Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1858
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Phenytoin Sodium (Injection, Solution)
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The addition of Phenytoin Sodium Injection solution to intravenous
infusions 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���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. 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. Status Epilepticus: In adults, a loading dose of
10 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���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���20 mg/kg of phenytoin
sodium intravenously will usually produce plasma concentrations of phenytoin
within the generally accepted therapeutic range (10���20 mcg/mL). The
drug should be injected slowly intravenously at a rate not exceeding 1���3
mg/kg/min. Phenytoin Sodium Injection 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 Phenytoin
Sodium Injection 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 Sodium Injection. If
administration of Phenytoin Sodium Injection 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 to
200 mg (2 to 4 mL) intramuscularly at approximately 4-hour intervals during
surgery and continued during the postoperative 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 I.M. phenytoin, alternative routes
should be explored, such as gastric intubation. For time periods less than
one week, the patient shifted back from I.M. administration should receive
one half the original oral dose for the same period of time the patient received
I.M. 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. Parenteral
drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.
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dailymed-instance:descripti... |
Phenytoin Sodium Injection, USP is a sterile, nonpyrogenic
solution of phenytoin sodium and water for injection. Each
milliliter (mL) contains phenytoin sodium 50 mg, propylene glycol 40% and
alcohol 10%. Headspace nitrogen gassed. Also contains sodium hydroxide for
pH adjustment; pH is 11.9 (10.0 to 12.3). The solution
contains no bacteriostat, antimicrobial agent or added buffer. Single-dose,
discard unused portion. NOTE: Do not use Injection if
it is hazy or contains a precipitate. Phenytoin Sodium,
USP is an anticonvulsant chemically designated 5,5-diphenyl hydantoin sodium
salt. 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 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 centersresponsible
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 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 oral dose should be properly adjusted to compensate for the slow, continuing
I.M. absorption to avoid toxic symptoms. Patients stabilized
on a daily oral regimen of phenytoin experience a drop in peak blood levels
to 50���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 principal metabolite, 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 I.M. 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 half
of the original oral dose (one third of the I.M. 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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dailymed-instance:supply |
Phenytoin Sodium Injection, USP, 50 mg/mL is supplied in
single-dose containers as follows: Store at 20 to 25��C (68��to 77��F). [See
USP Controlled Room Temperature.] HOSPIRA, INC., LAKE FOREST,
IL 60045 USA
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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���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. 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 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 or Stevens-Johnson syndrome 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 medicationis 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. 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
varying from slight tenderness to extensive necrosis and sloughing has been
noted. Subcutaneous or perivascular injection should be avoided. 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: Serum level determinations are especially helpful when possible
drug interactions are suspected.<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 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 to 5 grams. 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���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,
and Stevens-Johnson syndrome (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���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. Usage in Pregnancy: A number of reports suggests
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 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 the neonate after birth.
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Phenytoin Sodium Injection 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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