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Australian Journal of Pharmacy : March 2005
shpa HENYTOIN has been used for the treatment and prevention of seizures for well over half a century. Shortly after its development, and its effectiveness at treating seizures was demonstrated, it became apparent that an intravenous form of the drug was needed to treat con- ditions where an oral form was inappro- priate (for example, in the case of head injury or status epilepticus). However, phenytoin is poorly soluble in water and presented significant problems to those endeavouring to formulate an intravenous injectable form. It was found that solubility increased with pH, and when an alkaline aqueous solvent was combined with co-solvents of propylene glycol (40 per cent) and alcohol (10 per cent) and adjusted with sodium hydroxide to pH 12, a stable intravenous solution could be produced containing 50mg/mL of phenytoin. While such formulations have been the backbone of IV phenytoin therapy and have been extremely successful in clinical practice, they are not without their prob- lems. The most serious of these are hypotension and cardiac arrhythmias, thought to be due to the rate of adminis- tration of either phenytoin or propylene glycol. A number of studies conducted over the years seemed to indicate that rates of administration of IV phenytoin above 50mg/min exacerbated the problems caused by hypotension and arrhythmias. Current dose information includes an instruction not to exceed 50mg/min in adults or 25mg/min in the elderly. While the problems are well understood in the clinical setting, the difficulty of adminis- tering large doses by direct injection at low rates of administration have been ongoing. Over the years a number of studies have been undertaken to examine the stability hospital talk John Low, hospital pharmacist Injectable phenytoin—revisiting an old technical and clinical problem P injectable medicines can often present hospital-based practitioners with problems of a technical and clinical nature of IV phenytoin formulations in infusion solutions because such solutions would simplify administration, especially in emergency situations. While some studies concluded that any dilution of IV pheny- toin formulation would result in instability and crystallisation of the active ingredient, other studies indicated that dilution in sodium chloride 0.9 per cent may be acceptable. Thus, there were conflicting reports on the stability of phenytoin with sodium chloride 0.9 per cent and differing opinions on the advisability of their use. Also of note is that most of the studies are older than 20 years and were conducted using brands of IV phenytoin no longer available on the Australian market. A recent study undertaken by Milne, Foo, Sharley and Milne at the Royal Ade- laide Hospital endeavoured to clarify the findings from previous studies and deter- mine if they applied to Phenytoin Injec- tion (DBL)—the only formulation cur- rently available in Australia.1 The study was conducted using three different concentrations of phenytoin in 160 ? THE AUSTRALIAN JOURNAL OF PHARMACY VOL.86 MARCH 2005 sodium chloride 0.9 per cent. The con- centrations of 3, 6 and 10mg/mL were chosen to reflect the range of doses used for loading and maintenance. Infusion solutions were prepared in Viaflex (Bax- ter) 250mL and 100mL infusion bags using a 0.5mm in-line filter needle. Test solutions were prepared at similar con- centrations in a Butrenol extension set with the airway left unclamped and in open beakers (controls). Solutions were tested at zero, two, four and six hours for assayed concentration (both before and after filtration through a 0.45(m filter), particulate matter and pH. All testing was carried out between 20 and 22(C. In the results the authors noted: ‘...In the Viaflex bags there were no changes in the phenytoin concentration, minimal change in pH (<0.1) and no par- ticulate matter over six hours. In the extension sets and beakers, particulate matter was minimal at two hours and extensive beyond this time. There was an overall decrease of 0.30 and 0.32 pH units in samples from the extension sets and beakers...’. The study concluded that Phenytoin Injection (DBL) can be given as an IV infu- sion, provided it is prepared in a Viaflex bag and infused within two hours of preparation. The dispensing of injectable drugs is one significant difference between com- munity pharmacy and hospital pharmacy practice. These injectable medicines can often present hospital-based practitioners with problems of a technical and clinical nature. The above study clarified equivo- cal results from earlier studies and pro- vided useful information for the clinician faced with emergency situations. 1. Milna DJ, Foo J, Sharley NA, Milne RW. Pheny- toin infusion revisited: stability and administration. J Pharm Pract Res 2004; 34: 272–5.