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Label Changes for:

Cerebyx (fosphenytoin sodium) Injection

June 2015

Changes have been made to the PRECAUTIONS sections of the safety label.

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)

June 2015


  • The carcinogenic potential of fosphenytoin has not been assessed. In 2-year carcinogenicity studies, phenytoin (active metabolite of fosphenytoin) was administered in the diet at doses of 0, 10, 25, or 45 mg/kg/day (mice) and 0, 25, 50, or 100 mg/kg/day (rats). In mice, hepatocellular tumors were increased in males and females at the highest dose tested. No drug-related increase in tumors was observed in rats. The peak phenytoin levels at the highest doses tested were lower than those in humans at therapeutic concentrations. In published 2-year carcinogenicity studies, phenytoin was administered in the diet at up to 600 ppm (approximately 90 mg/kg/day) to mice and up to 2400 ppm (approximately 120 mg/kg/day) to rats. The incidence of hepatocellular tumors was increased in mice. No drug related increase in tumors was observed in rats.
  • An increase in structural chromosome aberrations were observed in cultured V79 Chinese hamster lung cells exposed to fosphenytoin in the presence of metabolic activation. No evidence of mutagenicity was observed in bacteria (Ames test) or Chinese hamster lung cells in vitro, and no evidence for clastogenic activity was observed in an in vivo mouse bone marrow micronucleus assay.
  • Fosphenytoin was administered to male and female rats during mating and continuing in females throughout gestation and lactation at doses of 50 mg PE/kg or higher. No effects on fertility were observed in males. In females, altered estrous cycles, delayed mating, prolonged gestation length, and developmental toxicity were observed at all doses, which were associated with maternal toxicity. The lowest dose tested is approximately 40% of the maximum human loading dose on a mg/m2 basis.


June 2014


Drug Interactions

Drugs that affect phenytoin concentrations: (*Miconazole, diazepam, diazoxide, rifampin, and theophylline added to the Drugs that affect phenytoin concentrations portion of the Drug Interactions section.)

  • Drugs that may increase plasma phenytoin concentrations include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, miconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2 antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin.
  • Drugs that may decrease plasma phenytoin concentrations include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampin, ritonavir, St. John’s Wort, theophylline, and vigabatrin.
  • Drugs that may either increase or decrease plasma phenytoin concentrations include: phenobarbital, valproic acid, and sodium valproate. Similarly, the effects of phenytoin on phenobarbital, valproic acid and sodium plasma valproate concentrations are unpredictable.

Drugs affected by phenytoin: (*Carbamazepine, chlorpropamide, clozapine, lamotrigine, methadone, nifedipine, nimodipine, and verapamil added to the Drugs affected by phenytoin portion of the Drug Interactions section.)

  • Phenytoin decreases plasma concentrations of active metabolites of albendazole, certain HIV antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), antiepileptic agents (carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, quetiapine), atorvastatin, chlorpropamide, clozapine, cyclosporine, digoxin, fluvastatin, folic acid, methadone, mexiletine, nifedipine, nimodipine, nisoldipine, praziquantel, simvastatin and verapamil. 


January 2014


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 and CEREBYX. Some of these events .....


Drug Interactions
  • addition of tacrolimus and albenazole


March 2013


Drug Interactions

Drugs affected by phenytoin

  • Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir.
  • Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other nondepolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher



November 2011


  • 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.


Serious Dermatologic Reactions
  • If a rash occurs, the patient should be evaluated 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…..


  • Coadministration of Cerebyx is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors


  • Local toxicity (Purple Glove Syndrome) Edema, discoloration, and pain distal to the site of injection (described as “purple glove syndrome”) have also been reported following peripheral intravenous Cerebyx injection. This may or may not be associated with extravasation. The syndrome may not develop for several days after injection.
Pediatric Use
  • The safety and efficacy of Cerebyx in pediatric patients has not been established
Drug Interactions
Drugs that affect phenytoin concentrations
  • fluorouracil