Pharmacy Practice

STABILITY

STUDIES OF DRUGS USED IN ONCOLOGY: THE ROLE OF THE HOSPITAL PHARMACIST

Jean Vigneron, PhD

In general, manufacturers provide minimal information relating to stability data. It is, therefore, the pharmacist who is responsible for the retrieval and interpretation of existing data of stability or to perform such studies in the pharmacy itself.

ince the first report of Falck et al [1] which demonstrated the mutagenicity in urine from nurses handling cytotoxic drugs, many articles have highlighted the potential danger upon the handling of these drugs. In order to protect staff against possible contamination, numerous guidelines have been published for the safe preparation of cytotoxic drugs within centralised units in the hospital pharmacy. One of the consequences of this is that the time between drug order, preparation and administration is extended considerably. Therefore, the pharmacist has to take into account, whether the stability of the reconstituted preparations is sufficient with regard to this extended processing time. Each preparation has to keep its physical and chemical properties from the beginning of the preparation until the end of the administration to the patient. In general, manufacturers provide minimal information relating to stability data; therefore it is the pharmacist who is responsible for the retrieval and interpretation of existing data of stability or to perform such studies.

numerous drugs has also been gathered in specialised databases where the user can find information on the influence of various factors (solvent, container, light, temperature, concentration, pH, filters) on the stability for each drug [2, 3, 4]. These databases are a considerable help for the daily practice of the hospital pharmacist but are not bibles. The user must consider them as a tool for his practice. But he must also have sufficient background knowledge about the design and implementation of stability studies in order to assess the research in comparison with his requirements, so that he can then make an informed decision.

To demonstrate the stability of capsules for paediatrics. Only a few dosage forms are suitable for use in children. If prepared in the pharmacy, stability studies must be carried out starting from powder or crushed tablets. Stability must be shown for long-term storage. Gambier et al, for example, showed one year stability for mercaptopurine capsules [9]. To increase the comfort of the patient. The most well known example is the VAD (vincristine (V), doxorubicin (A) and oral dexamethasone (D)) regimen which combines vincristine 0.4 mg/day and doxorubicin 9 mg/m2/day as a continuous intravenous infusion for four days. This regimen is a common treatment for multiple myeloma. However, the patient has to stay in hospital to receive the chemotherapy, with two continuous infusions a day. So as to avoid this, studies have been performed to demonstrate the stability of the admixture (vincristine, doxorubicin with sodium chloride) in various kinds of containers to allow administration to be given on an outpatient basis [10, 11]. The admixtures of these two drugs have also been shown to be stable at standard therapeutic doses for at least seven days [12]. To facilitate administration in the wards. Stability studies of mixtures like cyclophosphamide and mesna [13] or cytotoxic and antiemetic drugs [14] have been carried out to facilitate administration for both the medical staff and the patient.

Performing stability studies of cytotoxic drugs in the hospital pharmacy

There are several reasons for studying the stability of cytotoxic drugs: To enhance the stability of very short stability data. Drugs with very short stability data do not allow for preparation, transport and administration. For example, the manufacturer quotes 4hour stability for docetaxel and bortezomib. But three studies have demonstrated, respectively, a stability of one month [5] and one week [6, 7] for these drugs. To allow preparation for the weekend or for the treatment cycle. Protocols which include cytarabine often last four or seven days. A sufficient stability (29 days) was shown by Van Gansbecke to allow for drug preparation for the complete treatment cycle [8].

Researching stability data in the literature

There are many studies in drug stability published in specialised pharmaceutical journals, for example, European Journal of Hospital Pharmacy, International Journal of Pharmaceutical Compounding, American Journal of Health System Pharmacist, Annals of Pharmacotherapy and Hospital Pharmacy. Stability data for

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To save money. The most recent example of this is the study of the stability of bortezomib. Bortezomib is available as a lyophilisat at 3.5 mg (Velcade). However, the dose for an injection is 1.4 mg/m2. For a patient with a body area of 1.8 m2, the dose will be 2.5 mg. Therefore, one milligram of the drug will be wasted. Since the cost of a 3.5 mg vial is approximately 1,200, the cost of such waste is in the region of 340! Moreover, neurotoxicity of the drug often forces the physician to reduce the dose to 1 mg/m2 or 0.7 mg/m2 and, as a consequence of this, with an even greater waste and cost. However, two recent stability studies [9, 10] have demonstrated that the vial solution is stable for at least one week, thus allowing very important cost savings. To choose the best container for the preparation. With extended storage, chances for an interaction between the drug and the container will increase. This was shown by Demore et al., when they demonstrated that the use of polyvinylchloride (PVC) containers provokes the leaching of phtalates from Vepesid infusions because of the presence of polysorbate 80 in the formulation [15]. Therefore, the authors advise the use of polyethylene or polypropylene containers instead of PVC. zole [21], leading to an extended stability of 15 days, and acyclovir [22].

Conclusion
The role of the pharmacist is not only the preparation of oncology drugs, in their various forms: injections; infusions; cytotoxic and adjuvant therapy; but also to ensure that these preparations are stable up to and inclusive of administration to the patient. This should be ascertained by either researching stability data in the literature or reliable databases, or alternatively, the study has to be performed for the relevant drug or drug combination in the pharmacy itself.

Author
Jean Vigneron, PhD Department of Pharmacy Centre Hospitalier Universitaire Hpital Brabois Adultes Alle du Morvan F-54511 Vandoeuvre ls Nancy, France j.vigneron@chu-nancy.fr

References
1. Falck K, Grhn P, Sorsa M, Vainio H, Heinonen E, Hosti LR. Mutagenicity in urine of nurses handling cytotoxic drugs. Lancet 1979;1:125051. 2. Trissel LA. Handbook on injectable drugs.13th Edition. American Society of Health System Pharmacists. 3. King Guide to Parenteral Admixtures. www.kingguide.com 4. Vigneron J et al. Stabilis 3: Stability and compatibility of injectable drugs 2006 CD-Rom MAC and Windows. www.infostab.com 5. Thiesen J, Krmer I. Physico-chemical stability of docetaxel premix solution and docetaxel infusion solutions in PVC bags and polyolefine containers. Pharm World Sci 1999;21:137-41. 6. Andr P, Cisternino S, Chiadmi F, Toledano A, Schlatter J, Fain O, Fontan JE. Stability of bortezomib 1 mg/ml solution in plastic syringe and glass vial. Ann Pharmacother 2005;39:1462-6. 7. Friess D, Hguyen HC, Lipp HP. HPLCStabilittuntersuchungen zu rekonstituierten Bortezomib-Lsungen. Krankenhauspharmazie 2005;6:206-10. 8. Van Gansbecke B. Study of interactions between PVC bags for continuous infusion and a dilute solution of cytarabine. J Pharm Clin 1989;8:96-9. 9. Gambier N, Vigneron J, Mntr S, May I, Hoffman MA. Stability of 6-mercaptopurine in capsules for paediatric patients using a capillary electrophoresis assay. Eur J Hosp Pharm Science 2006; 12(1):13-5.

Stability studies of drugs frequently combined with chemotherapy

Antiemetic therapy: Various studies have evaluated the long-term stability of antiemetics to allow for preparation in advance. Storage in the refrigerator or in a freezer has been shown to be suitable for metoclopramide, alizapride, ondansetron or tropisetron [16, 17]. Another study demonstrated the possibility of mixing ondansetron, dexamethasone and lorazepam [18]. Adjuvant therapy: Studies have demonstrated sufficient stability for mesna [19] and dexrazoxane [20]. Anti-infective drugs: Long-term stability studies have been performed for voricona-

10. Beijnen JH, Neef C, Meuwissen OJAT, Rutten JJMH, Rosing H, Underberg WJM. Stability of intravenous admixtures of doxorubicin and vincristine. Am J Hosp Pharm 1986; 43:30227. 11. Nyhammar EK, Johansson SG, Seiving BE. Stability of doxorubicin hydrochloride and vincristine sulfate in two portable infusionpump reservoirs. Am J Health Syst Pharm 1996;53:1171-3. 12. Trittler R. Stability of intravenous admixtures of doxorubicin and vincristine confirmed by LC-MS. Eur J Hosp Pharm-S 2006;1:10-2. 13. Menard C, Bourguign,on C, Schlatter J, Vermerie N. Stability of cyclophosphamide and mesna admixtures in polyethylene infusion bags. Ann Pharmacother 2003;37:178992. 14. Mayron D, Gennaro AR. Stability and compatibility of topotecan hydrochloride with selected drugs. Am J Health Syst Pharm 1999;56:875-81. 15. Demor B, Vigneron J, Perrin A, Hoffman MA, Hoffman M. Leaching of diethyl hexyl phtalate from polyvinyl chloride bags into intravenous etoposide solution. J Clin Pharm Ther 2002;27:139-42. 16. Blaise N, Vigneron J, Perrin A, Noirez V, Hoffman MA, Hoffman M. Stability of refrigerated and frozen solutions of ondansetron hydrochloride. Eur J Hosp Pharm 1994;4(1)12-3. 17. Georget S, Vigneron J, Blaise N, Perrin A, Hoffman MA, Hoffman M. Stability of refrigerated and frozen solutions of tropisetron in either polyvinylchloride or polyolefin infusion bags. J Clin Pharm Ther 1997;22:257-60. 18. McGuire TR, Narducci WA, Fox JL. Compatibility and stability of ondansetron hydrochloride, dexamethasone, and lorazepam in injectable solutions. Am J Hosp Pharm 1993;50:1410-4. 19. Lux M, Vigneron J, Perrin A, Hoffman MA, Hoffman M. Etude de stabilit de solutions de mesna destines la perfusion. J Pharm Clin 1995;14:160-1. 20. Beijnen JH, Van Gijn R. Chemical stability of the cardioprotective agent ICRF-187 in infusion fluids. J Parenter Sci Technol 1993;47:166-71. 21. Cadrobbi J, Hecq JD, Lebrun C, Vanbeckbergen D, Jamart J, Galanti L. Longterm stability of voriconazole 4 mg/ml in dextrose 5% polyvinyl chloride bags at 4C. Eur J Hosp Pharm Science 2006;12(3):57-9. 22. Zhang Y, Trissel LA, Martinez JF, Gilbert DL. Stability of acyclovir sodium 1, 7, 10 mg/ml in 5% dextrose injection and in 0.9% sodium chloride injection. Am J Health Syst Pharm 1998;55:574-7.

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