Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1008
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Phenytoin Sodium (Injection, Solution)
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The addition of phenytoin solution to intravenous
infusion is not recommended due to lack of solubility and resultant
precipitation. Not
to exceed 50 mg per minute, intravenously in adults, and not exceeding
1 mg/kg/min to 3 mg/kg/min in neonates. There is a relatively
small margin between full therapeutic effect and minimally toxic doses
of this drug. The solution is suitable
for use as long as it remains free of haziness and precipitate. Upon
refrigeration or freezing, a precipitate might form; this will dissolve
again after the solution is allowed to stand at room temperature.
The product is still suitable for use. Only a clear solution should
be used. A faint yellow coloration may develop; however, this has
no effect on the potency of the solution. In
the treatment of status epilepticus, the intravenous route is preferred
because of the delay in absorption of phenytoin when administered
intramuscularly. Serum concentrations should
be monitored and care should be taken when switching a patient from
the sodium salt to the free acid form. Phenytoin
sodium injection is formulated with the sodium salt of phenytoin.
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. Parenteral drug
products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Status Epilepticus In adults, a loading dose of 10 mg/kg to 15
mg/kg should be administered slowly intravenously, at a rate not exceeding
50 mg per minute (this will require approximately 20 minutes in a
70 kg patient). The loading dose should be followed by maintenance
doses of 100 mg orally or intravenously every 6 to 8 hours. Recent work in neonates and children has shown that absorption
of phenytoin is unreliable after oral administration, but a loading
dose of 15 mg/kg to 20 mg/kg of phenytoin intravenously will usually
produce plasma concentrations of phenytoin within the generally accepted
therapeutic range (10 mcg/mL to 20 mcg/mL). The drug should be injected
slowly intravenously at a rate not exceeding 1 mg/kg/min to 3 mg/kg/min. Parenteral phenytoin should be injected slowly and directly into a large vein
through a large-gauge needle or intravenous catheter. Each injection
of intravenous phenytoin should be followed by an injection of sterile
saline through the same needle or catheter to avoid local venous irritation
due to alkalinity of the solution. Continuous infusion should be avoided;
the addition of parenteral phenytoin to intravenous infusion fluids
is not recommended because of the likelihood of precipitation. Continuous monitoring of the electrocardiogram and blood
pressure is essential. The patient should be observed for signs of
respiratory depression. Determination of phenytoin plasma levels is
advised when using phenytoin in the management of status epilepticus
and in the subsequent establishment of maintenance dosage. Other measures, including concomitant administration of
an intravenous benzodiazepine such as diazepam, or an intravenous
short-acting barbiturate, will usually be necessary for rapid control
of seizures because of the required slow rate of administration of
phenytoin. If administration of parenteral phenytoin
does not terminate seizures, the use of other anticonvulsants, intravenous
barbiturates, general anesthesia, and other appropriate measures should
be considered. Intramuscular administration
should not be used in the treatment of status epilepticus because
the attainment of peak plasma levels may require up to 24 hours. Neurosurgery Prophylactic dosage���100 mg to 200 mg (2 mL to 4
mL) intramuscularly at approximately 4-hour intervals during surgery
and continued during the post-operative period. When intramuscular administration is required for a patient previously
stabilized orally, compensating dosage adjustments are necessary to
maintain therapeutic plasma levels. An intramuscular dose 50% greater
than the oral dose is necessary to maintain these levels. When returned
to oral administration, the dose should be reduced by 50% of the original
oral dose for one week to prevent excessive plasma levels due to sustained
release from intramuscular tissue sites. If
the patient requires more than a week of IM phenytoin, alternative
routes should be explored, such as gastric intubation. For time periods
less than one week, the patient shifted back from IM administration
should receive one half the original oral dose for the same period
of time the patient received IM phenytoin. Monitoring plasma levels
would help prevent a fall into the subtherapeutic range. Serum blood
level determinations are especially helpful when possible drug interactions
are suspected.
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Phenytoin Sodium Injection, USP is a sterile, ready-mixed
solution containing in each mL phenytoin sodium 50 mg; propylene glycol
0.4 mL (40%); alcohol 10%; Water for Injection qs. Sodium hydroxide
is used to adjust pH to 12. Phenytoin sodium is related to the barbiturates
in chemical structure, but has a five-member ring. Chemically, phenytoin
sodium is sodium 5, 5-diphenyl-2, 4-imidazolidinedione. It has a molecular
weight of 274.25 and a molecular formula of CHNNaO. It has the following structural formula:
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Phenytoin is an anticonvulsant which may be useful
in the treatment of status epilepticus of the grand mal type. 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
post-tetanic potentiation at synapses. Loss of post-tetanic 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 grand mal seizures. The
plasma half-life in man after intravenous administration ranges from
10 to 15 hours. Optimum control without clinical signs of toxicity
occurs most often with serum levels between 10 mcg/mL and 20
mcg/mL. A fall in plasma levels may occur when
patients are changed from oral to intramuscular administration. The
drop is caused by slower absorption, as compared to oral administration,
due to the poor water solubility of phenytoin. Intravenous administration
is the preferred route for producing rapid therapeutic serum levels. There are occasions when intramuscular administration
may be required, i.e., postoperatively, in comatose patients, for
GI upsets. During these periods, a sufficient dose must be administered
intramuscularly to maintain the plasma level within the therapeutic
range. Where oral dosage is resumed following intramuscular usage,
the oraldose should be properly adjusted to compensate for the slow,
continuing IM absorption to avoid toxic symptoms. Patients stabilized on a daily oral regimen of phenytoin experience
a drop in peak blood levels to 50 to 60 percent of stable levels if
crossed over to an equal dose administered intramuscularly. However,
the intramuscular depot of poorly soluble material is eventually absorbed,
as determined by urinary excretion of 5-(p-hydroxyphenyl)-5-phenylhydantoin
(HPPH), the principalmetabolite, as well as the total amount of drug
eventually appearing in the blood. A short-term
(one week) study indicates that patients do not experience the expected
drop in blood levels when crossed over to the intramuscular route
if the phenytoin IM dose is increased by 50 percent over the previously
established oral dose. To avoid drug cumulation due to absorption
from the muscle depots, it is recommended that for the first week
back on oral phenytoin, the dose be reduced to halfof the original
oral dose (one third of the IM dose). Experience for periods greater
than one week is lacking and blood level monitoring is recommended.
For administration of phenytoin in patients who cannot take oral medication
for periods greater than a week, gastric intubation may be considered.
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Phenytoin is contraindicated in patients with a history
of hypersensitivity to hydantoin products. Because
of its effect on ventricular automaticity, phenytoin is contraindicated
in sinus bradycardia, sino-atrial block, second and third degree A-V
block, and patients with Adams-Stokes syndrome.
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Phenytoin Sodium Injection, USP is supplied in the
following: Store at 20 to 25��C (68 to 77��F). [See
USP Controlled Room Temperature.] Do not freeze. To prevent needle-stick injuries, needles should not be
recapped, purposely bent, or broken by hand. Revised: July, 2007
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IMPORTANT NOTE This drug must be administered slowly. In
adults, do not exceed 50 mg per minute intravenously. In neonates,
the drug should be administered at a rate not exceeding 1 mg/kg/min
to 3 mg/kg/min.
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General: The addition of phenytoin solution to intravenous
infusion is not recommended due to lack of solubility and resultant
precipitation. Phenytoin sodium injection should
be injected slowly (not exceeding 50 mg per minute in adults), directly
into a large vein through a large-gauge needle or intravenous catheter.
Each injection of intravenous phenytoin should be followed by an injection
of sterile saline through the same needle or intravenous catheter
to avoid local venous irritation due to the alkalinity of the solution.
Continuous infusion should be avoided. Soft
tissue irritation and inflammation has occurred at the site of injection
with and without extravasation of intravenous phenytoin. Soft tissue
irritation may vary from slight tenderness to extensive necrosis,
sloughing and in rare instances has led to amputation. Improper administration
including subcutaneous or perivascular injection should be avoided
to help prevent possibility of the above. The
liver is the site of biotransformation. Patients with impaired liver
function, elderly patients, or those who are gravely ill may show
early toxicity. A small percentage of individuals
who have been treated with phenytoin have been shown to metabolizethe 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. 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. 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.)<br/>Laboratory Tests: Phenytoin serum level determinations may be necessary
to achieve optimal dosage adjustments.<br/>Drug Interactions: There are many drugs which may increase or decrease
phenytoin levels or which phenytoin may affect. The most commonly
occurring drug interactions are listed below:<br/>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).<br/>Carcinogenesis:: See WARNINGS section
for information on carcinogenesis.<br/>Pregnancy:: See WARNINGS.<br/>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.
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The lethal dose in children is not known. The lethal
dose in adults is estimated to be 2 g to 5 g. The initial symptoms
are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperflexia,
lethargy, slurred speech, nausea, vomiting. The patient may become
comatose and hypertensive. 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 mcg/mL,
ataxia at 30 mcg/mL, dysarthria and lethargy appear when the
plasma concentration is over 40 mcg/mL, but as high a concentration
as 50 mcg/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 mcg/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 children. In acute overdosage the possibility of other CNS depressants, including
alcohol, should be borne in mind.
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Phenytoin Sodium
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Phenytoin Sodium (Injection, Solution)
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The most notable signs of toxicity associated with
the intravenous use of this drug are cardiovascular collapse and/or
central nervous system depression. Hypotension does occur when the
drug is administered rapidly by the intravenous route. The rate of administration is very important;
it should not exceed 50 mg per minute in adults, and 1 mg/kg/min to
3 mg/kg/min in neonates. At this rate, toxicity should be minimized. Cardiovascular Severe cardiotoxic reactions and fatalities
have been reported with atrial and ventricular conduction depression
and ventricular fibrillation. Severe complications are most commonly
encountered in elderly or gravely ill patients. 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 headaches 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, and constipation. 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). 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). Connective
Tissue System Coarsening of the facial
features, enlargement of the lips, gingival hyperplasia, hypertrichosis,
and Peyronie's disease. Injection Site Local irritation, inflammation, tenderness, necrosis, and sloughing
have been reported with or without extravasation of intravenous phenytoin. Other Systemic lupus erythematosus, periarteritis nodosa, toxic
hepatitis, liver damage, and immunoglobulin abnormalities may occur.
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Intravenous administration should not exceed 50 mg
per minute in adults. In neonates, the drug
should be administered at a rate not exceeding 1 mg/kg/min to 3 mg/kg/min. Severe cardiotoxic reactions and fatalities have been
reported with atrial and ventricular conduction depression and ventricular
fibrillation. Severe complications are most commonly encountered in
elderly or gravely ill patients. Phenytoin should
be used with caution in patients with hypotension and severe myocardial
insufficiency. Hypotension usually occurs when
the drug is administered rapidly by the intravenous route. The intramuscular route is not recommended for the treatment
of status epilepticus since blood levels of phenytoin in the therapeutic
range cannot be readily achieved with doses and methods of administration
ordinarily employed. 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 e.g., 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.<br/>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 malformation,
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 tomothers 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 the neonate after birth.
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Parenteral phenytoin is indicated for the control
of status epilepticus of the grand mal type, and prevention and treatment
of seizures occurring during neurosurgery.
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Phenytoin Sodium
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