PHENYTOIN

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) DPH
2) Diphenylhydantoin
3) 5,5-Diphenylhydantoin
4) 5,5-Diphenylimidazolidine-2,4-dione
5) Hydantoin, 5,5-diphenyl-
6) Molecular formula: C15-H12-N2-O2
7) CAS 57-41-0; 125-59-7

1) 3-Ethyl-5-phenylhydantoin
2) Hydantoin, 3-ethyl-5-phenyl-
3) Molecular Formula: C11-H12-N2-O2
4) CAS 86-35-1

1.2.1) MOLECULAR FORMULA
1) C15-H12-N2-O2.Na

Available Forms Sources

1) PHENYTOIN

a) Phenytoin 50 mg chewable tablet (Prod Info DILANTIN(R) INFATABS(R) oral chewable tablets, 2011).
b) Phenytoin oral suspension in concentrations of 125 mg/5 mL (Prod Info Dilantin-125(R) oral suspension, 2011).
c) Phenytoin sodium extended-release capsules 30 mg and 100 mg (Prod Info DILANTIN(R) oral extended release capsules, 2011; Prod Info DILANTIN(R) extended capsule, oral, 2009).
d) Phenytoin sodium parenteral solution 50 mg/mL (Prod Info Dilantin(R) intravenous injection solution, 2011).

2) ETHOTOIN

a) Ethotoin is available as 250 mg scored tablets (Prod Info PEGANONE(R) oral tablets, 2009).

1) Phenytoin sodium covers various anticonvulsant preparations, most notably Dilantin(R). Generic phenytoin preparations often exhibit erratic kinetics. Calculations based on kinetic parameters for Dilantin Kapseals(R) will frequently be wrong with overdoses of generic phenytoin.

1) Phenytoin and ethotoin are used for the control of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures. Phenytoin is also used for the prevention and treatment of seizures which may occur during or following neurosurgery (Prod Info Dilantin-125(R) oral suspension, 2011; Prod Info Dilantin(R) intravenous injection solution, 2011; Prod Info PEGANONE(R) oral tablets, 2009).
2) RECREATIONAL USE: There have been several reports in the literature of phenytoin being used as a recreational drug. Phenytoin was combined with crack cocaine and smoked (Jessen, 2004). In one case, a man ingested several crack cocaine rocks adulterated with phenytoin (Roldan, 2014). In one case, a young adult "sipped syrup" (phenytoin), smoked marijuana and drank alcohol to elicit a "high" and developed symptoms associated with phenytoin toxicity (Jessen, 2004).

Overview

Life Support

Clinical Effects

0.2.1)

A) This management includes phenytoin and ethotoin, both in the hydantoin class of anticonvulsants; however, phenytoin will be the primary drug discussed. Fosphenytoin is covered in a separate management.
B) USES: Phenytoin is primarily used as an anticonvulsant, both for status epilepticus and for seizure prevention.
C) PHARMACOLOGY: Phenytoin stabilizes neuronal membranes and decreases seizure activity by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during nerve impulse generation.
D) TOXICOLOGY: Phenytoin prolongs effective refractory period and suppresses ventricular pacemaker automaticity, thus shortening the action potential in the heart. The intravenous form of phenytoin is dissolved in 40% propylene glycol and 10% ethanol at a pH of 12. This formulation can have its own toxicity secondary to cardiac toxicity of propylene glycol (mechanism unknown) and tissue necrosis from infiltration (secondary to the alkaline nature of the formulation).
E) EPIDEMIOLOGY: There are thousands of exposures reported to poison centers every year, as it is a widely used anticonvulsant. However, deaths are extremely rare and severe manifestations occur in only a minority of cases.
F) WITH THERAPEUTIC USE

1) Significant adverse effects seen from intravenous use of phenytoin include venous irritation and pain, and thrombophlebitis. Extravasation can cause tissue necrosis. Adverse effects unrelated to plasma phenytoin levels include hypertrichosis, gingival hypertrophy, thickening of facial features, carbohydrate intolerance, folic acid deficiency, peripheral neuropathy, vitamin D deficiency, osteomalacia, and systemic lupus erythematosus (SLE). Some rarely seen but important adverse reactions include blood dyscrasias, dyskinesias, hepatitis, lymphadenopathy, lymphoma, pseudolymphoma, SLE-like syndrome, Steven-Johnson Syndrome, and toxic epidermal necrolysis.
2) Phenytoin is a known teratogen. Fetal hydantoin syndrome is characterized by microcephaly, mental retardation, craniofacial abnormalities, and digital hypoplasia. It occurs in 10% to 30% of exposed pregnancies.

G) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Nausea and vomiting may develop early after overdose. Nystagmus, ataxia, and mild CNS depression are common.
2) SEVERE TOXICITY: Large oral ingestions can cause more severe CNS depression, coma, and, rarely, respiratory depression. Rapid infusion of the parenteral formulation (faster than 50 mg/min) can cause hypotension, bradycardia, AV conduction delays, and ventricular dysrhythmias which may be fatal. It is felt that the cardiotoxicity of the intravenous formulation of phenytoin is secondary to the diluent, propylene glycol, and not the phenytoin itself.

0.2.20)

A) Ethotoin, phenytoin, and phenytoin sodium have been classified as FDA pregnancy category D. Fetal hydantoin syndrome occurs in 10% to 30% of exposed pregnancies. It may result in multisystem anomalies including CNS dysfunction, craniofacial anomalies, major malformations, and nail/digital hypoplasia. If used during pregnancy or if patient becomes pregnant, weigh the risks and benefits of use during pregnancy, inform the patient of the potential harm to the fetus, and measure phenytoin plasma concentrations periodically. Prevent potentially life-threatening bleeding disorders in the infant by administering vitamin K to the mother before delivery and then to the neonate after birth. Breastfeeding while taking phenytoin is not recommended. However, phenytoin is considered to be compatible with breastfeeding by the American Academy of Pediatrics and the World Health Organization. Monitor infant for side effects.

0.2.21)

A) Phenytoin is a suspect human carcinogen. Elevated risks for Hodgkin's disease, lymphosarcomas, and reticulum-cell sarcoma have been seen in patients receiving phenytoin therapy (HSDB , 1995). Patients treated with anticonvulsants have shown an elevated risk for cancers of the brain and CNS, but clustering within 10 years of hospitalization suggests that pre-existing brain tumors may have been the cause of the seizure disorders for which the phenytoin was prescribed (Olsen et al, 1989).
B) There is no evidence that phenytoin can cause liver cancer in humans from the 60 years of experience in its use; therefore the induction of liver tumors in mice is deemed not to be relevant to the human situation (Dethloff et al, 1996).

Laboratory Monitoring

1) Greater than 20 mcg/mL: far lateral nystagmus
2) Greater than 30 mcg/mL: 45 degrees lateral gaze nystagmus and ataxia
3) Greater than 40 mcg/mL: decreased mentation
4) Greater than 100 mcg/mL: death

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) For mild and moderate toxicity, treat with supportive care, as the patient eventually metabolizes the phenytoin. If the patient is awake and alert, administer a dose of activated charcoal. Protect the patient from self-injury secondary to ataxia.

B) MANAGEMENT OF SEVERE TOXICITY

1) For large phenytoin overdoses, treat with supportive care, which may include intubation for comatose patients. If seizures do occur, treat with benzodiazepines and evaluate for other causes of seizures.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital activated charcoal might be considered if the patient is awake, alert, and cooperative, and the exposure was relatively recent (within the last hour).
2) HOSPITAL: Activated charcoal could be considered if the patient is awake, alert, and cooperative, and the ingestions is relatively recent. Gastric lavage should be avoided in most phenytoin overdoses as it is not life-threatening.

D) AIRWAY MANAGEMENT

1) Perform endotracheal intubation in patients with significant CNS depression.

E) ANTIDOTE

1) None

F) EXTRAVASATION INJURY

1) If extravasation occurs, stop the infusion. Disconnect the IV tubing, but leave the cannula or needle in place. Attempt to aspirate the extravasated drug from the needle or cannula. If possible, withdraw 3 to 5 mL of blood and/or fluids through the needle/cannula. Administer hyaluronidase. Elevate the affected area. Apply a warm or cold compress as indicated. One study recommended applying a dry warm compress. However, another source recommended ice packs for 15 to 20 minutes at least 4 times daily. Administer analgesics for severe pain. If pain persists, there is concern for compartment syndrome, or injury is apparent, an early surgical consult should be considered. Close observation of the extravasated area is suggested. If tissue sloughing, necrosis or blistering occurs, treat as a chemical burn (ie, antiseptic dressings, silver sulfadiazine, antibiotics when applicable). Surgical or enzymatic debridement may be required. Risk of infection is increased in chemotherapy patients with reduced neutrophil count following extravasation. Consider culturing any open wounds. Monitor the site for the development of cellulitis, which may require antibiotic therapy.

G) ENHANCED ELIMINATION

1) There is some evidence that repeated doses of charcoal may enhance phenytoin elimination, but the evidence is weak that actually improves outcomes, and it should not be given in drowsy patients secondary to the risk of aspiration pneumonitis, so it is rarely indicated. In a systematic review of literature that included 51 studies, including 30 case reports/case series (31 patients), 17 pharmacokinetic studies (54 patients), 1 animal experiment, and 3 in vitro studies, the Extracorporeal Treatments in Poisoning (EXTRIP) workgroup (included international experts) concluded that phenytoin is moderately dialyzable, despite its high protein binding, and recommended the use of ECTR in selected patients with severe phenytoin toxicity. Despite a low quality of evidence for all recommendations, the following guideline was developed: ECTR is suggested if prolonged coma is present or expected. ECTR is reasonable if prolonged incapacitating ataxia is present or expected. ECTR is NOT recommended solely based on suspected ingested dose of phenytoin or based on serum phenytoin concentration. Discontinuation of ECTR is recommended in patients with apparent clinical improvement. The preferred ECTR is intermittent hemodialysis, with an acceptable alternative being intermittent hemoperfusion, if hemodialysis is not available.

H) PATIENT DISPOSITION

1) HOME CRITERIA: For unintentional ingestions where the patient is asymptomatic and the dose is less than 20 mg/kg, the patient can be observed at home.
2) OBSERVATION CRITERIA: Any intentional overdose or inadvertent overdoses above 20 mg/kg, or if symptomatic, the patient should be sent to a healthcare facility for observation. Patients should be observed for at least 4 to 6 hours, and should not be sent home until symptoms are clearly improving, or they are asymptomatic and serum concentrations are clearly declining.
3) ADMISSION CRITERIA: Patients who have worsening symptoms after 4 to 6 hours or with significant ataxia or CNS depression, and those with rising serum concentrations, should be admitted to the hospital. If the CNS depression is severe enough that there is respiratory depression or concern of airway protection, the patient should be admitted to an intensive care setting. Otherwise, most patients can be safely admitted to a hospital ward bed. Criteria for discharge from the hospital should include clinical symptomatic improvement, which should be reflected by declining phenytoin serum concentrations.
4) CONSULT CRITERIA: In patients with cardiac toxicity secondary to the intravenous formulation of phenytoin, it might be reasonable to consult a cardiologist. Neurologists are often very familiar with both the acute and chronic toxicity of phenytoin. Consult a medical toxicologist or poison center for patients with severe toxicity.

I) PITFALLS

1) Intravenous phenytoin should NEVER be infused rapidly (greater than 40 to 50 mg/min or more than 0.5 to 1 mg/kg/min) as this may cause myocardial depression and cardiac arrest. Since phenytoin is protein bound, patients with decreased protein binding have greater concentrations of free phenytoin and therefore greater toxicity at a given serum concentration. Two types of conditions cause decreased phenytoin protein binding: disease states that cause a decrease in serum albumin concentrations (ie, burns, hepatic cirrhosis, nephrotic syndrome, pregnancy, cystic fibrosis) and diseases that results in apparent decrease in affinity of phenytoin for serum albumin (ie, renal failure, severe jaundice, other medications, hyperbilirubinemia (total bilirubin greater than 15 mg/dL), and uremia (creatinine clearance less than 25 mL/minute with the unbound fraction increased two- to three-fold in uremia)). Small changes in dose can cause rapidly increasing serum concentrations and toxicity secondary to saturable metabolism.

J) PHARMACOKINETICS

1) Onset of action from intravenous dosing is immediate, while oral absorption is quite variable and slow. The volume of distribution following single IV doses in children (9.4 to 21.3 mg/kg) was 0.95 L/kg and declined with age, with a range of 1 to 1.5 L/kg below the age of 5 years to 0.6 to 0.8 L/kg above the age of 8 years. In adults, the volume of distribution ranges from 0.6 to 0.7 L/kg. Protein binding in adults is greater than 90%. Metabolism is hepatic and is dose-dependent and capacity-limited (Michaelis-Menten) pharmacokinetics. Major metabolites undergo enterohepatic recirculation. Less than 5% is excreted unchanged in the urine. Time to peak concentrations is 2 to 3 hours after immediate-release and 4 to 12 hours after extended-release formulations. Half-life of elimination ranges widely, from 7 to 42 hours, with an average of 22 hours.

K) TOXICOKINETICS

1) Phenytoin metabolism is saturable at high concentrations, leading to zero order elimination and very prolonged half-life. In large overdoses, patients may be symptomatic for days.

L) PREDISPOSING CONDITIONS

1) Patients with low albumin levels will have an increase in the free fraction of serum phenytoin concentrations and hence will have an increased pharmacologic response at the same total phenytoin concentration. Phenytoin is metabolized by several p450 enzymes and thus drugs that interact with p450 enzymes may cause changes in phenytoin concentrations. In addition, drugs that are highly protein-bound, such as warfarin or thyroid hormone, may compete with phenytoin for albumin binding and thus increase the concentration of free phenytoin.

M) DIFFERENTIAL DIAGNOSIS

1) The differential diagnosis for this ingestion includes other sedating medications, such as other antiepileptics or benzodiazepines, barbiturates, or opioids.

0.4.6)

A) In patients with parenteral overdoses, monitor mental status and intubate patients with significant CNS depression. Treat hypotension with intravenous fluids, add vasopressors if hypotension persists. Treat dysrhythmias with standard ACLS protocols. Thrombophlebitis and infiltrations should be treated supportively with pain medications such as NSAIDs and warm compresses.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.3)

A) WITH POISONING/EXPOSURE

1) HYPOTHERMIA: A case of phenytoin toxicity manifesting solely in the form of hypothermia has been reported (Alhaj & Alhaj, 2001). Hypothermia resolved following discontinuation of phenytoin and use of warming blankets. Lowry et al (2005) reported a one-month-old infant with hypothermia (92 degrees F rectally) and pink mottled skin following an unintentional overdose of oral phenytoin (Lowry et al, 2005).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) CATARACT

a) CASE REPORT: Subcapsular cataract formation was associated with ingestion of 400 mg/day of phenytoin over several weeks producing a toxic phenytoin concentration of 17.4 mcg/mL in a 26-year-old man (Mathers et al, 1987).

2) NYSTAGMUS

a) Nystagmus is commonly seen with toxic concentrations of phenytoin (Roldan, 2014; Kumar et al, 2012; Jessen, 2004; Kozer et al, 2002; Turkdogan et al, 2002; Brandolese et al, 2001; Lau et al, 2000; Grant & Schuman, 1993a). Absent nystagmus is a significant negative finding.
b) CASE REPORT: Both vertical and horizontal nystagmus were present 9 hours following an ingestion of 100 capsules of phenytoin 100 mg in a 21-year-old woman (Griffiths et al, 1987).
c) CASE REPORT: Periodic alternating nystagmus was reported in a 47-year-old chronic alcoholic receiving phenytoin 300 mg/day after an extra 1200 mg within 24 hours (Campbell, 1980).
d) CASE REPORT: Dysconjugate gaze and absent doll's eye movements were reported in a one-month-old infant following an unintentional overdose of oral phenytoin (40 mg 3 times/day for 10 days) (Lowry et al, 2005).

3) COLOR VISION DEFICIENCY

a) CASE REPORT: Xanthopsia and blurred vision were reported in a 19-year-old man with a history of seizures 2 days after receiving a phenytoin loading dose of 1000 mg over 20 minutes followed by a maintenance dose of 300 mg/day. Neurologic function remained normal. Visual symptoms gradually resolved with no permanent effects following drug withdrawal (Thakral et al, 2003).
b) Bayer et al (1997) report blue-yellow color vision deficiencies in patients with signs of phenytoin-induced neurotoxicity, with no correlation to phenytoin serum concentrations(Bayer et al, 1997).

4) OPHTHALMOPLEGIA

a) Nearly complete external ophthalmoplegia was reported with a rapid onset following overdose and a duration of one day (Grant & Schuman, 1993a).

5) OCULAR MOTOR ABNORMALITIES

a) CASE REPORT: A 55-year-old man, who was taking phenytoin sodium (300 mg/day) for generalized tonic clonic seizures, developed ocular motor disturbances, simulating bilateral internuclear ophthalmoplegia (INO), after ingesting about 2.5 g of phenytoin sodium. The cranial nerves evaluation showed mid-positioned eyes with bilateral 4 mm sized round pupils with preserved direct and consensual light reflexes. He had forwardly fixed gaze, could not follow moving objects, or move his eyes on command. Laboratory result revealed a serum phenytoin concentration of 77.9 mcg/mL (therapeutic range 20 to 40 mcg/mL). His symptoms gradually improved as his serum phenytoin levels decreased. On day 11, his eye movements were normal and his serum phenytoin concentration was 23.4 mcg/mL. He was discharged 14 days after presentation (Praveen-kumar & Desai, 2014).
b) OSCILLOPSIA, a very fine vertical or horizontal periodic dancing of the eyes, has been noted (Grant & Schuman, 1993a).

6) DIPLOPIA

a) Diplopia may occur (Roldan, 2014; Grillone & Myssiorek, 1992).

3.4.6)

A) WITH THERAPEUTIC USE

1) GINGIVAL HYPERPLASIA

a) Gingival hyperplasia has been reported with phenytoin therapy (Prod Info Dilantin-125(R) oral suspension, 2011; Prod Info DILANTIN(R) INFATABS(R) oral chewable tablets, 2011), occurring in 21% of children receiving folic acid to 88% of children with no folic-acid supplementation (Arya et al, 2011). It occurs within 2 to 3 months, peak severity is at 9 to 12 months (Grillone & Myssiorek, 1992a), and is often severe in young children. The degree of severity of drug-induced gingival hyperplasia has been correlated to increased dose and phenytoin serum levels, decreased age and weight of the patients, and poor oral hygiene (Addy et al, 1983). Folic acid supplementation is associated with prevention of gingival overgrowth in children taking phenytoin monotherapy (Arya et al, 2011).

Cardiovascular

3.5.2)

A) BRADYCARDIA

1) WITH THERAPEUTIC USE

a) Phenytoin administered intravenously at rates faster than 50 mg/minute may produce significant bradycardia and hypotension which can lead to atrial and then ventricular asystole (due to the diluent, propylene glycol) (Prod Info Dilantin(R) intravenous injection solution, 2011).
b) While most cases are reported in older patients with known cardiac disease, bradycardia, hypotension, and dysrhythmias have been observed in young healthy volunteers at acceptable infusion rates (50 mg/minute or less) (Barron, 1976; Earnest et al, 1983).
c) Complications will reportedly be minimized if IV phenytoin is administered in concentrations of 6.7 mg/mL or less and at rates of 40 mg/minute or less (Earnest et al, 1983).

B) CARDIOTOXICITY

1) WITH THERAPEUTIC USE

a) CHRONIC THERAPY: A 35-year-old man with a history of traumatic brain injury, epilepsy and pulmonary tuberculosis in a vegetative state, developed severe cardiotoxicity (i.e., junctional bradycardia, BP 87/75 mmHg) after receiving phenytoin 200 mg twice daily for approximately 5 months. Initial serum phenytoin was 91 mcg/mL, serum sodium was 121 mEq/L and serum potassium was 5.4 mEq/L. The patient was hemodynamically stabilized with temporary transvenous pacing, fluid resuscitation and inotropes. Electrolytes were corrected. ECG returned to normal sinus rhythm by day 3 with a phenytoin concentration of 67.3 mcg/mL. The patient gradually improved to baseline with intensive supportive care and the pacemaker was removed on day 13; phenytoin concentration was 2.65 mcg/mL (Su et al, 2009). The authors suggested that underlying metabolic derangements and a possible drug interaction with an anti-TB medication likely contributed to the toxicity observed in this patient.

C) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Hypotension appears to be common following intravenous phenytoin, and is concentration- and dose-related. Binder et al (1996) reported a 4.9% incidence of hypotension in a retrospective study of 164 cases of intravenous phenytoin toxicity in the emergency department setting (Binder et al, 1996). No apnea or dysrhythmias were reported in any cases.

D) CONDUCTION DISORDER OF THE HEART

1) WITH THERAPEUTIC USE

a) ORAL

1) In a retrospective review of 94 cases of phenytoin toxicity, ECG records were available in 71 patients. No abnormalities or hemodynamic instability were seen in any of the cases. Serum phenytoin concentrations were reported to range from 21.4 to 90 mcg/mL (Curtis et al, 1989).
2) No incidents of hypotension or dysrhythmia requiring treatment were revealed in 36 patients monitored by continuous single-lead ECG for a mean duration of 26.5 +/- 21.6 hours. Peak phenytoin concentration in these patients ranged from 40 to 76 mcg/mL (Wyte & Berk, 1989).

b) INTRAVENOUS

1) Atrial and ventricular conduction depression and ventricular fibrillation have been reported following high-dose infusions of phenytoin. These effects are more typically reported in elderly or gravely ill patients (Prod Info Dilantin(R) intravenous injection solution, 2011).

2) WITH POISONING/EXPOSURE

a) ORAL

1) Several cases of massive oral ingestion (10 g phenytoin or larger in an adult) with no development of hypotension or dysrhythmias have been described (Laubscher, 1966; Tichner & Enselberg, 1951; Griffiths et al, 1987; Weichbrodt & Elliott, 1987; Theil et al, 1961; Nauth-Misir, 1948; Mellick et al, 1989).
2) In a series of 38 phenytoin oral overdoses (36 chronic, 2 acute) no tachycardia, bradycardia, or cardiac dysrhythmias were noted (Wagner & Leikin, 1986).
3) In a retrospective review of 94 cases of phenytoin toxicity, ECG records were available in 71 patients. No abnormalities or hemodynamic instability were seen in any of the cases. Serum phenytoin concentrations were reported to range from 21.4 to 90 mcg/mL (Curtis et al, 1989).
4) No incidents of hypotension or dysrhythmia requiring treatment were revealed in 36 patients monitored by continuous single-lead ECG for a mean duration of 26.5 +/- 21.6 hours. Peak phenytoin concentration in these patients ranged from 40 to 76 mcg/mL (Wyte & Berk, 1989).
5) A retrospective study of 57 patients with acute phenytoin concentrations greater than 40 mcg/mL after oral overdose revealed no clinically significant cardiac abnormalities in 91% of cases. No deaths or circulatory complications were reported (Wyte & Berk, 1991).

b) INTRAVENOUS

E) CARDIAC ARREST

1) WITH THERAPEUTIC USE

a) Cardiotoxicity with hypotension, dysrhythmias, and cardiac arrest is a common complication of high dose phenytoin administered intravenously at a rate greater than 50 mg/minute. The vehicle for phenytoin, propylene glycol, is believed to be responsible for this effect (Prod Info Dilantin(R) intravenous injection solution, 2011).
b) CASE REPORT: Intravenous phenytoin administration was related to 8 deaths in elderly patients. Digoxin had been administered in 7 patients and 4 of these had evidence of digoxin toxicity.

1) Three patients were given rapid injections (1.7 to 2.5 mL/minute), while the remainder received 1 mL/minute or less.
2) Prior to death, sinus dysrhythmias, ventricular fibrillation, and asystole were noted (Gellerman & Martinez, 1967; Goldschlager & Karliner, 1967; Russell & Bousvaros, 1968; Unger & Sklaroff, 1967) (Zoneraich et al, 1976) (York & Coleridge, 1988).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Sudden asystole during a craniotomy procedure for aneurysm clipping after a mild subarachnoid hemorrhage is reported in a 49-year-old woman following a rapid unintentional infusion of 1500 mg of phenytoin. The patient was successfully resuscitated and the procedure completed, with full recovery noted by the ninth postoperative day (Berry et al, 1999).

Respiratory

3.6.2)

A) APNEA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A case of acute respiratory failure associated with eosinophilia was reported in an elderly patient who had been taking phenytoin 300 mg daily for 3 months. This and other signs were attributed to adverse drug reaction (Mahatma et al, 1989).

2) WITH POISONING/EXPOSURE

a) Apnea was reported in a fatal case (Laubscher, 1966).

B) ACUTE RESPIRATORY INSUFFICIENCY

1) WITH POISONING/EXPOSURE

a) Irregular shallow respirations and mild ventilatory deficiency have been described (Mellick et al, 1989).

C) PNEUMONIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Reversible interstitial pneumonitis, probably due to hypersensitivity, was seen in a 36-year-old man on therapeutic amounts of phenytoin (Michael & Rudin, 1981).

D) FIBROSIS OF LUNG

1) WITH THERAPEUTIC USE

a) CASE REPORT: A renopulmonary syndrome, requiring mechanical ventilation, was reported following 3 days of phenytoin therapy, including a 1000 mg loading dose. Lung biopsy revealed an interstitial fibrosis with lymphocytic and plasmacytic infiltration. No eosinophilic infiltration, vasculitis, or granuloma formation was present. Following discontinuation of phenytoin therapy and administration of corticosteroids, the patient recovered (Polman et al, 1998).

E) RADIOLOGIC INCREASED DENSITY OF LUNG

1) WITH THERAPEUTIC USE

a) Four days after beginning phenytoin therapy, a 32-year-old man with seizures secondary to head trauma, developed symptoms which mimicked a renopulmonary syndrome. The patient was febrile, dyspneic and developed renal failure. On chest x-ray, he had bilateral pulmonary infiltrates. After 5 days, phenytoin was stopped and prednisolone started with all symptoms resolving completely (Polman et al, 1998a).
b) Phenytoin-induced hypersensitivity reaction with bilateral pulmonary infiltrates and associated hypereosinophilia occurred in a 11-year-old boy receiving phenytoin 250 milligrams/day (Fruchter & Laptook, 1981).
c) An acute hypersensitivity reaction occurred in a 47-year-old man receiving phenytoin 100 milligrams every 6 hours. Clinical features of the reaction were shaking chills, cough, dyspnea, rash, and diffuse reticuloendothelial pulmonary infiltrates (Bayer et al, 1976).

Neurologic

3.7.2)

A) TOXIC ENCEPHALOPATHY

1) WITH THERAPEUTIC USE

a) ACUTE ENCEPHALOPATHY: The acute CNS effects include tremor of the hands, ataxia, nystagmus, and drowsiness.
b) CHRONIC ENCEPHALOPATHY: Chronic high blood concentrations may cause a "phenytoin encephalopathy" with increase in seizure frequency and the development of more tonic or opisthotonic components. Transient focal neurologic signs such as hemiparesis may be seen, especially in brain-damaged patients (Sandy, 1983).
c) CASE REPORT: Focal demyelination and loss of large myelinated fibers has been reported in one patient receiving 30 years of phenytoin treatment. The effects were seen to be partially reversible after 16 months phenytoin free (Ramirez et al, 1986).
d) Pleocytosis in the CSF is rare but has been reported as part of a delayed sensitivity reaction during therapeutic use (Duma et al, 1966).
e) A series of 11 patients on chronic therapy who developed elevated phenytoin concentrations underwent MRI. Five patients were found to have moderate to severe cerebellar atrophy; 2 patients never developed symptoms of phenytoin intoxication (Luef et al, 1994).

2) WITH POISONING/EXPOSURE

a) ACUTE ENCEPHALOPATHY: The acute CNS effects include tremor of the hands, ataxia, nystagmus, and drowsiness (Turkdogan et al, 2002).
b) CASE REPORT: Phenytoin toxicity resulting in encephalopathy and bilateral asterixis was reported in an 84-year-old man with a phenytoin serum concentration of 37 mg/L. On clinical examination, bilateral coarse intentional tremors, bilateral asterixis of the upper limbs, truncal ataxia, and a broad-based gait were reported. Signs of encephalopathy improved as his serum phenytoin concentration decreased (Chi et al, 2000).
c) Patients with phenytoin toxicity may present with neurological symptoms suggestive of meningo-encephalitis.

1) CASE REPORTS: A 2-year-old boy with a 15-day history of a head injury (linear fracture of the occipital bone), presented with fever, vomiting, lethargy, loss of speech, difficulty in walking and sitting, and multiple episodes of generalized tonic clonic seizures. Physical examination showed altered sensorium, terminal neck stiffness, nystagmus, decreased motor power, hyperreflexia in the lower limbs, and bilateral extensor plantar response. Although a diagnosis of meningo-encephalitis was made, all laboratory and diagnostic tests were normal. At this time, it was revealed that he had been receiving multiple loading doses of phenytoin at different healthcare facilities in the past 15 days without monitoring serum phenytoin concentrations. Laboratory results revealed a serum phenytoin concentration of 62.9 mcg/mL (normal: 10 to 20 mcg/mL). Following the discontinuation of phenytoin, his condition gradually improved with a repeat serum phenytoin concentration of 22.6 mcg/mL (Gupta et al, 2011).
2) CASE REPORT: A 3-year-old boy (weight, 10 kg) with a 13-day history of a head injury (fracture left frontal bone with associated extra dural hemorrhage), presented with fever, vomiting, 2 episodes of generalized tonic clonic seizures, and inability to walk and stand. Physical examination showed altered sensorium, nystagmus, urinary retention, decreased motor power in lower limbs and ataxia. Although a diagnosis of encephalitis was made, all laboratory and diagnostic tests were normal. At this time, it was revealed that he had been receiving phenytoin syrup 375 mg daily for the last 15 days. Laboratory results revealed a serum phenytoin concentration of 62.5 mcg/mL (normal: 10 to 20 mcg/mL). Following the discontinuation of phenytoin, his condition gradually improved and he was asymptomatic on day 9 (Gupta et al, 2011).

B) CEREBELLAR DISORDER

1) WITH THERAPEUTIC USE

a) Chronic phenytoin use has been implicated in chronic cerebellar degeneration causing ataxia unresponsive to discontinuation of the drug (Botez et al, 1985; Lindvall & Nilsson, 1984; Luef et al, 1996). Focal neurologic signs such as hemiparesis may also be present.
b) AKINETIC MUTISM: Phenytoin toxicity was associated with akinetic mutism in a 12-year-old epileptic girl. With a serum concentration greater than 40 mcg/mL, the girl displayed cyclical sleep/awake states, lacked mental acuity, was unable to speak, had orofacial dyskinesia and incontinence, and displayed no movements with either spontaneous or noxious stimuli. Mild cerebellar atrophy was seen on MRI. Phenytoin was discontinued and the patient started on carbamazepine. Within 2 months motor and mental activity returned to normal (Tutuncuoglu et al, 1997).

2) WITH POISONING/EXPOSURE

a) Cerebellar atrophy has been reported as a delayed and unusual effect following severe, acute overdoses. Acute phenytoin intoxication in a 25-year-old woman has been implicated in cerebellar atrophy (Alioglu et al, 2000). Clinical signs of encephalopathy and cerebellar dysfunction were noted on hospital admission (ataxia, nystagmus, diplopia, dysarthria, dysmetria, tremor). No signs of cerebellar atrophy were seen on MRI, but 8 months later MRI did show cerebellar atrophy. Brandolese et al (2001) also report a case of phenytoin toxicity resulting in dysarthria, nystagmus, dysmetria, hemifacial dyskinesia, and mental status changes (Brandolese et al, 2001).
b) CASE REPORT: A 21-year-old man had evidence of cerebellar atrophy by CT 4 weeks following an ingestion of 7 g phenytoin in a suicide attempt. Treatment included gastric lavage and plasmaphereses.

1) The phenytoin concentrations in plasma were more than 50 mcg/mL during the first two weeks, 18 mcg/mL after 20 days, and not detectable at six weeks after ingestion. At an 18-month follow-up, moderate dysarthria and dysmetria were detected (Masur et al, 1989).
2) There was no evidence of cerebellar atrophy by CT 8 months prior to intoxication. Four and one-half years after the suicide attempt, the CT showed the same degree of cerebellar atrophy and a moderate dysmetria was still present (Masur et al, 1990).

C) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures are a characteristic of an unusual type of phenytoin toxicity referred to as phenytoin encephalopathy, characterized by increasing seizures, electroencephalogram (EEG) changes, alteration in mental function, and certain motor and sensory disturbances. It is usually associated with toxic doses (but may appear in patients on usual doses) and is generally reversible upon discontinuation of phenytoin (Gupta et al, 2011; VanDerLinde & Campbell, 1977a; Shuttleworth et al, 1974; Vallarta et al, 1974).
b) CASE REPORT: Three patients, two with a prior history of seizure disorder, were reported to develop seizures following accidental or suicidal overdose of phenytoin.
c) Plasma concentrations at the time of presentation were 47, 73, and 49 mcg/mL, respectively (Stilman & Masdeu, 1985). Absent nystagmus is a significant negative finding. EEG readings may show marked slowing of alpha rhythm and the appearance of diffuse delta wave activity.
d) CASE SERIES: A retrospective study of 90 phenytoin-intoxicated patients (blood concentrations greater than 20 mcg/mL plus one or more clinical signs) revealed two cases with a highly probable causal relationship of seizures induced by phenytoin (Osorio et al, 1989).
e) CASE SERIES: Seizures occurred in 19% of one group of phenytoin-toxic patients (Murray et al, 1996).

D) COMA

1) WITH POISONING/EXPOSURE

a) CNS depression may be more pronounced in children following an acute overdose of oral phenytoin (Jacobsen et al, 1986-87). Coma has been reported in adults following overdoses of phenytoin (Lau et al, 2000).
b) CASE REPORT: Coma (GCS 3) and EEG showing diffuse abnormalities related to coma were reported in a 26-year-old woman following an overdose of approximately 12 g of phenytoin and an unknown amount of valproic acid. The patient recovered following serial doses of activated charcoal and symptomatic care (Buchwald, 2000).
c) CASE REPORT: Following the ingestion of several Chinese proprietary medicines, found later to be contaminated with phenytoin, a 33-year-old woman was admitted to the emergency department in a comatose condition with a phenytoin serum concentration of 48.5 mg/L. Her alertness gradually improved, but there was ataxia and bilateral ocular nystagmus 2 days later. Clinical signs resolved within 10 days with no permanent neurological defect (Lau et al, 2000).
d) CASE REPORT: Phenytoin toxicity consistent with upper motor neuron disease was reported in a middle aged female with elevated free phenytoin due to hypoalbuminemia. On clinical examination, bulbar weakness, diplopia, asymmetric motor weakness, hyperreflexia, and fasciculations were reported. The patient developed chest sepsis likely secondary to aspiration. After normalization of the corrected phenytoin concentration, motor weakness and respiratory function improved within 2 weeks (Veenith et al, 2009).

E) ATAXIA

1) WITH POISONING/EXPOSURE

a) Ataxia may be more pronounced in adults following an acute overdose of oral phenytoin (Jacobsen et al, 1986-87). Ataxia resulting in falls may occur as a result of phenytoin toxicity (Jessen, 2004; Pollak & Slayter, 1997). Ataxia has been reported following toxic serum concentrations of phenytoin (Mamiya et al, 2001).
b) CASE SERIES: In a retrospective review of 94 cases of phenytoin toxicity, ataxia was observed in 59 patients (63%) (Curtis et al, 1989).
c) CASE SERIES: In another study ataxia was seen in 88% of cases of phenytoin toxicity (Murray et al, 1996).
d) COCAINE ADULTERATION (CASE REPORT): A 26-year-old man ingested several crack cocaine rocks and was transported to an ED. He developed symptoms of cocaine toxicity (ie, anxiety, pallor, diaphoresis, agitation, tachycardia, and hypertension) 2 hours postingestion. He was treated with IV benzodiazepine boluses, however, he developed confusion, truncal ataxia, diplopia, slurred speech, and multidirectional nystagmus. At this time, phenytoin toxicity from cocaine adulteration was suspected and laboratory results revealed an elevated phenytoin concentration 48 mcg/mL (therapeutic range: 10 to 20 mcg/mL). Following further supportive care, he was discharged 72 hours after admission without further sequelae (Roldan, 2014).

F) MONOPLEGIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Monoplegia was reported to be associated with a serum phenytoin concentration of 28.1 mcg/mL in a 39-year-old woman ho had a hypertensive intracerebral hemorrhage two years earlier (Abdulhadi et al, 1987).

1) Symptoms resolved when the maintenance dose of phenytoin was decreased to produce a serum phenytoin concentration of 13.3 mcg/mL.

G) CHOREOATHETOSIS

1) WITH THERAPEUTIC USE

a) Phenytoin therapy has been associated with choreoathetosis, characterized by abnormal or jerky movements, lip smacking, continuous tongue movements, slurred speech, ataxia, dysarthria, and dystonic posturing. Choreoathetosis has occurred after days or years of therapy, and with phenytoin serum levels in the therapeutic or toxic range (Chalhub & DeVivo, 1976; Zinsmeister & Marks, 1976; Luhdorf & Lund, 1977; Rasmussen & Kristensen, 1977; Rosenblum et al, 1974; Kooiker & Sumi, 1974; McLellan & Swash, 1974; Krishnamoorthy et al, 1983). Attacks resolve after phenytoin withdrawal.
b) CASE REPORT: An elderly patient with hypoalbuminemia experienced choreoathetosis even at nontoxic blood phenytoin concentrations (Tomson, 1988).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Three patients with chronic phenytoin intoxication developed choreoathetoid movements (Shuttleworth et al, 1974a).
b) CASE REPORT: Choreoathetosis and opisthotonic posturing were reported in a 15-year-old boy after acute ingestion of 19.6 g of phenytoin(Mellick et al, 1989).
c) CASE REPORT: Dyskinesias as the only manifestation of phenytoin overdose were reported in a 20-year-old woman (Roullet et al, 1987).
d) CASE REPORT: Choreoathetosis, dystonia, ballismus, and asterixis have also been reported in patients with a phenytoin concentration above a therapeutic blood concentration (Lazaro, 1982).
e) CASE REPORT: A 4-year-old child presented with a 12-hour history of altered sensorium, involuntary head nodding movements, nystagmus, and a Glasgow coma scale of 10/15. Since her father was taking phenytoin, phenytoin intoxication was suspected. Laboratory results revealed a serum phenytoin concentration of 88 mcg/mL (therapeutic concentration: 10 to 20 mcg/mL). Activated charcoal therapy was not considered because it was about 42 hours postingestion. A week later, a repeat phenytoin serum concentration was still elevated (94 mcg/mL) and her sensorium was essentially unchanged. She gradually recovered following 4 sessions of charcoal hemoperfusion. She developed mild thrombocytopenia (platelet count of 90 to 100,000/mm) after the first session of charcoal hemoperfusion, which resolved on day 3. About 24 hours after each hemoperfusion, serum phenytoin concentrations were 56 mcg/mL, 26 mcg/mL, 23 mcg/mL, and 12 mcg/mL, respectively (Kumar et al, 2012).

H) DISTURBANCE IN SPEECH

1) WITH THERAPEUTIC USE

a) CASE REPORT: An 18-year-old man presented to his physicians office with complete mutism after 13 weeks of therapy with phenytoin 200 mg twice daily. Other presenting signs/symptoms of toxicity included motor tics, lateral gaze nystagmus, lower extremity coarse tremors and upper extremity athetoid-like movements. His phenytoin serum concentration was measured at 64.2 mcg/mL(Berigan & Watt, 1994).
b) Phenytoin toxicity was associated with akinetic mutism in a 12-year-old epileptic girl. With a serum level greater than 40 mcg/mL, the girl displayed cyclical sleep/awake states, lacked mental acuity, was unable to speak, had orofacial dyskinesia and incontinence, and displayed no movements with either spontaneous or noxious stimuli. Mild cerebellar atrophy was seen on magnetic resonance imaging (MRI). Phenytoin was discontinued and the patient started on carbamazepine. Within 2 months motor and mental activity returned to normal (Tutuncuoglu et al, 1997a).

2) WITH POISONING/EXPOSURE

a) Dysarthria may occur with toxic concentrations of phenytoin (Jessen, 2004; Grillone & Myssiorek, 1992).
b) CASE REPORT: A 19-year-old man developed dysarthria, nystagmus, ataxia and bilateral ankle clonus following the recreational use of phenytoin syrup, marijuana and alcohol. Upon admission 2 days after exposure, a serum phenytoin concentration was 45 mcg/mL; a toxicology screen was negative. Symptoms gradually improved as the phenytoin concentration decreased (Jessen, 2004).

I) CEREBELLAR INFARCTION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: One case of localized cerebellar necrosis has been associated with phenytoin overdose in a 32-month-old child. On admission, the phenytoin concentration was 72 mcg/mL and CT scan was normal; a repeat CT 6 months later revealed a zone of cerebellar necrosis without clinical signs (Cochat et al, 1987).
b) CASE REPORT: Severe cerebellar atrophy was described in a 38-year-old man following inadvertent administration of phenytoin 600 mg/day (instead of 300 mg/day) for 2 to 3 weeks. On hospital admission, a serum phenytoin concentration of 83.5 mcg/mL was reported. He had severe ataxia, urine incontinence and encephalopathy. Mild generalized atrophic changes in the cerebrum and cerebellum were seen on magnetic resonance brain scan. Recovery was slow, and the patient was discharged 30 days after admission (Kuruvilla & Bharucha, 1997).

J) HYPERREFLEXIA

1) WITH POISONING/EXPOSURE

a) Hyperreflexia is a frequent finding in overdose. The creatine kinase may be elevated due to agitation and muscle trauma (Mellick et al, 1989).

K) ALTERED MENTAL STATUS

1) WITH POISONING/EXPOSURE

a) Phenytoin toxicity may result in mental status changes, including confusion, combative behavior, memory impairment, agitation, hallucinations or delirium (Klaasen, 1998) (Kuruvilla & Bharucha, 1997; Pitner et al, 1998).
b) COCAINE ADULTERATION (CASE REPORT): A 26-year-old man ingested several crack cocaine rocks and was transported to an ED. He developed symptoms of cocaine toxicity (ie, anxiety, pallor, diaphoresis, agitation, tachycardia, and hypertension) 2 hours postingestion. He was treated with IV benzodiazepine boluses, however, he developed confusion, truncal ataxia, diplopia, slurred speech, and multidirectional nystagmus. At this time, phenytoin toxicity from cocaine adulteration was suspected and laboratory results revealed an elevated phenytoin concentration 48 mcg/mL (therapeutic range: 10 to 20 mcg/mL). Following further supportive care, he was discharged 72 hours after admission without further sequelae (Roldan, 2014).
c) CASE REPORT: A 4-year-old child presented with a 12-hour history of altered sensorium, involuntary head nodding movements, nystagmus, and a Glasgow coma scale of 10/15. Since her father was taking phenytoin, phenytoin intoxication was suspected. Laboratory results revealed a serum phenytoin concentration of 88 mcg/mL (therapeutic concentration: 10 to 20 mcg/mL). Activated charcoal therapy was not considered because it was about 42 hours postingestion. A week later, a repeat phenytoin serum concentration was still elevated (94 mcg/mL) and her sensorium was essentially unchanged. She gradually recovered following 4 sessions of charcoal hemoperfusion. She developed mild thrombocytopenia (platelet count of 90 to 100,000/mm) after the first session of charcoal hemoperfusion, which resolved on day 3. About 24 hours after each hemoperfusion, serum phenytoin concentrations were 56 mcg/mL, 26 mcg/mL, 23 mcg/mL, and 12 mcg/mL, respectively (Kumar et al, 2012).
d) CASE REPORTS: A 15-year-old child without a seizure disorder, ingested 1500 mg of phenytoin in a suicide attempt and presented 3 hours postingestion with ataxia, dysarthria, agitation, and generalized tonic-clonic seizure. Following supportive care, including multiple doses of activated charcoal and midazolam to control seizures and agitations, the child's condition gradually improved with extubation on day 4. The child's serum phenytoin concentrations at 14 hours and 21 hours postingestion were 30 mcg/mL and 39.64 mcg/mL, respectively, but gradually decreased to the therapeutic range 3 days postingestion (Gaies et al, 2011).
e) Patients with phenytoin toxicity may present with neurological symptoms suggestive of meningo-encephalitis.

L) DISORDER OF THE PERIPHERAL NERVOUS SYSTEM

1) WITH THERAPEUTIC USE

a) Sensory peripheral polyneuropathy has been observed in patients receiving phenytoin (Prod Info Dilantin-125(R) oral suspension, 2011; Prod Info DILANTIN(R) INFATABS(R) oral chewable tablets, 2011).
b) The literature on phenytoin-associated peripheral neuropathies has been reviewed. The clinical manifestations of peripheral nerve impairment among epileptic patients on long-term phenytoin therapy are reflexia in the lower extremities and sensory signs or symptoms. A subclinical state of peripheral nerve dysfunction as revealed by nerve conduction velocities on electromyogram (EMG) may also be present. The duration of therapy in patients with peripheral neuropathies is usually longer than 5 years and serum phenytoin levels have generally been higher than in unaffected patients. Although there is no correlation with either serum vitamin B12 or folate levels, deficiency at the tissue level has not been ruled out. Reversibility of phenytoin-induced peripheral nerve disorders is still not clear. It is important to screen for peripheral nerve dysfunction with peripheral nerve conduction velocities and electromyogram (EMG). Signs and symptoms have resolved following discontinuation of therapy or a correction of dose (So & Penry, 1981a).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH POISONING/EXPOSURE

a) Gastritis with nausea and vomiting may occur due to large amounts of undissolved drug in the stomach (Mellick et al, 1989).

B) DRUG-INDUCED ILEUS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A dosing miscalculation resulting in supratherapeutic dosing (40 mg 3 times/day for 10 days) of phenytoin in a one-month-old infant resulted in abdominal distension and ileus. Phenytoin serum concentration was reported to be 91.8 mcg/mL. Symptoms resolved following discontinuation of phenytoin (Lowry et al, 2005).

C) PANCREATITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Pancreatitis, with elevated amylase and lipase (1370 Units/L and 810 Units/L, respectively), was reported in a 26-year-old woman following the ingestion of approximately 12 g of phenytoin and an unknown amount of valproic acid. The patient recovered following symptomatic therapy (Buchwald, 2000).

Hepatic

3.9.2)

A) TOXIC HEPATITIS

1) WITH THERAPEUTIC USE

a) Toxic hepatitis and liver damage have been reported with phenytoin therapy (Prod Info Dilantin-125(R) oral suspension, 2011; Prod Info DILANTIN(R) INFATABS(R) oral chewable tablets, 2011).
b) The arene oxide metabolites of phenytoin may be involved in the pathogenesis of phenytoin-induced hepatotoxicity. Predisposition of some patients to phenytoin hepatotoxicity may be due to a heritable defect in response to arene oxides (Spielberg et al, 1981).
c) Twenty cases of hepatic injury associated with phenytoin therapy are presented. The interval between the beginning of therapy with phenytoin and the adverse drug reaction ranged from 1 to 8 weeks. Accompanying symptoms included fever (75%), rash (62.5%), eosinophilia (89%), and leukocytosis (100%). The morphological lesions included ground-glass transformation of liver cells, hepatocellular degeneration and/or necrosis, granulomatous reactions and infiltration of malignant cells of reticuloendothelial origin (Mullick & Ishak, 1980a).

B) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Mild elevation in LDH and SGOT were reported in a case of massive acute oral ingestion (Mellick et al, 1989).

Genitourinary

3.10.2)

A) BLOOD IN URINE

1) WITH THERAPEUTIC USE

a) There is no known clinical observation substantiating the reports which indicate phenytoin as a cause of red urine (Derby & Ward, 1983).

B) KIDNEY DISEASE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A case of nephrotic syndrome has been seen in a phenytoin-treated patient who also manifested a polyclonal gamma peak on serum electrophoresis. Other causes of renal signs were ruled out, and the patient improved dramatically after withdrawal of phenytoin therapy (Orlandini & Garini, 1989).
b) CASE REPORT: Renal dysfunction and rhabdomyolysis associated with a toxic reaction to phenytoin were reported in an adult man who was taking 300 mg daily phenytoin and phenobarbital 60 mg daily (Korman & Olson, 1989).
c) CASE REPORT: A 26-year-old man developed transient heavy proteinuria and glomerular podocytic lesions 3 weeks after beginning phenytoin therapy. He also had a fever and diffuse erythematous rash. Renal function was normal. Nephrotic range proteinuria (7.8 g/day) with 77% albumin was found. Serum albumin was 31 g/L and gamma-globulin was 14 g/L. A Coombs test was positive for IgG. After discontinuation of phenytoin, proteinuria decreased and was undetectable after 18 days (Messiaen et al, 1997).
d) CASE REPORT: An 83-year old woman developed phenytoin-induced nephrotic syndrome while on a low dosage (100 mg/day); after discontinuation of phenytoin, the clinical picture improved dramatically in a few days and proteinuria remained absent through a follow-up period of 60 days (Orlandini & Garini, 1989a).

C) RENAL FAILURE SYNDROME

1) WITH THERAPEUTIC USE

a) CASE REPORT: Renopulmonary syndrome is reported in early-onset phenytoin (4 days of therapy) toxicity in a 32-year-old man. Elevated serum urea of 18.5 mmol/L and serum creatinine of 607 micromoles/L were reported. Urinalysis revealed elevated red cells and leukocyturia with no casts. After stopping phenytoin and starting prednisolone, renal failure resolved by day 18 (Polman et al, 1998).

D) INTERSTITIAL NEPHRITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT/ADULT: A 63-year-old woman developed interstitial nephritis following treatment with phenytoin 600 mg/day for approximately 3 weeks. Although the patient was also receiving phenobarbital and cefazolin (known inducers of interstitial nephritis), it is believed that phenytoin was the most likely cause. Phenytoin-induced interstitial nephritis is believed to involve an immunologic mechanism which is consistent with the results of autopsy (chronic inflammatory infiltration of the liver, focal interstitial inflammatory infiltrate of the kidney and acute epidermal necrolysis) (Hoffman, 1981a).
b) CASE REPORT/CHILD: A 6-year-old epileptic treated with phenytoin 50 mg three times daily for one month developed a generalized scaly rash associated with symptoms of lethargy, fever, vomiting, and a seizure. Upon hospitalization the patient was febrile (40 degrees Celsius), noted to have hepatomegaly and a palpable spleen. Phenytoin was discontinued but jaundice became evident on the third hospital day associated with elevated liver function tests with the development of generalized lymphadenopathy on the seventh day. Creatinine clearance studies on the 18th hospital day demonstrated a value of 58 liters/24 hours/square meter with a renal biopsy that demonstrated interstitial nephritis with minimal granular changes. The patient was initiated on prednisone 40 mg/day which resulted in a rapid decrease in the patient's liver size, lymphadenopathy and the resolution of laboratory studies towards normal. Prednisone dosage reduction to 7.5 mg every other day was attempted but resulted in proteinuria requiring return to prednisone 10 mg every other day. Prednisone therapy was successfully discontinued 6 months later (Sheth et al, 1977).

E) PRIAPISM

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 34-year-old man on a total daily phenytoin dose of 540 mg experienced priapism, ataxia, confusion, and hyperactive reflexes. A blood phenytoin concentration was 38 mcg/mL and CT scan was normal. After treatment and reduction of phenytoin dose, priapism did not recur (Simsek & Ozyurt, 1988).

Hematologic

3.13.2)

A) MEGALOBLASTIC ANEMIA

1) WITH THERAPEUTIC USE

a) Megaloblastic anemia that is generally responsive to folic acid therapy has been reported in patients receiving phenytoin (Prod Info Dilantin-125(R) oral suspension, 2011; Prod Info DILANTIN(R) INFATABS(R) oral chewable tablets, 2011).

B) GRANULOMA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Reversible bone marrow granulomata were associated with phenytoin administration in an adult man (Eisenstein & Coleman, 1989).

C) THROMBOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) CASE REPORT: Fifteen days following initiation of phenytoin therapy (300 mg/day), severe thrombocytopenia (platelets, 8000/mm(3)), with a serum phenytoin concentration of 20 mg/L, was reported in a 36-year-old woman. Concurrent medications included dexamethasone and analgesics. The patient's platelet count returned to baseline after stopping phenytoin and administering several units of platelets and immune globulin therapy (Holtzer & Reisner-Keller, 1997).
b) CASE REPORT/TODDLER: A 2-year-old girl developed reversible thrombocytopenia 11 days after beginning phenytoin therapy. She had a Dandy-Walker malformation and ventriculoperitoneal shunt. She was started on phenytoin after a generalized tonic-clonic seizure following a fall with hematoma evacuation. At 11 days, she was lethargic and her platelet count was 14,000/microliter. Platelet counts returned to normal 5 days after phenytoin discontinuation (Alehan et al, 1999).

D) APLASTIC ANEMIA

1) WITH THERAPEUTIC USE

a) Aplastic anemia has occurred secondary to phenytoin administration, with the usual onset being 4 to 13 months after initiation of therapy (average, 9 months) (Robins, 1962a; Tomita et al, 1985a).
b) CASE REPORT: A 79-year-old man who had been taking phenytoin 200 mg/day for many years for seizure control presented with symptoms of pneumonia. He was found to have macrocytic unregenerative anemia, neutropenia, thrombocytopenia, and very low serum folate, and was diagnosed with aplastic anemia (AA). Serum phenytoin was 10 mcg/mL (therapeutic level 10 to 20 mcg/mL). Phenytoin was discontinued and he was treated with antibiotics, intravenous folic acid, and transfusions of packed red blood cells. One week later, hematological values were nearly normal, and bone marrow biopsy was normal. After prolonged convalescence, he was discharged without anticonvulsants and with normal hematological status. He experienced no seizures while hospitalized. The authors attributed the AA to the prolonged phenytoin treatment with concurrent folic acid deficiency and warned physicians to use caution when prescribing phenytoin for the elderly, in whom folic acid deficiency is not infrequent (Blain et al, 2002).

E) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) Leukopenia has been reported with phenytoin therapy (Prod Info Dilantin-125(R) oral suspension, 2011; Prod Info DILANTIN(R) INFATABS(R) oral chewable tablets, 2011).

F) HEMATOLOGY FINDING

1) WITH THERAPEUTIC USE

a) A cohort study investigating frequency of serious blood dyscrasias in patients taking anticonvulsants has reported the total overall rate for all patients was 3 to 4 per 100,000 prescriptions. Rates did not differ between phenytoin, phenobarbital, carbamazepine, or valproate throughout all age groups (Blackburn et al, 1998).

Dermatologic

3.14.2)

A) ERYTHEMA MULTIFORME

1) WITH THERAPEUTIC USE

a) Severe erythema multiforme, exfoliative dermatitis, and Stevens-Johnson syndrome have been reported as hypersensitivity reactions (Watts, 1962).

B) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE

1) WITH THERAPEUTIC USE

a) Toxic epidermal necrolysis has been reported as an adverse effect of phenytoin therapy, and is associated with high fever, eosinophilic necrosis of keratinocytes with subepidermal separation (Sun et al, 1994; Sherertz et al, 1985; Schmidt & Kluge, 1983a). Severe cutaneous drug reactions, including toxic epidermal necrolysis, have been associated with phenytoin therapy and with drug interactions between corticosteroids, H2-blockers, and phenytoin, all taken concurrently (Cohen et al, 1999).

C) STEVENS-JOHNSON SYNDROME

1) WITH THERAPEUTIC USE

a) Drug-induced Stevens-Johnson syndrome, an uncommon reaction characterized by atypical target lesions with widespread blisters on the face, mucous membranes, trunk and extremities, has been reported in patients receiving concomitant cranial radiotherapy and phenytoin therapy (Khafaga et al, 1999).
b) Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been described occasionally during the early stages of phenytoin therapy. In a case-control study of patients taking various antiepileptic agents, 73 cases of SJS or TEN were identified; of these, 14 were due to phenytoin ingestion. SJS and TEN generally occurred during the first 8 weeks of therapy (Rzany et al, 1999).
c) A 2.5-year-old girl developed Stevens-Johnson syndrome following the administration of phenytoin. Four days after the discontinuation of phenobarbital and the initiation of phenytoin, bullous lesions appeared on the child. By the eighth day, severe sloughing of the skin occurred over 75% of the body and Stevens- Johnson syndrome was diagnosed (Crosby et al, 1986).

D) EDEMA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Severe facial edema, including periorbital edema so severe that the eyelids cannot open, has been reported (Helmy & Tripplet, 1988).

E) INJECTION SITE INFLAMMATION

1) WITH THERAPEUTIC USE

a) PURPLE GLOVE SYNDROME

1) Purple glove syndrome (PGS) is described following intravenous infusions of phenytoin. The incidence of PGS in a series of 152 patients receiving IV phenytoin was 5.9% (9 patients). PGS is a progressive development of limb edema, discoloration, and pain after phenytoin administration, with some patients developing skin ulceration. Elderly patients and patients receiving large, multiple IV doses appear to be at greatest risk. The vehicles in phenytoin injections (propylene glycol, ethanol, and sodium hydroxide), which are irritants, may contribute to PGS, especially if extravasation occurs (O'Brien et al, 1998).

F) LUPUS ERYTHEMATOSUS

1) WITH THERAPEUTIC USE

a) Rare cases of lupus erythematosus have been reported in patients receiving phenytoin (Prod Info Dilantin-125(R) oral suspension, 2011; Prod Info DILANTIN(R) INFATABS(R) oral chewable tablets, 2011).

G) HYPERTRICHOSIS

1) WITH THERAPEUTIC USE

a) Hypertrichosis has been reported in patients receiving phenytoin (Prod Info Dilantin-125(R) oral suspension, 2011; Prod Info DILANTIN(R) INFATABS(R) oral chewable tablets, 2011).

H) COARSE FEATURES

1) WITH THERAPEUTIC USE

a) The coarsening of facial features has been reported in patients taking phenytoin (Prod Info Dilantin-125(R) oral suspension, 2011; Prod Info DILANTIN(R) INFATABS(R) oral chewable tablets, 2011).

Musculoskeletal

3.15.2)

A) REFLEX FINDING

1) WITH THERAPEUTIC USE

a) Hyper and hyporeflexia have commonly been reported and it is not uncommon for the examination to change over a short time period (Mellick et al, 1989).

B) OSTEOMALACIA

1) WITH THERAPEUTIC USE

a) CHRONIC EXPOSURE: Osteomalacia has been reported in patients receiving long-term phenytoin therapy (greater than 10 years) (Prod Info Dilantin-125(R) oral suspension, 2011; Prod Info DILANTIN(R) INFATABS(R) oral chewable tablets, 2011).

Endocrine

3.16.2)

A) HYPERGLYCEMIA

1) WITH THERAPEUTIC USE

a) Hyperglycemia (due to the inhibition of insulin release) and elevated serum glucose levels in diabetics have been reported in patients taking phenytoin (Prod Info Dilantin-125(R) oral suspension, 2011; Prod Info DILANTIN(R) INFATABS(R) oral chewable tablets, 2011).
b) CASE REPORT: An 11-year-old boy treated with 200 to 300 mg/day for 3 years along with other anticonvulsants developed ataxia, headache, vomiting, drowsiness, and glycosuria (plasma glucose of 280 mg/dL). Oral glucose tolerance test revealed results indicative of a diabetic curve and in addition, the patient's insulin levels were noted to be raised. Plasma phenytoin level at that time was determined to be 4.4 mg/dl. Discontinuation of phenytoin resulted in the phenytoin level of 2.2 mg/dl 5 days later with normal neurological signs at 3 days. One month later, the patient had a normal glucose tolerance test and was potentially convulsion free on primidone 250 mg/day (Treasure & Toseland, 1971a).

2) WITH POISONING/EXPOSURE

a) Hyperglycemia may rarely be noted and is due to altered carbohydrate tolerance. No significant change in electrolytes, glucose, WBC, or alkaline phosphatase occurred after acute phenytoin overdose (Wagner & Leikin, 1986).

B) HYPOGLYCEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A case of hypoglycemia following an intentional overdose of phenytoin (20 g) and zopiclone (225 mg) was reported in a 27-year-old man. There was no personal history of diabetes or alcohol abuse. Blood glucose initially increased, then declined and became refractory to treatment, which included hypertonic dextrose and a total of 32 g of dextrose, which was necessary to maintain blood glucose over 81 mg/dL between hour 23 and 25 (Manto et al, 1996a).

1) No evidence of a pancreatic tumor was reported. Laboratory tests included normal plasma ACTH and cortisol and normal urine cortisone. The authors suggested a mechanism of an escape from the inhibitory effects of DPH on insulin secretion, and/or increased sensitivity of the tissues to insulin (Manto et al, 1996a).

C) HYPOTHYROIDISM

1) WITH POISONING/EXPOSURE

a) Reversible hypothyroidism has been reported in multiple cases of chronic phenytoin toxicity (Betteridge & Fink, 2009; Sarich & Wright, 1996; Kushnir et al, 1985). One proposed mechanism dubbed "a vicious circle" involves the induction of hepatic monooxygenase by phenytoin leading to increased clearance of free T4. The resulting decreased serum concentrations of T4 results in decreased activity of hepatic NADPH cytochrome P-450 reductase leading to decreased rates of hydroxylation and inactivation of phenytoin (Sarich & Wright, 1996).

Immunologic

3.19.2)

A) LYMPHADENOPATHY

1) WITH THERAPEUTIC USE

a) Lymphadenopathy, including benign lymph node hyperplasia, pseudolymphoma, lymphoma and Hodgkin's disease, has been reported in patients receiving phenytoin. Lymph node involvement may occur with or without symptoms indicative of serum sickness, such as fever, rash and hepatic involvement (Prod Info Dilantin-125(R) oral suspension, 2011; Prod Info DILANTIN(R) INFATABS(R) oral chewable tablets, 2011).
b) Lymphadenopathy that mimics malignant lymphoma has been commonly reported. A few cases exist in which patients on anticonvulsant therapy developed malignant lymphoma, but the association is unproved (Helmy & Tripplet, 1988).

B) ACUTE ALLERGIC REACTION

1) WITH THERAPEUTIC USE

a) Hypersensitivity reactions are manifested by skin rashes, fever, neutropenia, and agranulocytosis and occur following chronic administration of therapeutic doses. Dermatitis and/or hepatitis is unlikely following acute overdose. Hypersensitivity reactions include severe erythema multiforme, exfoliative dermatitis, and Stevens-Johnson syndrome.
b) Hepatitis may be a hypersensitivity reaction, usually appearing with fever, lymphadenopathy, blood dyscrasia (neutropenia, agranulocytosis) (Crawford & Jones, 1962; Ebeid et al, 1989; Black & Fivenson, 1989).
c) TOXIC EPIDERMAL NECROLYSIS: A fatal necrolysis reaction was associated with prophylactic phenytoin therapy (Kelly & Hope, 1989).
d) Renal failure (Micheal & Mitch, 1976) (Agarwal et al, 1977), encephalopathy (Ambrosetto et al, 1977), myositis (Chaiken et al, 1950), cerebrospinal fluid pleocytosis (Duma et al, 1966), rhabdomyolysis (Engel et al, 1986) , and pulmonary infiltrates with hypereosinophilia (Fruchter & Laptook, 1981; Bayer et al, 1976) have also been noted.
e) VASCULITIS: Hypersensitivity vasculitis generally occurs 7 to 10 days after initiation of phenytoin therapy, but may occur after years of therapy. Most commonly, the skin is affected, with purpura or macular eruptions. Renal involvement, with hematuria, nephrotic syndrome and acute renal failure is also common. All organs may be affected, and autoimmune profile is generally negative (Parry et al, 1996).

Reproductive

3.20.1)

3.20.2)

A) CONGENITAL ANOMALY

1) In studies, increased frequencies of major malformations (eg, cardiac defects, orofacial clefts), minor abnormalities (eg, dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (eg, microcephaly), and mental deficiency have been reported in children born to women administered phenytoin during pregnancy (Prod Info Dilantin-125(R) oral suspension, 2015). Eye malformations (eg, abnormality of the lacrimal apparatus, congenital glaucoma, epicanthal folds, hypertelorism, optic nerve hypoplasia, ptosis, retinoschisis, and strabismus) have also been observed (Grant & Schuman, 1993).
2) FETAL HYDANTOIN SYNDROME: Chronic therapy with phenytoin during pregnancy has been associated with fetal hydantoin syndrome (FHS), characterized by intrauterine growth retardation, microcephaly, mental retardation, rigid metopic suture, inner epicanthal folds, eyelid ptosis, a broad depressed nasal bridge, nail and/or distal phalangeal hypoplasia, and inguinal hernia. Other effects are cardiovascular (patent ductus arteriosus), gastrointestinal, or genitourinary (renal anomalies, ambiguous genitalia, oral ectopia, pyloric stenosis) (Kogutt, 1984; Barr et al, 1974; Hanson et al, 1976; Hanson & Smith, 1975). The full syndrome has been found in 10% to 11% of exposed newborns and appears to have a genetic influence (Witter et al, 1981). Approximately 40% of newborns exposed to phenytoin in utero will exhibit some features of the disorder (Seeler et al, 1979). Isolated case reports describe polydactyly of the right foot (Yalcinkaya et al, 1997), placental lymphocytosis (Greco et al, 1973), and neonatal acne and suggest an association with phenytoin use during pregnancy (Stankler & Campbell, 1980).
3) Neocerebellar hypoplasia and multiple other malformations were seen in an infant born to a mother taking 175 mg phenytoin and 1 g sodium valproate daily throughout the pregnancy (Squier et al, 1990). Midface and digital hypoplasia have been associated with anticonvulsant-exposed (ie, phenytoin, phenobarbital, and carbamazepine) children. In some cases, these children may have cognitive dysfunction. In the presence of these conditions further developmental evaluation is suggested (Holmes et al, 2005).
4) Cardiac defects, cleft lip and palate, intrauterine growth retardation, and irregular ossification and hypoplasia of the distal phalanges have been noted (Schardein, 1985; Gaily, 1990).

B) ANIMAL STUDIES

1) Growth impairment, behavior abnormalities, and increased incidences of fetal malformations were observed when phenytoin was administered to animals at clinically relevant doses (Prod Info Dilantin-125(R) oral suspension, 2015).
2) Increased resorption and malformation rates were reported in pregnant rabbits given phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m(2) basis) (Prod Info DILANTIN KAPSEALS(R) extended oral capsules, 2007).

3.20.3)

A) PREGNANCY CATEGORY

1) ETHOTOIN (Prod Info PEGANONE(R) oral tablets, 2007).
2) PHENYTOIN (Prod Info Dilantin-125(R) oral suspension, 2015).
3) PHENYTOIN SODIUM (Prod Info DILANTIN KAPSEALS(R) extended oral capsules, 2007).

1) The manufacturers have classified the following as FDA pregnancy category D:
2) If used during pregnancy or if patient becomes pregnant, weigh the risks and benefits of use during pregnancy, inform the patient of the potential harm to the fetus, and measure phenytoin plasma concentrations periodically. Prevent potentially life-threatening bleeding disorders in the infant by administering vitamin K to the mother before delivery and then to the neonate after birth (Prod Info Dilantin-125(R) oral suspension, 2015).

B) PREGNANCY REGISTRY

1) Encourage enrollment in the North American Antiepileptic Drug (NAAED) Pregnancy Registry (1-888-233-2334) for any woman who becomes pregnant while being treated phenytoin (refer to http://www.aedpregnancyregistry.org/ for more information) (Prod Info Dilantin-125(R) oral suspension, 2015).

C) NEOPLASM

1) There have been isolated reports of malignancies, including neuroblastoma, in offspring of phenytoin-treated women (Prod Info DILANTIN KAPSEALS(R) extended oral capsules, 2007). Neoplasms in infants with fetal hydantoin syndrome (FHS) also have been reported (Allen et al, 1980; Ehrenbard & Chaganti, 1981; Cohen, 1981), suggesting that phenytoin may be a human transplacental carcinogen. However, other researchers studied the incidence of reported cases of neuroblastoma associated with FHS between 1976 and 1988 and concluded that, while there may be a slightly increased risk of neuroblastoma in children with FHS, there was no association between phenytoin use in pregnancy and postnatal neuroblastoma (Koren et al, 1989). Phenytoin has been linked with transplacental tumorigenesis of the kidney, ureter, and bladder (RTECS, 2001).

D) DEPRESSION OF CLOTTING FACTORS AND HEMORRHAGE

1) Phenytoin therapy can cause depression of clotting factors and hemorrhage in the newborn. This condition can be prevented with vitamin K administration to the mother before delivery and to the neonate. Phenytoin serum level monitoring throughout pregnancy is also recommended (Prod Info Dilantin-125(R) oral suspension, 2015; Prod Info DILANTIN KAPSEALS(R) extended oral capsules, 2007). However, in one study, no increased incidence of neonatal blood coagulation disorders was reported in a series of women taking phenytoin throughout pregnancy (Hey, 1999). In addition, no increased incidence of vitamin K deficiency in neonates was reported (Hey, 1999)

E) COGNITIVE IMPAIRMENT

1) Phenytoin exposure during pregnancy has been associated with impaired neurobehavioral development resulting in lower cognitive abilities. In a prospective study, children exposed in utero to phenytoin had mean lower global intelligence quotient (IQ) points than their matched controls (Scolnik et al, 1994).

F) MORE FREQUENT SEIZURES

1) Seizures may occur more frequently in pregnant women when phenytoin is used during pregnancy (Prod Info Dilantin-125(R) oral suspension, 2015).

G) ANIMAL STUDIES

1) Embryofetal death was observed when phenytoin was administered at clinically relevant doses (Prod Info Dilantin-125(R) oral suspension, 2015).
2) A syndrome comparable to fetal hydantoin syndrome has been produced in mice. Genetic strain differences were seen in susceptibility, and the induction of the disorder occurred in offspring of dams who did not have seizure disorders (Finnell et al, 1989). Some genetic differences have been linked with the H-2a haplotype in the H-2 major histocompatibility family on chromosome 17 in mice (Goldman et al, 1983), and others with a gene in the minor H-3 histocompatibility locus on chromosome 2 (Goldman, 1984).
3) Male rats exposed prenatally to levels of phenytoin sodium of 50 or 100 mg/kg on day 17 of gestation through day 7 postpartum had permanent reductions in seminal vesicle weight; female reproduction was normal (Shapiro & Babalola, 1987).

3.20.4)

A) BREAST MILK

1) Breastfeeding while taking phenytoin is not recommended (Prod Info Dilantin-125(R) oral suspension, 2015). However, phenytoin is considered to be compatible with breastfeeding by the American Academy of Pediatrics (Anon, 2001) and the World Health Organization (Anon, 1995). Monitor infant for side effects.
2) Phenytoin is excreted into human breast milk. The phenytoin milk to plasma ratios range from approximately 0.06 to 0.55 (Mirkin, 1971; Kaneko et al, 1979; Rane et al, 1974; Steen et al, 1982). Following a maternal dose of 100 mg 3 times a day, the peak concentration in breast milk was 4 mcg/mL (4 mg/L) 3 hours after oral ingestion (daily therapeutic dose in infants, 5 to 7 mg/kg) (Chaplin et al, 1982; Horning et al, 1975). With no further dosing, a stable level of 1 to 2 mcg/mL remained throughout the day (Horning et al, 1975).
3) One case has been reported in which a breastfed infant developed drowsiness, ecchymoses, and methemoglobinemia. The infant's mother was reported to have received 400 mg phenytoin and 390 mg of phenobarbital daily during pregnancy and the puerperium. The infant was noted to be cyanotic on the fourth day of life (confirmed to be associated with the methemoglobinemia) and upon rechallenge with the mother's breast milk 5 days later became cyanotic again (Finch & Lorber, 1954; Illingworth, 1953).
4) In one study, 38 breast-fed infants whose mothers received phenytoin 300 to 600 mg daily were followed. The infants did not develop any drowsiness or lethargy (Sparberg, 1963).

3.20.5)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info Dilantin-125(R) oral suspension, 2015).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS57-41-0 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) IARC Classification

a) Listed as: Phenytoin
b) Carcinogen Rating: 2B

1) The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.

B) IARC Carcinogenicity Ratings for CAS630-93-3 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

3.21.3)

A) LYMPHOMA

1) Phenytoin is a transplacental carcinogen and has been linked mainly with embryonal tumors of neural crest origin in the first 3 years of life. One case of childhood T-lymphocyte lymphoblastic lymphoma has been reported (Murray et al, 1996). One case of Epstein Barr virus-positive non-Hodgkin's lymphoma has been reported in a person after 20 years of phenytoin therapy; the lymphoma was preceded by benign reactive lymphadenopathy (Garcia-Suarez et al, 1996).

B) NEUROBLASTOMA

1) There have been isolated reports of malignancies, including neuroblastoma, in offspring of phenytoin-treated women (Prod Info Dilantin-125(R) oral suspension, 2015; Lipson & Bale, 1985; Koren et al, 1989a). Neoplasms in infants with fetal hydantoin syndrome (FHS) have also been reported (Allen et al, 1980; Ehrenbard & Chaganti, 1981; Cohen, 1981).

3.21.4)

A) HEPATOCELLULAR TUMORS

1) Increased incidences of hepatocellular tumors were observed in mice at phenytoin doses of 45 mg/kg/day (peak plasma levels below human therapeutic concentrations) and also in female mice at doses up to approximately 90 mg/kg/day (Prod Info Dilantin-125(R) oral suspension, 2015).

B) LYMPHOMA

1) Phenytoin sodium induced thymic lymphomas in female mice when given in the feed at a level of 60 mg/kg body weight/day for 168 days (HSDB , 1995). Thymic and mesenteric lymphomas and leukemias were induced in mice with IP doses of 0.6 mg/ animal/day for 66 days (HSDB , 1995).

C) LACK OF EFFECT

1) Phenytoin was not carcinogenic in rats when given at doses up to 100 mg/kg/day (peak plasma levels below human therapeutic concentrations) for 2 years. No increased incidences of tumors were observed when given to rats at doses up to approximately 120 mg/kg/day (Prod Info Dilantin-125(R) oral suspension, 2015).
2) Phenytoin was not carcinogenic in rats when given in the diet at levels of 0.025 or 0.05% for 2 years (Jang et al, 1987). It was also not carcinogenic in mice at dietary levels of 0.006 or 0.12% for 78 weeks (Maeda et al, 1988).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Obtain a basic metabolic panel, aspirin concentration, and acetaminophen concentration after deliberate overdose.
B) Monitor phenytoin concentrations every 4 hours until clearly declining.
C) Monitor serial neurologic examinations.
D) Obtain an ECG and institute continuous cardiac monitoring during and after rapid intravenous infusion or intravenous overdose.
E) Obtain serum albumin concentration as phenytoin toxicity may occur in the setting of normal total serum phenytoin concentrations, but elevated free phenytoin concentrations.
F) Some clinical effects reported in elevated phenytoin concentrations include:

4.1.2)

1) One study reported undetectable total serum phenytoin levels in a 52-year-old man with adequate phenytoin therapy. All laboratory results, including serum IgG, IgA, and IgM concentrations were normal and Human anti mouse antibody (HAMA) was undetectable. However, elevated levels of serum free kappa light chains (20 mg/L), urine free kappa light chains (43.1 mg/L), and urine kappa/lambda light chain ratio (17.52) were observed. It was concluded that the undetectable total serum phenytoin levels may have been caused by the assay interference from excess immunoglobulins (Rentmeester et al, 2015).

D) TOXICITY

1) Total serum phenytoin (free phenytoin concentration when possible) will allow assessment of severity.
2) Blood concentrations are available and generally seem to correlate with the acute neurological symptoms.

a) Nystagmus usually appears at about 20 mcg/mL, ataxia at about 30 mcg/mL, and drowsiness at a concentration of 40 mcg/mL. Death can occur at phenytoin concentrations greater than 100 mcg/mL.
b) Intoxication is rare with total phenytoin blood concentration under 20 mcg/mL, or unbound phenytoin concentrations below 1.5 mcg/L.

3) In acute oral overdose, a minimum of 2 serial concentrations are recommended, due to delayed absorption, even if the initial concentrations are negligible.

E) BLOOD/SERUM CHEMISTRY

1) Monitor renal and hepatic function tests in patients with significant toxicity.

4.1.4)

A) OTHER

1) MONITORING

a) Serial neurologic examinations may be necessary during follow-up in patients with severe phenytoin-induced ataxia. Magnetic resonance volumetry has been used to assess damage to the cerebellum after overdoses (Luef et al, 1996).
b) Obtain an ECG and institute continuous cardiac monitoring during and after rapid intravenous infusion or intravenous overdose.

2) HAIR

a) Tsatsakis et al (2000) reported hair sectional analysis with dissolution, liquid phase extraction procedures, and immunoassay or HPLC. These methods may determine a history of phenytoin drug use, with hair phenytoin concentration dependent on the drug dosage. Differences among drug doses according to hair color appeared significant (Tsatsakis et al, 2000).

Methods

1) These are very general guidelines, and considerable individual variation exists. Some phenytoin preparations contain phenobarbital. Several different methods are available for determining phenytoin concentrations.
2) Care must be taken with the Svensmark and Kristensen method, since ethosuximide, primidone, mephenytoin, metharbital, bishydroxy coumarin, phenylbutazone, oil of cloves, and oil of sassafrass may alter the laboratory results.
3) In general, current measurement methods are accurate and show good inter-test correlation (Painter et al, 1983).
4) It should be noted that oxalate and citrate anticoagulation show statistically significant depression of serum phenytoin measurements by EMIT and GLC methods (Godolphin et al, 1983).
5) Commonly used assays of phenytoin monitor total drug concentrations.

a) Quantitation of free drug may be more appropriate in evaluating patient response when pathophysiologic conditions (renal insufficiency and hypoalbuminemia) alter the plasma protein binding of phenytoin (Toler et al, 1990; Phelps et al, 1993).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients who have worsening symptoms after 4 to 6 hours or with significant ataxia or CNS depression, and those with rising serum concentrations, should be admitted to the hospital. If the CNS depression is severe enough that there is respiratory depression or concern of airway protection, the patient should be admitted to an intensive care setting. Otherwise, most patients can be safely admitted to a hospital ward bed. Criteria for discharge from the hospital should include clinical symptomatic improvement, which should be reflected by declining phenytoin serum concentrations.

6.3.1.2) HOME CRITERIA/ORAL

A) For unintentional ingestions where the patient is asymptomatic and the dose is less than 20 mg/kg, the patient can be observed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) In patients with cardiac toxicity secondary to the intravenous formulation of phenytoin, it might be reasonable to consult a cardiologist. Neurologists are often very familiar with both the acute and chronic toxicity of phenytoin. Consult a medical toxicologist or poison center for patients with severe toxicity.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Any intentional overdose or inadvertent overdoses above 20 mg/kg, or if symptomatic, the patient should be sent to a healthcare facility for observation. Patients should be observed for at least 4 to 6 hours, and should not be sent home until symptoms are clearly improving, or they are asymptomatic and serum concentrations are clearly declining.
B) Cardiac monitoring is not necessary following ORAL overdose (Wyte & Berk, 1989; Evers et al, 1997). This does not imply that all oral overdoses can safely be admitted to the medical floor. Some patients may require ICU admission for reasons other than cardiac monitoring (CNS or respiratory depression, suicide precautions, etc).

1) In a retrospective 4 year chart review of 44 patients with a diagnosis of oral phenytoin overdose (serum concentrations greater than 20 mcg/mL), ECG readings at time of admission in all 44 patients revealed no clinically significant phenytoin related abnormalities. No cardiovascular dysrhythmias or deaths were reported, even with serum concentrations as high as 75 mcg/mL (Evers et al, 1997).

6.3.2)

6.3.2.4) PATIENT TRANSFER/PARENTERAL

A) Cardiac monitoring is advisable following parenteral overdose or rapid infusions in adults and infants/pediatrics.
B) Some patients may require ICU admission.

Monitoring

Oral Exposure

6.5.1)

A) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

b) ADVERSE EFFECTS/CONTRAINDICATIONS

B) MULTIPLE DOSE ACTIVATED CHARCOAL

1) Multiple dose activated charcoal has not been shown to affect patient outcome, need for, or duration of hospitalization after phenytoin overdose. Routine use of multiple dose activated charcoal is generally not warranted; it may be considered in the rare patient with a life-threatening ingestion. Administration of a second dose of activated charcoal should be considered in patients with rising serum concentrations or worsening clinical condition despite gastric decontamination.
2) STUDIES

a) Administration of multiple doses of activated charcoal to volunteers receiving intravenous phenytoin resulted in a decrease in apparent half-life from 44.5 to 22.3 hours (Mauro et al, 1987).
b) Rowden et al (1990) reported a significant decrease in the area under the curve and in total body clearance associated with administration of activated charcoal in 15 normal volunteers who received 15 mg/kg of phenytoin by intravenous infusion (Rowden et al, 1990).
c) In a randomized, controlled study, patients with serum phenytoin concentrations of greater than 30 mg/L received either 50 g of activated charcoal orally every 4 hours (n=7 patients) or no activated charcoal (n=8 controls). Serum phenytoin concentrations were obtained every 6 hours for 1 day, then every 24 hours. A subtoxic phenytoin concentration was reached 11.6 to 196 hours (median time: 41.1 hours) in the control group and 13 to 33 hours (median time: 19.3 hours) in the multiple activated charcoal group (p=0.049). The multiple activated charcoal and control groups had median peak serum concentrations of 35.6 hours (range, 32.5 to 40 hours) and 40 hours (range, 32 to 47.6 hours), respectively (p=0.082). The multiple activated charcoal and control groups had median mini-mental status exam (MMSE) scores of 19.5 points (range, 16 to 29) and 20 points (range, 12 to 30), respectively. Overall, multiple doses of activated charcoal decreased the time to reach subtoxic concentrations of serum phenytoin. No adverse effects were observed in any patients (Skinner et al, 2012).
d) GENETIC POLYMORPHISMS: Administration of multiple-dose activated charcoal (MDAC) to 2 patients with chronic phenytoin toxicity, secondary to genetic polymorphisms of CYP2C9 and 2C19, resulted in a rapid and large reductions in the measured elimination half-lives (before MDAC: 117 hours and no apparent elimination; after MDAC: 27 and 44 hours, respectively). Another patient was not treated with multiple-dose activated charcoal and had a very prolonged elimination of phenytoin (178 hours) (Chan et al, 2015).

3) CASE REPORTS

a) Administration of activated charcoal 30 grams every 6 hours to a 38-year-old woman who had ingested 10 to 15 grams of phenytoin resulted in a peak serum concentration 42.5 hours postingestion (compared to historical controls of at least 4 days) and a return to therapeutic concentrations by 5.8 days (Weichbrodt & Elliott, 1987).
b) Weidle et al (1991) also found multiple dose activated charcoal to be useful when treating a 67-year-old woman with phenytoin toxicity (Weidle et al, 1991).
c) Multiple-dose activated charcoal given in 4 doses was used in lowering serum phenytoin in a patient with acute on chronic phenytoin toxicity; serum concentration declined from 186.7 micromoles/liter to within the therapeutic range within 36 hours (Howard et al, 1994).
d) In several pediatric cases, multiple-dose charcoal greatly decreased absorption of phenytoin (Dolgin et al, 1991; Ros & Black, 1989).

6.5.3)

A) SUPPORT

1) Most cases of intoxications may be managed conservatively with good symptomatic and supportive care. Signs and symptoms of toxicity may persist up to 7 to 10 days after ingestion. Serial neurologic examinations may be necessary in patients with severe ataxia. No antidote is currently available for phenytoin overdoses.

B) SEIZURE

1) Seizures are extremely rare after acute overdose, and their occurrence should initiate a search for other causes, unless the patient is epileptic.
2) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

3) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

4) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

5) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

6) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976b; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

7) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

C) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

D) BRADYCARDIA

1) ATROPINE/DOSE

a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.

1) There is no minimum dose (de Caen et al, 2015).
2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).

E) MONITORING OF PATIENT

1) Obtain a basic metabolic panel, aspirin concentration, and acetaminophen concentration after deliberate overdose.
2) Monitor phenytoin concentrations every 4 hours until clearly declining.
3) Monitor serial neurologic examinations.
4) Obtain an ECG and institute continuous cardiac monitoring during and after rapid intravenous infusion or intravenous overdose.

a) Cardiac telemetry monitoring is generally not necessary following oral overdoses (Evers et al, 1997).

5) Obtain serum albumin concentration as phenytoin toxicity may occur in the setting of normal total serum phenytoin concentrations, but elevated free phenytoin concentrations.
6) Some clinical effects reported in elevated phenytoin concentrations include:

a) greater than 20 mcg/mL: far lateral nystagmus
b) greater than 30 mcg/mL: 45 degrees lateral gaze nystagmus and ataxia
c) greater than 40 mcg/mL: decreased mentation
d) greater than 100 mcg/mL: death

F) EXPERIMENTAL THERAPY

1) ALBUMIN: Intravenous administration of albumin 25 g every 6 hours in an attempt to increase the bound fraction of phenytoin has been tried in a patient who overdosed on 6.2 g of phenytoin.

a) Symptoms were markedly decreased at a phenytoin concentration of 61.8 mcg/mL and serum albumin 6.6 mg/dL compared to earlier marked ataxia and lethargy with a phenytoin concentration of 54.6 mcg/mL and normal serum albumin.
b) Free serum phenytoin concentrations were not measured in this case, thus a beneficial effect cannot be directly attributed to the albumin (Black et al, 1987).

Enhanced Elimination

1) In a systematic review of literature that included 51 studies, including 30 case reports/case series (31 patients), 17 pharmacokinetic studies (54 patients), 1 animal experiment, and 3 in vitro studies, the Extracorporeal Treatments in Poisoning (EXTRIP) workgroup (included international experts) concluded that phenytoin is moderately dialyzable, despite its high protein binding, and recommended the use of ECTR in selected patients with severe phenytoin toxicity. Despite a low quality of evidence for all recommendations, the following guideline was provided (Anseeuw et al, 2016):

a) ECTR is suggested (Anseeuw et al, 2016):

1) If prolonged coma is present or expected.

b) ECTR is reasonable (Anseeuw et al, 2016):

1) If prolonged incapacitating ataxia is present or expected.

c) ECTR is NOT recommended (Anseeuw et al, 2016):

1) If solely based on suspected ingested dose of phenytoin or based on serum phenytoin concentration.

d) Discontinuation of ECTR is recommended (Anseeuw et al, 2016):

1) In patients with apparent clinical improvement.

e) The preferred ECTR is intermittent hemodialysis, with an acceptable alternative being intermittent hemoperfusion, if hemodialysis is not available (Anseeuw et al, 2016).

1) The addition of 2.5% albumin to dialysate significantly enhance dialytic clearance of valproic acid and carbamazepine, but did not increase clearance of phenytoin in one study (Churchwell et al, 2009).

1) Peritoneal dialysis or exchange transfusion appears to remove less than 1.5% and 11%, respectively, of total body burden and are of no value following acute phenytoin intoxication (Lindahl & Westerling, 1982).
2) Peritoneal dialysis with a 5% albumin dialysate removed approximately 15% of the total body burden over 9 hours and was considered ineffective in a 3-year-old boy with chronic phenytoin overdose (Czajka et al, 1980).
3) Narcy et al (1990) reported success in decreasing phenytoin concentrations in a newborn poisoned by an intravenous dose. Peritoneal dialysis removed 1.8 mg/hr of phenytoin and decreased the incidence of previously seen cardiac signs of toxicity. The authors postulated that peritoneal dialysis was successful in this infant due to a high unbound protein fraction and a high diffusion speed through the peritoneum (Narcy et al, 1990).

1) Diuresis is ineffective since less than 4% of the drug is excreted unchanged in the urine.

1) CASE REPORT: A 35-year-old woman with a severe iatrogenic intravenous phenytoin overdose with a peak plasma concentration of 117 mg/L was started on a combination of high-flux hemodialysis and activated charcoal hemoperfusion. The patient received a cumulative phenytoin dose of approximately 3150 mg (the maximum recommended dose 1500 mg in first 24 hours followed by 500 mg the following day) intravenously over 48 hours. After 4 hours of hemodiaperfusion with activated charcoal, the patient showed signs of clinical improvement with a phenytoin concentration of 74 mg/L. Two more sessions were performed for ongoing clinical symptoms and an elevated phenytoin concentration. Calculated half-life was reduced to between 7 to 13 hours during these procedures, as compared to between 40 to 100 hours with no intervention. No adverse events occurred. The patient was clinically stable and made an uneventful recovery (Eyer et al, 2008).
2) CASE REPORT: A 49-year-old woman with a recent history of hepatic failure, hyperammonemia, metabolic encephalopathy, coma and facial epilepsy was started on phenytoin. Because of ongoing severe hypoalbuminemia and persistent coma, a free phenytoin concentration was 4.7 mcg/mL (normal values 1 to 2 mcg/mL). The patient was started on a combination of high-flux dialyzer and hemoperfusion using a charcoal filter containing 300 g active charcoal. It was found that the combination of hemodialysis/hemoperfusion was able to significantly reduce the amount of free phenytoin. To evaluate the efficacy of each procedure separately, phenytoin concentrations were obtained before the dialyzer and between the dialyzer and charcoal filter. High-flux dialysis was found to lower free phenytoin fraction concentrations faster, with an average extraction of 38% (+/- 5%), as compared to 16% (+/- 6%) by charcoal. No rebound effects were observed. By day 3, the patient regained consciousness, but died 3 weeks later due to a bowel infarction with refractory lactic acidosis and shock (DeSchoenmakere et al, 2005). The authors concluded that the combination of therapies enhanced the overall clearance of phenytoin and improved clinical signs of toxicity. Further study with a larger patient group is suggested.
3) CASE REPORT: A 32-year-old man presented to the ED with ataxia and nystagmus one hour after ingesting approximately 17.5 grams of phenytoin. A phenytoin concentration, obtained 6 hours postadmission, was 96 mg/L. Over the next several days, following decontamination with activated charcoal, the patient was intubated due to obtundation and an increased risk of aspiration following emesis. His phenytoin concentration, on hospital day 8, remained elevated at 76 mg/L, therefore hemodialysis (HD) was performed. Although his phenytoin concentration decreased to 51.7 after the 4-hour HD session, his clinical status remained unchanged. On day 10, hemoperfusion (HP) was performed. Again, after the 4-hour HP session, his phenytoin concentration decreased to 38 mg/L, however his clinical status remained unchanged, and his phenytoin concentration rebounded to 52 mg/L 30 hours later. Over the next 2 weeks the patient's phenytoin concentration continued to decrease and he was extubated. Over the next year, the patient continued to have residual cognitive and functional impairment that gradually improved with rehabilitation (Miller et al, 2006).

1) CASE REPORT: A 4-year-old child presented with a 12-hour history of altered sensorium, involuntary head nodding movements, nystagmus, and a Glasgow coma scale of 10/15. Since her father was taking phenytoin, phenytoin intoxication was suspected. Laboratory results revealed a serum phenytoin concentration of 88 mcg/mL (therapeutic concentration: 10 to 20 mcg/mL). Activated charcoal therapy was not considered because it was about 42 hours postingestion. A week later, a repeat phenytoin serum concentration was still elevated (94 mcg/mL) and her sensorium was essentially unchanged. She gradually recovered following 4 sessions of charcoal hemoperfusion. She developed mild thrombocytopenia (platelet count of 90 to 100,000/mm) after the first session of charcoal hemoperfusion, which resolved on day 3. About 24 hours after each hemoperfusion, serum phenytoin concentrations were 56 mcg/mL, 26 mcg/mL, 23 mcg/mL, and 12 mcg/mL, respectively (Kumar et al, 2012).
2) CASE REPORT: A 77-year-old man being treated prophylactically with phenytoin 100 mg 3 times daily following a head injury developed ataxia and dizziness 7 days after the start of therapy. The phenytoin plasma concentration was 39.3 mg/L approximately 18 hours after the last dose, and thrombocytopenia and hematuria were also present on admission. Despite phenytoin withdrawal the plasma concentration remained elevated due to slow metabolism, and the patient underwent four 9-hour charcoal hemoperfusion sessions with the concentration decreasing to 3 mg/L. The patient also received colony stimulating factor and antibiotics for a gradual decline in his absolute neutrophil count with a nadir of 0.015 x 10(9)/L along with fever. No residual effects were reported and the patient was discharged on hospital day 26 (Sung et al, 2004).
3) Kawasaki et al (2000) reported on the successful use of charcoal hemoperfusion in the treatment of a phenytoin overdose. Plasma concentrations of total and free phenytoin fell rapidly, from 40.0 mcg/mL and 3.6 mcg/mL to 16.2 mcg/mL and 1.5 mcg/mL, respectively, following 3 hours of hemoperfusion. The fraction of protein-bound phenytoin remained constant (approximately 90%). Bound phenytoin was reported to dissociate from plasma proteins in the presence of activated charcoal, becoming adsorbed to the charcoal. In this case, charcoal hemoperfusion was effective for the removal of a drug that binds to plasma proteins with a low binding constant (Kawasaki et al, 2000).

1) Plasmapheresis removes only a small amount of the burden of phenytoin, and in one case the plasma concentration had even increased after plasma exchange (White et al, 1987). Plasmapheresis is of limited value (Silberstein & Shaw, 1986; Larsen et al, 1986).

1) Continuous venous-venous hemofiltration (CVVH) with charcoal filter has been used in an 8-month-old child who sustained bradyasystolic arrest after infusion of 750 mg fosphenytoin over 15 minutes. Serum phenytoin concentrations were 77.2 mcg/mL (total) 1 hour after infusion, 73.8 mcg/mL (total) and 13 mcg/mL (free) 8 hours later, and 82 mcg/mL (total) 16 hours later. Approximately 24 hours after the infusion CVVH was performed for 4 hours. About one hour after completion of CVVH, total and free serum phenytoin concentrations were 33.9 mcg/mL and 3.9 mcg/mL, respectively (Rose et al, 1998).

1) Multiple dose activated charcoal has not been shown to affect patient outcome, need for or duration of hospitalization after phenytoin overdose. Routine use of multiple dose activated charcoal is generally not warranted; it may be considered in the rare patient with a life threatening ingestion. Administration of a second dose of activated charcoal should be considered in patients with rising serum concentrations or worsening clinical condition despite gastric decontamination.
2) STUDIES

3) CASE REPORTS

a) Administration of activated charcoal 30 g every 6 hours to a 38-year-old woman who had ingested 10 to 15 g of phenytoin resulted in a peak serum concentration 42.5 hours postingestion (compared to historical controls of at least 4 days) and a return to therapeutic concentrations by 5.8 days (Weichbrodt & Elliott, 1987).
b) Weidle et al (1991) also found multiple dose activated charcoal to be useful when treating a 67-year-old woman with phenytoin toxicity (Weidle et al, 1991).
c) Multiple-dose activated charcoal given in 4 doses was used in lowering serum phenytoin in a patient with acute on chronic phenytoin toxicity; a serum concentration declined from 186.7 micromoles/liter to within the therapeutic range within 36 hours (Howard et al, 1994).
d) In several pediatric cases, multiple-dose charcoal greatly decreased absorption of phenytoin (Dolgin et al, 1991; Ros & Black, 1989).

Abstracts

Case Reports

1) A 15-year-old boy ingested 19.6 g of phenytoin (392 mg/kg). He was found comatose with evidence of vomiting, shallow respirations, choreoathetoid movements, and occasional opisthotonus. Hyperreflexia and ankle clonus were present (Mellick et al, 1989).

a) Gastric lavage was performed and multiple dose activated charcoal was initiated. The peak phenytoin concentration occurred on the second day at 100.8 mcg/mL. During the first 3 days, combativeness, severe agitation, and responsiveness only to pain were noted.
b) Laboratory findings on the third day included elevated creatine phosphokinase (6267 Units/L) and elevated LFTs (LDH 2247 Units/L, SGOT 171 Units/L, total bilirubin 1.4 mg/dL). By the fifth day he was oriented and ataxic with serum concentrations of 42 mcg/mL. He was discharged to psychiatric care on day 8.

1) A neonate born prematurely to a drug-abusing mother was accidentally dosed with 55 mg/kg phenytoin instead of the calcium gluconate that was ordered. Phenytoin blood concentration was 93.2 mcg/mL, and the infant became unresponsive and apneic. With supportive care, the patient recovered without incident. The erroneous medication administration was attributed to the similarity of the drug product packages (Lombardi et al, 1989).
2) A one-month-old girl was unintentionally dosed with phenytoin 40 mg 3 times/day for 10 days, instead of the intended dose of 15 mg 3 times/day. The patient presented with hypothermia, abdominal distension and ileus, as well as poor responsiveness. Phenytoin serum concentration was reported to be 91.8 mcg/mL. Symptoms resolved following discontinuation of phenytoin (Lowry et al, 2005).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) SEIZURE DISORDER

1) ETHOTOIN

a) Initial dose, 1 g or less, daily, orally in 4 to 6 divided doses; may be increased over a period of several days up to a maintenance dose of 2 to 3 g daily (Prod Info Peganone(R) oral tablets, 2013).

2) PHENYTOIN

a) CHEWABLE ORAL TABLETS: 2 tablets (50 mg each) 3 times daily; usual maintenance dose 6 to 8 tablets/day (300 to 400 mg/day); MAX: 12 tablets/day (600 mg/day) (Prod Info Dilantin(R) Infatabs(R) oral chewable tablets, 2014)
b) EXTENDED-RELEASE CAPSULES: 100 mg orally 3 times a day; usual maintenance dose is 100 mg orally 3 to 4 times a day. Doses up to 200 mg orally 3 times a day may be used if necessary. Patients established on 100 mg 3 times a day may take one 300-mg extended-release capsule once daily (Prod Info Dilantin(R) oral extended release capsules, 2014; Prod Info DILANTIN(R) extended capsule, oral, 2009).
c) ORAL SUSPENSION: 125 mg (5 mL) 3 times daily; adjust dose every 7 to 10 days as necessary (maximum: 625 mg/day) (Prod Info DILANTIN-125(R) oral suspension, 2003).
d) INJECTABLE SOLUTION: 100 to 200 mg IM every 4 hours during surgery and continued during the postoperative period (Prod Info phenytoin sodium intravenous, intramuscular injection, 2010)
e) INJECTABLE SOLUTION, NONEMERGENT: 10 to 15 mg/kg IV loading dose (at a rate not exceeding 50 mg/min), followed maintenance doses 100 mg orally or IV every 6 to 8 hours (Prod Info Dilantin(R) intravenous injection solution, 2011; Prod Info phenytoin sodium intravenous, intramuscular injection, 2010).
f) INJECTABLE SOLUTION, SUBSTITUTION FOR ORAL PHENYTOIN: Continue same total daily dose, at a rate not exceeding 50 mg/min IV (Prod Info Dilantin(R) intravenous injection solution, 2011).

7.2.2)

A) SEIZURE DISORDER

1) ETHOTOIN

a) Initial oral dose should not exceed 750 mg daily; maintenance dose ranges from 500 to 1 g daily (Prod Info Peganone(R) oral tablets, 2013).

2) PHENYTOIN

a) CHEWABLE ORAL TABLETS: 5 mg/kg/day in 2 or 3 divided doses; usual maintenance dose 4 to 8 mg/kg. MAX: 300 mg/day. Children over the age of 6 years may require minimum adult dose of 300 mg/day (Prod Info Dilantin(R) Infatabs(R) oral chewable tablets, 2014).
b) EXTENDED-RELEASE CAPSULES: Initial dose, 5 mg/kg/day orally divided equally into 2 or 3 doses; maintenance dose, 4 to 8 mg/kg/day. MAX: 300 mg/day. Children over the age of 6 years may require minimum adult dose of 300 mg/day (Prod Info Dilantin(R) oral extended release capsules, 2014).
c) INJECTABLE SOLUTION, NONEMERGENT: 15 to 20 mg/kg IV loading dose, at a rate not exceeding 1 to 3 mg/kg/min or 50 mg/min (whichever is slower) (Prod Info Dilantin(R) intravenous injection solution, 2011).
d) INJECTABLE SOLUTION, SUBSTITUTION FOR ORAL PHENYTOIN: continue same total daily dose at a rate not exceeding 1 to 3 mg/kg/min or 50 mg/min (whichever is slower) (Prod Info Dilantin(R) intravenous injection solution, 2011).
e) ORAL SUSPENSION, ORAL TABLETS (Infatabs(R)): 5 mg/kg/day divided equally into 2 or 3 doses to a subsequent MAXIMUM of 300 mg/day; usual maintenance dose is 4 to 8 mg/kg/day; children over the age of 6 years may require minimum adult dose (300 mg/day) (Prod Info DILANTIN(R) KAPSEALS(R) oral capsule, 2003; Prod Info DILANTIN-125(R) oral suspension, 2003).
f) MAINTENANCE THERAPY: The average mg/kg/day oral dose required to achieve a phenytoin level of 15 mcg/mL was as follows: (Bauer & Blouin, 1983)
g) 0.5 to 3 years of age, 9.7 mg/kg/day.
h) 4 to 6 years of age, 7.5 mg/kg/day.
i) 7 to 9 years of age, 7 mg/kg/day.
j) 10 to 16 years of age, 6 mg/kg/day.

Minimum Lethal Exposure

1) ORAL: Estimates of the minimal lethal dosage are unreliable. Deaths are very rare even with massive acute oral overdosage and have been reported mostly with the relatively serious hypersensitivity reactions seen with chronic use. The lowest published lethal dose in a human child is 100 mg/kg (RTECS , 2001).

1) PEDIATRIC

a) One 7-year-old boy who ingested 2 g phenytoin (100 mg/kg) presented comatose, but later developed vigorous motor activity, tetanic spasms, and Kussmaul respirations. He died 42 hours postingestion (Schmeiser, 1952).
b) A 4.5-year-old girl ingested 2 g phenytoin (160 mg/kg), and hyperactivity was the first sign of intoxication, but this progressed to ataxia, miosis, epigastric pain, and generalized pruritus. Later the ataxia worsened with the patient becoming lethargic and unresponsive and she lapsed into a coma. Eighty hours after the onset of symptoms the patient died (Laubscher, 1966).
c) A 3-year-old boy who ingested 3.2 g phenytoin (220 mg/kg) became lethargic, then comatose without reflexes. He experienced several minor seizures and died 34 hours postingestion (Petty et al, 1957).

2) ADULT

a) CHRONIC THERAPY: A 35-year-old man with a history of traumatic brain injury, epilepsy and pulmonary tuberculosis in a vegetative state developed severe cardiotoxicity (ie, junctional bradycardia, hypotension) after receiving phenytoin 200 mg twice daily for approximately 5 months. After transvenous pacing and intensive supportive care, the patient returned to baseline within 2 weeks (Su et al, 2009). The authors suggested that underlying metabolic derangements and a possible drug interaction (receiving an anti-TB agent) may have contributed to phenytoin toxicity in this patient.
b) ACUTE: Two adult men, a 37-year-old and an 18-year-old, were found dead in their homes after taking overdoses of phenytoin the previous evening. Phenytoin serum concentrations in each patient several hours postmortem were 45 mcg/mL and 48 mcg/mL, respectively (Coutselinis et al, 1975).

1) INTRAVENOUS: Death may be seen after rapid intravenous administration of phenytoin from severe hypoperfusion with intractable shock, cardiac standstill, ventricular fibrillation, or respiratory arrest. These effects are nearly always rate related (Prod Info Dilantin(R) intravenous injection solution, 2011).

Maximum Tolerated Exposure

1) Many cases of mild to moderately acute overdoses with phenytoin are reported. Also a few cases of acute overdose are reported in which patients survived ingestion of large amounts of oral phenytoin.

1) ADULT

a) ORAL TOXICITY

1) There have been reports in the literature of adults ingesting between 4.5 g (Robinson, 1940; Black et al, 1987; Weichbrodt & Elliott, 1987; Blair et al, 1968; Miller et al, 2006; Theil et al, 1961; Grosz, 1956) up to 25 g of phenytoin (Nauth-Misir, 1948).
2) A 20-year-old epileptic male ingested 15 g of primidone and 12 g of phenytoin (17 mg/kg), and had a phenytoin plasma concentration of 130 mcg/mL approximately 96 hours after ingestion. Peritoneal dialysis was begun and phenytoin plasma concentrations decreased from 130 mcg/mL to 30 mcg/mL over a 12-hour period, with recovery of greater than 450 mg phenytoin in the dialysate. In this case, it appears that peritoneal dialysis contributed to the lowering of phenytoin plasma concentrations (Blair et al, 1968).
3) An 18-year-old pregnant epileptic ingested phenobarbital 2.4 grams and phenytoin 21.5 grams. At 138 hours postingestion the phenytoin concentration was 50 mcg/mL. Because of a lack of improvement in the patient's condition, she received hemodialysis for 6 hours. Phenytoin plasma concentrations dropped from 50 mcg/mL to 4 mcg/mL following dialysis. Although attempts to measure phenytoin in the dialysate were unsuccessful, it appears that dialysis contributed to the decrease in phenytoin concentrations (Theil et al, 1961).
4) A 15-year-old boy with absence seizures ingested 19.6 g of phenytoin. The peak phenytoin concentration occurred 2 days postingestion and was 100.8 mcg/mL (Mellick et al, 1989).
5) A 38-year-old man with a history of a right ganglia hemorrhage, seizures and diabetes mellitus ingested an unknown amount of alcohol and 10 g of phenytoin (133 mg/kg) and was initially alert and complaining of nausea and vomiting with evidence of ataxia. Serum phenytoin concentration peaked on day 15 at 90 mcg/mL. Despite aggressive supportive care including whole bowel irrigation (ileus developed and treatment was stopped) and charcoal hemoperfusion, the patient had persistently elevated phenytoin concentrations and progressing cerebellar toxicity. Phenytoin concentrations eventually dropped with the administration of multidose charcoal, but the patient was discharged to a rehabilitation center 100 days after admission with permanent cerebellar dysfunction (Craig, 2004).
6) A 32-year-old man presented to the ED with ataxia and nystagmus 1 hour after ingesting approximately 17.5 g of phenytoin. Despite decontamination with activated charcoal, the patient's serum phenytoin concentration peaked at 96 mg/L approximately 7 hours postingestion. Over the next several days, the patient was intubated, due to obtundation and a risk of aspiration following emesis. His phenytoin concentrations also fluctuated following hemodialysis and hemoperfusion sessions, although his clinical status remained unchanged. Gradually, his phenytoin concentration decreased and he was extubated. Over the next year, the patient continued to experience residual cognitive and functional impairment which slowly improved with rehabilitation (Miller et al, 2006).

b) INTRAVENOUS TOXICITY

1) INADVERTENT EXPOSURE: A peak phenytoin plasma concentration of 117 mg/L was reported in a 35-year-old woman after receiving a cumulative phenytoin intravenous dose of approximately 3150 mg over 48 hours. She developed symptoms of violent agitation, confusion, drowsiness with nystagmus, dysarthria and cerebellar ataxia. The patient recovered completely following several sessions of hemodialysis and hemoperfusion (Eyer et al, 2008).
2) Following a change in phenytoin oral dosing (100 mg 3 times per day) to the same dose given intravenously, phenytoin toxicity was reported in a 52-year-old man 5 days later. Neurologic findings, including mandibular tremor, encephalopathy and nystagmus (not related to his hydrocephalus) were reported, as well as a phenytoin serum concentration of 42 mcg/mL (Turkdogan et al, 2002).

2) PEDIATRIC

a) A 2.5-year-old boy ingested approximately 2.8 g phenytoin suspension (249 mg/kg). At 70 hours postingestion, the phenytoin plasma concentration was 112 mcg/mL. Peritoneal dialysis was begun and 16 hours later the concentration dropped to 75 mcg/mL. After 36 hours of dialysis the phenytoin serum concentration was 35 mcg/mL. However, analysis of the dialysis showed only "trace" phenytoin. The contribution of the dialysis to the lowering of the plasma concentrations in the patient is questionable based on the dialysate findings and the slow decrease in phenytoin concentrations (Tenckhoff et al, 1968).

1) Severe phenytoin intoxication may result from altered protein binding associated with disease states. Agitation, lethargy, lack of response to deep pain, and bilateral clonus developed in a 25-year-old HIV positive woman while receiving a maintenance dose of phenytoin of 400 mg/day. Her total serum phenytoin concentration was 10.9 mcg/mL with a free phenytoin concentration of 4.9 mcg/mL (normal 1 to 2 mcg/mL) (Toler et al, 1990).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) PHENYTOIN

a) An upper limit for therapeutic phenytoin serum concentration is generally considered at 20 mcg/mL. In some cases, though, supratherapeutic concentrations are required to control seizures. In a 9-year-old girl, concentrations as high as 40 mcg/mL were necessary to control her seizure disorder (Kozer et al, 2002). No signs of toxicity, other than nystagmus, were evident at this serum concentration.

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) SUMMARY

a) THERAPEUTIC CONCENTRATIONS: 10 to 20 mcg/mL (Blaser et al, 1989).
b) TOXIC EFFECTS: Usually seen at concentrations greater than 30 mcg/mL (Boyd, 1986). Commonly, nystagmus develops at concentrations around 20 mcg/mL. At 30 mcg/mL, ataxia develops and lethargy is seen at about 40 mcg/mL (Gilman et al, 1990).
c) CASE REPORTS

1) CHRONIC THERAPY: A peak phenytoin plasma concentration of 91 mcg/mL was observed in a 35-year-old man with a history of traumatic brain injury, epilepsy and pulmonary tuberculosis in a vegetative state. Severe cardiotoxicity (ie, junctional bradycardia, hypotension) occurred after receiving phenytoin 200 mg twice daily for approximately 5 months (Su et al, 2009). The authors suggested that underlying metabolic derangements and a possible drug interaction (receiving an anti-TB agent) may have also contributed to phenytoin toxicity in this patient.
2) A peak phenytoin plasma concentration of 117 mg/L was reported in a 35-year-old woman after receiving a cumulative phenytoin intravenous dose of approximately 3150 mg over 48 hours. She developed significant CNS toxicity and recovered completely following several sessions of hemodialysis and hemoperfusion (Eyer et al, 2008).
3) A phenytoin concentration of 41 mcg/mL was reported at 9 hours following an ingestion of 100 capsules of phenytoin 100 mg in a 21-year-old woman (Griffiths et al, 1987).
4) In one series of patients, admission phenytoin serum concentrations following an overdose were not a useful predictor of length of hospital stay (Curtis et al, 1989).
5) Plasma concentrations as high as 112 and 108 mg/mL have been reported in intoxicated children (Larsen & Larsen, 1989).
6) In a case of severe phenytoin toxicity following 10 days of therapeutic dosing (100 mg 3 times daily) in a patient homozygous for CYP2C9*3, a serum concentration of greater than 100 mg/L was reported. Clinical manifestations of dysarthria, nystagmus, dysmetria, left hemifacial dyskinesia, and mental status changes were reported (Brandolese et al, 2001).
7) FREE PHENYTOIN: The proportion of phenytoin in the blood not bound to protein is an important measure of potential toxicity.

a) Levels of free phenytoin less than 1.5 mcg/mL had no signs of toxicity; 1.5 to 3 mcg/mL was seen with mild intoxication; 3.5 to 5 mcg/mL was associated with some signs of toxicity in all subjects and concentrations greater than 5 mcg/mL were associated with severe intoxication in all subjects (Larsen & Larsen, 1989).

Workplace Standards

1) Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 2B ; Listed as: Phenytoin

a) 2B : The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

1) Not Listed

Toxicity Information

7.7.1)

A) PHENYTOIN

1) LD50- (ORAL)MOUSE:

a) 150 mg/kg (RTECS, 2001)

2) LD50- (ORAL)RAT:

a) 1635 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

1) A report of 4 critically ill patients who were started on phenytoin following seizures during their ICU stay developed elevated free phenytoin concentrations and clinical signs of phenytoin toxicity with mildly elevated or normal total phenytoin concentrations. All patients had serum albumin concentrations less than 2 g/dL (Lindow & Wijdicks, 1994).
2) These patients are at risk of overdosage when given normal therapeutic doses and frequently manifest signs of toxicity (Toler et al, 1990; Driscoll et al, 1988; Tomson, 1988).
3) Patients at high risk for hypoproteinemia include the elderly, those who are HIV positive, and those with chronic debilitating disease.

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

References

General Bibliography

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PHENYTOIN

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

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Neurologic

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Genitourinary

Hematologic

Dermatologic

Musculoskeletal

Endocrine

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Methods

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Monitoring

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Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography