PHENYTOIN SOD
DESCRIPTION:
NOT FOR ONCE A DAY DOSING
Dilantin is an antiepileptic drug.
Dilantin (phenytoin) is related to the barbiturates in chemical structure, but
has a five-membered ring. The chemical name is 5,5-diphenyl-2,4-
imidazolidinedione.
ACTIONS/CLINICAL PHARMACOLOGY:
Phenytoin is an antiepileptic drug which can be useful in the treatment of
epilepsy. The primary site of action appears to be THE MOTOR CORTEX where spread
of seizure activity is inhibited. Possibly by promoting sodium efflux from
neurons, phenytoin tends to STABILIZE the threshold against hyperexcitability
caused by excessive stimulation or environmental changes capable of reducing
membrane sodium gradient. This includes the reduction of posttetanic
potentiation at synapses. Loss of posttetanic potentiation prevents cortical
seizure foci from detonating adjacent cortical areas. Phenytoin reduces the
maximal activity of brain stem centers responsible for the tonic phase of tonic-
clonic (grand mal) seizures.
Clinical studies using Dilantin Infatabs have shown an average plasma half-life
of 14 hours with a range of 7 to 29 hours. Steady-state therapeutic levels are
achieved at least 7 to 10 days (5-7 half-lives) after initiation of therapy with
recommended doses of 300 mg/day.
When serum level determinations are necessary, they should be obtained at least
5-7 half-lives after treatment initiation, dosage change, or addition or
subtraction of another drug to the regimen so that equilibrium or steady-state
will have been achieved. Trough levels provide information about clinically
effective serum level range and confirm patient compliance and are obtained just
prior to the patient's next scheduled dose. Peak levels indicate an individual's
threshold for emergence of dose- related side effects and are obtained at the
time of expected peak concentration. For Dilantin Infatabs peak levels occur 1
1/2-3 hours after administration.
Optimum control without clinical signs of toxicity occurs more often with serum
levels between 10 and 20 mcgm/ml, although some mild cases of tonic-clonic
(grand mal) epilepsy may be controlled with lower serum levels of phenytoin.
In most patients maintained at a steady dosage, stable phenytoin serum levels
are achieved. There may be wide interpatient variability in phenytoin serum
levels with equivalent dosages. Patients with unusually low levels may be
noncompliant or hypermetabolizers of phenytoin. Unusually high levels result
from liver disease, congenital enzyme deficiency or drug interactions which
result in metabolic interference. The patient with large variations in phenytoin
plasma levels, despite standard doses, presents a difficult clinical problem.
Serum level determinations in such patients may be particularly helpful. As
phenytoin is highly protein bound, free phenytoin levels may be altered in
patients whose protein binding characteristics differ from normal.
Most of the drug is excreted in the bile as inactive metabolites which are then
reabsorbed from the intestinal tract and excreted in the urine. Urinary
excretion of phenytoin and its metabolites occurs partly with glomerular
filtration but more importantly, by tubular secretion. Because phenytoin is
hydroxylated in the liver by an enzyme system which is saturable at HIGH PLASMA
LEVELS small incremental doses may increase the half-life and produce very
substantial increases in serum levels, when these are in the upper range. The
steady-state level may be disproportionately increased, with resultant
intoxication, from an increase in dosage of 10% or more.
Clinical studies show that chewed and unchewed Dilantin Infatabs are
bioequivalent, yield approximately equivalent plasma levels, and are more
rapidly absorbed than 100-mg Dilantin Kapseals.(R)
INDICATIONS AND USAGE:
Dilantin Infatabs (Phenytoin Tablets, USP) are indicated for the control of
generalized tonic- clonic (grand mal) and complex partial (psychomotor, temporal
lobe) seizures and prevention and treatment of seizures occurring during or
following neurosurgery. Phenytoin serum level determinations may be necessary
for optimal dosage adjustments (see DOSAGE AND ADMINISTRATION and
ACTIONS/CLINICAL PHARMACOLOGY sections).
CONTRAINDICATIONS:
Phenytoin is contraindicated in those patients who are hypersensitive to
phenytoin or other hydantoins.
WARNINGS:
Abrupt withdrawal of phenytoin in epileptic patients may precipitate status
epilepticus. When, in the judgment of the clinician, the need for dosage
reduction, discontinuation, or substitution of alternative antiepileptic
medication arises, this should be done gradually. However, in the event of an
allergic or hypersensitivity reaction, rapid substitution of alternative therapy
may be necessary. In this case, alternative therapy should be an antiepileptic
drug not belonging to the hydantoin chemical class.
There have been a number of reports suggesting a relationship between phenytoin
and the development of lymphadenopathy (local or generalized) including benign
lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's Disease.
Although a cause and effect relationship has not been established, the
occurrence of lymphadenopathy indicates the need to differentiate such a
condition from other types of lymph node pathology. Lymph node involvement may
occur with or without symptoms and signs resembling serum sickness eg, fever,
rash and liver involvement. In all cases of lymphadenopathy, follow-up
observation for an extended period is indicated and every effort should be made
to achieve seizure control using alternative antiepileptic drugs.
Acute alcoholic intake may increase phenytoin serum levels while chronic
alcoholic use may decrease serum levels.
In view of isolated reports associating phenytoin with exacerbation of
porphyria, caution should be exercised in using this medication in patients
suffering from this disease.
USAGE IN PREGNANCY
A number of reports suggest an association between the use of antiepileptic
drugs by women with epilepsy and a higher incidence of birth defects in children
born to these women. Data are more extensive with respect to phenytoin and
phenobarbital, but these are also the most commonly prescribed antiepileptic
drugs; less systematic or anecdotal reports suggest a possible similar
association with the use of all known antiepileptic drugs.
The reports suggesting a higher incidence of birth defects in children of drug-
treated epileptic women cannot be regarded as adequate to prove a definite cause
and effect relationship. There are intrinsic methodologic problems in obtaining
adequate data on drug teratogenicity in humans: genetic factors or the epileptic
condition itself, may be more important than drug therapy in leading to birth
defects. The great majority of mothers on antiepileptic medication deliver
normal infants. It is important to note that antiepileptic drugs should not be
discontinued in patients in whom the drug is administered to prevent major
seizures, because of the strong possibility of precipitating status epilepticus
with attendant hypoxia and threat to life. In individual cases where the
severity and frequency of the seizure disorder are such that the removal of
medication does not pose a serious threat to the patient, discontinuation of the
drug may be considered prior to and during pregnancy, although it cannot be said
with any confidence that even minor seizures do not pose some hazard to the
developing embryo or fetus. The prescribing physician will wish to weigh these
considerations in treating or counseling epileptic women of childbearing
potential.
In addition to the reports of increased incidence of congenital malformations,
such as cleft lip/palate and heart malformations in children of women receiving
phenytoin and other antiepileptic drugs, there have more recently been reports
of a fetal hydantoin syndrome. This consists of prenatal growth deficiency,
microcephaly and mental deficiency in children born to mothers who have received
phenytoin, barbiturates, alcohol, or trimethadione. However, these features are
all interrelated and are frequently associated with intrauterine growth
retardation from other causes.
There have been isolated reports of malignancies, including neuroblastoma, in
children whose mothers received phenytoin during pregnancy.
An increase in seizure frequency during pregnancy occurs in a high proportion of
patients, because of altered phenytoin absorption or metabolism. Periodic
measurement of serum phenytoin levels is particularly valuable in the management
of a pregnant epileptic patient as a guide to an appropriate adjustment of
dosage. However, postpartum restoration of the original dosage will probably be
indicated.
Neonatal coagulation defects have been reported within the first 24 hours in
babies born to epileptic mothers receiving phenobarbital and/or phenytoin.
Vitamin K has been shown to prevent or correct this defect and has been
recommended to be given to the mother before delivery and to the neonate after
birth.
PRECAUTIONS:
GENERAL
The liver is the chief site of biotransformation of phenytoin; patients with
impaired liver function, elderly patients, or those who are gravely ill may show
early signs of toxicity.
A small percentage of individuals who have been treated with phenytoin have been
shown to metabolize the drug slowly. Slow metabolism may be due to limited
enzyme availability and lack of induction; it appears to be genetically
determined.
Phenytoin should be discontinued if a skin rash appears (see "WARNINGS" section
regarding drug discontinuation). If the rash is exfoliative, purpuric, or
bullous or if lupus erythematosus, Stevens-Johnson syndrome, or toxic epidermal
necrolysis is suspected, use of this drug should not be resumed, and alternative
therapy should be considered (see ADVERSE REACTIONS). If the rash is of a milder
type (measles-like or scarlatiniform), therapy may be resumed after the rash has
completely disappeared. If the rash recurs upon reinstitution of therapy,
further phenytoin medication is contraindicated.
Phenytoin and other hydantoins are contraindicated in patients who have
experienced phenytoin hypersensitivity. Additionally, caution should be
exercised if using structurally similar (eg barbiturates, succinimides,
oxazolidinediones and other related compounds) in these same patients.
Hyperglycemia, resulting from the drug's inhibitory effects on insulin release,
has been reported. Phenytoin may also raise the serum glucose level in diabetic
patients.
Osteomalacia has been associated with phenytoin therapy and is considered to be
due to phenytoin's interference with Vitamin D metabolism.
Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic
causes. Appropriate diagnostic procedures should be performed as indicated.
Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic
(grand-mal) and absence (petit mal) seizures are present, combined drug therapy
is needed.
Serum levels of phenytoin sustained above the optimal range may produce
confusional states referred to as "delirium," "psychosis," or "encephalopathy,"
or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of
acute toxicity, plasma levels are recommended. Dose reduction of phenytoin
therapy is indicated if plasma levels are excessive; if symptoms persist,
termination is recommended. (See WARNINGS).
INFORMATION FOR PATIENTS
Patients taking phenytoin should be advised of the importance of adhering
strictly to the prescribed dosage regimen, and of informing the physician of any
clinical condition in which it is not possible to take the drug orally as
prescribed, eg, surgery, etc.
Patients should also be cautioned on the use of other drugs or alcoholic
beverages without first seeking the physician's advice.
Patients should be instructed to call their physician if skin rash develops.
The importance of good dental hygiene should be stressed in order to minimize
the development of gingival hyperplasia and its complications.
LABORATORY TESTS
Phenytoin serum level determinations may be necessary to achieve optimal dosage
adjustments.
DRUG INTERACTIONS
There are many drugs which may increase or decrease phenytoin levels or which
phenytoin may affect. Serum level determinations for phenytoin are especially
helpful when possible drug interactions are suspected. The most commonly
occurring drug interactions are listed below:
1. Drugs which may increase phenytoin serum levels include: acute alcohol
intake, amiodarone, chloramphenicol, chlordiazepoxide, diazepam, dicumarol,
disulfiram, estrogens, H2-antagonists, halothane, isoniazid, methylphenidate,
phenothiazines, phenylbutazone, salicylates, succinimides, sulfonamides,
tolbutamide, trazodone.
2. Drugs which may decrease phenytoin serum levels include: carbamazepine,
chronic alcohol abuse, reserpine, and sucralfate. Moban(R) brand of Molindone
Hydrochloride contains calcium ions which interfere with the absorption of
phenytoin. Ingestion times of phenytoin and antacid preparations containing
calcium should be staggered in patients with low serum phenytoin levels to
prevent absorption problems.
3. Drugs which may either increase or decrease phenytoin serum levels include:
phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of
phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is
unpredictable.
4. Although not a true drug interaction, tricyclic antidepressants may
precipitate seizures in susceptible patients and phenytoin dosage may need to be
adjusted.
5. Drugs whose efficacy is impaired by phenytoin include: corticosteroids,
coumarin anticoagulants, digitoxin, doxycycline, estrogens, furosemide, oral
contraceptives, quinidine, rifampin, theophylline, vitamin D.
DRUG/LABORATORY TEST INTERACTIONS
Phenytoin may cause decreased serum levels of protein-bound iodine (PBI). It may
also produce lower than normal values for dexamethasone or metyrapone tests.
Phenytoin may cause increased serum levels of glucose, alkaline phosphatase, and
gamma glutamyl transpeptidase (GGT).
CARCINOGENESIS
See 'WARNINGS' section for information on carcinogenesis.
PREGNANCY
See WARNINGS section.
NURSING MOTHERS
Infant breast-feeding is not recommended for women taking this drug because
phenytoin appears to be secreted in low concentrations in human milk.
DRUG INTERACTIONS:
There are many drugs which may increase or decrease phenytoin levels or which
phenytoin may affect. Serum level determinations for phenytoin are especially
helpful when possible drug interactions are suspected. The most commonly
occurring drug interactions are listed below:
1. Drugs which may increase phenytoin serum levels include: acute alcohol
intake, amiodarone, chloramphenicol, chlordiazepoxide, diazepam, dicumarol,
disulfiram, estrogens, H2-antagonists, halothane, isoniazid, methylphenidate,
phenothiazines, phenylbutazone, salicylates, succinimides, sulfonamides,
tolbutamide, trazodone.
2. Drugs which may decrease phenytoin serum levels include: carbamazepine,
chronic alcohol abuse, reserpine, and sucralfate. Moban(R) brand of Molindone
Hydrochloride contains calcium ions which interfere with the absorption of
phenytoin. Ingestion times of phenytoin and antacid preparations containing
calcium should be staggered in patients with low serum phenytoin levels to
prevent absorption problems.
3. Drugs which may either increase or decrease phenytoin serum levels include:
phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of
phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is
unpredictable.
4. Although not a true drug interaction, tricyclic antidepressants may
precipitate seizures in susceptible patients and phenytoin dosage may need to be
adjusted.
5. Drugs whose efficacy is impaired by phenytoin include: corticosteroids,
coumarin anticoagulants, digitoxin, doxycycline, estrogens, furosemide, oral
contraceptives, quinidine, rifampin, theophylline, vitamin D.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
CENTRAL NERVOUS SYSTEM: The most common manifestations encountered with
phenytoin therapy are referable to this system and are usually dose-related.
These include nystagmus, ataxia, slurred speech, decreased coordination and
mental confusion. Dizziness, insomnia, transient nervousness, motor twitchings,
and headache have also been observed.
There have also been rare reports of phenytoin induced dyskinesias, including
chorea, dystonia, tremor and asterixis, similar to those induced by
phenothiazine and other neuroleptic drugs.
A predominantly sensory peripheral polyneuropathy has been observed in patients
receiving long-term phenytoin therapy.
GASTROINTESTINAL SYSTEM: Nausea, vomiting, constipation, toxic hepatitis and
liver damage.
INTEGUMENTARY SYSTEM: Dermatological manifestations sometimes accompanied by
fever have included scarlatiniform or morbilliform rashes. A morbilliform rash
(measles-like) is the most common; other types of dermatitis are seen more
rarely. Other more serious forms which may be fatal have included bullous,
exfoliative or purpuric dermatitis, lupus erythematosus, Stevens-Johnson
syndrome, and toxic epidermal necrolysis (see PRECAUTIONS section).
HEMOPOIETIC SYSTEM: Hemopoietic complications, some fatal, have occasionally
been reported in association with administration of phenytoin. These have
included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and
pancytopenia with or without bone marrow suppression. While macrocytosis and
megaloblastic anemia have occurred, these conditions usually respond to folic
acid therapy. Lymphadenopathy including benign lymph node hyperplasia,
pseudolymphoma, lymphoma, and Hodgkin's Disease have been reported (see WARNINGS
section).
CONNECTIVE TISSUE SYSTEM: Coarsening of the facial features, enlargement of the
lips, gingival hyperplasia, hypertrichosis, and Peyronie's Disease.
CARDIOVASCULAR: Periarteritis nodosa.
IMMUNOLOGIC: Hypersensitivity syndrome (which may include, but is not limited
to, symptoms such as arthralgias, eosinophilia, fever, liver dysfunction,
lymphadenopathy or rash), systemic lupus erythematosus, and immunoglobulin
abnormalities.
OVERDOSAGE:
The lethal dose in pediatric patients is not known. The lethal dose in adults is
estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and
dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech,
nausea, vomiting. The patient may become comatose and hypotensive. Death is due
to respiratory and circulatory depression.
There are marked variations among individuals with respect to phenytoin plasma
levels where toxicity may occur. Nystagmus on lateral gaze usually appears at 20
mcgm/ml, ataxia at 30 mcgm/ml, dysarthria and lethargy appear when the plasma
concentration is over 40 mcgm/ml, but as high a concentration as 50 mcgm/ml has
been reported without evidence of toxicity. As much as 25 times the therapeutic
dose has been taken to result in a serum concentration over 100 mcgm/ml with
complete recovery.
TREATMENT
Treatment is nonspecific since there is no known antidote.
The adequacy of the respiratory and circulatory systems should be carefully
observed and appropriate supportive measures employed. Hemodialysis can be
considered since phenytoin is not completely bound to plasma proteins. Total
exchange transfusion has been used in the treatment of severe intoxication in
pediatric patients.
In acute overdosage the possibility of other CNS depressants, including alcohol,
should be borne in mind.
DOSAGE AND ADMINISTRATION:
When given in equal doses, Dilantin Infatabs yield higher plasma levels than
Dilantin Kapseals.(R) For this reason serum concentrations should be monitored
and care should be taken when switching a patient from the sodium salt to the
free acid form.
Dilantin(R) Kapseals,(R) Dilantin Parenteral, and Dilantin with Phenobarbital
are formulated with the sodium salt of phenytoin. The free acid form of
phenytoin is used in Dilantin-30 Pediatric and Dilantin-125 Suspensions and
Dilantin Infatabs. Because there is approximately an 8% increase in drug content
with the free acid form over that of the sodium salt, 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.
GENERAL
Not for once a day dosing.
Dosage should be individualized to provide maximum benefit. In some cases, serum
blood level determinations may be necessary for optimal dosage adjustments--the
clinically effective serum level is usually 10-20 mcgm/ml. With recommended
dosage, a period of seven to ten days may be required to achieve steady-state
blood levels with phenytoin and changes in dosage (increase or decrease) should
not be carried out at intervals shorter than seven to ten days.
Dilantin Infatabs can be either chewed thoroughly before being swallowed or
swallowed whole.
ADULT DOSAGE
Patients who have received no previous treatment may be started on two Infatabs
three times daily, and the dose is then adjusted to suit individual
requirements. For most adults, the satisfactory maintenance dosage will be six
to eight Infatabs daily; an increase to twelve Infatabs daily may be made, if
necessary.
PEDIATRIC DOSAGE
Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent
dosage individualized to a maximum of 300 mg daily. A recommended daily
maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years old and
adolescents may require the minimum adult dose (300 mg/day). If the daily dosage
cannot be divided equally, the larger dose should be given before retiring.
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