We have performed a search for articles published in English language through Medline/PubMed and Scholar Google. The following keywords were used: [“ondansetron”] and [“stability” or “compatibility” or “coadministered” or “admixtures”]. In PubMed the search details were: “ondansetron[Title] AND (stability[All Fields] OR compatibility[All Fields] OR admixtures[All Fields] OR coadministered[All Fields])” founding 61 articles. A similar searching in Scholar Google provides 57 articles. Finally, the data presented in the electronic databases Stabilis® and Micromedex® solutions and in the was taken into account to complete the review adding 19 more articles to the search. The PRISMA2 recommendations have been followed to prepare this review about the ondansetron stability.

Studied articles in this review use intravenous admixtures. Plastic syringes and Y-site administration were discarded, except in case of Y-site incompatibilities. They were taken into account because these combinations will be also incompatible for infusion bags administration.

The terms room or ambient temperature are used in this review and they make reference to 20-25 °C. The accepted levels of stability are a remaining percentage of the drugs higher of 90%.

Previously to describe the ondansetron chemical stability with other compounds, a description of its own stability is necessary. When the drug is stored at -20 °C in normal saline or dextrose in a concentration range from 0.25 to 1 mg/ml the reported chemical stability is at least 90 days3-5. At 4 °C, most of the published articles found a 14 days stability for ondansetron solutions with concentrations from 0.024 to 1 mg/ml in normal saline and dextrose 5%3,4,6,7. Also Ringer injection8 was found compatible with ondansetron hydrochloride (0.016 mg/ml) for seven days at refrigerated temperature. When ondansetron (0.24 mg/ml) is refrigerated in an elastomeric device for pump infusion, its demonstrated chemical stability is 31 days9. Furthermore, in case of ambient temperature (22-25°C), 48 hours of chemical stability are reported by most of the authors in the concentration range between 0.03 and 1 mg/ml in normal saline solution and dextrose3,4 and chemical stability of ondansetron (0.024-0.096 mg/ml) in lactate Ringer injection6 was fourteen days at room or refrigerated temperature.

Finally, when ondansetron is delivered by a portable infusion-pump reservoirs at near-body-body temperature (30 °C) a chemical stability up to 24 hours for 0.24 mg/ml and up to one week was reported for 2 mg/ml samples9.

Admixtures with ondansetron and other medication were evaluated to determine their compatibility.

Therefore, for additional pain treatment, ondansetron can be blended at different conditions/concentrations in binary mixtures with meperidine hy- drochloride10, tramadol11, hydromorphone hydrochloride and with morphine sulfate12. Otherwise, ondansetron hydrochloride and naloxone hydrochloride admixture was also studied13.

Ondansetron plus another immunosuppressant or antiemetic treatment mixed in the same solutions was also demonstrated (dexamethasone sodium phosphate14,15, methylprednisolone16, fosaprepitant17).

Additionally it is compatible with chemotherapeutic agents like cyclophosphamide with dextrose and normal saline solution18, cisplatin19, cytarabine, doxorubicin hydrochloride, etoposide and methotrexate sodium20.

Also for binary mixtures, recently a twelve hours chemical stability has been found for ondansetron/haloperidol admixtures at room temperature in normal saline solution or dextrose21.

A summary with the stability results of the admixtures that can be used in clinical practice is presented in table 1.

Finally, ternary blends have been studied. Ondansetron (0.44 mg/ml), dexamethasone sodium phosphate (0.28 mg/ml) and lorazepam (0.028 mg/ml) in dextrose 5% solution at ambient light and temperature have demonstrate a 24 hours of chemical stability22. Admixtures with ondansetron, doxorubicin and other chemotherapeutic agent were also tested at 30 °C23, but it is not cited the light storage conditions; ondansetron (0.48 mg/ml), doxorubicin (0.4 mg/ml) and vincristine sulphate (0.014 mg/ml) in normal saline and elastomer have shown 24 hours of chemical stability. Change the material to PVC and increasing the concentrations of each drug to the double, the shown chemical stability increases until five days. With dacar- bazine (8 mg/ml), ondansetron (0.64 mg/ml) and doxorubicin (0.8 mg/ ml) at 30 °C in elastomer or PVC have shown 24 hours stability. Recently a physicochemical stability of 15 days for mixtures containing fosaprepi- tant (0.6-3.0 mg/ml), ondansetron (0.03-0.16 mg/ml) and dexamethasone (0.03-0.16 mg/ml)24 in viaflo infusion bags have been established under different storage conditions of light (4 and 25 °C) and temperature (under light exposure or protected from light).

Several incompatibilities of ondansetron with other drugs have been reported (physicochemical incompatibility, precipitation due to pH of the so- lution)25-51. For example, dantrolene sodium precipitates from solutions with a pH less than 8.8, including dextrose and sodium chloride solutions. Then the combination with ondansetron is not possible in these solutions43.

Another like azathioprine sodium or cefepime hydrochloride and ondansetron (1 mg/ml) in normal saline or dextrose were found incompatible by Y-site administration simulation at room temperature37,38.

Also, biologic compounds as trastuzumab49, rituximab50 and gemtuzu- mab ozogamicin51 were found incompatible with ondansetron in normal saline solution.

As a general view, table 2 summarizes the incompatibilities.

Finally, the ternary blend with ondansetron (0.008 mg/ml), mesna (1.25 mg/ml) and furosemide (0.02 mg/ml) was found chemically unstable36.