Yes

Antiarrhythmic Agent, Class I-B; Anticonvulsant, Hydantoin

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

D

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; pregnancy

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 can occur.

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

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, 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 arrhythmias, 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 the facial features, hypertrichosis

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 inducer

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 concentrations.

Valproic acid may increase, decrease, or have no effect on phenytoin serum concentrations.

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

Primidone: Increase the rate of conversion of to phenobarbital resulting in increased phenobarbital serum concentrations.

Ticlopidine increases serum phenytoin concentrations to increase toxicity of phenytoin.

Acetaminophen: Phenytoin may enhance the hepatotoxic potential.

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

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 response.

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 dependent

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 the heart

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

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: 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 following:

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 2- to 3-fold 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

Bioavailability: Dependent upon formulation administered

Time to peak serum concentration (dependent upon formulation administered): Oral:

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

Food:

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 throughout therapy.

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 days.

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

Therapeutic range:

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

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

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

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

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 mmol/L)

Lethal: >100 mg/mL (SI: >400 mmol/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 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 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 in patients with low serum albumin:

If measured total phenytoin concentration is 5 mcg/mL and patient's serum albumin is:

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 albumin is:

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 albumin is:

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) + 0.1]

Adjustment of serum concentration in patients with renal failure (Cl_cr less than or equal to 10 mL/minute)

If measured total phenytoin concentration 5 mcg/mL and patient's serum albumin is:

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 albumin is:

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 albumin is:

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) + 0.1]

glucose, alkaline phosphatase (S); thyroxine (S), calcium (S)

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.

No information available to require special precautions

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.

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 breast-feeding.

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 site

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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