Cerebyx (fosphenytoin sodium) Injection

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug eva luation and Research (CDER) – November 2011

Summary View¹

BOXED WARNING

• WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION RATES. The rate of intravenous CEREBYX administration should not exceed 150 mg phenytoin sodium equivalents (PE) per minute because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous CEREBYX. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed.

WARNINGS

Serious Dermatologic Reactions

• If a rash occurs, the patient should be eva luated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below).
• Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry….

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin. Some of these events have been fatal or life-threatening. DRESS…..

• Fosphenytoin Sodium

  Pronunciation: (fos-FEN-i-toin SOE-dee-um)Class: Anticonvulsant, Hydantoin

  Trade Names:Cerebyx- Injection 150 mg (phenytoin sodium 100 mg)- Injection 750 mg (phenytoin sodium 500 mg)

  Pharmacology

  Fosphenytoin is a prodrug, which is converted to the active metabolite phenytoin. Appears to act at motor cortex by inhibiting spread of seizure activity. Possibly works by promoting sodium efflux from neurons, thereby stabilizing threshold against hyperexcitability.

  Pharmacokinetics

  Absorption

  T _max is about 30 min. Bioavailability is 100% with IM dosing.

  Distribution

  Protein binding is 95% to 99%, about 88% for phenytoin. Vd is 4.3 to 10.8 L.

  Metabolism

  Fosphenytoin converts to phenytoin by hydrolysis. Phenytoin is extensively metabolized in the liver.

  Elimination

  The half-life is about 15 min; the mean half-life is 12 to 28.9 (phenytoin). Fosphenytoin is primarily excreted in the urine as metabolites.

  Special Populations

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  Renal Function Impairment

  Increased fraction of unbound phenytoin may occur.

  Hepatic Function Impairment

  Increased fraction of unbound phenytoin may occur.

  Elderly

  Cl decreases about 20% in patients over 70 yr.

  Hypoalbuminemia

  Increased fraction of unbound phenytoin may occur.

  Indications and Usage

  Short-term parenteral administration when other means of phenytoin administration are unavailable, inappropriate, or