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Parenteral fosphenytoin, diazepam rectal gel for refractory seizures, status epilepticus

Last updated on November 17, 2020

Parenteral fosphenytoin, diazepam rectal gel for refractory seizures, status epilepticusStatus epilepticus is a persistent, generalized tonic-clonic seizure that occurs in some 60,000 Americans each year, primarily children but also frequently people over age 60. One third of patients are known epileptics and one third have no history of epilepsy (in half of these, the seizures are a first manifestation of epilepsy). Seizures can also be nonepileptic; origins can be toxic, metabolic, traumatic, hypoxic, electrolytic, pharmacologic, hemorrhagic, neoplastic, infectious, or febrile; seizures can also result from substance abuse or withdrawal.

In their review of the emergency treatment of status epilepticus, Runge and Allen divided the clinical presentation of status epilepticus into four groups: (1) prolonged seizures; (2) repeated generalized convulsive seizures with no interictal recovery; (3) nonconvulsive seizures that produce a continuous or fluctuating alteration in consciousness; and (4) repeated partial seizures manifested as focal motor convulsion or neurologic deficit without altered consciousness. Generalized tonic-clonic status epilepticus is the most dramatic and thus commands the most attention, according to Runge and Allen. However, all types of status epilepticus are neurologic emergencies that require immediate intervention to prevent brain damage. Whereas the level of mortality is usually determined by the underlying cause of the seizure, morbidity increases with the duration of the episode.

The mainstay of therapy for status epilepticus is the parenteral administration of an antiepileptic drug (AED), preferably by the intravenous (IV) route, although intramuscular (IM) injection may be necessary if prompt venous access is not available. The FDA has approved about two dozen antiepileptic drugs, but only four are commonly used parenterally: phenytoin, phenobarbital, diazepam, and lorazepam. Pentobarbital, thiopental, and midazolam are also used parenterally, although usually for refractory or end-stage status epilepticus. Lidocaine and propofol are also used, and valproic acid can be administered rectally or via nasogastric tube for absence seizures (a parenteral formulation is under investigation). None of these agents is without problems. For one thing, adverse CNS side effects are not uncommon. For another, these drugs require alkalinization and/or propylene glycol for solubilization; thus both IV and IM administration are highly irritating.

First-line therapy for status epilepticus involves the intravenous administration of a benzodiazepine- diazepam or lorazepam-which controls seizures in 79% of patients. For patients who do not respond to the initial dose, a second dose is given, although repeated doses do cause respiratory and CNS depression. Phenytoin is considered a second-line drug; it has a prolonged infusion time and a slow onset of action, causes painful local reactions, and carries the risks of extravasation and tissue necrosis. Phenytoin is not water soluble, and so is formulated with 40% propylene glycol and 10% ethanol in water for injection, adjusted to pH 12. The alkaline pH is highly irritating and can seriously damage tissue, and the propylene glycol is associated with hypotension and probably with cardiac arrhythmias that may accompany the intravenous administration of phenytoin. Phenytoin cannot even be used intramuscular because of poor absorption, crystallization, and tissue destruction.

Recently, the FDA approved two new products for refractory seizures and/or status epilepticus: fosphenytoin (Cerebyx/Warner Lambert) and diazepam rectal gel (Diastat/Athena). Diazepam gel was approved for rectal administration in the management of selected, refractory, epileptic patients on stable antiepileptic drug regimens who require intermittent use of diazepam to control bouts of increased seizure activity. Parenteral fosphenytoin was approved for the control of generalized convulsive status epilepticus, for the prevention and treatment of seizures occurring during neurosurgery, and as short-term substitution for oral phenytoin.

Fosphenytoin is a phosphate ester of phenytoin that has been classified “1S” (new molecular entity) by the FDA. It is freely soluble in aqueous solutions, including standard intravenous solutions. After administration, fosphenytoin is rapidly converted (within 8-15 minutes) to phenytoin by phosphatases found in a number of tissues. Unlike phenytoin, fosphenytoin can be given rapidly IV and promptly achieves therapeutic levels. It is rapidly absorbed when given intramuscular, and is well tolerated. The drug is 100% bioavailable, and it is bioequivalent to phenytoin (10 mL fosphenytoin is equivalent to 5 mg intravenous phenytoin). Side effects are minor and transient. Unlike benzodiazepines and barbiturates, fosphenytoin does not cause respiratory or CNS depression; thus patients can breathe well enough to compensate for metabolic acidosis, and think well enough after recovery to cooperate with diagnostic evaluation.

In a study of 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mg/minute, seizures were terminated in 37 patients (85%) within 30 minutes of administration. Side effects included dizziness, nystagmus, and ataxia. In a comparative study of 90 patients given intravenous fosphenytoin and 22 given intravenous phenytoin, disruption of infusion occurred in 21% of IV fosphenytoin patients (primarily due to systemic burning, pruritus, and/or paresthesia) compared with 67% of IV phenytoin patients (primarily due to pain and burning at the infusion site). Paresthesia and pruritus were more common in fosphenytoin than phenytoin patients (paresthesias: 4.4% and 0%, respectively; pruritus: 49% and 4.5%, respectively). Pediatric studies have shown that fosphenytoin has the same efficacy, safety, tolerability, and pharmacokinetics in children aged 5 to 18 years as in adults (up to age 40).

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