Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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Fosphenytoin sodium is a water-soluble prodrug intended for parenteral administration. Its active metabolite is phenytoin. Unlike phenytoin, fosphenytoin does not require propylene glycol and high alkalinity to bring it into solution. Fosphenytoin is rapidly and completely absorbed after intramuscular or intravenous administration. Intravenous fosphenytoin produces fewer local side effects than intravenous phenytoin and has not been associated with serious cardiovascular adverse events. Therefore, it is a useful replacement for parenteral phenytoin. Fosphenytoin was approved by the United States Food and Drug Administration in 1996.
Fosphenytoin is a prodrug of phenytoin.
Pharmacodynamics. Following intramuscular injection, fosphenytoin is converted into anticonvulsant phenytoin by nonspecific phosphatases in the blood. The mechanism of action is like that of phenytoin. Modulation of sodium channels is the primary anticonvulsant mechanism. Fosphenytoin has equivalent anticonvulsant activity to phenytoin against seizures induced by maximal electroshock in mice following intraperitoneal, oral, or intravenous administration.
Pharmacokinetics. The important features of fosphenytoin pharmacokinetics are as follows and vary according to whether it is administered by intravenous or intramuscular injection:
• Following intravenous infusion, maximum plasma phenytoin concentrations are reached at the end of the infusion and have a half-life of approximately 15 minutes.
• Following intramuscular injection, peak plasma concentrations are reached in 30 minutes. Plasma concentrations following intramuscular injection are lower than those following intravenous injection but are more sustained.
• The bioavailability of phenytoin after fosphenytoin is virtually 100%.
• The ratio of mean area under the curve of phenytoin after intravenous and intramuscular fosphenytoin is 1:17.
• Fosphenytoin is nearly completely bound to human plasma proteins and displaces phenytoin from protein binding sites.
• One mmol of fosphenytoin gives rise to 1 mmol of phenytoin and yields 2 metabolites: phosphate and formaldehyde. The latter is converted into formate, which in turn is metabolized by a folate-dependent mechanism. However, the concentrations of these 2 metabolites do not suffice to produce any important biological effects when fosphenytoin is administered in therapeutic doses.
• Metabolism and elimination of phenytoin following administration of fosphenytoin is like that described for phenytoin. The major site of metabolism is the liver with excretion in urine.
• In patients with epilepsy, plasma concentrations of free and total phenytoin are maintained in the therapeutic range for several days after conversion from orally administered phenytoin to intramuscular fosphenytoin.
• Fosphenytoin sodium injection given orally is absorbed more rapidly and to a significantly greater extent than phenytoin sodium injection given orally to healthy volunteers (10).
• Fosphenytoin loading doses of at least 15 mg/kg of actual body weight are more likely to lead to desired free phenytoin concentrations, but obese female patients need a larger weight-based dose than male patients to achieve similar phenytoin concentrations (04).
• Because of multiple factors that affect the pharmacokinetics of acutely ill patients, the currently used method of calculating a fosphenytoin reloading dose does not consistently result in therapeutic concentrations (1.5 to 2.5 mcg/mL). A study has shown that of the fosphenytoin reloading doses administered, 48% resulted in a therapeutic concentration of free phenytoin on the subsequent day, with the remaining 52% resulting in nontherapeutic levels (15). The authors’ evaluation of reloading dose calculation strategies indicated that creation of a new pharmacokinetic model with less emphasis on volume of distribution may more consistently result in therapeutic concentrations.
Noncomparative studies. A 4-center, open-label study of fosphenytoin was conducted in 43 patients with epilepsy maintained on monotherapy with oral phenytoin twice a day. Patients received an intravenous or intramuscular dose of fosphenytoin at a dose equivalent to the morning dose of phenytoin. The intravenous infusion rate was 75 mg per minute, and intramuscular doses were given as 1 or 2 injections. Fosphenytoin was found to be an effective parenteral anticonvulsant with better tolerability than currently available parenteral preparations of phenytoin.
Comparative studies. A randomized study in patients with subtherapeutic phenytoin concentrations who presented within 48 hours of a seizure showed no significant difference between intravenous loading with phenytoin and fosphenytoin, although both were superior to oral loading.
A retrospective observational cohort study found that patients at risk of seizures were discharged from the emergency department earlier with the loading of intramuscular fosphenytoin compared to intravenous phenytoin (01).
A randomized clinical trial of levetiracetam versus fosphenytoin for seizure prevention in traumatic brain injury or subarachnoid hemorrhage showed that levetiracetam is associated with better outcome than fosphenytoin (19). However, apart from severity of generalized slowing, focal slowing and epileptiform discharges on EEG were not associated with outcomes in these patients.
A retrospective study of seizure prophylaxis in children with supratentorial intracranial hemorrhage that compared fosphenytoin and levetiracetam found the latter to be somewhat more effective in the control of seizures, although there was a significant difference in the onset of late seizures after 1 week (02).
Fosphenytoin is indicated for the control of generalized convulsive status epilepticus and may be substituted for oral phenytoin on a short-term basis.
Fosphenytoin is indicated for short-term parenteral administration when other means of phenytoin administration are unavailable, inappropriate, or deemed less advantageous. The safety and effectiveness of fosphenytoin in this manner has not been systematically evaluated for more than 5 days.
• Intravenous fosphenytoin has been used for the management of neuropathic pain, particularly, acute trigeminal neuralgia crisis.
• Intravenous fosphenytoin was reported to be safe and effective for treatment of acute encephalopathy with seizures in children (12).
Fosphenytoin is contraindicated in:
• Patients who have a demonstrated hypersensitivity to fosphenytoin, any of its ingredients, or to phenytoin.
• Patients with sinus bradycardia, sinoatrial block, second- and third-degree atrioventricular block, and Adams-Stokes syndrome.
The goal of fosphenytoin use is for the control of seizures by loading dose and maintenance doses of either fosphenytoin intramuscular or phenytoin oral. If intravenous fosphenytoin does not achieve control of seizures, use of other anticonvulsants and measures should be considered. One alternative is the control of seizures with intravenous diazepam and maintenance with intramuscular fosphenytoin.
Oral phenytoin is the most cost-effective loading method in most settings, and intravenous fosphenytoin is the most expensive option. The adverse effect profiles of intravenous fosphenytoin and phenytoin are similar in the published literature, and there is no evidence of clear benefit that would justify the higher price of the fosphenytoin compared to phenytoin (05). Another cost-effectiveness analysis in traumatic brain injury patients showed that prophylaxis starting with fosphenytoin is more cost-effective than levetiracetam at all reasonable prices whereas both were equally effective in reducing the seizure potential (06).
Guidelines of the American Epilepsy Society recommended intravenous phenytoin or fosphenytoin (if available) as the antiepileptic of choice after benzodiazepines (08). A comparative study of fosphenytoin and continuous intravenous midazolam as second-line treatment for pediatric status epilepticus in Japan showed that efficacy of both was similar (14). In a retrospective study, a loading dose of 20 mg/kg intravenous fosphenytoin was effective as well as safe in controlling seizures in 88% of children with status epilepticus. Seizure control and adverse effects had only a weak relation with serum phenytoin levels achieved in this study (18).
Fosphenytoin is prescribed and dispensed in phenytoin equivalent units. The loading dose is 15 to 20 mg phenytoin equivalent per kg administered at 150 phenytoin equivalent per minute. This can be reduced appropriately if the patient is already on oral phenytoin therapy and serum phenytoin concentrations are available.
In 2007, the Food and Drug Administration approved the first generic formulation of fosphenytoin sodium injection 50 mg/mL strength for short-term parenteral administration when other means of phenytoin administration are unavailable, inappropriate, or deemed less advantageous.
Anesthesia. No relevant information.
Pregnancy. Precautions for pregnant women using phenytoin are as follows:
• An increase of seizure frequency may occur during pregnancy because of altered phenytoin absorption or metabolism. Periodic measurements of phenytoin levels to guide dosage adjustment are recommended.
• Several reports suggest an association between the use of antiepileptic drugs, including phenytoin, in pregnancy and a higher incidence of birth defects. For details see the Physicians’ Desk Reference.
• Neonatal coagulation defects have been reported within the first 24 hours in babies born to mothers receiving phenytoin. Vitamin K has been shown to correct or prevent this defect.
• Only small amounts of phenytoin are found in breastmilk and usually cause no difficulties in breastfed infants. Breastfeeding during phenytoin monotherapy has not been reported to adversely affect infant development. If phenytoin is required by the mother, breastfeeding need not be discontinued.
Pediatric. Safety in pediatric patients has not been established.
Geriatric. Fosphenytoin excretion is decreased in the elderly. Lower doses and a slower rate of administration should be used.
Hepatic and renal disease. An increase in systemic adverse effects may occur following intravenous fosphenytoin loading doses in patients with renal or hepatic disease who have a decreased ability to bind fosphenytoin and phenytoin. Close monitoring and reduction in the infusion rate by 25% to 50% are recommended when intravenous loading doses of fosphenytoin are administered in these patients (07).
Fosphenytoin should be used with caution in end-stage renal disease because of the risk of hyperphosphatemia.
Interactions are the same as those of phenytoin. There is a large list of drugs (listed in Physicians’ Desk Reference) that may increase or decrease the level of phenytoin or that may be affected by phenytoin.
Intravenous fosphenytoin does not interact with intravenous diazepam, which is also used for control of status epilepticus. Concurrent use of fosphenytoin in patients on oxycodone may result in decreased analgesia due to conversion of oxycodone to inactive metabolites and can be avoided using hydromorphone, morphine, or oxymorphone (16).
In volunteers, fosphenytoin is well tolerated at intravenous doses up to 1200 mg phenytoin equivalents, using infusion rates 3 times the maximum recommended for phenytoin. In patients with epilepsy, transient postinjection cramping in the leg, tingling, mild irritation at the injection site, dizziness, ataxia, and nystagmus have all been reported. Pendular nystagmus is attributed to instability of the oculomotor neural integrator due to delays in feedback from the cerebellum and resolves following postictal recovery (17). Phenytoin-induced dyskinesias have been reported in infants but are rare. Hemidyskinesias with nystagmoid eye movements developed in an infant with Sturge-Weber syndrome following use of intravenous fosphenytoin but resolved after discontinuation of this drug (20). Right cerebral infarction was the presumed underlying cause of phenytoin-induced hemidyskinesia.
Paresthesias of the groin, back, lower abdomen, and head or neck rarely occur during infusion of phenytoin but have been reported in up to 30% of volunteers and patients receiving fosphenytoin. These paresthesias usually occur during intravenous administration of higher doses and at higher infusion rates and resolve rapidly without sequelae. Purple glove syndrome is a rare complication of intravenous phenytoin use that usually presents with pain, swelling, and discoloration at the injection site, which spreads to the distal limb (03). A case of purple glove syndrome has been reported in a patient receiving fosphenytoin, which resolved following discontinuation of therapy and treatment with methylprednisolone (13).
The most important adverse reaction following the use of intravenous fosphenytoin is cardiovascular collapse and CNS depression. Hypotension can occur when the rate of administration is faster than 150 mg per minute. In patients presenting with acute cerebral symptoms, intravenous infusion of fosphenytoin may cause significant decrease in blood pressure, which is not seen in similar patients receiving intravenous levetiracetam (09). In a study, hypotension occurred in 39% of patients receiving an intravenous infusion of fosphenytoin for status epilepticus, and old age as well as systemic infection increased the risk of hypotension (11). The U.S. Food and Drug Administration's Adverse Event Reporting System databank contains numerous reports of adverse cardiac events likely related to fosphenytoin infusion, including cardiac deaths. It is recommended that cardiac monitoring be used when administering intravenous fosphenytoin to high-risk patients.
The emergence of treatment-related adverse events has been studied in clinical trials in patients who were on oral phenytoin therapy and were switched to intramuscular fosphenytoin. Headache, nausea, vomiting, and nystagmus are reported more frequently in patients receiving intramuscular fosphenytoin.
Management. Most of the adverse effects subside spontaneously and may require observation of patients a few hours longer following the administration of fosphenytoin.
• Severe reaction at the site of administration may require changing the site of injection for any subsequent administration.
• If hypotension develops, intravenous infusion may be stopped until the blood pressure normalizes and the infusion should be restarted at a lower rate.
K K Jain MD
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.See Profile
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