Phenytoin

Pronunciation

Pronunciation: FEN-i-toin
Class: Hydantoin Phenytoin

Trade Names

Dilantin Infatab
- Tablets, chewable 50 mg

Dilantin-125
- Suspension, oral 125 mg/5 mL

Phenytoin Sodium

Dilantin
- Capsules, ER 30 mg
- Capsules, ER 100 mg

Phenytek
- Capsules, ER 200 mg
- Capsules, ER 300 mg

Phenytoin Sodium
- Injection 50 mg/mL

Dilantin Capsules (Canada)
Dilantin-30 Suspension (Canada)
Taro-Phenytoin (Canada)

Pharmacology

Appears to act at the motor cortex by inhibiting the spread of seizure activity. Possibly works by promoting sodium efflux from neurons, thereby stabilizing threshold against hyperexcitability. Also decreases posttetanic potentiation at synapses.

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Pharmacokinetics

Absorption

Slow and variable (oral); poor in neonates; rapid (IV); slow but complete (IM). Steady state is 7 to 10 days. T max is 4 to 12 h (ER capsules); 1.5 to 3 h ( Infatabs , Dilantin-125 , and oral suspension).

Distribution

Distributes into CSF, saliva, semen, GI fluids, bile, and breast milk; and crosses the placenta. Protein binding is high (more than 90%), but may be lower in neonates (84%).

Metabolism

Hydroxylated in the liver by an enzyme system, which is saturable at high plasma levels.

Elimination

Mostly excreted in bile as inactive metabolites, then reabsorbed from the intestinal tract and excreted in the urine (as metabolites). Plasma half-life is 22 h (oral phenytoin), 14 h ( Infatabs ), and 10 to 15 h (IV). Excretion is enhanced by alkaline urine.

Indications and Usage

Control of generalized tonic-clonic and complex partial (psychomotor, temporal lobe) seizures; prevention and treatment of seizures occurring during or after neurosurgery (excludes oral suspension); control of tonic-clonic type of status epilepticus (parenteral administration).

Unlabeled Uses

Rectal administration.

Contraindications

Hypersensitivity to phenytoin or other hydantoins; Adams-Stokes syndrome, second- and third-degree AV block, sinoatrial block, sinus bradycardia (injection only).

Dosage and Administration

Individualize dose within clinically effective therapeutic serum level of 10 to 20 mcg/mL.

Seizures
Adults

PO 100 mg (or 125 mg of suspension) 3 times daily initially.

Maintenance

300 to 400 mg/day. An increase to 600 mg/day (625 mg/day of suspension) may be made if necessary. Sometimes initial 1 g loading dose is divided into 3 doses (400, 300, and 300 mg) and is given at 2-h intervals. Once seizure control is established, ER form (300 mg) may be administered for once-daily dosing.

Children

PO 5 mg/kg/day in 2 to 3 divided doses initially.

Maintenance

4 to 8 mg/kg/day (max, 300 mg/day).

Status Epilepticus
Adults

IV Loading dose of 10 to 15 mg/kg via slow IV, not exceeding 50 mg/min. Then PO/IV 100 mg every 6 to 8 h.

Children

IV Loading dose of 15 to 20 mg/kg at rate not exceeding 1 to 3 mg/kg/min.

Neurosurgery Prophylaxis
Adults

IM 100 to 200 mg at 4-h intervals during surgery and postoperatively.

General Advice

  • Shake oral suspension well.
  • Do not administer discolored capsules.
  • Only ER capsules are recommended for once-daily dosage.
  • Do not crush or allow patient to chew ER capsules.
  • Tablets may be chewed thoroughly before swallowing, or swallowed whole.
  • Dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.
  • For parenteral administration, direct IV administration is recommended.
  • Administer IV slowly into large vein via large-gauge needle or cannula. Do not exceed rate of 50 mg/min for adults or 1 to 3 mg/kg/min in newborns. Immediately flush with normal saline solution. Avoid continuous infusion.
  • Avoid IM route when possible. If IM administration is needed for longer than 1 wk, consider alternatives such as gastric intubation. Not recommended in status epilepticus because the attainment of peak plasma levels may require up to 24 h.
  • When patient is stabilized with oral phenytoin and switched from oral to IM route, dosage must be increased by 50%. When patient returns to oral form after IM administration, give half of the original oral dosage for 1 wk.
  • Addition of phenytoin injection solution to IV fluids is not recommended because of the lack of solubility and likelihood of precipitation.
  • Do not use parenteral solution if precipitates form that will not dissolve at room temperature.
  • Do not use parenteral solution if it is hazy; faint, clear yellow color is acceptable for use.

Storage/Stability

Store ER tablets, capsules, and suspension at 68° to 77°F. Store injection and chewable tablets at 59° to 86°F. Protect tablets and capsules from moisture. Do not freeze injection or oral suspension and protect from light.

Drug Interactions

Acetaminophen

The potential hepatotoxicity of acetaminophen may be increased when long-term doses of hydantoins are coadministered. The therapeutic effects of acetaminophen may be reduced with simultaneous phenytoin therapy.

Alcohol

Acute alcohol ingestion may increase phenytoin plasma levels, while long-term use may decrease plasma concentrations. Monitor phenytoin plasma concentrations and adjust the phenytoin dose as needed.

Amiodarone

Increased serum phenytoin concentrations with symptoms of toxicity. Phenytoin may decrease amiodarone serum levels. Monitor drug concentrations and observe patients for phenytoin toxicity or loss of amiodarone therapeutic effect when this combination is used. Adjust the dose of either drug as needed.

Antacids (containing calcium), molindone

Calcium ions may interfere with phenytoin absorption. In patients with low serum phenytoin levels, stagger ingestion times of orally administered phenytoin and antacid preparations containing calcium to prevent absorption problems. The commercial molindone products contain calcium ions that interfere with the absorption of phenytoin.

Anticoagulants (eg, warfarin)

Increased phenytoin serum concentrations with possible toxicity. Increased and decreased PT/INR responses have been reported. May increase or decrease the anticoagulant effect of warfarin. Monitor the response of the patient and adjust the dose of either drug as needed.

Antineoplastic agents (eg, bleomycin), chloral hydrate, ciprofloxacin, corticosteroids, diazoxide, enteral nutrition therapy, folic acid, reserpine, sirolimus, sucralfate, vigabatrin

Phenytoin serum concentrations may be reduced, decreasing the efficacy. Monitor phenytoin serum levels and adjust the phenytoin dose appropriately.

Azole antifungal agents (eg, itraconazole)

Phenytoin plasma levels may be elevated, increasing the risk of toxicity, while itraconazole, ketoconazole, and voriconazole plasma levels may be reduced, decreasing efficacy. If coadministration cannot be avoided, monitor phenytoin plasma concentrations and observe the clinical response of the patient. Adjust the dose of either drug as needed.

Barbiturates

The effect of barbiturates on hydantoins is unpredictable. Phenobarbital may either increase or decrease plasma phenytoin concentrations. The addition of phenytoin may increase barbiturate serum concentrations. Monitor serum concentrations of both drugs, seizure activity, and clinical symptoms when initiating or discontinuing either drug. Adjust treatment as needed.

Benzodiazepines (eg, midazolam), cimetidine, disulfiram, erlotinib, estrogens, fluconazole, fluorouracil, fluoxetine, fluvoxamine, halothane, isoniazid, methylphenidate, omeprazole, phenacemide, salicylates (eg, aspirin), sertraline, succinimides (eg, ethosuximide), sulfonamides (eg, sulfadiazine), ticlopidine, trazodone, trimethoprim

Phenytoin serum concentrations may be elevated, increasing the pharmacologic effects and the risk of toxicity. Monitor phenytoin concentrations and observe the clinical response of the patient. Adjust the phenytoin dose as needed.

Carbamazepine

The effect of carbamazepine on phenytoin is variable. Phenytoin decreases serum carbamazepine levels. Monitor serum concentrations of both drugs, particularly when starting or stopping either drug. Adjust the dose of carbamazepine and/or phenytoin as needed.

Chloramphenicol

Increased serum phenytoin concentrations with potential toxicity. Chloramphenicol concentrations may be increased or decreased. Measure concentrations of both drugs and observe the patient for signs of phenytoin toxicity. Adjust the dose of either drug as needed.

Colesevelam

Colesevelam may bind to and impair oral absorption of oral phenytoin. Administer phenytoin 4 h prior to colesevelam. Measure phenytoin concentrations and adjust the dose as needed.

Cyclosporine

Cyclosporine concentrations may be decreased, resulting in a decrease in the immunosuppressive activity of cyclosporine, which may predispose patients to transplant rejection. Measure cyclosporine concentrations and monitor for evidence of transplant rejection. Adjust the cyclosporine dose as needed.

Digoxin, doxycycline, everolimus, felodipine, gefitinib, haloperidol, imatinib, irinotecan, ixabepilone, levodopa, loop diuretics (eg, furosemide), maraviroc, methadone, mexiletine, mirtazapine, nisoldipine, praziquantel, quetiapine, quinidine, temsirolimus, teniposide, tolvaptan, vitamin D

The effects of these agents may be impaired. Monitor for a decrease in therapeutic effect and increase the dose of these agents as needed.

Disopyramide

Disopyramide concentrations and bioavailability may be decreased, while anticholinergic actions may be enhanced. Monitor the response of the patient and adjust the disopyramide dose as needed.

Dronedarone, NNRTIs (eg, etravirine), tyrosine kinase receptor inhibitors (eg, dasatinib, lapatinib, nilotinib)

Plasma concentrations of these agents may be reduced by phenytoin, decreasing the pharmacologic effects. Avoid coadministration.

Efavirenz

Phenytoin concentrations may be elevated, increasing the pharmacologic effect and risk of adverse reactions. Efavirenz plasma concentrations may be reduced, decreasing the pharmacologic effects. Monitor concentrations of both drugs and observe the patient response. Adjust the dose of efavirenz and/or phenytoin as needed.

Erlotinib

Phenytoin concentrations may be elevated, increasing the pharmacologic effect and risk of adverse reactions. Measure phenytoin concentrations and monitor the patient's response when starting, stopping, or changing the erlotinib dose. Erlotinib plasma concentrations may be reduced, decreasing the pharmacologic effects. If alternate treatment lacking CYP3A4 activity is not available, consider increasing the erlotinib starting dose at 2 wk intervals. If the dose is adjusted upward, reduce the erlotinib dose to the indicated erlotinib starting dose immediately after stopping phenytoin.

Estrogens (eg, conjugated estrogens, ethinyl estradiol), hormonal contraceptives, progestins (eg, levonorgestrel, norgestrel)

Phenytoin levels may be increased by estrogens or hormonal contraceptives. Pharmacologic effects of estrogens, hormonal contraceptives, and progestins may be decreased. Alternative or nonhormonal contraception is recommended during hydantoin therapy. Also, monitor phenytoin concentrations and observe the clinical response of the patient. Adjust the phenytoin dose as needed.

Exemestane

Exemestane plasma concentrations may be reduced, decreasing the pharmacologic effects. The recommended dosage of exemestane is 50 mg once daily after a meal if phenytoin is coadministered. If phenytoin is discontinued, reduce the exemestane dosage to 25 mg once daily with a meal.

Felbamate

Serum phenytoin concentrations may be increased, possibly resulting in an increase in the pharmacologic and toxic effects of phenytoin. Phenytoin may also decrease felbamate concentrations. Monitor phenytoin and felbamate concentrations, and observe patients for changes in seizure control. Adjust the dose of either drug as needed.

Food

The anticonvulsant effects of phenytoin may be altered by food. Administer phenytoin consistently with respect to meals in order to avoid fluctuations in the amount of phenytoin absorbed. In patients receiving continuous tube feedings, higher doses of phenytoin may be necessary. Monitor phenytoin plasma concentrations, and adjust the dose as needed.

HMG-CoA reductase inhibitors (eg, atorvastatin, simvastatin)

HMG-CoA reductase inhibitor concentrations may be reduced, decreasing the pharmacologic effect. Monitor the clinical response of the patient. If an interaction is suspected, consider administering alternative therapy. Pravastatin may be less likely to interact.

Metyrapone

Phenytoin may cause subnormal response to metyrapone. Consider using oral metyrapone doses of as much as twice the usual amount.

Nondepolarizing muscle relaxants (eg, cisatracurium, pancuronium, vecuronium)

Nondepolarizing muscle relaxants may have a shorter than expected duration of action or be less effective. Nondepolarizing muscle relaxant dosages may need to be increased. Monitor for reduced effectiveness.

Phenothiazines (eg, fluphenazine, prochlorperazine, thioridazine)

An increase in the pharmacologic effects of phenytoin and a decrease in the effectiveness of thioridazine may be observed. Measure phenytoin concentrations and monitor the patient for signs of toxicity. Adjust the phenytoin dose as needed.

Primidone

May increase concentrations of primidone and primidone metabolites, increasing the effects. Closely monitor primidone and primidone metabolites and the patient's response following any alteration in phenytoin therapy. Adjust the primidone dose as needed.

Protease inhibitors (eg, lopinavir/ritonavir)

Certain protease inhibitors and phenytoin plasma concentrations may be reduced during coadministration, decreasing the therapeutic effects of both drugs. Measure phenytoin concentrations. Adjust the dose of phenytoin or lopinavir/ritonavir as needed.

Ranolazine

Serum levels of ranolazine may be reduced, decreasing the pharmacologic effects. Avoid coadministration.

Rifamycins (eg, rifabutin, rifampin)

Serum phenytoin levels may be decreased, resulting in a possible decrease in the pharmacologic effects of phenytoin. Phenytoin may impair efficacy of rifampin. Measure phenytoin concentrations and observe the response of the patient when rifabutin or rifampin is started or stopped. Adjust the phenytoin dose as needed. An increased rifampin dosage may be necessary.

Sodium valproate, valproic acid

Coadministration may either increase or decrease phenytoin plasma concentrations, while those of valproic acid may be decreased. Phenytoin toxicity may occur at therapeutic total plasma concentrations. Monitor the levels of the free concentrations of phenytoin and serum valproic acid levels. Adjust dose of either drug as needed.

Sympathomimetics (eg, dopamine)

May cause profound hypotension and, possibly, cardiac arrest. Use phenytoin with extreme caution.

Tacrolimus

Tacrolimus serum concentrations may be reduced, decreasing the efficacy, while phenytoin concentrations may be elevated, increasing the pharmacologic effects and adverse reactions. Monitor serum concentrations of both tacrolimus and phenytoin. Adjust the dose of phenytoin or tacrolimus as needed.

Theophyllines

Effects of either agent may be decreased. When either medication is added to or removed from a patient's regimen, monitor plasma levels of each drug and adjust the doses as needed.

Tolbutamide

Serum phenytoin levels may be increased. Measure phenytoin concentrations. If an interaction is suspected, adjust the phenytoin dose as needed. Phenytoin may cause an increase in blood glucose levels, necessitating a higher dose of sulfonylurea for control of hyperglycemia.

Topiramate

Topiramate may increase the effects of phenytoin, while phenytoin may decrease the pharmacologic effects of topiramate. Measure phenytoin concentrations and observe the response of the patient when topiramate is started or stopped. Adjust the phenytoin dose as needed. A decreased topiramate dose may be needed when phenytoin is stopped after concurrent use.

Tricyclic antidepressants (eg, amitriptyline)

May precipitate seizures, necessitating phenytoin dosage adjustments. The pharmacologic effects of phenytoin may be elevated, increasing the pharmacologic effects and risk of toxicity. Measure phenytoin concentrations and observe the response of the patient when a tricyclic antidepressant is started or stopped. If an interaction is suspected, adjust the phenytoin dose as needed.

Laboratory Test Interactions

Phenytoin may interfere with metyrapone and dexamethasone tests, causing inaccurate results because of increased metabolism of these agents. Phenytoin may cause a decrease in serum levels of protein-bound iodine. In addition, phenytoin may cause increased levels of glucose, alkaline phosphatase, and GGT.

Adverse Reactions

Cardiovascular

Atrial and ventricular conduction depression, CV collapse, hypotension; ventricular fibrillation (IV use).

CNS

Asterixis, ataxia, chorea, decreased coordination, dizziness, dystonia, headache, insomnia, mental confusion, motor twitching, nystagmus, sensory peripheral neuropathy, slurred speech, transient nervousness, tremor; CNS depression (IV use).

Dermatologic

Bullous, exfoliative, or purpuric dermatitis; hypertrichosis; lupus erythematosus; morbilliform or scarlatiniform rashes, sometimes accompanied by fever; Stevens-Johnson syndrome; TEN.

GI

Constipation, nausea, vomiting.

Hematologic

Agranulocytosis, benign lymph node hyperplasia, granulocytopenia, Hodgkin disease, immunoglobulin abnormalities, leukopenia, lymphoma, macrocytosis, megaloblastic anemia, pancytopenia with or without bone marrow suppression, pseudolymphoma, thrombocytopenia.

Hepatic

Liver damage, toxic hepatitis.

Hypersensitivity

Anticonvulsant hypersensitivity syndrome, including symptoms such as arthralgias, eosinophilia, fever, liver dysfunction, lymphadenopathy, or rash.

Local

Inflammation, local irritation, necrosis, sloughing; tenderness (IV use).

Miscellaneous

Coarsening of facial features, gingival hyperplasia, lip enlargement, periarteritis nodosa, Peyronie disease, SLE.

Precautions

Monitor

Monitor serum concentrations and take care when switching a patient from one doseform to another. Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Monitor patients for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.


Pregnancy

Category D . Possible risk of birth defects must be considered along with hazard to the fetus from seizures in untreated epileptic women.

Lactation

Excreted in breast milk.

Hypersensitivity

Contraindicated in patients who have experienced phenytoin hypersensitivity; use with caution in patients using structurally similar compounds (eg, barbiturates, oxazolidinediones, succinimides).

Renal Function

Patients with a history of renal disease should not receive the oral loading dose.

Hepatic Function

Patients with a history of hepatic disease should not receive the oral loading dose.

Special Risk Patients

Use drug with caution in patients with alcohol abuse, hepatic impairment, hypotension, porphyria, and severe myocardial insufficiency. Patients with hepatic impairment, elderly patients, and those who are gravely ill may show early signs of toxicity.

Acute toxicity

Serum levels of phenytoin above the optimal range may produce confusional states or, rarely, irreversible cerebellar dysfunction.

Anticonvulsant hypersensitivity syndrome

A rare, drug-induced multiorgan syndrome that is potentially fatal and characterized by fever, rash, lymphadenopathy, and other multiorgan pathologies (often hepatic) may occur. Symptoms usually occur 2 to 4 wk after first drug exposure but have been reported in patients taking anticonvulsants for longer periods of time. Black patients, patients with a personal or family history of this syndrome, and immunosuppressed patients are at a higher risk.

Bioavailability

Because products vary in bioavailability, brand interchange is not recommended.

CV effects

Severe cardiotoxic reactions and fatalities have occurred with IV use.

Enteral feedings

Concomitant use may result in lower than expected phenytoin serum levels. Avoid coadministration.

Free phenytoin levels

Consider in patients with hypoalbuminemia, renal or hepatic impairment, or critical illness.

Hyperglycemia

Has been reported and may be caused by the inhibitory effects of phenytoin on insulin release. May also raise serum glucose levels in patients with diabetes.

Lymphadenopathy

A relationship between phenytoin use and the development of lymphadenopathy (local or generalized) has been suggested. May occur with or without symptoms and signs resembling serum sickness (eg, fever, liver involvement, rash).

Osteomalacia

Has been associated with phenytoin therapy and is thought to be caused by interference with vitamin D metabolism.

Seizures

Drug should not be given to treat seizures caused by hypoglycemia, other metabolic causes, or absence epilepsy.

Skin reactions

May rarely cause serious skin reactions, such as exfoliative dermatitis, Stevens-Johnson syndrome, and TEN, which can be fatal. The risk of such reactions may be greater in patients of Asian ancestry who are positive for HLA-B*1502.

Slow metabolism

A small percentage of patients treated with phenytoin have been shown to metabolize the drug slowly, possibly caused by limited enzyme availability and lack of induction.

Suicidal behavior and ideation

Antiepileptic drugs, including phenytoin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Balance the risk of suicidal thoughts or behaviors with the risk of untreated illness.

Withdrawal

Abrupt withdrawal may precipitate status epilepticus. Dosage must be reduced or other anticonvulsant medicine substituted gradually. In the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary.

Overdosage

Symptoms

Ataxia, coma, dysarthria, hyperreflexia, hypotension, lethargy, nausea, nystagmus, respiratory and CV depression, slurred speech, tremor, vomiting.

Patient Information

  • Advise patient to take medication consistently with respect to meals in order to avoid fluctuations in the amount of phenytoin absorbed.
  • Teach patient to shake oral suspension well and use a calibrated measuring device to ensure accurate dosing.
  • Instruct patient taking capsules not to use discolored ones.
  • Tell patient to notify health care provider if skin rash develops.
  • Instruct patient to report the following symptoms to health care provider: ataxia, drowsiness, gingival hyperplasia, jaundice, nystagmus, and/or severe nausea or vomiting.
  • Counsel patients and their caregivers and families that antiepileptic drugs, including phenytoin, may increase the risk of suicidal thoughts and behavior, and advise them of the need to be alert for the emergence or worsening of symptoms of depression; any unusual changes in mood or behavior; or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct them to report behaviors of concern immediately to a health care provider.
  • Caution patient to consult with health care provider before using alcohol or taking any other drug, including OTC medications.
  • Warn patient that stopping medication too quickly may precipitate seizures. Stress that dose should be changed only under health care provider's direction.
  • Inform patient that it is important to maintain good oral hygiene and to inform dentist of phenytoin therapy.
  • Instruct patients with diabetes that changes may occur in blood sugars and to monitor and report any abnormal results to health care provider.
  • Advise patient to carry medical identification (eg, card, bracelet) that identifies illness and medication.
  • Instruct patient to inform surgeon, health care provider, or dentist that they take this medication before any surgical, emergency, or dental procedure.
  • Advise patient that drug may cause drowsiness and to use caution while driving or performing other tasks requiring mental alertness.

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