Diphenylhydantoin; DPH; Phenytoin Sodium; Phenytoin Sodium, Extended; Phenytoin
Antiarrhythmic Agent, Class I-B; Anticonvulsant, Hydantoin
Management of generalized tonic-clonic (grand mal), complex partial seizures;
prevention of seizures following head trauma/neurosurgery
Clinical effects on the fetus: Crosses the placenta. Cardiac defects and
multiple other malformations reported; characteristic pattern of malformations
called "fetal hydantoin syndrome"; hemorrhagic disease of newborn due to fetal
vitamin K depletion, maternal folic acid deficiency may occur. Epilepsy itself,
number of medications, genetic factors, or a combination of these probably
influence the teratogenicity of anticonvulsant therapy. Benefit:risk ratio
usually favors continued use during pregnancy and breast-feeding.
Breast-feeding/lactation: Crosses into breast milk
Clinical effects on the infant: Methemoglobinemia, drowsiness and decreased
sucking reported in 1 case. American Academy of Pediatrics considers
compatible with breast-feeding.
Hypersensitivity to phenytoin, other hydantoins, or any component; sinus
bradycardia; SA block; second- or third-degree heart block (except in patients
with a functioning artificial pacemaker); Adams-Stokes syndrome;
Avoid abrupt withdrawal in patients with a seizure disorder (can precipitate
seizures including status epilepticus). Alcohol ingestion can significantly
affect the pharmacokinetics of phenytoin. Use cautiously in malnutrition (more
free drug circulating), significant hepatic disease (adjust dose), or with other
highly protein bound drugs. Use with caution in hypotension (I.V. form contains
propylene glycol). I.V. form may cause hypotension. Hypersensitivity reactions
I.V. effects: Hypotension, bradycardia, cardiac arrhythmias, cardiovascular
collapse (especially with rapid I.V. use), venous irritation and pain,
Dose-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,
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 arrhythmias, cardiovascular
Central nervous system: Psychiatric changes, slurred speech, dizziness,
drowsiness, headache, insomnia
Gastrointestinal: Constipation, nausea, vomiting, gingival hyperplasia,
enlargement of lips
Hematologic: Leukopenia, thrombocytopenia, agranulocytosis
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 the facial features,
Symptoms of overdose include unsteady gait, slurred speech, confusion,
nausea, hypothermia, fever, hypotension, respiratory depression, coma
Treatment is supportive for hypotension; treat with I.V. fluids and place
patient in Trendelenburg position; seizures may be controlled with diazepam 5-10
mg (0.25-0.4 mg/kg in children)
CYP2C9 and 2C19 enzyme substrate; CYP1A2, 2B6, 2C, 3A3/4, and 3A5-7 enzyme
Phenytoin may decrease the effect of oral contraceptives, itraconazole,
mebendazole, methadone, oral midazolam, valproic acid, cyclosporine,
theophylline, doxycycline, quinidine, mexiletine, disopyramide.
Amiodarone or disulfiram decreases metabolism of phenytoin.
Isoniazid, chloramphenicol, or fluconazole may increase phenytoin serum
Valproic acid may increase, decrease, or have no effect on phenytoin serum
Dopamine: Phenytoin may increase the effect of dopamine (enhanced
Primidone: Increase the rate of conversion of to phenobarbital resulting in
increased phenobarbital serum concentrations.
Ticlopidine increases serum phenytoin concentrations to increase toxicity of
Acetaminophen: Phenytoin may enhance the hepatotoxic potential.
Acetazolamide: Concurrent use with phenytoin may result in an increased risk
Phenytoin may increase the metabolism of alprazolam, amiodarone, bromfenac,
carbamazepine, clozapine, cyclosporine, diazepam, disopyramide, doxycycline,
felbamate, furosemide, itraconazole, lamotrigine, mebendazole, meperidine,
methadone, metyrapone, mexiletine, midazolam, oral contraceptives, quetiapine,
quinidine, tacrolimus, teniposide, theophylline, thyroid hormones, triazolam,
and valproic acid resulting in decreased levels/effect.
Trimethoprim, sulfamethoxazole, valproic acid, sulfamethizole,
sulfaphenazole, trimethoprim, nifedipine, omeprazole, phenylbutazone,
phenobarbital, amiodarone, chloramphenicol, cimetidine, ciprofloxacin,
disulfiram, enoxacin, norfloxacin, felbamate, fluconazole, fluoxetine, influenza
vaccine, isoniazid, and metronidazole inhibit the metabolism of phenytoin
resulting in increased serum phenytoin concentrations/effects; monitor.
Carbamazepine, cisplatin, diazoxide, ethanol (chronic), folic acid,
phenobarbital, pyridoxine, and rifampin may enhance the metabolism of phenytoin
resulting in decreased serum concentrations.
Concurrent use of I.V. phenytoin with dopamine may result in an increased
risk of hypotension.
Phenytoin may inhibit the anti-Parkinson effect of levodopa.
Concurrent use of phenytoin and lithium has resulted in lithium intoxication.
Phenytoin enhances the conversion of primidone to phenobarbital resulting in
elevated phenobarbital serum concentrations.
Sucralfate may reduce the GI absorption of phenytoin.
Valproic acid and sulfisoxazole may displace phenytoin from binding sites.
Vigabatrin and theophylline may reduce phenytoin serum concentrations.
Warfarin: Phenytoin transiently increased the hypothrombinemia response to
warfarin initially; this is followed by an inhibition of the hypoprothombinemic
Phenytoin is stable as long as it remains free of haziness and precipitation
Use only clear solutions; parenteral solution may be used as long as there is
no precipitate and it is not hazy, slightly yellowed solution may be used
Refrigeration may cause precipitate, sometimes the precipitate is resolved by
allowing the solution to reach room temperature again
Drug may precipitate at a pH <11.5
May dilute with normal saline for I.V. infusion; stability is concentration
Standard diluent: Dose/100 mL NS
Minimum volume: Concentration should be maintained at 1-10 mg/mL secondary to
stability problems (stable for 4 hours)
Comments: Maximum rate of infusion: 50 mg/minute
IVPB dose should be administered via an in-line 0.22-5 micron filter because
of high potential for precipitation I.V. form is highly incompatible
with many drugs and solutions such as dextrose in water, some saline solutions,
amikacin, bretylium, cephapirin, dobutamine, heparin, insulin, levorphanol,
lidocaine, meperidine, metaraminol, morphine, norepinephrine, potassium
chloride, vitamin B complex with C
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
Onset of action: I.V.: Within 30 minutes to 1 hour; onset of fosphenytoin may
be more rapid due to more rapid infusion
Absorption: Oral: Slow
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
Neonates: Up to 20% free
Infants: Up to 15% free
Adults: 90% to 95%
Others: Increased free fraction (decreased protein binding)
Patients with hyperbilirubinemia, hypoalbuminemia, uremia. Refer to the
Disease states resulting in a decrease in serum albumin
concentration: Burns, hepatic cirrhosis, nephrotic syndrome, pregnancy,
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), Clcr
<25 mL/minute (unbound fraction is increased 2- to 3-fold in uremia)
Metabolism: Follows dose-dependent capacity-limited (Michaelis-Menten)
pharmacokinetics with increased Vmax in infants >6 months of age
and children versus adults
Bioavailability: Dependent upon formulation administered
Time to peak serum concentration (dependent upon formulation administered):
Extended-release capsule: Within 4-12 hours
Immediate release preparation: Within 2-3 hours
Elimination: Highly variable clearance dependent upon intrinsic hepatic
function and dose administered; increased clearance and decreased serum
concentrations with febrile illness; <5% excreted unchanged in urine; major
metabolite (via oxidation) HPPA undergoes enterohepatic recycling and
elimination in urine as glucuronides
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: 15-20 mg/kg in a single or divided dose, followed by
100-150 mg/dose at 30-minute intervals up to a maximum of 1500 mg/24 hours;
maintenance dose: 300 mg/day or 5-6 mg/kg/day in 3 divided doses or 1-2 divided
doses using extended release
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.
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.
Alcohol: Additive CNS depression has been reported with hydantoins
Alcohol (acute use): Inhibits metabolism of phenytoin; avoid or limit use;
watch for sedation
Alcohol (chronic use): Stimulates metabolism of phenytoin; avoid or limit use
Folic acid: Low erythrocyte and CSF folate concentrations. 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.
Calcium: Hypocalcemia has been reported in patients taking prolonged
high-dose therapy with an anticonvulsant. Phenytoin may decrease calcium
absorption. Monitor calcium serum concentration and for bone disorders (eg,
rickets, osteomalacia). Some clinicians have given an additional 4,000
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
Glucose: Hyperglycemia and glycosuria may occur in patients receiving
high-dose therapy. Monitor blood glucose concentration, especially in patients
with impaired renal function.
Tube feedings: Tube feedings decrease phenytoin bioavailability; to avoid
decreased serum levels with continuous NG feeds, hold feedings for 2 hours prior
to and 2 hours after phenytoin administration, if possible. There is a variety
of opinions on how to administer phenytoin with enteral feedings. BE CONSISTENT
Blood pressure, vital signs (with I.V. use), plasma phenytoin level, CBC,
liver function tests
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
Children and Adults: Toxicity is measured clinically, and some patients
require levels outside the suggested therapeutic range
Toxic: 30-50 mg/mL;
Lethal: >100 mg/mL
Total phenytoin: 10-20 mg/mL (children and
8-15 mg/mL (neonates)
Concentrations of 5-10 mg/mL may be therapeutic
some patients but concentrations <5 mg/mL are not
likely to be effective
50% of patients show decreased frequency of seizures at concentrations >10
86% of patients show decreased frequency of seizures at concentrations >15
Add another anticonvulsant if satisfactory therapeutic response is not
achieved with a phenytoin concentration of 20 mg/mL
Free phenytoin: 1-2.5 mg/mL
Toxic: <30-50 mg/mL (SI: <120-200
Lethal: >100 mg/mL (SI: >400
When to draw levels: This is dependent on the disease state being
treated and the clinical condition of the patient
Slow absorption minimizes 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
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
In stable patients requiring long-term therapy, generally monitor levels at
3- to 12-month intervals
Adjustment of serum concentration in patients with low serum
If measured total phenytoin concentration is 5 mcg/mL and patient's serum
3.5 g/dL: Adjusted total phenytoin concentration: 6 mcg/mL*
3 g/dL: Adjusted total phenytoin concentration: 7 mcg/mL*
2.5 g/dL: Adjusted total phenytoin concentration: 8 mcg/mL*
2 g/dL: Adjusted total phenytoin concentration: 10 mcg/mL*
If measured total phenytoin concentration is 10 mcg/mL and patient's serum
3.5 g/dL: Adjusted total phenytoin concentration: 13 mcg/mL*
3 g/dL: Adjusted total phenytoin concentration: 14 mcg/mL*
2.5 g/dL: Adjusted total phenytoin concentration: 17 mcg/mL*
2 g/dL: Adjusted total phenytoin concentration: 20 mcg/mL*
If measured total phenytoin concentration is 15 mcg/mL and patient's serum
3.5 g/dL: Adjusted total phenytoin concentration: 19 mcg/mL*
3 g/dL: Adjusted total phenytoin concentration: 21 mcg/mL*
2.5 g/dL: Adjusted total phenytoin concentration: 25 mcg/mL*
2 g/dL: Adjusted total phenytoin concentration: 30 mcg/mL*
*Adjusted concentration = measured total concentration/[(0.2 x albumin) +
Adjustment of serum concentration in patients with renal failure
(Clcr less than or equal to 10 mL/minute)
If measured total phenytoin concentration 5 mcg/mL and patient's serum
4 g/dL: Adjusted total phenytoin concentration: 10 mcg/mL*
3.5 g/dL: Adjusted total phenytoin concentration: 11 mcg/mL*
3 g/dL: Adjusted total phenytoin concentration 13: mcg/mL*
2.5 g/dL: Adjusted total phenytoin concentration: 14 mcg/mL*
2 g/dL: Adjusted total phenytoin concentration: 17 mcg/mL*
If measured total phenytoin concentration 10 mcg/mL and Patient's serum
4 g/dL: Adjusted total phenytoin concentration: 20 mcg/mL*
3.5 g/dL: Adjusted total phenytoin concentration: 22 mcg/mL*
3 g/dL: Adjusted total phenytoin concentration: 25 mcg/mL*
2.5 g/dL: Adjusted total phenytoin concentration: 29 mcg/mL*
2 g/dL: Adjusted total phenytoin concentration: 33 mcg/mL*
If measured total phenytoin concentration 15 mcg/mL and patient's serum
4 g/dL: Adjusted total phenytoin concentration 30 mcg/mL*
3.5 g/dL: Adjusted total phenytoin concentration 33 mcg/mL*
3 g/dL: Adjusted total phenytoin concentration 38 mcg/mL*
2.5 g/dL: Adjusted total phenytoin concentration 43 mcg/mL*
2 g/dL: Adjusted total phenytoin concentration 50 mcg/mL*
*Adjusted concentration = measured total concentration/[(0.1 x albumin) +
thyroxine (S), calcium
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: Local
No information available to require special precautions
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
Take this drug as directed, with food. Do not change brands or discontinue
without consulting prescriber. Follow good oral hygiene practices and have
frequent dental checkups. If diabetic, monitor your serum glucose regularly as
directed by prescriber; insulin dosage may need to be adjusted. You may
experience dizziness, confusion, or vision changes; use caution when driving or
engaging in tasks requiring alertness until response to drug is known. If GI
upset occurs, frequent small meals may help. May discolor urine (red/pink).
Report rash; unresolved nausea or vomiting; slurring speech or coordination
difficulties; swollen glands; swollen, sore, or bleeding gums; yellowish color
to skin or eyes; unusual bleeding and/or bruising; erection problems; difficulty
breathing; or palpitations. Do not crush or open extended-release capsules.
Pregnancy/breast-feeding precautions: Do not get pregnant; use barrier
contraceptive measures to prevent possible harm to the fetus (effectiveness of
oral contraceptives may be affected by phenytoin). Consult prescriber if
Maintenance doses usually start 12 hours after loading dose; shake oral
suspension well prior to each dose; do not exceed I.V. infusion rate of 1-3
mg/kg/minute or 50 mg/minute; I.V. injections should be followed by normal
saline flushes through the same needle or I.V. catheter to avoid local
irritation of the vein; avoid extravasation; avoid I.M. use due to erratic
absorption, pain on injection, and precipitation of drug at injection
Capsule, as sodium:
Extended: 30 mg, 100 mg
Prompt: 100 mg
Injection, as sodium: 50 mg/mL (2 mL, 5 mL)
Suspension, oral: 30 mg/5 mL (5 mL, 240 mL); 125 mg/5 mL (5 mL, 240 mL)
Tablet, chewable: 50 mg
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