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The more important adverse clinical events caused by the IV use of CEREBYX or phenytoin are cardiovascular collapse and/or central nervous system depression. Hypotension can occur when either drug is administered rapidly by the IV route. The rate of administration is very important; for CEREBYX, it should not exceed 150 mg PE/min. The adverse clinical events most commonly observed with the use of CEREBYX in clinical trials were nystagmus, dizziness, pruritus, paresthesia, headache, somnolence, and ataxia. With two exceptions, these events are commonly associated with the administration of IV phenytoin. Paresthesia and pruritus, however, were seen much more often following CEREBYX administration and occurred more often with IV CEREBYX administration than with IM CEREBYX administration. These events were dose and rate related; most alert patients (41 of 64; 64%) administered doses of ≥ 15 mg PE/kg at 150 mg PE/min experienced discomfort of some degree. These sensations, generally described as itching, burning, or tingling, were usually not at the infusion site. The location of the discomfort varied with the groin mentioned most Frequently as a site of involvement. The paresthesia and pruritus were transient events that occurred within several minutes of the start of infusion and generally resolved within 10 minutes after completion of CEREBYX infusion. Some patients experienced symptoms for hours. These events did not increase in severity with repeated administration. Concurrent adverse events or clinical laboratory change suggesting an allergic process were not seen (see PRECAUTIONS, Sensory Disturbances). Approximately 2% of the 859 individuals who received CEREBYX in premarketing clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal were pruritus (0.5%), hypotension (0.3%), and bradycardia (0.2%).

Dose and Rate Dependency of Adverse Events Following IV CEREBYX: The incidence of adverse events tended to increase as both dose and infusion rate increased. In particular, at doses of ≥ 15mg PE/kg and rates ≥ 150 mg PE/min, transient pruritus, tinnitus, nystagmus, somnolence, and ataxia occurred 2 to 3 times more often than at lower doses or rates.

Incidence In Controlled Clinical Trials

All adverse events were recorded during the trials by the clinical investigators using terminology of their own choosing. Similar types of events were grouped into standardized categories using modified COSTART dictionary terminology. These categories are used in the tables and listings below with the frequencies representing the proportion of individuals exposed to CEREBYX or comparative therapy. The prescriber should be aware that these figures cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied.

Incidence in Controlled Clinical Trials -IV Administration To Patients With Epilepsy or Neurosurgical Patients: Table 2 lists treatment-emergent adverse events that occurred in at least 2% of patients treated with IV CEREBYX at the maximum dose and rate in a randomized, double-blind, controlled clinical trial where the rates for phenytoin and CEREBYX administration would have resulted in equivalent systemic exposure to phenytoin.

TABLE 2: Treatment-Emergent Adverse Event Incidence Following IV Administration at the Maximum Dose and Rate to Patients With Epilepsy or Neurosurgical Patients (Events in at Least 2% of CEREBYX -Treated Patients)

BODY SYSTEM Adverse Event IV CEREBYX N=90 IV Phenytoin N=22
BODY AS A WHOLE
  Pelvic Pain 4.4 0.0
  Asthenia 2.2 0.0
  Back Pain 2.2 0.0
  Headache 2.2 4.5
CARDIOVASCULAR
  Hypotension 7.7 9.1
  Vasodilatation 5.6 4.5
  Tachycardia 2.2 0.0
DIGESTIVE
  Nausea 8.9 13.6
  Tongue Disorder 4.4 0.0
  Dry Mouth 4.4 4.5
  Vomiting 2.2 9.1
NERVOUS
  Nystagmus 44.4 59.1
  Dizziness 31.1 27.3
  Somnolence 20.0 27.3
  Ataxia 11.1 18.2
  Stupor 7.7 4.5
  Incoordination 4.4 4.5
  Paresthesia 4.4 0.0
  Extrapyramidal Syndrome 4.4 0.0
  Tremor 3.3 9.1
  Agitation 3.3 0.0
  Hypesthesia 2.2 9.1
  Dysarthria 2.2 0.0
  Vertigo 2.2 0.0
  Brain Edema 2.2 4.5
SKIN AND APPENDAGES
  Pruritus 48.9 4.5
SPECIAL SENSES
  Tinnitus 8.9 9.1
  Diplopia 3.3 0.0
  Taste Perversion 3.3 0.0
  Amblyopia 2.2 9.1
  Deafness 2.2 0.0

Incidence in Controlled Trials -IM Administration to Patients With Epilepsy: Table 3 lists treatment-emergent adverse events that occurred in at least 2% of CEREBYX-treated patients in a double-blind, randomized, controlled clinical trial of adult epilepsy patients receiving either IM CEREBYX substituted for oral Dilantin or continuing oral Dilantin. Both treatments were administered for 5 days.

TABLE 3: Treatment-Emergent Adverse Event Incidence Following Substitution of IM CEREBYX for Oral Dilantin in Patients With Epilepsy (Events in at Least 2% of CEREBYX -Treated Patients)

BODY SYSTEM Adverse Event IM CEREBYX
N=179
Oral Dilantin
N=61
BODY AS A WHOLE
  Headache 8.9 4.9
  Asthenia 3.9 3.3
  Accidental Injury 3.4 6.6
DIGESTIVE
  Nausea 4.5 0.0
  Vomiting 2.8 0.0
HEMATOLOGIC AND LYMPHATIC
  Ecchymosis 7.3 4.9
NERVOUS
  Nystagmus 15.1 8.2
  Tremor 9.5 13.1
  Ataxia 8.4 8.2
  Incoordination 7.8 4.9
  Somnolence 6.7 9.8
  Dizziness 5.0 3.3
  Paresthesia 3.9 3.3
  Reflexes Decreased 2.8 4.9
SKIN AND APPENDAGES
  Pruritus 2.8 0.0

Adverse Events During All Clinical Trials

CEREBYX has been administered to 859 individuals during all clinical trials. All adverse events seen at least twice are listed in the following, except those already included in previous tables and listings. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: Frequent adverse events are defined as those occurring in greater than 1/100 individuals; Infrequent adverse events are those occurring in 1/100 to 1/1000 individuals.

Body as a Whole: Frequent: fever, injection-site reaction, infection, chills, face edema, injection-site pain; Infrequent: sepsis, injection-site inflammation, injection-site edema, injection-site hemorrhage, flu syndrome, malaise, generalized edema, shock, photosensitivity reaction, cachexia, cryptococcosis.

Cardiovascular: Frequent: hypertension; Infrequent: cardiac arrest, migraine, syncope, cerebral hemorrhage, palpitation, sinus bradycardia, atrial flutter, bundle branch block, cardiomegaly, cerebral infarct, postural hypotension, pulmonary embolus, QT interval prolongation, thrombophlebitis, ventricular extrasystoles, congestive heart failure.

Digestive: Frequent: constipation; Infrequent: dyspepsia, diarrhea, anorexia, gastrointestinal hemorrhage, increased salivation, liver function tests abnormal, tenesmus, tongue edema, dysphagia, flatulence, gastritis, ileus.

Endocrine: Infrequent: diabetes insipidus.

Hematologic and Lymphatic: Infrequent: thrombocytopenia, anemia, leukocytosis, cyanosis, hypochromic anemia, leukopenia, lymphadenopathy, petechia.

Metabolic and Nutritional: Frequent: hypokalemia; Infrequent: hyperglycemia, hypophosphatemia, alkalosis, acidosis, dehydration, hyperkalemia, ketosis.

Musculoskeletal: Frequent: myasthenia; Infrequent: myopathy, leg cramps, arthralgia, myalgia.

Nervous: Frequent: reflexes increased, speech disorder, dysarthria, intracranial hypertension, thinking abnormal, nervousness, hypesthesia; Infrequent: confusion, twitching, Babinski sign positive, circumoral paresthesia, hemiplegia, hypotonia, convulsion, extrapyramidal syndrome, insomnia, meningitis, depersonalization, CNS depression, depression, hypokinesia, hyperkinesia, brain edema, paralysis, psychosis, aphasia, emotional lability, coma, hyperesthesia, myoclonus, personality disorder, acute brain syndrome, encephalitis, subdural hematoma, encephalopathy, hostility, akathisia, amnesia, neurosis.

Respiratory: Frequent: pneumonia; Infrequent: pharyngitis, sinusitis, hyperventilation, rhinitis, apnea, aspiration pneumonia, asthma, dyspnea, atelectasis, cough increased, sputum increased, epistaxis, hypoxia, pneumothorax, hemoptysis, bronchitis.

Skin and Appendages: Frequent: rash; Infrequent: maculopapular rash, urticaria, sweating, skin discoloration, contact dermatitis, pustular rash, skin nodule.

Special Senses: Frequent: taste perversion; Infrequent: deafness, visual field defect, eye pain, conjunctivitis, photophobia, hyperacusis, mydriasis, parosmia, ear pain, taste loss.

Urogenital: Infrequent: urinary retention, oliguria, dysuria, vaginitis, albuminuria, genital edema, kidney failure, polyuria, urethral pain, urinary incontinence, vaginal moniliasis.

Post-Marketing Experience

The following adverse reactions have been identified during postapproval use of fosphenytoin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. There have been post-marketing reports of anaphylactoid reaction and anaphylaxis.

Other Phenytoin-Associated Adverse Events

Dyskinesia.