0B03C1, Baxter Canada. g Luer-Lok 10- and 20-mL polypropylene syringes, BD-Canada, Mississauga, Ontario. h Forma 3911 environmental chambers, Thermo Scientific, Nepean, Ontario. i Model 2100N nephelometer, Hach, Mississauga, Ontario.
1. Cersosimo RJ. Oxaliplatin-associated neuropathy: a review. Ann Pharmacother. 2005; 39:128-35. 2. Gamelin L, Boisdron-Celle M, Della R et al. Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 161 patients receiving oxaliplatin combined with 5-fluorouracil and leucovorin for advanced colorectal cancer. Clin Cancer Res. 2004; 10:4055-61. 3. De Gramont A, Boni C, Navarro N et al. Oxaliplatin/5FU/LV in the adjuvant treatment of stage II and stage III colon cancer: efficacy results with a median follow-up of 4 years. J Clin Oncol. 2005; 23(suppl):abstract 3501. 4. Hochster HS, Grothey A, Shpilsky A et al. Effect of intravenous (IV) calcium
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and magnesium (Ca/Mg) versus placebo on response to FOLFOX + bevacizumab (BEV) in the CONcePT trial. J Clin Oncol. 2008; 26(suppl):abstract 4010. 5. Particulate matter in injections (general information chapter 788). In: The United States pharmacopeia, 33rd rev., and The national formulary, 28th ed. Rockville, MD: United States Pharmacopeial Convention; 2010. 6. Chan P, Bishop A, Kupiec TC et al. Compatibility of ceftobiprole medocaril with selected drugs during simulated Y-site administration. Am J Health-Syst Pharm. 2008; 65:1545-51.
Natasha Beauregard, Pharmacy Student Université de Montréal Montreal, Quebec Canada Nicolas Bertrand, B.Pharm., M.Sc., Pharmacist and Doctoral Student Université de Montréal Annick Dufour, B.Pharm., M.Sc., Pharmacist Charles Lemoyne Hospital Longueuil, Quebec Olivier Blaizel, B.Pharm., Pharmacist Charles Lemoyne Hospital Grégoire Leclair, B.Pharm., Ph.D., Pharmacist and Assistant Professor of Pharmaceutics Université de Montréal P.O. Box 6128 Downtown Station Montreal, Quebec Canada, H3C 3J7
[email protected]
Jean-Marc Forest, B.Pharm., M.Sc., and Jean-François Delisle, B.Sc., B.Pharm., M.Sc., are acknowledged for their critical reading of this letter. The financial contributions of SanofiAventis Canada Inc., the Canadian Foundation for Innovation, and the Fonds de Recherche du Québec-Santé are also acknowledged. The authors have declared no potential conflicts of interest. DOI 10.2146/ajhp110342
