Class: Hydantoins
VA Class: CN400
CAS Number: 57-41-0
Brands: Dilantin, Dilantin Infatabs, Phenytek
- IV Administration Rate
Must be administered IV slowly.b
Do not exceed 50 mg/minute in adults.b
Do not exceed 1–3 mg/kg per minute in pediatric patients.b
REMS:
FDA approved a REMS for phenytoin to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().
Introduction
Phenytoin is a hydantoin-derivative anticonvulsant.b
Uses for Phenytoin Sodium
Tonic-Clonic Seizures
Mainly in the prophylactic management of tonic-clonic (grand mal) seizures with complex symptomatology (psychomotor seizures).a b c d
Partial Seizures
Mainly in the prophylactic management of partial seizures with complex symptomatology (psychomotor and temporal lobe seizures).a b c d
Effective in controlling partial seizures with autonomic symptoms†.b
Absence (Petit Mal) Seizures
Not recommended for the treatment of pure absence (petit mal) seizures† since the drug may increase the frequency of these seizures; however, may be useful in conjunction with succinimide or oxazolidinedione anticonvulsants in the management of combined absence and tonic-clonic seizures.b
Neurosurgical Seizures
Prevention and treatment of seizures occurring during and following neurosurgery.a b
Status Epilepticus
Diazepam generally considered the drug of choice for termination of status epilepticus.b
Alternatively, concurrent IV administration of phenytoin (or fosphenytoin) and diazepam is a treatment of choice for termination of status epilepticus.b c
May be used parenterally, preferably by IV administration, in the treatment of status epilepticus; however, the usefulness of the drug in this condition is limited by the need for slow administration and its slow onset of action. Fosphenytoin is an alternative.b c
Cardiac Arrhythmias
Useful IV in the treatment of ventricular tachycardia† and paroxysmal atrial tachycardia†, particularly when conventional antiarrhythmic agents or cardioversion is ineffective.b
Useful orally for maintenance therapy in the management of cardiac arrhythmias†.b
Cardiac Glycoside Intoxication
Drug of choice IV for the treatment of arrhythmias caused by cardiac glycoside intoxication†.b
Neuropathic Pain
May have beneficial effects in the symptomatic treatment of chronic pain arising from peripheral neuropathic syndromes† (e.g., trigeminal neuralgia†).b
Phenytoin Sodium Dosage and Administration
General
Seizure Disorders
Carefully and slowly adjust dosage according to individual requirements and response.b
When a patient is transferred from phenytoin to another anticonvulsant, gradually reduce the phenytoin dosage over a period of about 1 week while at the same time therapy is instituted with a low dose of the replacement drug.b
When phenytoin replaces phenobarbital or any other barbiturate anticonvulsant, reduce the dose of the barbiturate gradually over a period of 1 week to prevent withdrawal symptoms.b
Withdraw phenytoin slowly to avoid precipitating seizures or status epilepticus.b
Oral Loading-Dose Regimens
Therapeutic serum phenytoin concentrations can be achieved more rapidly (in 2–24 hours) by the use of an oral loading-dose regimen.b
Various regimens have been suggested, and clinicians should consult published protocols for information on specific regimens.b (See Pediatric Patients and also Adults under Dosage for suggested regimen.)
Reserve oral loading-dose regimens for patients in a clinic or hospital setting where serum phenytoin concentrations can be closely monitored.b
Patients with a history of renal or liver disease should not receive an oral loading-dose regimen.b
Administration
Phenytoin and its sodium salt are administered orally.b
Phenytoin sodium also may be administered by direct IV injection for the initial treatment of status epilepticus and for the prophylaxis of seizures during neurosurgery.b
Phenytoin sodium also has been infused IV† cautiously.b d HID (See Dilution under IV Administration.)
Avoid sub-Q or perivascular injection because of risk of soft tissue irritation and inflammation. Administer IM only as a last resort. (See IM Administration.)
Oral Administration
Only extended phenytoin sodium capsules should be used for once-daily dosing regimens.
When refilling a prescription for a preparation previously labeled as phenytoin sodium capsules, the pharmacist should determine whether the brand has been reformulated, whether the brand is now extended phenytoin sodium capsules or prompt phenytoin sodium capsules, and which one the clinician intends that the patient continue to receive.b
Monitor serum phenytoin concentrations when a patient is switched from extended phenytoin sodium capsules to prompt phenytoin sodium capsules.b
Do not use oral formulations containing phenytoin as the base (e.g., suspensions, chewable tablets) for once-daily dosing regimens.b
Minimize loss of phenytoin oral suspension during oral administration via a nasogastric tube (secondary to adherence to PVC tubing) by diluting (e.g., threefold) the suspension with a compatible diluent (e.g., sterile water, 5% dextrose, 0.9% sodium chloride) prior to administration, combined with flushing the tube with at least 20 mL of diluent after administration.b
IV Administration
Inject IV preferably directly into a large vein through a large-gauge needle or IV catheter.b
Following IV injection, inject 0.9% sodium chloride injection through the same needle or catheter to reduce local venous irritation from alkaline solution.b HID
Generally not recommended for use in IV infusions† because of the possibility that precipitation may occur; however, can be infused IV safely provided adequate precautions are taken.b (See Dilution.)
Dilution
IV infusion† is feasible provided appropriate precautions are taken, such as maintaining an optimal pH (e.g., ≥10 for 1 mg/mL dilutions), using a suitable infusion fluid (i.e., 0.9% sodium chloride injection or lactated Ringer’s), using a sufficiently diluted solution (e.g., <6.7 mg/mL), starting the infusion immediately after preparation and completing administration within a relatively short period, using a 0.22-mcm inline filter, and carefully observing the admixture.b d HID
One suggested technique: Add 1 g to 1 L 0.9% sodium chloride or lactated Ringer’s to provide a concentration of 1 mg/mL; these solutions generally have a pH ≥10 but final pH is not predictable.d HID Infuse IV† with caution; start the infusion immediately after preparation, complete within a relatively short period, and watch closely for possible crystallization.HID Use a 0.22-mcm inline filter during infusion.d HID
Crystallization generally occurs in more acidic solutions (e.g., dilutions in 5% dextrose), which should not be used.e HID (See Solution Compatibility under Stability.)
Alternatively, fosphenytoin sodium (Cerebyx), a prodrug of phenytoin, can be used for IV infusion.c
Rate of Administration
Adults: ≤50 mg/minute; preferably ≤25–50 mg/minute.b g
Pediatric patients: ≤1–3 mg/kg per minute; preferably, 0.5–1.5 mg/kg per minute.b f g
Neonates: ≤1–3 mg/kg per minute;HID preferably ≤0.5 mg/kg per minute.f
IM Administration
Administer IM only as a last resort because of erratic absorption from IM injection sites.b
May be of some value for sustaining established therapeutic plasma concentrations when oral administration is not feasible.b
Information regarding IM administration for >1 week is lacking; consider alternate routes for administering phenytoin (e.g., gastric intubation) when oral administration is not feasible for >1 week.b
Fosphenytoin sodium can be administered IM for short-term replacement of oral phenytoin.b
Dosage
Each 100 mg of phenytoin sodium contains approximately 92 mg of phenytoin; consider the difference when switching from the base to its sodium salt or vice versa.b
Pediatric Patients
Seizure Disorders
Oral
Usual dosage: Initially, 5 mg/kg or 250 mg/m2 daily in 2 or 3 equally divided doses; total dosage ≤300 mg daily.b
Therapeutic serum concentrations achieved more rapidly with a 500- to 600-mg oral loading dose, in divided doses, followed by usual maintenance dosage 24 hours after initiating loading dose.c
Adjust subsequent dosage carefully and slowly according to the patient’s requirements.b
Neonates, maintenance dosage: Usually, 3–5 mg/kg daily.g
Infants 1–12 months of age, maintenance dosage: Usually, 4–8 mg/kg daily.b
Children 1–11 years of age, maintenance dosage: 4–10 mg/kg daily.g
Adolescents, 12–17 years of age, maintenance dosage: 4–8 mg/kg daily.g
Status Epilepticus
IV
15–20 mg/kg, at a rate ≤1–3 mg/kg per minute.b
Preferably, 10–15 mg/kg, at a usual rate of 0.5–1.5 mg/kg per minute (maximum total dose of 20 mg/kg in 24 hours).b
Replace parenteral administration with oral therapy as soon as possible.b
Adults
Seizure Disorders
Prompt-Release preparations
Oral
Usual dosage: Initially, 100 mg 3 times daily.b
A period of 5–10 days may be required to achieve anticonvulsant effects.b
Increases to >300 mg daily may lead to markedly increased serum phenytoin concentrations; therefore, adjust dosage above this level carefully and slowly.b
Therapeutic serum concentrations achieved more rapidly with a 1-g oral loading dose given as 400, 300, and 300 mg at 2-hour intervals, followed by usual maintenance dosage 24 hours after initiating loading dose.b
Increase daily dosage gradually, if necessary, in increments of 100 mg every 2–4 weeks until desired response is achieved.b
Dosing at 100 mg 4 times daily may benefit some patients, and others may require dosages up to 200 mg 3 times daily.b
Optimum daily dose: Varies considerably but usually in the range of 4–7 mg/kg (300–600 mg daily for most adults).b g
IM
Increase the IM dosage by 50% over the previously established oral dosage.b
First week back on oral therapy, reduce oral dosage to one-half the original oral dosage to avoid drug accumulation resulting from eventual absorption from the IM injection site; monitoring of serum concentrations recommended.b
Limit IM therapy to 1 week. (See IM Administration under Administration.)
Extended-Release Preparations
Oral
For patients stabilized on a dosage of 100 mg 3 times daily, once-daily dosing with 300 mg as extended phenytoin sodium capsules may be considered.b
Do not use prompt phenytoin sodium capsules nor oral phenytoin base suspensions or chewable tablets for once-daily dosing.b
Status Epilepticus
IV
Initially, 10–15 mg/kg, by direct IV administration at a rate ≤50 mg/minute; the initial dose should be followed by IV or oral maintenance doses of 100 mg every 6–8 hours.b
Preferably, 15–18 mg/kg, at a rate ≤25–50 mg/minute (maximum total dose of 1.5 g in 24 hours).b g
Oral therapy should replace parenteral administration as soon as possible.b
Cardiac Arrhythmias
Ventricular Tachycardia
Oral
100 mg 2–4 times daily.b
IV
100 mg by direct IV injection at 5-minute intervals until the arrhythmia is abolished or undesirable effects appear or until a total of 1 g is given.b
Paroxysmal Atrial Tachycardia
Oral
100 mg 2–4 times daily.b
IV
100 mg by direct IV injection at 5-minute intervals until the arrhythmia is abolished or undesirable effects appear or until a total of 1 g is given.b
Cardiac Glycoside Intoxication
Oral
100 mg 2–4 times daily.b
IV
100 mg by direct IV injection at 5-minute intervals until the arrhythmia is abolished or undesirable effects appear or until a total of 1 g is given.b
Prescribing Limits
Pediatric Patients
Seizure Disorders
Oral
Total dosage should not exceed 300 mg daily.b
Status Epilepticus
IV
Maximum total dose of 20 mg/kg in 24 hours.b
Adults
Seizure Disorders
Prompt-Release Preparations
Oral
Increases in dosage to >300 mg daily may lead to markedly increased serum phenytoin concentrations; therefore, adjust dosage above this level carefully and slowly.b
IM
Generally limit IM therapy to 1 week. (See IM Administration under Administration.)
The first week back on oral therapy, reduce the oral dosage to one-half the original oral dosage to avoid drug accumulation resulting from eventual absorption from the IM injection site; monitor serum concentrations.b
Status Epilepticus
IV
Maximum total dose of 1.5 g in 24 hours.b
Cardiac Arrhythmias
Ventricular Tachycardia
IV
Maximum total IV dose of 1 g.b
Paroxysmal Atrial Tachycardia
IV
Maximum total IV dose of 1 g.b
Cardiac Glycoside Intoxication
IV
Maximum IV dose of 1 g.b Do not use oral loading-dose regimens.b
Special Populations
Hepatic Impairment
Consider reduced maintenance dosage in hepatic cirrhosis.g Do not use oral loading-dose regimens.b
Renal Impairment
Do not use oral loading-dose regimens.b
End-stage renal impairment generally can receive usual loading and maintenance dosages initially, adjusting as necessary.g
Geriatric Patients
May show early signs of toxicity.a
Geriatric patients with heart disease: It has been recommended that the drug be given at a rate of 50 mg over 2–3 minutes.b
Obese Patients
Ideal or nonobese weight probably correlates best with maintenance dosages.g Loading doses may require adjustment for increased volume of distribution.g
Pregnancy
Monitor phenytoin therapy closely (phenytoin concentrations may decline) to ensure optimum seizure control.g h
Cautions for Phenytoin Sodium
Contraindications
IV use contraindicated in patients with sinus bradycardia, SA block, second- or third-degree AV block, or Adams-Stokes syndrome.b
Known hypersensitivity to phenytoin or any ingredient in the respective formulation or to other hydantoins.b
Warnings/Precautions
Warnings
Shares the toxic potentials of the hydantoin-derivative anticonvulsants, and the usual precautions of anticonvulsant therapy should be observed.b c
Withdrawal
Abrupt withdrawal can precipitate status epilepticus.a Reduce dosage or substitute other anticonvulsants cautiously and slowly.a b
Porphyria
May exacerbate porphyria; use with caution.b
Lymphadenopathy
If lymphadenopathy occurs, differentiate the condition from other types of lymph node pathology and observe the patient closely for an extended period; use alternative anticonvulsants, if possible, for seizure control.b
IM Injection
Not recommended IM for status epilepticus because of delayed and unpredictable blood concentrations.b
Cardiovascular Effects
Hypotension if administered too rapidly IV.b
May cause severe, potentially life-threatening cardiotoxic reactions (e.g., decreased cardiac output, atrial or ventricular conduction depression, ventricular depression).b IV, may be due in part to propylene glycol (cardiac depressant) in parenteral formulation.g
Cardiac and Respiratory Disorders
Administer IV only with extreme caution to patients with respiratory depression, myocardial infarction, frank or impending CHF, or otherwise damaged myocardium, and in patients in whom a sudden change in blood pressure may lead to serious complications (e.g., those with hypotension or severe myocardial insufficiency).b
Alcohol
Acute alcohol intake may increase serum phenytoin concentrations and chronic alcohol use may decrease serum concentrations.a
Sensitivity Reactions
Rash
If a rash develops, discontinue phenytoin; do not resume if the rash is exfoliative, purpuric, or bullous or if lupus erythematosus, Stevens-Johnson syndrome, or toxic epidermal necrolysis is suspected.b
Possible increased risk of developing toxic epidermal necrolysis or Stevens-Johnson syndrome in individuals of Asian ancestry who carry the human leukocyte antigen (HLA)-B*1502 allele.103 104 105 FDA is evaluating the relationship between use of phenytoin and serious dermatologic reactions in individuals with the HLA-B*1502 allele.103 Screening for presence of HLA-B*1502 allele before initiating phenytoin therapy not recommended at this time.103 Phenytoin should not be used as an alternative to carbamazepine in HLA-B*1502-positive patients.103
If the rash is morbilliform or scarlatiniform, therapy may be restarted after the rash has completely disappeared; if the rash recurs when phenytoin is restarted, further phenytoin therapy is contraindicated.b
Structurally Similar Compounds
Caution if using structurally similar compounds (e.g., barbiturates, succinimides, oxazolidinediones) in patients who have experienced phenytoin hypersensitivity.b
Major Toxicities
Blood Concentrations
Concentrations <25 mcg/mL: Most patients tolerate.b
Concentrations of 25 mcg/mL: In some patients, are associated with nystagmus, ataxia, and diplopia.b
Concentrations >30 mcg/mL: Drowsiness and lethargy, and rarely asterixis, may result.b
Concentrations >50 mcg/mL: Extreme lethargy and, occasionally, comatose states occur.b
Some patients metabolize phenytoin slowly and thus exhibit signs of toxicity even with low to moderate dosage.b
IV Phenytoin Toxicity
Most important signs of toxicity associated with the IV use of phenytoin sodium are cardiovascular collapse and/or CNS depression.b
Hypotension occurs if the drug is administered too rapidly by the IV route.b
Administer the drug slowly at a rate not exceeding 50 mg/minute to minimize these effects.b
In geriatric patients with heart disease, it has been recommended that the drug be given at a rate of 50 mg over 2–3 minutes; personnel and equipment should be readily available for administration of artificial respiration since severe complications are most common in geriatric or debilitated patients.b
General Precautions
Osteomalacia
Has been associated with phenytoin therapy and is thought to be caused by phenytoin’s interference with vitamin D metabolism.
Hyperglycemia
In large doses, may increase blood glucose concentrations resulting in hyperglycemia and glycosuria.a b
Average doses do not regularly elevate blood glucose or increase insulin requirements in diabetic patients, but a few patients have experienced fatal, hyperosmolar, nonketotic coma in which phenytoin may have played at least an accessory etiologic role.b
Hypertrichosis
Usually confined to extremities but can affect trunk and face and may be irreversible.b
Slow Metabolizers
A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly; this appears to be genetically determined and may be due to limited enzyme availability and lack of induction.a
Seizures Due to Hypoglycemia or Other Metabolic Causes
Not indicated for seizures due to hypoglycemia or other metabolic causes; appropriate diagnostic procedures should be performed as indicated.b
Specific Populations
Pregnancy
Category D.h
Evidence of significant risk of fetal congenital abnormalities, fetal hydantoin syndrome (consisting of prenatal growth deficiency, microcephaly, and mental deficiency), and hemorrhage at birth.h
Use during pregnancy only when clearly needed;b risk-to-benefit ratio generally favors continued use during pregnancy in women whose seizure control depends on the drug.h
In addition to reports of a fetal hydantoin syndrome, there have been rare reports of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.b
Because of altered absorption or metabolism of phenytoin during pregnancy, an increased frequency of seizures may occur in pregnant women receiving the drug.b
If administered during pregnancy, serum phenytoin concentrations should be monitored and dosage adjusted accordingly to the lowest possible level required to control seizures; however, restoration of the patient’s usual dosage will probably be necessary postpartum.b h
Consider monitoring maternal folate concentration and administering supplemental folic acid early in pregnancy or before conception as indicated.h
Lactation
Distributed into breast milk.b h However, use generally is considered compatible with breast-feeding.h
Geriatric Use
Liver is the chief site for biotransformation; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity.a
Hepatic Impairment
Liver is the chief site for biotransformation; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity.a
Renal Impairment
In large doses, may increase blood glucose concentrations resulting in hyperglycemia and glycosuria; patients with impaired renal function may be most susceptible to this effect.a b
Common Adverse Effects
Adverse GI effects include nausea and vomiting, constipation, epigastric pain, dysphagia, loss of taste, anorexia, and weight loss.b Adverse CNS effects include mental confusion, nystagmus, ataxia, blurred vision, diplopia, toxic amblyopia, dizziness, insomnia, transient nervousness, motor twitching, and headache.b
Phenytoin frequently produces gingival hyperplasia, especially in children, which occasionally is so severe that it may require surgical removal.b
Interactions for Phenytoin Sodium
Specific Drugs or Laboratory Tests
Drug or Test | Interaction | Comments |
---|---|---|
Alcohol intake, acute | May increase serum phenytoin concentrationsa | |
Alcohol intake, chronic | May decrease serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Amiodarone | May increase serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Antacids, calcium-containing | Calcium ions interfere with GI absorption of phenytoinb | Ingestion times of phenytoin and antacid preparations containing calcium should be staggered in patients with low serum phenytoin concentrations to prevent absorption problemsb |
Anticoagulants, coumarin | Efficacy is impaired by phenytoina | |
Antidepressants, tricyclic | Antidepressant may precipitate seizures in susceptible patientsa | Phenytoin dosage may need adjustmentb |
Carbamazepine | May decrease serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Chloramphenicol | May increase serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Chlordiazepoxide | May increase serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Corticosteroids | Efficacy is impaired by phenytoina | |
Diazepam | May increase serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Dicumarol | May increase serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Disulfiram | May increase serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Doxycycline | Efficacy impaired by phenytoina | |
Estrogens | May increase serum phenytoin concentrationsa Efficacy impaired by phenytoina | Monitor and adjust dosage accordingly Observe for possible decreased estrogen efficacy |
Furosemide | Efficacy impaired by phenytoina | |
H2-Antagonists | May increase serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Halothane | May increase serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Isoniazid | May increase serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Methylphenidate | May increase serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Oral contraceptives | Efficacy impaired by phenytoina | |
Phenobarbital | May increase or decrease serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Phenothiazines | May increase serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Quinidine | Efficacy impaired by phenytoina | Monitor and adjust dosage accordingly |
Reserpine | May decrease serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Rifampin | Efficacy impaired by phenytoina | |
Salicylates | May increase serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Succinimides | May increase serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Sucralfate | May decrease serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Sulfonamides | May increase serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Test, alkaline phosphatase, serum | May increase serum alkaline phosphatase concentrations | |
Test, dexamethasone | Phenytoin may cause slight decreases in urinary 17-hydroxycorticosteroids and 17-ketosteroids while urinary 6-β-hydroxycortisol excretion is increasedb Phenytoin may produce lower than normal values for the dexamethasone test | |
Test, γ-glutamyl transferase (γ-glutamyltranspeptidase, GGT, GGTP) | Phenytoin may produce increased serumγ-glutamyl transferase (γ-glutamyltranspeptidase, GGT, GGTP) concentrations | |
Test, metyrapone | Phenytoin may cause slight decreases in urinary 17-hydroxycorticosteroids and 17-ketosteroids while urinary 6-β-hydroxycortisol excretion is increasedb Phenytoin may produce lower than normal values for the metyrapone testsb | |
Test, protein-bound iodine (PBI) | Patients receiving phenytoin have shown reduced protein-bound iodine (PBI) test values without lowered triiodothyronine (T3) values and without clinical symptoms of hypothyroidism; free thyroxine concentrations may also be decreasedb | The 24-hour I 131 thyroidal uptake is apparently not affected Phenytoin may produce increased resin or red cell T3 uptake valuesb Lowered PBI values do not occur unless phenytoin is administered for 1 week or longer, and altered values persist for 7–10 days after phenytoin is discontinuedb |
Theophylline | Efficacy impaired by phenytoina | Monitor and adjust dosage accordingly |
Tolbutamide | May increase serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Trazodone | May increase serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Valproic acid | May increase or decrease serum phenytoin concentrationsa | Monitor and adjust dosage accordingly |
Vitamin D | Efficacy impaired by phenytoina |
Phenytoin Sodium Pharmacokinetics
Absorption
Bioavailability
Studies using Dilantin have shown that phenytoin and its sodium salt are usually completely absorbed from the GI tract.b
Extended phenytoin sodium capsules, peak: 4–12 hours.b
Extended phenytoin sodium capsules are formulated so that they undergo slower dissolution with more prolonged absorption than prompt phenytoin sodium capsules.b
Bioavailability may vary enough among oral phenytoin sodium preparations of different manufacturers to result in toxic serum concentrations or a loss of seizure control; this should be considered before dispensing a brand or dosage form, which differs from that currently taken by a patient.b Consult FDA’s Approved Drug Products and Therapeutic Equivalence Evaluations (Orange Book).
IM: Absorption may be erratic due to precipitation at injection site.b g
Plasma Concentrations
Anticonvulsant effect: 10–20 mcg/mL.g
Antiarrhythmic effect: 10–20 mcg/mL.g (See Blood Concentrations under Major Toxicities for other concentrations.)
Prompt phenytoin capsules, peak: 1.5–3 hours.b
Extended phenytoin sodium, peak: 4–12 hours.b
Serum concentration determinations: Obtain at least 5–7 half-lives after treatment initiation, change in dosage, or addition or subtraction of another drug to the regimen, so that steady-state drug levels may be achieved.b
Therapeutic plasma concentrations, oral: Achieved after about 1 week of therapy.b
Following oral administration, therapeutic plasma concentrations can be obtained more rapidly and maintained by administering an initial oral loading dose.b
Therapeutic plasma concentrations, IV: Within 1–2 hours.b
Distribution
Extent
Crosses the placenta.h
Distributed into breast milk.b h
Plasma Protein Binding
Approximately 95%.b
Elimination
Metabolism
Oxidation by the liver to an inactive metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH).b
This metabolism is a saturable process; therefore, small increases in dosage may produce substantial increases in plasma phenytoin concentrations.b
Elimination Route
Capacity-limited elimination, decreasing with increasing concentration.g
Inactive metabolite (HPPH) is excreted in urine, mainly as the glucuronide;b approximately 60–75% of the daily dose is excreted in this form.b
Half-life
Oral: About 22 hours.b
IV: Ranges from 10–15 hours.b
Special Populations
Total plasma phenytoin concentrations are lower in chronic uremic patients than in non-uremic patients, which suggests an altered metabolic disposition of the drug in patients with uremia.b
Stability
Storage
Oral
Tablets
Tight, light- and moisture-resistant containers at <30°C.a b
Suspension
Tight, light-resistant containers at 20–25°C; avoid freezing.b d
Extended and Prompt Capsules
Tight, light- and moisture-resistant containers at <30°C, although one manufacturer recommends storage of their extended phenytoin sodium capsules (Phenytek) at controlled room temperatures of 15–30°C.b
Parenteral
Injection
15–30°C; avoid freezing.b
A precipitate may form if the injection is refrigerated or frozen; however, this will dissolve after warming to room temperature.b
Slight yellowish discoloration of the injection will not affect potency or efficacy, but the injection should not be used if the solution is not clear or if a precipitate is present.b
Precipitation of free phenytoin will occur at a pH of ≤11.5.b
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Parenteral
Phenytoin sodium injection is physically and/or chemically incompatible with some drugs, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature).b
Solution CompatibilityHID
Incompatible |
---|
Dextrose 5% in sodium chloride 0.9% |
Dextrose 5% in water |
Fat emulsion 10%, IV |
Ringer’s injection, lactated |
Sodium chloride 0.45%e HID |
Variable |
Sodium chloride 0.9%e HID |
Drug Compatibility
Compatible |
---|
Verapamil HCl |
Incompatible |
Amikacin sulfate |
Bretylium tosylate |
Dobutamine HCl |
Lidocaine HCl |
Lincomycin HCl |
Meperidine HCl |
Metaraminol bitartrate |
Morphine sulfate |
Nitroglycerin |
Norepinephrine bitartrate |
Pentobarbital sodium |
Procaine HCl |
Streptomycin sulfate |
Compatible |
---|
Esmolol HCl |
Famotidine |
Fluconazole |
Foscarnet sodium |
Tacrolimus |
Incompatible |
Amphotericin B cholesteryl sulfate complex |
Cefepime HCI |
Ceftazidime |
Ciprofloxacin |
Clarithromycin |
Diltiazem HCl |
Enalaprilat |
Fenoldopam mesylate |
Fentanyl citrate |
Heparin sodium |
Heparin sodium with hydrocortisone sodium succinate |
Hydromorphone HCl |
Lansoprazole |
Linezolid |
Methadone HCl |
Morphine sulfate |
Potassium chloride |
Propofol |
Sufentanil citrate |
Theophylline |
Vitamin B complex with C |
Actions
Limitation of seizure propagation by reduction of post-tetanic potentiation (PTP), possibly by reducing the passive influx of sodium ions or by increasing the efficiency of the sodium pump so that excess accumulation of intracellular sodium does not occur during tetanic stimulation.c
Loss of PTP also prevents cortical seizure foci from detonating adjacent cortical areas.c
Exhibits antiarrhythmic properties similar to those of quinidine or procainamide.b
Although little effect on the electrical excitability of cardiac muscle, it decreases the force of contraction, depresses pacemaker action, and improves atrioventricular conduction, particularly when it has been depressed by digitalis glycosides.b
Prolongs the effective refractory period relative to the action potential duration.b
May produce hypotension following IV administration.b
Little hypnotic activity.b
Advice to Patients
Importance of cautioning patients not to use other drugs or alcoholic beverages without first seeking the clinician’s advice.a
Importance of instructing patients to contact a clinician if skin rash develops.a
Importance of stressing good dental hygiene in order to minimize the development of gingival hyperplasia and its complications.a
Advise patient of possible development of hypertrichosis and lymphadenopathy.a b
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Oral | Suspension | 125 mg/5 mL* | Dilantin-125 |
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