New Intravenous Medications for Status Epilepticus

ABSTRACT & COMMENTARY
Source: Löscher W, Hönack D. Intravenous carbamazepine: Comparison of different parenteral formulations in a mouse model of convulsive status epilepticus. Epilepsia 1997;38:106-113.

Presently, neurologists have only a small and sometimes potentially toxic choice in applying intravenous (IV) antiepileptic agents to treat status epilepticus. IV phenytoin solubilized in 40% propylene glycol and 10% ethanol can cause hypotension, and administration must be limited to a rate of 50 mg/min. The high pH (12) often leads to phlebitis (Jamerson B, et al. Pharmacotherapy 1994;14:47-52). IV phenobarbital, diazepam, and lorazepam are also solubilized in propylene glycol and are potent sedatives and respiratory depressants. Fosphenytoin, a water-soluble phenytoin prodrug, is now available as an alternative to IV phenytoin (Wilder B. Neurology 1996;46 [Suppl 1]:S1-S2). Löscher and Hönack now report progress toward an intravenous formulation of carbamazepine (CBZ).

CBZ is not on the market in a parenteral formulation owing to its insolubility in aqueous vehicles. However, CBZ forms a water-soluble inclusion complex with 2-hydroxypropyl-b-cyclodextrin (HPBCD). Löscher and Hönack used this new formulation to treat transauricular electrical stimulation-induced convulsive status epilepticus in mice. These authors also assessed the mice for HPBCD:CBZ-induced sedation and ataxia in "open field" tests.

Intravenous administration of the HPBCD:CBZ solution reduced the severity and number of seizures in this murine model. The antiepileptic effect appeared when the transauricular electrical stimulation was applied as early as 30 seconds and as late as 30 minutes after the HPBCD:CBZ injection. It was seen at CBZ doses of 5, 10, and 20 mg/kg (all P < 0.05). There were no sedative or ataxic side effects with the HPBCD vehicle alone or the HPBCD:CBZ solution.

Fosphenytoin is the disodium phosphate ester of phenytoin developed for parenteral administration. After IV or intramuscular (IM) injection, it is completely converted to phenytoin by organ and blood phosphatases, with a conversion half-life of 10 minutes (Browne T, et al. Neurology 1996;46 [Suppl 1]:S3-S7). Fosphenytoin is labelled, bottled, and marketed in "phenytoin equivalents" (PE) (i.e., mg of phenytoin freed after hydrolysis).

Because it is in aqueous solution, and not in a propylene glycol vehicle, IV fosphenytoin produces little or no hypotension. Therefore, it can be administered at rates as high as 150 mg PE/minute, compared with a maximum rate of 50 mg/min for IV phenytoin. However, the prodrug (fosphenytoin) must undergo metabolic conversion to the active compound (phenytoin). An IV infusion of 1200 mg PE of fosphenytoin at 150 mg PE/min provides a peak of free phenytoin level in eight minutes. By contrast, after an IV infusion of 1200 mg of phenytoin at 50 mg/min, a peak free phenytoin level is reached in 20 minutes (Browne T, et al. Neurology 1996;46 [Suppl 1]:S3-S7).

Fosphenytoin can be mixed with normal saline and 5% dextrose solutions; IV phenytoin precipitates in dextrose solutions. Fosphenytoin can also be administered IM without producing sterile abscesses.

The pH of fosphenytoin is 8.6-9.0, compared with 12.0 for IV phenytoin. The lower level measurably reduces the risk of causing phlebitis. In a double-blind crossover study, Jamerson et al administered IV phenytoin or fosphenytoin to 12 healthy volunteers (Jamerson B, et al. Pharmacotherapy 1994;14:47-52). Phenytoin produced a significantly higher degree of pain at the infusion site in all subjects (P < 0.05). In eight of the phenytoin administrations, but none of the fosphenytoin administrations, visible phlebitis developed and produced palpable venous cords in six.

COMMENTARY

Although IV phenytoin is the drug of choice for the emergency treatment of status epilepticus, it suffers from serious drawbacks, including causing hypotension and phlebitis and insolubility in dextrose solutions. Although HPBCD:CBZ is in the early stages of development, it may prove to be a viable alternative. The pH is more normal, and CBZ is not a respiratory or cardiovascular depressant.

IV valproate has been on the market in Europe for more than a decade. In one large study of 318 hospitalized seizure patients, IV valproate was substituted for oral valproate for a median of two days (median number of doses = 4/patient) (Devinsky O, et al. Ann Neurol 1995;38:670-674). No adverse effects beyond those expected with oral administration were seen with the IV valproate formulation. IV valproate is not on the market in the United States, and its efficacy against status epilepticus has not been systematically evaluated.

Fosphenytoin is superior to IV phenytoin in terms of tolerability, admixture compatibility, and routes of administration (IV + IM). Because of rapid fosphenytoin IV loading and metabolic hydrolysis, clinical efficacy of fosphenytoin equals that of IV phenytoin (Ramsay R, et al. Neurology 1996;46 [Suppl 1]:S17-S19).

Although the tolerability of fosphenytoin is greater than that of phenytoin and the efficacy is the same, loading doses of fosphenytoin cost 10 times more than the comparable loading doses of phenytoin. In this era of cost-conscious medicine, this presents hospital formulary committees with a difficult question. Are the clearly decreased side effects of fosphenytoin worth the marked increased cost? Parke-Davis has discontinued the manufacture of IV Dilantin, but IV phenytoin is still available from generic manufacturers. The "standard of care" in this clinical setting is yet to be determined. —drl