Fosphenytoin Side Effects

Brand Names: Cerebyx

Please note - some side effects for Fosphenytoin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Fosphenytoin - for the Consumer

Fosphenytoin

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Fosphenytoin:

Burning, numbness, or tingling; dizziness; drowsiness; headache; nausea; pelvic pain; taste changes; vomiting.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bone pain; butterfly-shaped rash on the face; clumsiness or unsteadiness; confusion; dark urine; delirium; fast, slow, or irregular heartbeat; fever; hearing problems (eg, ringing in the ears, hearing loss); high blood sugar (increased thirst, hunger, or urination; rapid breathing; flushing; fruit-like breath odor); mental or mood changes; muscle weakness or cramping; pain, swelling, or redness at the injection site; red, swollen, blistered, or peeling skin; severe or persistent dizziness or drowsiness; signs of infection (eg, fever, chills, sore throat); slurred speech; stomach pain; swollen lymph nodes; swollen or tender gums; tremor; unusual bruising or bleeding; unusual eye movements; unusual muscle movements; vision changes; yellowing of the skin or eyes.

Fosphenytoin Side Effects - for the Professional

Fosphenytoin

The more important adverse clinical events caused by the IV use of Fosphenytoin sodium injection 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 Fosphenytoin sodium injection, it should not exceed 150 mg PE/min.

The adverse clinical events most commonly observed with the use of Fosphenytoin sodium injection 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 Fosphenytoin sodium injection administration and occurred more often with IV Fosphenytoin sodium injection administration than with IM Fosphenytoin sodium injection administration. These events were dose and rate related; most alert patients (41 of 64; 64%) administered doses of ³15 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 Fosphenytoin sodium injection 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.

Approximately 2% of the 859 individuals who received Fosphenytoin sodium injection 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 Fosphenytoin sodium injection: The incidence of adverse events tended to increase as both dose and infusion rate increased. In particular, at doses of 111 15mg PE/kg and rates 111 150 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 Fosphenytoin sodium injection 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 Fosphenytoin sodium injection at the maximum dose and rate in a randomized, double-blind, controlled clinical trial where the rates for phenytoin and Fosphenytoin sodium injection administration would have resulted in equivalent systemic exposure to phenytoin.

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

Adverse Events During All Clinical Trials

Fosphenytoin sodium injection 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.

Side Effects by Body System

General

In general, cardiovascular collapse and central nervous system depression are the most important adverse sequelae and are more common in debilitated patients, during rapid administration rates, and with higher doses (e.g. >15 mg/kg at 150 mg/min).

The severity and/or frequency of adverse side effects due to fosphenytoin (and phenytoin, the active metabolite) may be increased in patients with renal and/or hepatic disease or in those with hypoalbuminemia. Fosphenytoin conversion to phenytoin may be increased without a concomitant increase in phenytoin clearance.

Nervous system

Nervous system side effects commonly reported have included transient paresthesias (described as itching, burning or tingling) at a site distant from the injection site (most commonly the groin area). Somnolence, nystagmus, dizziness, stupor, and ataxia (which may be signs of toxicity) have also been reported.

The paresthesia reaction is more common with fosphenytoin than phenytoin and does not appear to be an allergic process. The paresthesias usually begin several minutes within the start of the infusion and resolve within 10 minutes after completion of the infusion. Continuation of the infusion during the paresthesia side effect does not appear to result in permanent adverse effects, although the outcome has not been studied in a controlled fashion.

Other less common nervous system effects have included increased reflexes, speech disorder, dysarthria, intracranial hypertension, and nervousness.

Cardiovascular

Cardiovascular side effects including hypotension, hypertension, bradycardia, tachycardia, and vasodilation have been reported. A case of hypocalcemia-like ECG changes has also been reported.

Cardiovascular side effects appear to be more common with intravenous (versus intramuscular) administration. Elderly and/or debilitated patients may be at greatest risk for cardiovascular complications.

Gastrointestinal

Gastrointestinal side effects have included nausea, tongue and taste disorder, constipation, dry mouth, vomiting, and gingival hyperplasia.

Local

Transient pruritus has been reported to occur more frequently with higher doses and faster infusion rates.

Local injection-site pain tends to be more common with phenytoin than with fosphenytoin. However, infusion disruptions due to systemic burning, itching and/or paresthesia occur more frequently with fosphenytoin than with phenytoin. Pruritus in the perineum appears to be common. Localized injection site pain and burning result in more infusion discontinuations in patients treated with phenytoin. Intramuscular fosphenytoin is well tolerated, with transient mild to moderate itching being the most common local effect. In general, intravenous infusions of fosphenytoin and phenytoin are completed in 5 to 7 and 15 to 20 minutes, respectively. Shorter infusion times with fosphenytoin may result in less local irritation.

Local side effects have included transient pruritus.

Other

Other side effects have included tinnitus, fevers, and infrequent headaches.

Tinnitus has been reported with higher doses and infusion rates.

Hematologic

Hematologic side effects including ecchymosis have been reported infrequently.

Serious, sometimes fatal hematologic events have been reported with phenytoin. Thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, lymphadenopathy, and pancytopenia with or without bone marrow suppression have occurred with phenytoin use. Fatalities have been reported. In cases of severe blood dyscrasias, selection of an alternative to fosphenytoin therapy may be the most prudent decision.

Lymphadenopathy (local or generalized) has been reported with phenytoin use and while a causal relationship has not been determined, differentiation from other lymph node pathologies should be made. Any patient who develops lymphadenopathy should be observed for an extended period of time and alternative seizure control medications should be instituted if at all possible.

Metabolic

Slow metabolism (due to a genetic lack of inducing enzyme) has occurred rarely in patients treated with phenytoin.

Metabolic side effects such as hypokalemia may occur.

Musculoskeletal

Musculoskeletal side effects have included myasthenia.

Dermatologic

Pruritus with fosphenytoin is a dose related reaction which has been reported to develop more frequently if the drug is administered intravenously. The groin is the area affected most frequently. The pruritus may last for hours.

Dermatologic side effects including pruritus (up to 49% in one major clinical trial), bullous rash, exfoliative dermatitis, gingival hyperplasia, and erythema multiforme have been reported.

Hepatic

Hepatic side effects including acute hepatotoxicity have been reported with the use of phenytoin. Therefore, if hepatotoxicity occurs with the use of fosphenytoin, the drug should be discontinued and not readministered.

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