Cerebyx (Fosphenytoin Sodium) - Summary

CEREBYX SUMMARY

CEREBYX®
(Fosphenytoin Sodium Injection)

Cerebyx® (fosphenytoin sodium injection) is a prodrug intended for parenteral administration; its active metabolite is phenytoin. Each Cerebyx vial contains 75 mg/mL fosphenytoin sodium (hereafter referred to as fosphenytoin) equivalent to 50 mg/mL phenytoin sodium after administration. Cerebyx is supplied in vials as a ready-mixed solution in Water for Injection, USP, and Tromethamine, USP (TRIS), buffer adjusted to pH 8.6 to 9.0 with either Hydrochloric Acid, NF, or Sodium Hydroxide, NF. Cerebyx is a clear, colorless to pale yellow, sterile solution.

Cerebyx 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 Cerebyx in this use has not been systematically evaluated for more than 5 days.

Cerebyx can be used for the control of generalized convulsive status epilepticus and prevention and treatment of seizures occurring during neurosurgery. It can also be substituted, short-term, for oral phenytoin.

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NEWS HIGHLIGHTS

Published Studies Related to Cerebyx (Fosphenytoin)

Fosphenytoin. [2009.06]
BACKGROUND: Fosphenytoin, phosphate ester pro-drug of phenytoin, was developed to overcome complications associated with parenteral phenytoin administration in treatment of acute symptomatic seizures, short-term prophylaxis and treatment of repetitive or prolonged seizures and status epilepticus. OBJECTIVE: To evaluate the current position of fosphenytoin in treatment algorithms compared to phenytoin... CONCLUSION: Published literature shows that intravenous fosphenytoin has a similar adverse effect profile than phenytoin when it is administered as recommended. There is no evidence of clear benefit that would justify the higher price of the fosphenytoin compared to phenytoin.

Fosphenytoin may cause hemodynamically unstable bradydysrhythmias. [2006.01]
The prodrug fosphenytoin (FOS) was recently introduced as an alternative to phenytoin (PTN) and has since become a first line therapy for status epilepticus...

Hyperphosphatemia due to fosphenytoin in a pediatric ESRD patient. [2005.08]
Fosphenytoin is indicated for the treatment of generalized convulsions and seizures occurring during neurosurgery.Due to this risk of hyperphosphatemia, we recommend that fosphenytoin should be used with caution in the end-stage renal disease population.

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Clinical Trials Related to Cerebyx (Fosphenytoin)

The Study of NPC-06 - Investigation of Safety, Efficacy and Pharmacokinetics of Fosphenytoin [Recruiting]
The study is to evaluate safety, efficacy and pharmacokinetics of intravenously administered fosphenytoin in patients with neurosurgery, head trauma, epilepsy or status epilepticus who are requiring a loading dose of phenytoin.

IV Keppra in the Emergency Department for Prevention of Early Recurrent Seizures [Recruiting]
This study is looking at three seizure medicines. Patients with seizures are usually treated with phenytoin (Dilantin)or Fosphenytoin. These medicines can be given by IV or by mouth. Another seizure medicine, levetiracetam (Keppra) can now be given this way also. This study will compare IV phenytoin (Dilantin)and IV fosphenytoin to levetiracetam (Keppra) in patients who have had a recent seizure. Only patients with a history of seizures can be involved. The patient must present to the emergency department within 4 hours of a seizure. The purpose of this study is to compare these three drugs, phenytoin (Dilantin), fosphenytoin, and levetiracetam (Keppra). The investigators are looking to see if these drugs can prevent another seizure in the next 24 hours. We are also looking fro any possible side effects.

Antiepileptic Drugs and Vascular Risk Markers [Recruiting]
The purpose of this study is to determine if certain seizure medications raise levels of cholesterol and other blood components which could increase the risk of heart attacks and strokes.

Ph. I Dasatinib/Protracted Temo in Recurrent Malignant Glioma [Not yet recruiting]
The primary objective of this study is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of dasatinib when combined with protracted, daily temozolomide (TMZ). Secondary objectives are: To further evaluate the safety and tolerability of dasatinib plus protracted, daily TMZ; 2. To evaluate the pharmacokinetics of dasatinib when administered with protracted, daily TMZ among recurrent malignant glioma patients who are on and not on CYP-3A enzyme inducing anti-epileptic drugs (EIAEDs); 3. To evaluate for anti-tumor activity with this regimen in this patient population.

Intravenous Levetiracetam as First-Line Anticonvulsive Treatment in Patients With Non-Convulsive Status Epilepticus [Recruiting]
Status epilepticus (SE) represents the most common life-threatening neurological emergency requiring treatment on an intensive care unit. The incidence in Western European countries is about 12-18/100'000. Immediate and effective treatment of SE is obviously essential because of the deleterious effects of continuous seizures on the brain and the whole organism. Guidelines emphasize the use of benzodiazepines (BZD) as first-line anticonvulsive drugs. Alternatively, i/v Phenytoin (PHE), fosphenytoin (FOS), and valproate (VPA) were also tested as first-line anticonvulsants in SE. Direct comparison of PHE with lorazepam (LZP)

showed significant superiority of LZP (evidence class I). Other trials i/v PHE or - VPA are

of evidence class III or IV. BZD, VPA, and PHE have clinical and pharmacological disadvantages. BZD may cause respiratory depression or sedation and may be not suitable for patients with COPD or ambiguous in patients with BZD addiction. Some compounds also may induce tachyphylaxis or accumulate under concomitant renal failure. PHE has saturable metabolism subject to Michaelis-Menten kinetics increasing the risk of overdosing in an acute setting causing liver damage, serious cardiac arrhythmias, hypotension, cerebellar degeneration, peripheral neuropathy and local/systemic skin reactions. Although of unequivocal efficacy, PHE should no longer be used for long-term because of its adverse effects after chronic administration (irreversible cerebellar degeneration causing debilitating ataxia, painful polyneuropathy, and osteopenia increasing the risk of fractures). Metabolism by and self-induction of the hepatic CYP450 system make PHE prone to interactions with several other drugs, notably other antiepileptics. VPA may cause liver failure, hemorrhagic complications, pancreatitis, and hyperammonemic encephalopathy. To summarize, these three first-line agents for the treatment of SE may cause serious side effects in several patients with SE.

Levetiracetam (LEV) is broad-spectrum antiepileptic drug. It binds to the presynaptic vesicular protein 2A abundantly present in different regions of the brain; LEV presynaptically modulates transmitter release, but the exact mechanism(s) remain unclear. Data also revealed that LEV stabilizes GABAA receptors upon repetitive activation what is important in treatment of SE because GABAA receptors undergo significant changes of subunit conformation within minutes after sustained activation like during SE. These changes render GABAA receptors the less anticonvulsive, the longer SE lasts. Levetiracetam has a favorable pharmacological profile with large safety margins. Its partly extrahepatic hydrolyzation bypasses the CYP450 system; renal excretion is 60-70% unchanged, and 23-27% metabolized. Dosage needs adjustment when renal function is impaired. LEV lacks interactions with any drugs yet. Drowsiness is the most common side-effect while respiration, liver and kidney function, and the blood system are not affected. LEV shows an important clinical effect even after the first dose and maximal efficacy within the first week of drug-intake. The favorable clinico-pharmacological profile predilects LEV for the first-line treatment of SE, especially in patients with multi-organ failure, sepsis, coma etc.. About 10 % of comatous patients may be in non-convulsive SE (NCSE) on ICU's. These patients are under polymedication whereby interactions of the anticonvulsants approved yet for the treatment of NCSE with their other drugs may have fatal effects. Conversely, non-interacting anticonvulsants would represent an advantage for the treatment of NCSE for these patients.

Recently, the i/v formulation of LEV was approved by the FDA for the use in patients, but not specifically for the treatment of SE. Data about the single-dose bioavailability of i/v-LEV in comparison to oral tablets as well as multiple-dose pharmacokinetics and tolerability in healthy subjects were recently published. In addition, the administration of i/v-LEV dosages ranging from 2000-4000 mg within 15 minutes and of dosages ranging from 1500-2500 mg within 5 minutes was safe and well tolerated, and led to efficacious drug levels in a randomized, single-blind, placebo-controlled safety and pharmacokinetic study in healthy volunteers.

Slight somnolence is expected to be the only adverse effect of i/v LEV, sharply contrasting with the sedation up to coma after i/v benzodiazepines. Thus, even severely ill patients will be accessible to neurological tests under LEV which is a big advantage in this clinical difficult setting of NCSE.

I-v LEV is considered an ideal candidate for the first-line use (before benzodiazepines) in patients with NCSE, especially in those with important comorbidity and concomitant polymedication. Thus, we would like to test the feasibility, safety, and efficacy of i/v-LEV as first-line medication in a open-label, single-center, prospective pilot study as outlined below.

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