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Table.  
Stability of a 300-μg/mL Solution of Melphalan Under Room Conditions and Refrigeration
Stability of a 300-μg/mL Solution of Melphalan Under Room Conditions and Refrigeration
1.
Kaneko  A, Suzuki  S.  Eye-preservation treatment of retinoblastoma with vitreous seeding. Jpn J Clin Oncol. 2003;33(12):601-607.
PubMedArticle
2.
Munier  FL, Soliman  S, Moulin  AP, Gaillard  MC, Balmer  A, Beck-Popovic  M.  Profiling safety of intravitreal injections for retinoblastoma using an anti-reflux procedure and sterilisation of the needle track. Br J Ophthalmol. 2012;96(8):1084-1087.
PubMedArticle
3.
Alkeran [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2007.
4.
Tabibi  SE, Cradock  JC.  Stability of melphalan in infusion fluids. Am J Hosp Pharm. 1984;41(7):1380-1382.
PubMed
5.
Schaiquevich  P, Buitrago  E, Taich  P,  et al.  Pharmacokinetic analysis of melphalan after superselective ophthalmic artery infusion in preclinical models and retinoblastoma patients. Invest Ophthalmol Vis Sci. 2012;53(7):4205-4212.
PubMedArticle
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Research Letter
November 2014

Stability of Melphalan Solution for Intravitreal Injection for Retinoblastoma

Author Affiliations
  • 1Clinical Pharmacokinetics Unit, Hospital de Pediatría J. P. Garrahan, Buenos Aires, Argentina
  • 2Department of Pharmacy, Hospital de Pediatría J. P. Garrahan, Buenos Aires, Argentina
  • 3National Scientific and Technical Research Council (CONICET), Hospital de Pediatría J. P. Garrahan, Buenos Aires, Argentina
JAMA Ophthalmol. 2014;132(11):1372-1373. doi:10.1001/jamaophthalmol.2014.2324

Intravitreal injections for the treatment of retinoblastoma have been gaining relevance among ophthalmologists, supported by reports on outcome and improvement of the administration technique.1 Currently, doses up to 30 μg per injection are used according to an extensively described technique for intravitreal injection that minimizes the risk of extraocular dissemination of tumor cells.2

The commercial form of melphalan (Alkeran) contains 50 mg of melphalan to be reconstituted in 10 mL of vehicle,3 but each intravitreal injection consists of 30 μg of melphalan (its 1667th part). The rest of the vial is discarded. Specifically in countries with limited resources, this procedure may be optimized to prevent disposal of active agent and preserve it for future patients. The package insert states that after dilution (<0.45 mg/mL) of the reconstituted commercial formulation with sterile saline, the administration should be completed within 60 minutes of reconstitution because of the instability of melphalan.3 This degradation corresponds to a spontaneous hydrolysis to monohydroximelphalan and dihydroximelphalan.3,4 A solution of 400 μg/mL of melphalan in saline at 20°C lost 10% of its content in 4.5 hours; the same loss was attained after 2.4 hours at 25°C, a common room temperature in many clinical centers.4

We evaluated the stability of melphalan solution after reconstitution of the commercial product and serial dilution with saline to a final concentration of 300 μg/mL. This concentration was chosen because in our practice we administer 0.1 mL, the volume that contains the most common clinical dose of 30 μg.

Methods

Reconstitution of melphalan was developed as stated in the package insert.3 After obtaining the 5-mg/mL solution, serial dilutions with saline were made to obtain a 300-μg/mL solution. This final solution was placed in different syringes to determine the stability of melphalan at different times in room conditions (25°C and laboratory light, solution A), stored in a refrigerator (5°C, solution B), and stored in a freezer (−20°C, solution C). Solutions A and B were quantified for melphalan immediately after reconstitution and after 1, 2, 3, 4, 6, and 24 hours. Solution C was analyzed after 6 months of storage by thawing unassisted at room temperature but protected from light. In all cases, 3 aliquots of each syringe were analyzed for melphalan using high-performance liquid chromatography and fluorescence as previously described.5

Results

After 1 hour at room temperature, there was no loss of melphalan. However, the mean loss increased to 68.06% after 24 hours (Table). A 300-μg/mL solution of melphalan was stable at room conditions for 2 hours after reconstitution and dilution, as less than 5% of melphalan content (mean, 4.89%) was lost during this interval.

Similarly, melphalan loss from solutions stored at refrigeration was not significant up to 3 hours (Table). Thereafter, melphalan degraded by more than 10% of that which would be acceptable for patient injection.

Interestingly, melphalan solutions stored at −20°C for 6 months had a mean (SD) difference of 2.57% (1.22%) compared with the fresh solution.

Discussion

Our results show that in clinical practice after melphalan reconstitution and dilution with sterile saline at a concentration of 300 μg/mL for a 30-μg intravitreal dose, the solution should be kept no longer than 2 hours at ambient conditions (25°C) or 3 hours when refrigerated. Additionally, we showed that once a vial of melphalan is reconstituted and diluted to 300 μg/mL, it can be stored at −20°C for 6 months without loss of significant amounts of the drug. However, we emphasize the need to maintain sterile conditions at all times.

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Article Information

Corresponding Author: Paula Schaiquevich, PhD, Unidad de Farmacocinética Clínica, Hospital de Pediatría J. P. Garrahan, Combate de los Pozos 1881, C1245AAL, Buenos Aires, Argentina (paula.schaiquevich@gmail.com).

Published Online: July 31, 2014. doi:10.1001/jamaophthalmol.2014.2324.

Author Contributions: Dr Schaiquevich had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: Buitrago, Lagomarsino, Schaiquevich.

Drafting of the manuscript: Buitrago, Lagomarsino, Schaiquevich.

Critical revision of the manuscript for important intellectual content: Mato, Schaiquevich.

Statistical analysis: Buitrago, Lagomarsino, Schaiquevich.

Obtained funding: Schaiquevich.

Study supervision: Mato, Schaiquevich.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

References
1.
Kaneko  A, Suzuki  S.  Eye-preservation treatment of retinoblastoma with vitreous seeding. Jpn J Clin Oncol. 2003;33(12):601-607.
PubMedArticle
2.
Munier  FL, Soliman  S, Moulin  AP, Gaillard  MC, Balmer  A, Beck-Popovic  M.  Profiling safety of intravitreal injections for retinoblastoma using an anti-reflux procedure and sterilisation of the needle track. Br J Ophthalmol. 2012;96(8):1084-1087.
PubMedArticle
3.
Alkeran [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2007.
4.
Tabibi  SE, Cradock  JC.  Stability of melphalan in infusion fluids. Am J Hosp Pharm. 1984;41(7):1380-1382.
PubMed
5.
Schaiquevich  P, Buitrago  E, Taich  P,  et al.  Pharmacokinetic analysis of melphalan after superselective ophthalmic artery infusion in preclinical models and retinoblastoma patients. Invest Ophthalmol Vis Sci. 2012;53(7):4205-4212.
PubMedArticle
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