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Special Alerts

Antiepileptics: Increased Risk of Suicidal Behavior or Ideation - February, 2008

The U.S. Food and Drug Administration (FDA) is informing healthcare professionals of an increased risk of suicidality (suicidal behavior or ideation) observed from analysis of clinical studies using various antiepileptic medications compared to placebo. The analysis was performed on 199 placebo-controlled studies involving 43,892 patients (27,863 treated patients versus 16,029 placebo patients) aged ?5 years receiving one of the following 11 drugs: Carbamazepine (Carbatrol®, Equetro™, Tegretol®, Tegretol® XR), felbamate (Felbatol®), gabapentin (Neurontin®), lamotrigine (Lamictal®), levetiracetam (Keppra®), oxcarbazepine (Trileptal®), pregabalin (Lyrica®), tiagabine (Gabitril®), topiramate (Topamax®), valproate (Depakote®, Depakote® ER, Depakene®, Depacon®), and zonisamide (Zonegran®). Studies examined medication efficacy in a variety of disorders, including epilepsy, psychiatric disorders (eg, depression, bipolar disorder), and other conditions (eg, migraine, neuropathic pain). According to the FDA, the results revealed a statistically significant increased risk of suicidality in 0.43% treated patients compared to 0.22% placebo patients, or an estimated 2.1 per 1000 (95% CI: 0.7, 4.2) more patients in the treated groups relative to placebo. This increased risk was reported anywhere from 1 week of therapy through 24 weeks. However, most trials were ?24 weeks duration and the risk of suicide extending beyond 24 weeks is currently unknown. The relative risk of suicidal behavior or ideation in the treated patients was higher for patients with epilepsy (RR=3.6) compared to patients treated for psychiatric (RR=1.6) or other conditions (RR=2.3). Overall, the incidence of suicidal behavior or ideation occurred consistently across all demographic subgroups and with each of the drugs studied. Of note, four patients receiving an antiepileptic committed suicide relative to none in the placebo groups.

Forthcoming product labeling changes are likely to extend to all antiepileptic drugs and not limited to the drugs used in the studies, pending discussions scheduled for the upcoming advisory committee meeting. Healthcare professionals and family members/caregivers are encouraged to monitor patients receiving any antiepileptic medication for signs/symptoms of suicidality (eg, anxiety, depression, behavior changes). Patients should not stop taking their antiepileptic therapy unless advised by a healthcare professional.

Additional information can be found at http://www.fda.gov/medwatch/safety/2008/safety08.htm#Antiepileptic

Medication Safety Issues

Sound-alike/look-alike issues:

Phenytoin may be confused with phenelzine, phentermine

Dilantin® may be confused with Dilaudid®, diltiazem, Dipentum®

High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication (I.V. formulation) among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

International issues:

Dilantin® may be confused with Dolantine® which is a brand name for pethidine in Belgium and Switzerland

Pronunciation

(FEN i toyn)

U.S. Brand Names

• Dilantin®
• Phenytek®

Index Terms

• Diphenylhydantoin
• DPH
• Phenytoin Sodium
• Phenytoin Sodium, Extended
• Phenytoin Sodium, Prompt

Generic Available

Yes: Excludes chewable tablet

Canadian Brand Names

• Dilantin®

Pharmacologic Category

• Antiarrhythmic Agent, Class Ib
• Anticonvulsant, Hydantoin

Pharmacologic Category Synonyms

• Class Ib Antiarrhythmic Agent
• Vaughan-Williams Class Ib Antiarrhythmic
• AED, Hydantoin
• Anti-epileptic Drug, Hydantoin
• Hydantoin Anticonvulsant

Use

Management of generalized tonic-clonic (grand mal), complex partial seizures; prevention of seizures following head trauma/neurosurgery

Use: Unlabeled/Investigational

Ventricular arrhythmias, including those associated with digitalis intoxication, prolonged QT interval and surgical repair of congenital heart diseases in children; epidermolysis bullosa

Pregnancy Risk Factor

D

Pregnancy Implications

Phenytoin crosses the placenta. Congenital malformations (including a pattern of malformations termed the “fetal hydantoin syndrome” or “fetal anticonvulsant syndrome”) have been reported in infants. Isolated cases of malignancies (including neuroblastoma) and coagulation defects in the neonate following delivery have also been reported. Epilepsy itself, the number of medications, genetic factors, or a combination of these probably influence the teratogenicity of anticonvulsant therapy. Total plasma concentrations of phenytoin are decreased by 56% in the mother during pregnancy; unbound plasma (free) concentrations are decreased by 31%. Because protein binding is decreased, monitoring of unbound plasma concentrations is recommended. Concentrations should be monitored through the 8th week postpartum. The use of folic acid throughout pregnancy and vitamin K during the last month of pregnancy is recommended. A pregnancy registry is available for women exposed to antiepileptic drug (including phenytoin) at the Genetics and Teratology Unit Massachusetts General Hospital, 1-888-233-2334.

Lactation

Enters breast milk/not recommended (AAP rates “compatible”)

Breast-Feeding Considerations

Phenytoin is excreted in breast milk; however, the amount to which the infant is exposed is considered small. The manufacturers of phenytoin do not recommend breast-feeding during therapy, however, the AAP considers it to be usually compatible. Women should be counseled of the possible risks and benefits associated with breast-feeding while on phenytoin.

Contraindications

Hypersensitivity to phenytoin, other hydantoins, or any component of the formulation; pregnancy

Warnings/Precautions

Concerns related to adverse effects:

• Blood dyscrasias: A spectrum of hematologic effects have been reported with use (eg, neutropenia, leukopenia, thrombocytopenia, pancytopenia, and anemias); patients with a previous history of adverse hematologic reaction to any drug may be at increased risk. Early detection of hematologic change is important; advise patients of early signs and symptoms including fever, sore throat, mouth ulcers, infections, easy bruising, petechial or purpuric hemorrhage.

• Dermatologic reactions: Severe reactions, including toxic epidermal necrolysis and Stevens-Johnson syndromes, although rarely reported, have resulted in fatalities; drug should be discontinued if there are any signs of rash.

• Hypersensitivity syndrome: Acute hepatotoxicity associated with a hypersensitivity syndrome characterized by fever, skin eruptions, and lymphadenopathy has been reported to occur within the first 2 months of treatment; discontinue if skin rash or lymphadenopathy occurs.

• Osteomalacia: Has been reported.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with sinus bradycardia, SA block, or AV block.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Hypoalbuminemia: Use with caution in patients with any condition associated with low serum albumin levels, which will increase the free fraction of phenytoin in the serum and, therefore, the pharmacologic response.

• Porphyria: Use with caution in patients with porphyria.

• Seizures: May increase frequency of petit mal seizures.

Concurrent drug therapy issues:

• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.

Special populations:

• Debilitated patients: Use with caution in patients who are debilitated.

• Elderly: Use with caution in the elderly.

Dosage form specific issues:

• Injectable: I.V. form may cause hypotension, skin necrosis at I.V. site; avoid I.V. administration in small veins.

Other warnings/precautions:

• Serum levels: Sedation, confusional states, or cerebellar dysfunction (loss of motor coordination) may occur at higher total serum concentrations, or at lower total serum concentrations when the free fraction of phenytoin is increased.

• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.

Adverse Reactions

I.V. effects: Hypotension, bradycardia, cardiac arrhythmia, cardiovascular collapse (especially with rapid I.V. use), venous irritation and pain, thrombophlebitis

Effects not related to plasma phenytoin concentrations: Hypertrichosis, gingival hypertrophy, thickening of facial features, carbohydrate intolerance, folic acid deficiency, peripheral neuropathy, vitamin D deficiency, osteomalacia, systemic lupus erythematosus

Concentration-related effects: Nystagmus, blurred vision, diplopia, ataxia, slurred speech, dizziness, drowsiness, lethargy, coma, rash, fever, nausea, vomiting, gum tenderness, confusion, mood changes, folic acid depletion, osteomalacia, hyperglycemia

Related to elevated concentrations:

>20 mcg/mL: Far lateral nystagmus

>30 mcg/mL: 45° lateral gaze nystagmus and ataxia

>40 mcg/mL: Decreased mentation

>100 mcg/mL: Death

Cardiovascular: Hypotension, bradycardia, cardiac arrhythmia, cardiovascular collapse

Central nervous system: Psychiatric changes, slurred speech, dizziness, drowsiness, headache, insomnia

Dermatologic: Rash

Gastrointestinal: Constipation, nausea, vomiting, gingival hyperplasia, enlargement of lips

Hematologic: Leukopenia, thrombocytopenia, agranulocytosis

Hepatic: Hepatitis

Local: Thrombophlebitis

Neuromuscular & skeletal: Tremor, peripheral neuropathy, paresthesia

Ocular: Diplopia, nystagmus, blurred vision

Rarely seen effects: SLE-like syndrome, lymphadenopathy, hepatitis, Stevens-Johnson syndrome, blood dyscrasias, dyskinesias, pseudolymphoma, lymphoma, venous irritation and pain, coarsening of facial features, hypertrichosis

Drug Interactions

Substrate of CYP2C9 (major), 2C19 (major), 3A4 (minor); Induces CYP2B6 (strong), 2C8 (strong), 2C9 (strong), 2C19 (strong), 3A4 (strong)

Acetaminophen: Phenytoin may enhance the hepatotoxic potential of acetaminophen overdoses

Acetazolamide: Concurrent use with phenytoin may result in an increased risk of osteomalacia

Acyclovir: May decrease phenytoin serum levels; limited documentation; monitor

Allopurinol: May increase phenytoin serum concentrations; monitor

Antacids: May decrease absorption of phenytoin; separate oral doses by several hours

Antiarrhythmics: Phenytoin may increase the metabolism of antiarrhythmics, decreasing their clinical effect; includes disopyramide, propafenone, and quinidine; amiodarone also may increase phenytoin concentrations (see CYP inhibitors)

Anticonvulsants: Phenytoin may increase the metabolism of anticonvulsants; includes barbiturates, carbamazepine, ethosuximide, felbamate, lamotrigine, tiagabine, topiramate, and zonisamide; does not appear to affect gabapentin or levetiracetam; felbamate and gabapentin may increase phenytoin levels; monitor

Antineoplastics: Several chemotherapeutic agents have been associated with a decrease in serum phenytoin levels; includes cisplatin, bleomycin, carmustine, methotrexate, and vinblastine; monitor phenytoin serum levels. Limited evidence also suggest that enzyme-inducing anticonvulsant therapy may reduce the effectiveness of some chemotherapy regimens (specifically in ALL). Teniposide and methotrexate may be cleared more rapidly in these patients.

Antipsychotics: Phenytoin may enhance the metabolism (decrease the efficacy) of antipsychotics; monitor for altered response; dose adjustment may be needed; also see note on clozapine

Benzodiazepines: Phenytoin may decrease the serum concentrations of some benzodiazepines; monitor for decreased benzodiazepine effect

Beta-blockers: Metabolism of beta-blockers may be increased and clinical effect decreased; atenolol and nadolol are unlikely to interact given their renal elimination

Calcium channel blockers: Phenytoin may enhance the metabolism of calcium channel blockers, decreasing their clinical effect; calcium channel blockers (diltiazem, nifedipine) have been reported to increase phenytoin levels (case report); monitor.

Capecitabine: May increase the serum concentrations of phenytoin; monitor

Chloramphenicol: Phenytoin may increase the metabolism of chloramphenicol and chloramphenicol may inhibit phenytoin metabolism; monitor for altered response

Cimetidine: May increase the serum concentrations of phenytoin; monitor.

Ciprofloxacin: May decrease serum phenytoin concentrations; monitor.

Clozapine: Phenytoin may decrease levels/effects of clozapine; monitor.

CNS depressants: Sedative effects may be additive with other CNS depressants; monitor for increased effect; includes ethanol, barbiturates, sedatives, antidepressants, opioid analgesics, and benzodiazepines

Corticosteroids: Phenytoin may increase the metabolism of corticosteroids, decreasing their clinical effect; also see dexamethasone

Cyclosporine and tacrolimus: Levels may be decreased by phenytoin; monitor

CYP2B6 substrates: Phenytoin may decrease the levels/effects of CYP2B6 substrates. Example substrates include bupropion, efavirenz, promethazine, selegiline, and sertraline.

CYP2C9 inducers: May decrease the levels/effects of phenytoin. Example inducers include carbamazepine, phenobarbital, rifampin, rifapentine, and secobarbital.

CYP2C9 Inhibitors may increase the levels/effects of phenytoin. Example inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, sulfonamides and tolbutamide.

CYP2C8 Substrates: Phenytoin may decrease the levels/effects of CYP2C8 substrates. Example substrates include amiodarone, paclitaxel, pioglitazone, repaglinide, and rosiglitazone.

CYP2C9 Substrates: Phenytoin may decrease the levels/effects of CYP2C9 substrates. Example substrates include bosentan, celecoxib, dapsone, fluoxetine, glimepiride, glipizide, losartan, montelukast, nateglinide, paclitaxel, sulfonamides, trimethoprim, warfarin, and zafirlukast.

CYP2C19 inducers: May decrease the levels/effects of phenytoin. Example inducers include aminoglutethimide, carbamazepine, phenytoin, and rifampin.

CYP2C19 inhibitors: May increase the levels/effects of phenytoin. Example inhibitors include delavirdine, fluconazole, fluvoxamine, gemfibrozil, isoniazid, omeprazole, and ticlopidine.

CYP2C19 substrates: Phenytoin may decrease the levels/effects of CYP2C19 substrates. Example substrates include citalopram, diazepam, methsuximide, propranolol, proton pump inhibitors, sertraline, and voriconazole.

CYP3A4 substrates: Phenytoin may decrease the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, clarithromycin, cyclosporine, erythromycin, estrogens, mirtazapine, nateglinide, nefazodone, nevirapine, protease inhibitors, tacrolimus, and venlafaxine.

Digoxin: Effects and/or levels of digitalis glycosides may be decreased by phenytoin

Disulfiram: May increase serum phenytoin concentrations; monitor

Dopamine: Phenytoin (I.V.) may increase the effect of dopamine (enhanced hypotension)

Doxycycline: Phenytoin may enhance the metabolism of doxycycline, decreasing its clinical effect; higher dosages may be required

Estrogens: Phenytoin may increase the metabolism of estrogens, decreasing their clinical effect; monitor

Folic acid: Replacement of folic acid has been reported to increase the metabolism of phenytoin, decreasing its serum concentrations and/or increasing seizures

HMG-CoA reductase inhibitors: Phenytoin may increase the metabolism of these agents, reducing their clinical effect; monitor

Itraconazole: Phenytoin may decrease the effect of itraconazole

Levodopa: Phenytoin may inhibit the anti-Parkinson effect of levodopa

Lithium: Concurrent use of phenytoin and lithium has resulted in lithium intoxication

Methadone: Phenytoin may enhance the metabolism of methadone resulting in methadone withdrawal

Methylphenidate: May increase serum phenytoin concentrations; monitor

Metronidazole: May increase the serum concentrations of phenytoin; monitor.

Neuromuscular-blocking agents: Duration of effect may be decreased by phenytoin

Omeprazole: May increase serum phenytoin concentrations; monitor

Oral contraceptives: Phenytoin may enhance the metabolism of oral contraceptives, decreasing their clinical effect; an alternative method of contraception should be considered

Primidone: Phenytoin enhances the conversion of primidone to phenobarbital resulting in elevated phenobarbital serum concentrations

Quetiapine: Serum concentrations may be substantially reduced by phenytoin, potentially resulting in a loss of efficacy; limited documentation; monitor

SSRIs: May increase phenytoin serum concentrations; fluoxetine and fluvoxamine are known to inhibit metabolism via CYP enzymes; sertraline and paroxetine have also been shown to increase concentrations in some patients; monitor

Sucralfate: May reduce the GI absorption of phenytoin; monitor

Theophylline: Phenytoin may increase metabolism of theophylline derivatives and decrease their clinical effect; theophylline may also increase phenytoin concentrations

Thyroid hormones (including levothyroxine): Phenytoin may alter the metabolism of thyroid hormones, reducing its effect; there is limited documentation of this interaction, but monitoring should be considered

Ticlopidine: May increase serum phenytoin concentrations and/or toxicity; monitor

Tricyclic antidepressants: Phenytoin may increase metabolism of tricyclic antidepressants and decrease their clinical effect; sedative effects may be additive; tricyclics may also increase phenytoin concentrations

Topiramate: Phenytoin may decrease serum levels of topiramate; topiramate may increase the effect of phenytoin

Trazodone: Serum levels of phenytoin may be increased; limited documentation; monitor

Trimethoprim: May increase serum phenytoin concentrations; monitor

Valproic acid (and sulfisoxazole): May displace phenytoin from binding sites; valproic acid may increase, decrease, or have no effect on phenytoin serum concentrations

Vigabatrin: May reduce phenytoin serum concentrations; monitor

Warfarin: Phenytoin transiently increased the hypothrombinemia response to warfarin initially; this is followed by an inhibition of the hypoprothrombinemic response

Ethanol/Nutrition/Herb Interactions

Ethanol:

Acute use: Avoid or limit ethanol (inhibits metabolism of phenytoin). Watch for sedation.

Chronic use: Avoid or limit ethanol (stimulates metabolism of phenytoin).

Food: Phenytoin serum concentrations may be altered if taken with food. If taken with enteral nutrition, phenytoin serum concentrations may be decreased. Tube feedings decrease bioavailability; hold tube feedings 1-2 hours before and 1-2 hours after phenytoin administration. May decrease calcium, folic acid, and vitamin D levels.

Herb/Nutraceutical: Avoid evening primrose (seizure threshold decreased). Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

Storage

Capsule, tablet: Store below 30°C (86°F). Protect from light and moisture.

Oral suspension: Store at room temperature of 20°C to 25°C (68°F to 77°F); do not freeze. Protect from light.

Solution for injection: Store at room temperature of 15°C to 30°C (59°F to 86°F). Use only clear solutions free of precipitate and haziness; slightly yellow solutions may be used. Precipitation may occur if solution is refrigerated and may dissolve at room temperature.

Reconstitution

I.V.: Further dilution of the solution for I.V. infusion is controversial and no consensus exists as to the optimal concentration and length of stability. Stability is concentration and pH dependent. Based on limited clinical consensus, NS or LR are recommended diluents; dilutions of 1-10 mg/mL have been used and should be administered as soon as possible after preparation (some recommend to discard if not used within 4 hours). Do not refrigerate.

Compatibility

Incompatible in D₅NS, D₅W, fat emulsion 10%, 1/2NS; variable stability (consult detailed reference) in NS

Y-site administration: Compatible: Esmolol, famotidine, fluconazole, foscarnet, tacrolimus. Incompatible: Amphotericin B cholesteryl sulfate complex, ciprofloxacin, clarithromycin, diltiazem, enalaprilat, gatifloxacin, heparin, heparin with hydrocortisone sodium succinate, hydromorphone, linezolid, potassium chloride, propofol, sufentanil, theophylline, vitamin B complex with C. Variable (consult detailed reference): TPN.

Compatibility in syringe: Incompatible: Hydromorphone, sufentanil.

Compatibility when admixed: Compatible: Bleomycin, sodium bicarbonate, verapamil. Incompatible: Amikacin, aminophylline, bretylium, chloramphenicol, dimenhydrinate, diphenhydramine, dobutamine, hydroxyzine, insulin (regular), kanamycin, levorphanol, lidocaine, lincomycin, meperidine, metaraminol, morphine, nitroglycerin, norepinephrine, penicillin G potassium, pentobarbital, phenobarbital, phenylephrine, phytonadione, procainamide, procaine, prochlorperazine edisylate, promazine, promethazine, streptomycin, vancomycin, vitamin B complex with C.

Mechanism of Action

Stabilizes neuronal membranes and decreases seizure activity by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses; prolongs effective refractory period and suppresses ventricular pacemaker automaticity, shortens action potential in the heart

Pharmacodynamics/Kinetics

Onset of action: I.V.: ?0.5-1 hour

Absorption: Oral: Slow

Distribution: V_d:

Neonates: Premature: 1-1.2 L/kg; Full-term: 0.8-0.9 L/kg

Infants: 0.7-0.8 L/kg

Children: 0.7 L/kg

Adults: 0.6-0.7 L/kg

Protein binding:

Neonates: ?80% (?20% free)

Infants: ?85% (?15% free)

Adults: 90% to 95%

Others: Decreased protein binding

Disease states resulting in a decrease in serum albumin concentration: Burns, hepatic cirrhosis, nephrotic syndrome, pregnancy, cystic fibrosis

Disease states resulting in an apparent decrease in affinity of phenytoin for serum albumin: Renal failure, jaundice (severe), other drugs (displacers), hyperbilirubinemia (total bilirubin >15 mg/dL), Cl_cr <25 mL/minute (unbound fraction is increased two- to threefold in uremia)

Metabolism: Follows dose-dependent capacity-limited (Michaelis-Menten) pharmacokinetics with increased V_max in infants >6 months of age and children versus adults; major metabolite (via oxidation), HPPA, undergoes enterohepatic recirculation

Bioavailability: Form dependent

Half-life elimination: Oral: 22 hours (range: 7-42 hours)

Time to peak, serum (form dependent): Oral: Extended-release capsule: 4-12 hours; Immediate release preparation: 2-3 hours

Excretion: Urine (<5% as unchanged drug); as glucuronides

Clearance: Highly variable, dependent upon intrinsic hepatic function and dose administered; increased clearance and decreased serum concentrations with febrile illness

Dosage

Status epilepticus: I.V.:

Infants and Children: Loading dose: 15-20 mg/kg in a single or divided dose; maintenance dose: Initial: 5 mg/kg/day in 2 divided doses; usual doses:

6 months to 3 years: 8-10 mg/kg/day

4-6 years: 7.5-9 mg/kg/day

7-9 years: 7-8 mg/kg/day

10-16 years: 6-7 mg/kg/day, some patients may require every 8 hours dosing

Adults: Loading dose: Manufacturer recommends 10-15 mg/kg, however, 15-20 mg/kg is generally recommended; maximum rate: 50 mg/minute

Anticonvulsant: Children and Adults: Oral:

Loading dose: 15-20 mg/kg; based on phenytoin serum concentrations and recent dosing history; administer oral loading dose in 3 divided doses given every 2-4 hours to decrease GI adverse effects and to ensure complete oral absorption; maintenance dose: same as I.V.

Neurosurgery (prophylactic): 100-200 mg at approximately 4-hour intervals during surgery and during the immediate postoperative period

Dosing adjustment/comments in renal impairment or hepatic disease: Safe in usual doses in mild liver disease; clearance may be substantially reduced in cirrhosis and plasma level monitoring with dose adjustment advisable. Free phenytoin levels should be monitored closely.

Administration: Oral

Suspension: Shake well prior to use. Absorption is impaired when phenytoin suspension is given concurrently to patients who are receiving continuous nasogastric feedings. A method to resolve this interaction is to divide the daily dose of phenytoin and withhold the administration of nutritional supplements for 1-2 hours before and after each phenytoin dose.

Administration: I.M.

Although approved for I.M. use, I.M. administration is not recommended due to erratic absorption and pain on injection. Fosphenytoin may be considered.

Administration: I.V.

Vesicant. Fosphenytoin may be considered for loading in patients who are in status epilepticus, hemodynamically unstable or develop hypotension/bradycardia with I.V. administration of phenytoin. Phenytoin may be administered by IVP or IVPB administration. The maximum rate of I.V. administration is 50 mg/minute. Highly sensitive patients (eg, elderly, patients with pre-existing cardiovascular conditions) should receive phenytoin more slowly (eg, 20 mg/minute).

Administration: Other

SubQ administration is not recommended because of the possibility of local tissue damage (due to high pH).

Administration: I.V. Detail

An in-line 0.22-5 micron filter is recommended for IVPB solutions due to the high potential for precipitation of the solution. Avoid extravasation. Following I.V. administration, NS should be injected through the same needle or I.V. catheter to prevent irritation.

pH: 10.0-12.3

Monitoring Parameters

Blood pressure, vital signs (with I.V. use), plasma phenytoin level, CBC, liver function tests

Reference Range

Timing of serum samples: Because it is slowly absorbed, peak blood levels may occur 4-8 hours after ingestion of an oral dose. The serum half-life varies with the dosage and the drug follows Michaelis-Menten kinetics. The average adult half-life is about 24 hours. Steady-state concentrations are reached in 5-10 days.

Children and Adults: Toxicity is measured clinically, and some patients require levels outside the suggested therapeutic range

Therapeutic range:

Total phenytoin: 10-20 mcg/mL (children and adults), 8-15 mcg/mL (neonates)

Concentrations of 5-10 mcg/mL may be therapeutic for some patients but concentrations <5 mcg/mL are not likely to be effective

50% of patients show decreased frequency of seizures at concentrations >10 mcg/mL

86% of patients show decreased frequency of seizures at concentrations >15 mcg/mL

Add another anticonvulsant if satisfactory therapeutic response is not achieved with a phenytoin concentration of 20 mcg/mL

Free phenytoin: 1-2.5 mcg/mL

Toxic: >30 mcg/mL (SI: <120-200 ?mol/L)

Lethal: >100 mcg/mL (SI: >400 ?mol/L)

When to draw levels: This is dependent on the disease state being treated and the clinical condition of the patient

Key points:

Slow absorption of extended capsules and prolonged half-life minimize fluctuations between peak and trough concentrations, timing of sampling not crucial

Trough concentrations are generally recommended for routine monitoring. Daily levels are not necessary and may result in incorrect dosage adjustments. If it is determined essential to monitor free phenytoin concentrations, concomitant monitoring of total phenytoin concentrations is not necessary and expensive.

After a loading dose: Draw level within 48-96 hours

Rapid achievement: Draw within 2-3 days of therapy initiation to ensure that the patient's metabolism is not remarkably different from that which would be predicted by average literature-derived pharmacokinetic parameters; early levels should be used cautiously in design of new dosing regimens

Second concentration: Draw within 6-7 days with subsequent doses of phenytoin adjusted accordingly

If plasma concentrations have not changed over a 3- to 5-day period, monitoring interval may be increased to once weekly in the acute clinical setting

In stable patients requiring long-term therapy, generally monitor levels at 3- to 12-month intervals

Adjustment of serum concentration: See tables.

Dietary Considerations

Folic acid: Phenytoin may decrease mucosal uptake of folic acid; to avoid folic acid deficiency and megaloblastic anemia, some clinicians recommend giving patients on anticonvulsants prophylactic doses of folic acid and cyanocobalamin. However, folate supplementation may increase seizures in some patients (dose dependent). Discuss with healthcare provider prior to using any supplements.

Calcium: Hypocalcemia has been reported in patients taking prolonged high-dose therapy with an anticonvulsant. Some clinicians have given an additional 4000 units/week of vitamin D (especially in those receiving poor nutrition and getting no sun exposure) to prevent hypocalcemia.

Vitamin D: Phenytoin interferes with vitamin D metabolism and osteomalacia may result; may need to supplement with vitamin D

Tube feedings: Tube feedings decrease phenytoin absorption. To avoid decreased serum levels with continuous NG feeds, hold feedings for 1-2 hours prior to and 1-2 hours after phenytoin administration, if possible. There is a variety of opinions on how to administer phenytoin with enteral feedings. Be consistent throughout therapy.

Sodium content of 1 g injection: 88 mg (3.8 mEq)

Patient Education

Do not take any new medication during therapy without consulting prescriber. Take exactly as directed, preferably on an empty stomach. Do not alter dose or discontinue without consulting prescriber. Do not crush, break, or chew extended release capsules. Shake liquid suspension well before using. Follow recommended diet, avoid alcohol, and maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. May cause gum or mouth soreness (use good oral hygiene and have frequent dental exams); drowsiness, dizziness, nervousness, or headache (use caution when driving or engaging in tasks that require alertness until response to drug is known); or nausea or vomiting (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). Report chest pain, irregular heartbeat, or palpitations; slurred speech, unsteady gait, coordination difficulties, or change in mentation; skin rash; unresolved nausea, vomiting, or constipation; swollen glands; swollen, sore, or bleeding gums; unusual bruising or bleeding; acute persistent fatigue; vision changes; or other persistent adverse effects. Pregnancy/breast-feeding precautions: Do not get pregnant; use contraceptive measures to prevent possible harm to the fetus (effectiveness of oral contraceptives may be affected by phenytoin). Consult prescriber if breast-feeding.

Geriatric Considerations

Elderly may have reduced hepatic clearance due to age decline in phase I metabolism. Elderly may have low albumin which will increase free fraction and, therefore, pharmacologic response. Monitor closely in those who are hypoalbuminemic. Free fraction measurements advised, also elderly may display a higher incidence of adverse effects (cardiovascular) when using the I.V. loading regimen; therefore, recommended to decrease loading I.V. dose to 25 mg/minute.

Anesthesia and Critical Care Concerns/Other Considerations

Because phenytoin induces the metabolism of many drugs, it may alter their effective blood concentration.

The vehicle which contains propylene glycol and ethanol may cause hypotension, bradycardia, arrhythmias, or asystole refractory to defibrillation. Phenytoin 50 mg/mL contains propylene glycol 414.4 mg/mL (40% v/v). Rapid intravenous administration may cause hypotension. Infuse at a rate no greater than 50 mg/minute in adults and 25 mg/minute in the elderly.

Patients on chronic phenytoin therapy require larger and more frequent doses of nondepolarizing muscle relaxants to attain the same degree of muscle relaxation. This is probably due to increased levels of alpha₁-acid glycoprotein released by the liver (which bind free phenytoin) during hepatic enzyme induction.

Status Epilepticus: A randomized, double-blind trial (Treiman, 1998) evaluated the efficacy of four treatments in overt status epilepticus. Treatment arms were designed based upon accepted practices of North American neurologists. The treatments were: 1) lorazepam 0.1 mg/kg, 2) diazepam 0.15 mg/kg followed by phenytoin 18 mg/kg, 3) phenytoin 18 mg/kg alone, and 4) phenobarbital 15 mg/kg. Treatment was considered successful if the seizures were terminated (clinically and by EEG) within 20 minutes of start of therapy without seizure recurrence within 60 minutes from the start of therapy. Patients who failed the first treatment received a second and a third, if necessary. Patients did not receive randomized treatments after the first one but the treating physician remained blinded. Treatment success: Lorazepam 64.9%, phenobarbital 58.2%, diazepam/phenytoin 55.8%, and phenytoin alone 43.6%. Using an intention to treat analysis, there was no statistical difference between the groups. Results of subsequent treatments in patients who failed the first therapy indicated that response rate significantly dropped regardless of treatment. Aggregate response rate to the second treatment was 7.0% and third treatment 2.3%.

Cardiovascular Considerations

Rapid intravenous administration may cause hypotension. Infuse at a rate no greater than 50 mg/minute in adults and 25 mg/minute in the elderly. Phenytoin has antiarrhythmic properties (Class Ib) which are not often clinically relevant at standard doses.

Dental Health: Effects on Dental Treatment

Gingival hyperplasia is a common problem observed during the first 6 months of phenytoin therapy appearing as gingivitis or gum inflammation. To minimize severity and growth rate of gingival tissue begin a program of professional cleaning and patient plaque control within 10 days of starting anticonvulsant therapy.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Nursing: Physical Assessment/Monitoring

Assess potential for numerous interactions with other prescriptions, OTC medications, or herbal products patient may be taking (see extensive list of Drug Interactions). Assess results of laboratory tests, therapeutic effectiveness, and adverse response when beginning therapy and at regular intervals during treatment. When discontinuing oral formulation, taper dose gradually; abrupt discontinuance can cause status epilepticus. Teach patient proper use (oral), side effects/appropriate interventions, and adverse symptoms to report. I.V.: Monitor blood pressure. Infusion site should be monitored closely (vesicant). Patient should be monitored closely for adverse/toxic results.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, extended release, as sodium: 100 mg

Dilantin®: 30 mg [contains sodium benzoate], 100 mg

Phenytek®: 200 mg, 300 mg

Capsule, prompt release, as sodium: 100 mg

Injection, solution, as sodium: 50 mg/mL (2 mL, 5 mL) [contains alcohol and propylene glycol]

Suspension, oral: 100 mg/4 mL (4 mL); 125 mg/5 mL (240 mL)

Dilantin®: 125 mg/5 mL (240 mL) [contains alcohol <0.6%, sodium benzoate; orange vanilla flavor]

Tablet, chewable:

Dilantin®: 50 mg

Pricing: U.S. (www.drugstore.com)

Capsules (Dilantin)

30 mg (90): $39.99

100 mg (90): $41.99

Capsules (Phenytek)

200 mg (30): $31.99

300 mg (30): $39.99

Capsules (Phenytoin Sodium Extended)

100 mg (90): $31.99

Capsules (Phenytoin Sodium Prompt)

100 mg (100): $25.99

Chewable (Dilantin Infatabs)

50 mg (90): $46.99

Suspension (Dilantin)

125 mg/5 mL (237): $59.99

Suspension (Phenytoin)

125 mg/5 mL (237): $28.99

References

“American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk,” Pediatrics, 2001, 108(3):776-89.

Au Yeung SC and Ensom MH, “Phenytoin and Enteral Feedings: Does Evidence Support an Interaction?” Ann Pharmacother, 2000, 34(7-8):896-905.

Bauer LA and Blouin RA, “Phenytoin Michaelis-Menten Pharmacokinetics in Caucasian Pediatric Patients,” Clin Pharmacokinet, 1983, 8(6):545-9.

Berigan T and Watt TJ, “Dilantin® Toxicity Presenting as Mutism Following Severe Head Injury: Case Report,” Mil Med, 1994, 159(7):533-4.

Black J, Hannaman T, and Malone C, “The Relationship of Serum Albumin Level to Phenytoin Toxicity,” J Clin Pharmacol, 1987, 27(3):249-50.

Bleck TB, Seizures, Stroke, and Other Neurologic Emergencies. In: Zimmerman JL, Roberts PR, eds. Multidisciplinary Critical Care Review, Des Plains, IL: Society of Critical Care Medicine; 2003:325-34.

Chapman MG, Smith M, and Hirsch NP, “Status Epilepticus,” Anaesthesia, 2001, 56(7):648-59.

Chiba K, Ishizaki T, Miura H, et al, “Michaelis-Menten Pharmacokinetics of Diphenylhydantoin and Application in the Pediatric Age Patient,” J Pediatr, 1980, 96(3 Pt 1):479-84.

Dela Cruz FG, Kanter MZ, Fischer JH, et al, “Efficacy of Individualized Phenytoin Sodium Loading Doses Administered by Intravenous Infusion,” Clin Pharm, 1988, 7(3):219-24.

Dooley G and Vasan N, “Dilantin® Hyperplasia: A Review of the Literature,” J N Z Soc Periodontol, 1989, 68:19-22.

Doyle MF, Anderson S, Cerrezuela C, et al, “Sezary Syndrome Associated With Phenytoin Therapy,” Acta Haematol, 1994, 92(4):204-7.

Hagg S and Spigset O, “Anticonvulsant Use During Lactation,” Drug Saf, 2000, 22(6):425-40.

Iacopino AM, Doxey D, Cutler CW, et al, “Phenytoin and Cyclosporine A Specifically Regulate Macrophage Phenotype and Expression of Platelet-Derived Growth Factor and Interleukin-1 In Vitro and In Vivo: Possible Molecular Mechanism of Drug-Induced Gingival Hyperplasia,” J Periodontol, 1997, 68(1):73-83.

Kerrick JM, Wolff DL, and Graves NM, “Predicting Unbound Phenytoin Concentrations in Patients Receiving Valproic Acid: A Comparison of Two Prediction Methods,” Ann Pharmacother, 1995, 29(5):470-4.

Lombardi TP, Gailey RA, and Bryant BG, “Phenytoin Overdose in Neonate Attributable to Product Packaging Similarities,” Am J Hosp Pharm, 1989, 46(10):1999-2000.

Lowenstein DH, “Treatment Options for Status Epilepticus,” Curr Opin Pharmacol, 2005, 5(3):334-9.

Manno EM, “New Management Strategies in the Treatment of Status Epilepticus,” Mayo Clin Proc, 2003, 78(4):508-18.

Mansur LI, Murrow RW, Garrelts JC, et al, “Rebound of Plasma Free Phenytoin Concentration Following Plasmapheresis in a Patient With Thrombotic Thrombocytopenic Purpura,” Ann Pharmacother, 1995, 29(6):592-5.

McAuley JW and Anderson GD, “Treatment of Epilepsy in Women of Reproductive Age: Pharmacokinetic Considerations,” Clin Pharmacokinet, 2002, 41(8):559-79.

Nussinovitch M, Soen G, Volovitz B, et al, “Urinary Retention Related to Phenytoin Therapy,” Clin Pediatr (Phila), 1995, 34(7):382-3.

Pihlstrom BL, “Prevention and Treatment of Dilantin-Associated Gingival Enlargement,” Compendium, 1990, 14:S506-10.

“Practice Parameter: Management Issues for Women With Epilepsy (Summary Statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology,” Epilepsia, 1998, 39(11):1226-31.

Rabinowicz AL, Hinton DR, Dyck P, et al, “High-Dose Tamoxifen in Treatment of Brain Tumors: Interaction With Antiepileptic Drugs,” Epilepsia, 1995, 36(5):513-5.

Rowden AM, Spoor JE, Bertino JS Jr, “The Effect of Activated Charcoal on Phenytoin Pharmacokinetics,” Ann Emerg Med, 1990, 19(10):1144-7.

Saito K, Mori S, Iwakura M, et al, “Immunohistochemical Localization of Transforming Growth Factor Beta, Basic Fibroblast Growth Factor and Heparin Sulphate Glycosaminoglycan in Gingival Hyperplasia Induced by Nifedipine and Phenytoin,” J Periodontal Res, 1996, 31(8):545-5.

Suzuki Y, Mimaki T, Cox S, et al, “Phenytoin Age-Dose-Concentration Relationship in Children,” Ther Drug Monit, 1994, 16(2):145-50.

“Treatment of Convulsive Status Epilepticus. Recommendations of the Epilepsy Foundation of America's Working Group on Status Epilepticus,” JAMA, 1993, 270(7):854-9.

Treiman DM, Meyers PD, Walton NY, et al, “A Comparison of Four Treatments for Generalized Convulsive Status Epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group,” N Engl J Med, 1998, 339(12):792-8.

Zhou LX, Pihlstrom B, Hardwick JP, et al, “Metabolism of Phenytoin by the Gingiva of Normal Humans: The Possible Role of Reactive Metabolites of Phenytoin in the Initiation of Gingival Hyperplasia,” Clin Pharmacol Ther, 1996, 60(2):191-8.

International Brand Names

• Aleviatin (JP, TW)
• Antisacer (PT)
• Aurantin (IT)
• Clerin (PY)
• Clerin LR (PY)
• Cumatil (CO)
• Di-Hydan (BE, FR, LU)
• Difetoin (HR)
• Dilantin (AU, FR, HK, ID, IN, MY, PH, PK, TH, VE)
• Dintoina (IT)
• Diphantoine (BE, NL)
• Diphantoine Z (NL)
• Diphedan (HU)
• Ditoin (HK, MY, TH)
• Ditomed (TH)
• Epamin (AR, BO, BR, CN, CO, CR, DO, EC, GT, HN, MX, NI, PA, PE, PR, PY, SV, UY, VE)
• Epanutin (AE, AT, BE, BF, BH, BJ, CI, CY, CZ, DE, EG, ES, ET, FI, GB, GH, GM, GN, GR, HN, HU, IE, IL, IQ, IR, JO, KE, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, NE, NG, NL, OM, QA, SA, SC, SD, SE, SL, SN, SY, TN, TR, TZ, UG, UY, YE, ZA, ZM, ZW)
• Epanutin [caps] (PL)
• Epilan-D (AT, BG, CZ)
• Epilantin (PH)
• Epileptin (TW)
• Epinat (NO)
• Eptoin (IN)
• Felantin (PE)
• Fenatoin NM (SE)
• Fenidantoin S (MX)
• Fenitoina (ES)
• Fenitoina Rubio (ES)
• Fenitoina Sodica (IT)
• Fenitron (MX)
• Fenytoin (DE, DK)
• Fomiken (MX)
• Hidanil (CO)
• Hidantoína (MX)
• Hydantin (FI)
• Hydantol (JP)
• Ikaphen (ID)
• Kutoin (ID)
• Lantidin (PH)
• Lehydan (SE)
• Movileps (ID)
• Neosidantoina (ES)
• Pepsytoin-100 (TH)
• Phenhydan (AT, CH, DE, EE, HU, LU)
• Phenilep (ID)
• Phenytoin KP (TH)
• Phenytoinum (PL)
• Pyoredol (AR, FR)
• Sinergina (ES)
• Utoin (TH)

Lexi-Comp.com

Last full review/revision May 2008

Content last modified May 2008