CARBAMAZEPINE
DESCRIPTION:
WARNING
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE
BEEN REPORTED IN ASSOCIATION WITH THE USE
OF TEGRETOL. DATA FROM A POPULATION-BASED
CASE CONTROL STUDY DEMONSTRATE THAT THE
RISK OF DEVELOPING THESE REACTIONS IS 5-8
TIMES GREATER THAN IN THE GENERAL
POPULATION. HOWEVER, THE OVERALL RISK OF
THESE REACTIONS IN THE UNTREATED GENERAL
POPULATION IS LOW, APPROXIMATELY SIX
PATIENTS PER ONE MILLION POPULATION PER
YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS
PER ONE MILLION POPULATION PER YEAR FOR
APLASTIC ANEMIA.
ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT
DECREASED PLATELET OR WHITE BLOOD CELL
COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH
THE USE OF TEGRETOL, DATA ARE NOT AVAILABLE
TO ESTIMATE ACCURATELY THEIR INCIDENCE OR
OUTCOME. HOWEVER, THE VAST MAJORITY OF THE
CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO
THE MORE SERIOUS CONDITIONS OF APLASTIC
ANEMIA OR AGRANULOCYTOSIS.
BECAUSE OF THE VERY LOW INCIDENCE OF
AGRANULOCYTOSIS AND APLASTIC ANEMIA, THE
VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES
OBSERVED IN MONITORING OF PATIENTS ON
TEGRETOL ARE UNLIKELY TO SIGNAL THE
OCCURRENCE OF EITHER ABNORMALITY.
NONETHELESS, COMPLETE PRETREATMENT
HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS
A BASELINE. IF A PATIENT IN THE COURSE OF
TREATMENT EXHIBITS LOW OR DECREASED WHITE
BLOOD CELL OR PLATELET COUNTS, THE PATIENT
SHOULD BE MONITORED CLOSELY.
DISCONTINUATION OF THE DRUG SHOULD BE
CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT
BONE MARROW DEPRESSION DEVELOPS.
BEFORE PRESCRIBING TEGRETOL, THE PHYSICIAN SHOULD BE THOROUGHLY FAMILIAR WITH
THE DETAILS OF THIS PRESCRIBING INFORMATION, PARTICULARLY REGARDING USE WITH
OTHER DRUGS, ESPECIALLY THOSE WHICH ACCENTUATE TOXICITY POTENTIAL.
Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for
trigeminal neuralgia, Its chemical name is 5H-
dibenz(b,f)azepine-5-carboxamide.
Carbamazepine USP is a white to off-white powder, practically insoluble in water
and soluble in alcohol and in acetone. Its molecular weight is 236.27.
Inactive Ingredients. ACTIONS/CLINICAL PHARMACOLOGY:
In controlled clinical trials, Tegretol has been shown to be effective in the
treatment of psychomotor and grand mal seizures, as well as trigeminal
neuralgia.
MECHANISM OF ACTION
Tegretol has demonstrated anticonvulsant properties in rats and mice with
electrically and chemically induced seizures. It appears to act by reducing
polysynaptic responses and blocking the post-tetanic potentiation. Tegretol
greatly reduces or abolishes pain induced by stimulation of the infraorbital
nerve in cats and rats. It depresses thalamic potential and bulbar and
polysynaptic reflexes, including the linguomandibular reflex in cats. Tegretol
is chemically unrelated to other anticonvulsants or other drugs used to control
the pain of trigeminal neuralgia. The mechanism of action remains unknown.
The principal metabolite of Tegretol, carbamazepine-10, 11-epoxide, has
anticonvulsant activity as demonstrated in several in vivo animal models of
seizures. Though clinical activity for the epoxide has been postulated, the
significance of its activity with respect to the safety and efficacy of Tegretol
has not been established.
PHARMACOKINETICS
In clinical studies, Tegretol suspension, conventional tablets, and XR tablets
delivered equivalent amounts of drug to the systemic circulation. However, the
suspension was absorbed somewhat faster, and the XR tablet slightly slower, than
the conventional tablet. The bioavailability of the XR tablet was 89% compared
to suspension. Following a b.i.d. dosage regimen, the suspension provides higher
peak levels and lower trough levels than those obtained from the conventional
tablet for the same dosage regimen. On the other hand, following a t.i.d. dosage
regimen, Tegretol suspension affords steady-state plasma levels comparable to
Tegretol tablets given b.i.d. when administered at the same total mg daily dose.
Following a b.i.d. dosage regimen, Tegretol-XR tablets afford steady-state
plasma levels comparable to conventional Tegretol tablets given q.i.d., when
administered at the same total mg daily dose. Tegretol in blood is 76% bound to
plasma proteins. Plasma levels of Tegretol are variable and may range from 0.5-
25 mcgm/mL, with no apparent relationship to the daily intake of the drug. Usual
adult therapeutic levels are between 4 and 12 mcgm/mL. In polytherapy, the
concentration of Tegretol and concomitant drugs may be increased or decreased
during therapy, and drug effects may be altered (see PRECAUTIONS, Drug
Interactions). Following chronic oral administration of suspension, plasma
levels peak at approximately 1.5 hours compared to 4-5 hours after
administration of conventional Tegretol tablets, and 3-12 hours after
administration of Tegretol-XR tablets. The CSF/serum ratio is 0.22, similar to
the 24% unbound Tegretol in serum. Because Tegretol induces its own metabolism,
the half-life is also variable. Autoinduction is completed after 3-5 weeks of a
fixed dosing regimen. Initial half- life values range from 25-65 hours,
decreasing to 12-17 hours on repeated doses. Tegretol is metabolized in the
liver. Cytochrome P450 3A4 was identified as the major isoform responsible for
the formation of carbamazepine-10, 11-epoxide from Tegretol. After oral
administration of 14C- carbamazepine, 72% of the administered radioactivity was
found in the urine and 28% in the feces. This urinary radioactivity was composed
largely of hydroxylated and conjugated metabolites, with only 3% of unchanged
Tegretol.
The pharmacokinetic parameters of Tegretol disposition are similar in children
and in adults. However, there is a poor correlation between plasma
concentrations of carbamazepine and Tegretol dose in children. Carbamazepine is
more rapidly metabolized to carbamazepine-10, 11-epoxide (a metabolite shown to
be equipotent to carbamazepine as an anticonvulsant in animal screens) in the
younger age groups than in adults. In children below the age of 15, there is an
inverse relationship between CBZ-E/CBZ ratio and increasing age (in one report
from 0.44 in children below the age of 1 year to 0.18 in children between 10-15
years of age).
The effects of race and gender on carbamazepine pharmacokinetics have not been
systematically evaluated.
INDICATIONS AND USAGE:
EPILEPSY
Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting
efficacy of Tegretol as an anticonvulsant was derived from active drug-
controlled studies that enrolled patients with the following seizure types:
1. Partial seizures with complex symptomatology (psychomotor, temporal lobe).
Patients with these seizures appear to show greater improvement than those with
other types.
2. Generalized tonic-clonic seizures (grand mal).
3. Mixed seizure patterns which include the above, or other partial or
generalized seizures. Absence seizures (petit mal) do not appear to be
controlled by Tegretol (see PRECAUTIONS, General).
TRIGEMINAL NEURALGIA
Tegretol is indicated in the treatment of the pain associated with true
trigeminal neuralgia.
Beneficial results have also been reported in glossopharyngeal neuralgia.
This drug is not a simple analgesic and should not be used for the relief of
trivial aches or pains.
CONTRAINDICATIONS:
Tegretol should not be used in patients with a history of previous bone marrow
depression, hypersensitivity to the drug, or known sensitivity to any of the
tricyclic compounds, such as amitriptyline, desipramine, imipramine,
protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with
monoamine oxidase inhibitors is not recommended. Before administration of
Tegretol, MAO inhibitors should be discontinued for a minimum of 14 days, or
longer if the clinical situation permits.
WARNINGS:
WARNING
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE
BEEN REPORTED IN ASSOCIATION WITH THE USE
OF TEGRETOL. DATA FROM A POPULATION-BASED
CASE CONTROL STUDY DEMONSTRATE THAT THE
RISK OF DEVELOPING THESE REACTIONS IS 5-8
TIMES GREATER THAN IN THE GENERAL
POPULATION. HOWEVER, THE OVERALL RISK OF
THESE REACTIONS IN THE UNTREATED GENERAL
POPULATION IS LOW, APPROXIMATELY SIX
PATIENTS PER ONE MILLION POPULATION PER
YEAR FOR AGRANULOCYTOSIS AND TWO PATIENT
PER ONE MILLION POPULATION PER YEAR FOR
APLASTIC ANEMIA.
ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT
DECREASED PLATELET OR WHITE BLOOD CELL
COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH
THE USE OF TEGRETOL, DATA ARE NOT AVAILABLE
TO ESTIMATE ACCURATELY THEIR INCIDENCE OR
OUTCOME. HOWEVER, THE VAST MAJORITY OF THE
CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO
THE MORE SERIOUS CONDITIONS OF APLASTIC
ANEMIA OR AGRANULOCYTOSIS.
BECAUSE OF THE VERY LOW INCIDENCE OF
AGRANULOCYTOSIS AND APLASTIC ANEMIA, THE
VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES
OBSERVED IN MONITORING OF PATIENTS ON
TEGRETOL ARE UNLIKELY TO SIGNAL THE
OCCURRENCE OF EITHER ABNORMALITY.
NONETHELESS, COMPLETE PRETREATMENT
HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS
A BASELINE. IF A PATIENT IN THE COURSE OF
TREATMENT EXHIBITS LOW OR DECREASED WHITE
BLOOD CELL OR PLATELET COUNTS, THE PATIENT
SHOULD BE MONITORED CLOSELY.
DISCONTINUATION OF THE DRUG SHOULD BE
CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT
BONE MARROW DEPRESSION DEVELOPS.
Patients with a history of adverse hematologic reaction to any drug may be
particularly at risk.
Severe dermatologic reactions, including toxic epidermal necrolysis (Lyell's
syndrome) and Stevens-Johnson syndrome, have been reported with Tegretol. These
reactions have been extremely rare. However, a few fatalities have been
reported.
Tegretol has shown mild anticholinergic activity; therefore, patients with
increased intraocular pressure should be closely observed during therapy.
Because of the relationship of the drug to other tricyclic compounds, the
possibility of activation of a latent psychosis and, in elderly patients, of
confusion or agitation should be borne in mind.
USAGE IN PREGNANCY
Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of
carbamazepine during pregnancy and congenital malformations, including spina
bifida. In treating or counseling women of childbearing potential, the
prescribing physician will wish to weigh the benefits of therapy against the
risks. If this drug is used during pregnancy, or if the patient becomes pregnant
while taking this drug, the patient should be apprised of the potential hazard
to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be
a higher prevalence of teratogenic effects associated with the use of
anticonvulsants in combination therapy. Therefore, if therapy is to be
continued, monotherapy may be preferable for pregnant women.
In humans, transplacental passage of carbamazepine is rapid 30-60 minutes), and
the drug is accumulated in the fetal tissues, with higher levels found in liver
and kidney than in brain and lung.
Carbamazepine has been shown to have adverse effects in reproduction studies in
rats when given orally in dosages 10-25 times the maximum human daily dosage
(MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times the MHDD on a mg/m(squared)
basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250
mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate,
1; talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing
offspring demonstrated a lack of weight gain and an unkempt appearance at a
maternal dosage level of 200 mg/kg.
Antiepileptic drugs should not be discontinued abruptly 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 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.
Tests to detect defects using currently accepted procedures should be considered
a part of routine prenatal care in child-bearing women receiving carbamazepine.
There have been a few cases of neonatal seizures and/or respiratory depression
associated with maternal Tegretol and other concomitant anticonvulsant drug use.
A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also
been reported in association with maternal Tegretol use. These symptoms may
represent a neonatal withdrawal syndrome.
PRECAUTIONS:
GENERAL
Before initiating therapy, a detailed history and physical examination should be
made.
Tegretol should be used with caution in patients with a mixed seizure disorder
that includes atypical absence seizures, since in these patients Tegretol has
been associated with increased frequency of generalized convulsions (see
INDICATIONS AND USAGE).
Therapy should be prescribed only after critical benefit-to-risk appraisal in
patients with a history of cardiac, hepatic, or renal damage; adverse
hematologic reaction to other drugs; or interrupted courses of therapy with
Tegretol.
Since a given dose of Tegretol suspension will produce higher peak levels than
the same dose given as the tablet, it is recommended that patients given the
suspension be started on lower doses and increased slowly to avoid unwanted side
effects (see DOSAGE AND ADMINISTRATION).
INFORMATION FOR PATIENTS
Patients should be made aware of the early toxic signs and symptoms of a
potential hematologic problem, such as fever, sore throat, rash, ulcers in the
mouth, easy bruising, petechial or purpuric hemorrhage, and should be advised to
report to the physician immediately if any such signs or symptoms appear.
Since dizziness and drowsiness may occur, patients should be cautioned about the
hazards of operating machinery or automobiles or engaging in other potentially
dangerous tasks.
LABORATORY TESTS
Complete pretreatment blood counts, including platelets and possibly
reticulocytes and serum iron, should be obtained as a baseline. If a patient in
the course of treatment exhibits low or decreased white blood cell or platelet
counts, the patient should be monitored closely. Discontinuation of the drug
should be considered if any evidence of significant bone marrow depression
develops.
Baseline and periodic evaluations of liver function, particularly in patients
with a history of liver disease, must be performed during treatment with this
drug since liver damage may occur. The drug should be discontinued immediately
in cases of aggravated liver dysfunction or active liver disease.
Baseline and periodic eye examinations, including slit-lamp, funduscopy, and
tonometry, are recommended since many phenothiazines and related drugs have been
shown to cause eye changes.
Baseline and periodic complete urinalysis and BUN determinations are recommended
for patients treated with this agent because of observed renal dysfunction.
Monitoring of blood levels (see ACTIONS/CLINICAL PHARMACOLOGY) has increased the
efficacy and safety of anticonvulsants. This monitoring may be particularly
useful in cases of dramatic increase in seizure frequency and for verification
of compliance. In addition, measurement of drug serum levels may aid in
determining the cause of toxicity when more than one medication is being used.
Thyroid function tests have been reported to show decreased values with Tegretol
administered alone.
Hyponatremia has been reported in association with Tegretol use, either alone or
in combination with other drugs.
Interference with some pregnancy tests has been reported.
DRUG INTERACTIONS
There has been a report of a patient who passed an orange rubbery precipitate in
his stool the day after ingesting Tegretol suspension immediately followed by
Thorazine(R) solution. Subsequent testing has shown that mixing Tegretol
suspension and chlorpromazine solution (both generic and brand name) as well as
Tegretol suspension and liquid Mellaril(R) resulted in the occurrence of this
precipitate. Because the extent to which this occurs with other liquid
medications is not known, Tegretol suspension should not be administered
simultaneously with other liquid medicinal agents or diluents. (See Dosage and
Administration).
Clinically meaningful drug interactions have occurred with concomitant
medications and include, but are not limited to, the following:
AGENTS THAT MAY AFFECT TEGRETOL PLASMA LEVELS
CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma
carbamazepine levels. Drugs that have been shown, or would be expected, to
increase plasma carbamazepine levels include
cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin,
clarithromycin, fluoxetine, loratadine, terfenadine, isoniazid, niacinamide,
nicotinamide, propoxyphene, ketoconazole, itraconazole, verapamil, valproate.*
CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have
been shown, or that would be expected, to decrease plasma carbamazepine levels
include
cisplatin, doxorubicin HCl, felbamate,** rifampin, phenobarbital, phenytoin,
primidone, theophylline.
----------
*increased levels of the active 10, 11-epoxide
**decreased levels of carbamazepine and increased levels of the 10, 11-epoxide
----------
EFFECT OF TEGRETOL ON PLASMA LEVELS OF CONCOMITANT AGENTS
Increased levels: clomipramine HCl, phenytoin, primidone
Tegretol induces hepatic CYP activity. Tegretol causes, or would be expected to
cause, decreased levels of the following:
acetaminophen, alprazolam, clonazepam, clozapine, dicumarol, doxycycline,
ethosuximide, haloperidol, methsuximide, oral contraceptives, phensuximide,
phenytoin, theophylline, valproate, warfarin.
Concomitant administration of carbamazepine and lithium may increase the risk of
neurotoxic side effects.
Alterations of thyroid function have been reported in combination therapy with
other anticonvulsant medications.
Breakthrough bleeding has been reported among patients receiving concomitant
oral and subdermal implant contraceptives and their reliability may be adversely
affected.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Carbamazepine, when administered to Sprague- Dawley rats for two years in the
diet at doses of 25, 75, and 250 mg/kg/day, resulted in a dose- related increase
in the incidence of hepatocellular tumors in females and of benign interstitial
cell adenomas in the testes of males.
Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-
Dawley rats. Bacterial and mammalian mutagenicity studies using carbamazepine
produced negative results. The significance of these findings relative to the
use of carbamazepine in humans is, at present, unknown.
USAGE IN PREGNANCY
PREGNANCY CATEGORY D (See WARNINGS).
Tegretol has been shown to have adverse effects in reproduction studies in rats
when given orally in dosages 10-25 times the maximum human daily dosage of 1200
mg. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250
mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate,
1; talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing
offspring demonstrated a lack of weight gain and an unkempt appearance at a
maternal dosage level of 200 mg/kg.
In humans, transplacental passage of Tegretol is rapid (30-60 minutes), and the
drug is accumulated in fetal tissues, with higher levels found in liver and
kidney than in brain and lung.
There are no adequate and well-controlled studies in pregnant women.
Epidemiological data suggest that there may be an association between the use of
carbamazepine during pregnancy and congenital malformations, including spina
bifida. Tegretol should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be
a higher prevalence of teratogenic effects associated with the use of
anticonvulsants in combination therapy. Therefore, monotherapy is recommended
for pregnant women.
It is important to note that anticonvulsant 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 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.
LABOR AND DELIVERY
The effect of Tegretol on human labor and delivery is unknown.
NURSING MOTHERS
Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of
the concentration in breast milk to that in maternal plasma is about 0.4 for
Tegretol and about 0.5 for the epoxide. The estimated doses given to the newborn
during breast feeding are in the range of 2-5 mg daily for Tegretol and 1-2 mg
daily for the epoxide.
Because of the potential for serious adverse reactions in nursing infants from
carbamazepine, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the
mother.
PEDIATRIC USE
Substantial evidence of Tegretol's effectiveness for use in the management of
children with epilepsy (see Indications for specific seizure types) is derived
from clinical investigations performed in adults and from studies in several in
vitro systems which support the conclusion that (1) the pathogenetic mechanisms
underlying seizure propagation are essentially identical in adults and children,
and (2) the mechanism of action of carbamazepine in treating seizures is
essentially identical in adults and children.
Taken as a whole, this information supports a conclusion that the generally
accepted therapeutic range of total carbamazepine in plasma (i.e., 4-12 mcg/mL)
is the same in children and adults.
The evidence assembled was primarily obtained from short-term use of
carbamazepine. The safety of carbamazepine in children has been systematically
studied up to 6 months. No longer- term data from clinical trials is available.
GERIATRIC USE
No systematic studies in geriatric patients have been conducted.
DRUG INTERACTIONS:
There has been a report of a patient who passed an orange rubbery precipitate in
his stool the day after ingesting Tegretol suspension immediately followed by
Thorazine(R) solution. Subsequent testing has shown that mixing Tegretol
suspension and chlorpromazine solution (both generic and brand name) as well as
Tegretol suspension and liquid Mellaril(R) resulted in the occurrence of this
precipitate. Because the extent to which this occurs with other liquid
medications is not known, Tegretol suspension should not be administered
simultaneously with other liquid medicinal agents or diluents. (See Dosage and
Administration).
Clinically meaningful drug interactions have occurred with concomitant
medications and include, but are not limited to, the following:
AGENTS THAT MAY AFFECT TEGRETOL PLASMA LEVELS
CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma
carbamazepine levels. Drugs that have been shown, or would be expected, to
increase plasma carbamazepine levels include
cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin,
clarithromycin, fluoxetine, loratadine, terfenadine, isoniazid, niacinamide,
nicotinamide, propoxyphene, ketaconazole, itraconazole, verapamil, valproate.*
CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have
been shown, or that would be expected, to decrease plasma carbamazepine levels
include
cisplatin, doxorubicin HCl, felbamate,** rifampin, phenobarbital, phenytoin,
primidone, theophylline.
----------
*increased levels of the active 10, 11-epoxide
**decreased levels of carbamazepine and increased levels of the 10, 11-epoxide
----------
EFFECT OF TEGRETOL ON PLASMA LEVELS OF CONCOMITANT AGENTS
Increased levels: clomipramine HCl, phenytoin, primidone
Tegretol induces hepatic CYP activity. Tegretol causes, or would be expected to
cause, decreased levels of the following:
acetaminophen, alprazolam, clonazepam, clozapine, dicumarol, doxycycline,
ethosuximide, haloperidol, methsuximide, oral contraceptives, phensuximide,
phenytoin, theophylline, valproate, warfarin.
Concomitant administration of carbamazepine and lithium may increase the risk of
neurotoxic side effects.
Alterations of thyroid function have been reported in combination therapy with
other anticonvulsant medications.
Breakthrough bleeding has been reported among patients receiving concomitant
oral contraceptives and their reliability may be adversely affected.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
If adverse reactions are of such severity that the drug must be discontinued,
the physician must be aware that abrupt discontinuation of any anticonvulsant
drug in a responsive epileptic patient may lead to seizures or even status
epilepticus with its life-threatening hazards.
The most severe adverse reactions have been observed in the hemopoietic system
(see boxed WARNING), the skin, and the cardiovascular system.
The most frequently observed adverse reactions, particularly during the initial
phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and
vomiting. To minimize the possibility of such reactions, therapy should be
initiated at the low dosage recommended.
The following additional adverse reactions have been reported:
HEMOPOIETIC SYSTEM: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow
depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, acute
intermittent porphyria.
SKIN: Pruritic and erythematous rashes, urticaria, toxic epidermal necrolysis
(Lyell's syndrome) (see WARNINGS), Stevens-Johnson syndrome (see WARNINGS),
photosensitivity reactions, alterations in skin pigmentation, exfoliative
dermatitis, erythema multiforme and nodosum, purpura, aggravation of
disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases,
discontinuation of therapy may be necessary. Isolated cases of hirsutism have
been reported, but a causal relationship is not clear.
CARDIOVASCULAR SYSTEM: Congestive heart failure, edema, aggravation of
hypertension, hypotension, syncope and collapse, aggravation of coronary artery
disease, arrhythmias and AV block, thrombophlebitis, thromboembolism, and
adenopathy or lymphadenopathy.
Some of these cardiovascular complications have resulted in fatalities.
Myocardial infarction has been associated with other tricyclic compounds.
LIVER: Abnormalities in liver function tests, cholestatic and hepatocellular
jaundice, hepatitis.
PANCREATIC: Pancreatitis
RESPIRATORY SYSTEM: Pulmonary hypersensitivity characterized by fever, dyspnea,
pneumonitis, or pneumonia.
GENITOURINARY SYSTEM: Urinary frequency, acute urinary retention, oliguria with
elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria,
glycosuria, elevated BUN, and microscopic deposits in the urine have also been
reported.
Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at
dosage levels of 50-400 mg/kg/day. Additionally, rats receiving Tegretol in the
diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-
related incidence of testicular atrophy and aspermatogenesis. In dogs, it
produced a brownish discoloration, presumably a metabolite, in the urinary
bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to
humans is unknown.
NERVOUS SYSTEM: Dizziness, drowsiness, disturbances of coordination, confusion,
headache, fatigue, blurred vision, visual hallucinations, transient diplopia,
oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary
movements, peripheral neuritis and paresthesias, depression with agitation,
talkativeness, tinnitus, and hyperacusis.
There have been reports of associated paralysis and other symptoms of cerebral
arterial insufficiency, but the exact relationship of these reactions to the
drug has not been established.
Isolated cases of neuroleptic malignant syndrome have been reported with
concomitant use of psychotropic drugs.
DIGESTIVE SYSTEM: Nausea, vomiting, gastric distress and abdominal pain,
diarrhea, constipation, anorexia, and dryness of the mouth and pharynx,
including glossitis and stomatitis.
EYES: Scattered punctate cortical lens opacities, as well as conjunctivitis,
have been reported. Although a direct causal relationship has not been
established, many phenothiazines and related drugs have been shown to cause eye
changes.
MUSCULOSKELETAL SYSTEM: Aching joints and muscles, and leg cramps.
METABOLISM: Fever and chills. Inappropriate antidiuretic hormone (ADH)
secretion syndrome has been reported. Cases of frank water intoxication, with
decreased serum sodium (hyponatremia) and confusion, have been reported in
association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased
levels of plasma calcium have been reported.
OTHER: Isolated cases of a lupus erythematosus- like syndrome have been
reported. There have been occasional reports of elevated levels of cholesterol,
HDL cholesterol, and triglycerides in patients taking anticonvulsants.
A case of aseptic meningitis, accompanied by myoclonus and peripheral
eosinophilia, has been reported in a patient taking carbamazepine in combination
with other medications. The patient was successfully dechallenged, and the
meningitis reappeared upon rechallenge with carbamazepine.
DRUG ABUSE AND DEPENDENCE:
No evidence of abuse potential has been associated with Tegretol, nor is there
evidence of psychological or physical dependence in humans.
OVERDOSAGE:
ACUTE TOXICITY
Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac
arrest and a 24-year-old man died of pneumonia and hypoxic encephalopathy);
children, 4 g (a 14-year-old girl died of a cardiac arrest, 1.6 g (a 3-year- old
girl died of aspiration pneumonia).
Highest known doses survived: adults, 30 g (31-year-old woman); children, 10 g
(6-year-old boy); small children, 5 g (3-year-old girl).
Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-
2680; guinea pigs, 920.
SIGNS AND SYMPTOMS
The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances
are the most prominent. Cardiovascular disorders are generally milder, and
severe cardiac complications occur only when very high doses (>60 g) have been
ingested.
RESPIRATION: Irregular breathing, respiratory depression.
CARDIOVASCULAR SYSTEM: Tachycardia, hypotension or hypertension, shock,
conduction disorders.
NERVOUS SYSTEM AND MUSCLES: Impairment of consciousness ranging in severity to
deep coma. Convulsions, especially in small children. Motor restlessness,
muscular twitching, tremor, athetoid movements, opisthotonos, ataxia,
drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism,
psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by
hyporeflexia.
GASTROINTESTINAL TRACT: Nausea, vomiting.
KIDNEYS AND BLADDER: Anuria or oliguria, urinary retention.
LABORATORY FINDINGS: Isolated instances of overdosage have included
leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. EEG may show
dysrhythmias.
COMBINED POISONING: When alcohol, tricyclic antidepressants, barbiturates, or
hydantoins are taken at the same time, the signs and symptoms of acute poisoning
with Tegretol may be aggravated or modified.
TREATMENT
The prognosis in cases of severe poisoning is critically dependent upon prompt
elimination of the drug, which may be achieved by inducing vomiting, irrigating
the stomach, and by taking appropriate steps to diminish absorption. If these
measures cannot be implemented without risk on the spot, the patient should be
transferred at once to a hospital, while ensuring that vital functions are
safeguarded. There is no specific antidote.
ELIMINATION OF THE DRUG: Induction of vomiting.
Gastric lavage. Even when more than 4 hours have elapsed following ingestion of
the drug, the stomach should be repeatedly irrigated, especially if the patient
has also consumed alcohol.
MEASURES TO REDUCE ABSORPTION: Activated charcoal, laxatives.
MEASURES TO ACCELERATE ELIMINATION: Forced diuresis.
Dialysis is indicated only in severe poisoning associated with renal failure.
Replacement transfusion is indicated in severe poisoning in small children.
RESPIRATORY DEPRESSION: Keep the airways free; resort, if necessary, to
endotracheal intubation, artificial respiration, and administration of oxygen.
HYPOTENSION, SHOCK: Keep the patient's legs raised and administer a plasma
expander. If blood pressure fails to rise despite measures taken to increase
plasma volume, use of vasoactive substances should be considered.
CONVULSIONS: Diazepam or barbiturates.
WARNING: Diazepam or barbiturates may aggravate respiratory depression
(especially in children), hypotension, and coma. However, barbiturates should
NOT be used if drugs that inhibit monoamine oxidase have also been taken by the
patient either in overdosage or in recent therapy (within 1 week).
SURVEILLANCE: Respiration, cardiac function (ECG monitoring), blood pressure,
body temperature, pupillary reflexes, and kidney and bladder function should be
monitored for several days.
TREATMENT OF BLOOD COUNT ABNORMALITIES: If evidence of significant bone marrow
depression develops, the following recommendations are suggested: (1) stop the
drug, (2) perform daily CBC, platelet, and reticulocyte counts, (3) do a bone
marrow aspiration and trephine biopsy immediately and repeat with sufficient
frequency to monitor recovery.
Special periodic studies might be helpful as follows: (1) white cell and
platelet antibodies, (2) 59Fe--ferrokinetic studies, (3) peripheral blood cell
typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone marrow
culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2
and F hemoglobin, and (7) serum folic acid and B12 levels.
A fully developed aplastic anemia will require appropriate, intensive monitoring
and therapy, for which specialized consultation should be sought.
DOSAGE AND ADMINISTRATION:
Tegretol suspension in combination with liquid chlorpromazine or thiordiazine
results in precipitate formation, and in the case of chlorpromazine, there has
been a report of a patient passing an orange rubbery precipitate in the stool
following coadministration of the two drugs. (See Drug Interactions). Because
the extent to which this occurs with other liquid medications is not know,
Tegretol suspension should not be administered simultaneously with other liquid
medications or diluents.
(See table below)
Monitoring of blood levels has increased the efficacy and safety of
anticonvulsants (see PRECAUTIONS, Laboratory Tests). Dosage should be adjusted
to the needs of the individual patient. A low initial daily dosage with a
gradual increase is advised. As soon as adequate control is achieved, the dosage
may be reduced very gradually to the minimum effective level. Medication should
be taken with meals.
Since a given dose of Tegretol suspension will produce higher peak levels than
the same dose given as the tablet, it is recommended to start with low doses
(children 6-12 years: 1/2 teaspoon q.i.d.) and to increase slowly to avoid
unwanted side effects.
Conversion of patients from oral Tegretol tablets to Tegretol suspension:
Patients should be converted by administering the same number of mg per day in
smaller, more frequent doses (i.e., b.i.d. tablets to t.i.d. suspension).
Tegretol-XR is an extended-release formulation for twice-a-day administration.
When converting patients from Tegretol conventional tablets to Tegretol-XR, the
same total daily mg dose of Tegretol-XR should be administered. TEGRETOL-XR
TABLETS MUST BE SWALLOWED WHOLE AND NEVER CRUSHED OR CHEWED. Tegretol-XR tablets
should be inspected for chips or cracks. Damaged tablets should not be consumed.
Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these
coatings may be noticeable in the stool.
EPILEPSY (see INDICATIONS AND USAGE)
ADULTS AND CHILDREN OVER 12 YEARS OF AGE- -INITIAL: Either 200 mg b.i.d. for
tablets and XR tablets, or 1 teaspoon q.i.d. for suspension (400 mg/day).
Increase at weekly intervals by adding up to 200 mg/day using a b.i.d. regimen
of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the
optimal response is obtained. Dosage generally should not exceed 1000mg daily in
children 12-15 years of age, and 1200 mg daily in patients above 15 years of
age. Doses up to 1600 mg daily have been used in adults in rare instances.
MAINTENANCE: Adjust dosage to the minimum effective level, usually 800-1200 mg
daily.
CHILDREN 6-12 YEARS OF AGE--INITIAL: Either 100 mg b.i.d. for tablets or XR
tablets, or 1/2 teaspoon q.i.d. for suspension (200 mg/day). Increase at weekly
intervals by adding up to 100 mg/day using a b.i.d. regimen of Tegretol-XR or a
t.i.d. or q.i.d. regimen of the other formulations until the optimal response is
obtained. Dosage generally should not exceed 1000mg daily. MAINTENANCE: Adjust
dosage to the minimum effective level, usually 400-800 mg daily.
CHILDREN UNDER 6 YEARS OF AGE--INITIAL: 10-20 mg/kg/day b.i.d. or t.i.d. as
tablets, or q.i.d. as suspension. Increase weekly to achieve optimal clinical
response administered t.i.d. or q.i.d. MAINTENANCE: Ordinarily, optimal clinical
response is achieved at daily doses below 35 mg/kg. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine
whether or not they are in the therapeutic range. No recommendation regarding
the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be
made. COMBINATION THERAPY: Tegretol may be used alone or with other
anticonvulsants. When added to existing anticonvulsant therapy, the drug should
be added gradually while the other anticonvulsants are maintained or gradually
decreased, except phenytoin, which may have to be increased (see PRECAUTIONS,
Drug Interactions, and Pregnancy Category C).
TRIGEMINAL NEURALGIA (see INDICATIONS AND USAGE)
INITIAL: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or
1/2 teaspoon q.i.d. for suspension, for a total daily dose of 200 mg. This daily
dose may be increased by up to 200 mg/day using increments of 100 mg every 12
hours for tablets or XR tablets, or 50 mg (1/2 teaspoon) q.i.d. for suspension,
only as needed to achieve freedom from pain. Do not exceed 1200 mg daily.
MAINTENANCE: Control of pain can be maintained in most patients with 400-800 mg
daily. However, some patients may be maintained on as little as 200 mg daily
while others may require as much as 1200 mg daily. At least once every 3 months
throughout the treatment period, attempts should be made to reduce the dose to
the minimum effective level or even to discontinue the drug.
TABLE CONTINUES BELOW
DOSAGE INFORMATION
-------------------------³------------------------------------------------------------------³---------------------------------------------------------------
³ Initial Dose ³ Subsequent Dose
-------------------------³------------------------------------------------------------------³----------------------------------------------------------------
Indication ³ Tablet* XR** Suspension ³ Tablet* XR** Suspension
------------------------³-------------------------------------------------------------------³----------------------------------------------------------------
EPILEPSY ³ ³
³ ³
Under ³ 10-20 10-20 ³ Increase Increase
6 yr ³ mg/kg/day mg/kg/day ³ weekly to weekly to
³ b.i.d. or q.i.d. ³ achieve achieve
³ t.i.d. ³ optimal optimal
³ ³ clinical clinical
³ ³ response, response,
³ ³ t.i.d. or t.i.d. or
³ ³ q.i.d. q.i.d.
-----------------------³--------------------------------------------------------------------³----------------------------------------------------------------
6-12 yr ³ 100 mg 100 mg 1/2 tsp ³ Add up Add Add up
³ b.i.d. b.i.d. q.i.d. ³ to 100 100 mg to 1 tsp
³ (200 (200 (200 ³ mg/day /day at (100 mg
³ mg/day) mg/ day) mg/day) ³ at weekly /day) at
³ ³ weekly intervals, weekly
³ ³ intervals, b.i.d intervals,
³ ³ t.i.d. or t.i.d. or
³ ³ q.i.d. q.i.d.
-----------------------³--------------------------------------------------------------------³------------------------------------------------------------------
Over ³ 200 mg 200 mg 1 tsp ³ Add up Add up Add up
12 yr ³ b.i.d. b.i.d. q.i.d. ³ to 200 to 200 to 2 tsp
³ (400 (400 (400 ³ mg/day mg/day (200 mg
³ mg/day) mg/day) mg/day) ³ at at /day)
³ ³ weekly weekly at
³ ³intervals, intervals, weekly
³ ³ t.i.d. o r b.i.d. intervals,
³ ³ q.i.d. t.i.d or
³ ³ q.i.d.
-----------------------³--------------------------------------------------------------------³---------------------------------------------------------------------
TRIGEMINAL ³ ³
NEURALGIA ³ 100 mg 100 mg 1/2 tsp ³ Add Add Add
³ b.i.d. b.i.d. q.i.d. ³ up to up to up to
³ (200 (200 (200 mg ³(200 mg (200 mg 2 tsp (200
³ mg/day) mg/day) /day) ³/day) in /day) in mg/day)
³ ³increments increments in
³ ³of 100 mg of 100 mg increments
³ ³ every every of 50 mg
³ ³ 12 hr 12 hr (1/2 tsp)
³ ³ q.i.d.
--------------------------------------------------------------------------------------------------------------------------------------------------------------------
TABLE CONTINUED DOSAGE INFORMATION
-----------------------³--------------------------------------------------------------------------------------------------------------------------------------------
³ Maximum Daily Dose
-----------------------³-------------------------------------------------------------------------------------------------------------------------------------------
Indication ³ Tablet* XR** Suspension
----------------------³--------------------------------------------------------------------------------------------------------------------------------------------
EPILEPSY ³
³
Under ³ 35 mg/kg/24 hr 35 mg/kg/24 hr
6 yr ³ (see Dosage and (see Dosage and
³ Administration Administration
³ section above) section above)
---------------------³-------------------------------------------------------------------------------------------------------------------------------------------
6-12 yr ³ 1000 mg/24 hr
---------------------³--------------------------------------------------------------------------------------------------------------------------------------------
Over ³ 1000 mg/24 hr (12-15 yr)
12 yr ³ 1200 mg/24 hr (>15 yr)
³ 1600 mg/24 hr
³ (adults, in rare instances
---------------------³--------------------------------------------------------------------------------------------------------------------------------------------
TRIGEMINAL ³
NEURALGIA ³ 1200 mg/24 hr
-----------------------------------------------------------------------------------------------------------------------------------------------------------------
* Tablet = Chewable or conventional tablets
** XR = Tegretol(R)-XR extended-release tablets
************************************************************************