(carbamazepine) Extended-Release Capsules
100 mg, 200 mg and 300 mg
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION
WITH THE USE OF CARBAMAZEPINE. 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 CARBAMAZEPINE,
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 CARBAMAZEPINE 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 Carbatrol, 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.
CARBATROL* is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as 100 mg, 200 mg and 300 mg extended-release capsules of Carbamazepine, USP. Carbamazepine is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27. Its chemical name is 5H-dibenz[b,f]azepine-5-carboxamide, and its structural formula is:
Carbatrol is a multi-component capsule formulation consisting of three different types of beads: immediate-release beads, extended-release beads, and enteric-release beads. The three bead types are combined in a specific ratio to provide twice daily dosing of Carbatrol.
Inactive ingredients: citric acid, colloidal silicon dioxide, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, povidone, sodium lauryl sulfate, talc, triethyl citrate and other ingredients.
The 100 mg capsule shells contain gelatin-NF, FD&C Blue #2, Yellow Iron Oxide, and titanium dioxide and are imprinted with white ink; the 200 mg capsule shells contain gelatin-NF, FD&C Red #3, FD&C Yellow #6, Yellow Iron Oxide, FD&C Blue #2, and titanium dioxide, and are imprinted with white ink; and the 300 mg capsule shells contain gelatin-NF, FD&C Blue #2, FD&C Yellow #6, Red Iron Oxide, Yellow Iron Oxide, and titanium dioxide, and are imprinted with white ink.
Carbatrol is indicated for use as an anticonvulsant drug. Evidence supporting
efficacy of carbamazepine 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 improvements 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 carbamazepine
(see PRECAUTIONS, General).
Carbatrol 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.
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 patients. A low initial daily
dosage with gradual increase is advised. As soon as adequate control is achieved,
the dosage may be reduced very gradually to the minimum effective level. The
Carbatrol capsules may be opened and the beads sprinkled over food, such as
a teaspoon of applesauce or other similar food products if this method of administration
is preferred. Carbatrol capsules or their contents should not be crushed or
chewed. Carbatrol can be taken with or without meals.
Carbatrol is an extended-release formulation for twice a day administration.
When converting patients from immediate release carbamazepine to Carbatrol extended-release
capsules, the same total daily mg dose of carbamazepine should be administered.
Epilepsy (see INDICATIONS AND USAGE)
Adults and children over 12 years of age. Initial: 200 mg twice
daily. Increase at weekly intervals by adding up to 200 mg/day until the optimal
response is obtained. Dosage generally should not exceed 1000 mg per day 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.
Maintenance: Adjust dosage to the minimum effective level, usually 800-1200
Children under 12 years of age: Children taking total daily dosages
of immediate-release carbamazepine of 400mg or greater may be converted
to the same total daily dosage of Carbatrol extended-release capsules, using
a twice daily regimen. 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 Carbatrol for use
at doses above 35 mg/kg/24 hours can be made.
Combination Therapy: Carbatrol 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
Trigeminal Neuralgia (see INDICATIONS AND
Initial: On the first day, start with one 200 mg capsule. This daily
dose may be increased by up to 200 mg/day every 12 hours 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.
Carbatrol (carbamazepine) extended-release capsules is supplied in three dosage
100 mg-Two-piece hard gelatin capsule (bluish green opaque body and cap) printed
with the Shire logo in white ink.
Supplied in bottles of 120 NDC 54092-171-12
200 mg-Two-piece hard gelatin capsule (light gray opaque body with bluish green
opaque cap) printed with the Shire logo in white ink.
Supplied in bottles of 120 .NDC 58521-172-12
300 mg-Two-piece hard gelatin capsule (black opaque body with bluish green
opaque cap) printed with the Shire logo in white ink.
Supplied in bottles of 120 .NDC 58521-173-12
Store at 25° C (77°
F); excursions permitted to 15-30° C (59-86°
F) [see USP controlled room temperature].
PROTECT FROM LIGHT AND MOISTURE.
Manufactured for: Shire US Inc.
725 Chesterbrook Blvd, Wayne PA 19087
1-800-828-2088, Made in U.S.A.
Ó 2005 Shire US Inc.
FDA revision date: 1/24/06
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
If necessary, the Carbatrol capsules can be opened and the contents sprinkled
over food, such as a teaspoon of applesauce or other similar food products.
Carbatrol capsules or their contents should not be crushed or chewed.
Carbatrol may interact with some drugs. Therefore, patients should be advised
to report to their doctors the use of any other prescription or nonprescription
medication or herbal products.
In controlled clinical trials, carbamazepine has been shown to be effective
in the treatment of psychomotor and grand mal seizures, as well as trigeminal
Mechanism of Action
Carbamazepine 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. Carbamazepine
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. Carbamazepine 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 carbamazepine, 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 carbamazepine
has not been established.
Carbamazepine (CBZ): Taken every 12 hours, carbamazepine extended-release
capsules provide steady state plasma levels comparable to immediate-release
carbamazepine tablets given every 6 hours, when administered at the same total
mg daily dose.
Following a single 200 mg oral extended-release dose of carbamazepine, peak
plasma concentration was 1.9 ± 0.3 mg/mL
and the time to reach the peak was 19 ± 7 hours.
Following chronic administration (800 mg every 12 hours), the peak levels were
11.0 ± 2.5 mg/mL
and the time to reach the peak was 5.9 ± 1.8
hours. The pharmacokinetics of extended-release carbamazepine is linear over
the single dose range of 200-800 mg.
Carbamazepine is 76% bound to plasma proteins. Carbamazepine is primarily metabolized
in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible
for the formation of carbamazepine-10, 11-epoxide. Since carbamazepine induces
its own metabolism, the half-life is also variable. Following a single extended-release
dose of carbamazepine, the average half-life range from 35-40 hours and 12-17
hours on repeated dosing. The apparent oral clearance following a single dose
was 25 ± 5 mL/min and following multiple dosing
was 80 ± 30 mL/min.
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 carbamazepine.
Carbamazepine-10, 11-epoxide (CBZ-E): Carbamazepine-10, 11-epoxide is
considered to be an active metabolite of carbamazepine. Following a single 200
mg oral extended-release dose of carbamazepine, the peak plasma concentration
of carbamazepine-10, 11-epoxide was 0.11 ± 0.012
mg/mL and the time to reach the peak was 36 ±
6 hours. Following chronic administration of a extended-release dose of carbamazepine
(800 mg every 12 hours), the peak levels of carbamazepine-10, 11-epoxide were
2.2 ± 0.9 mg/mL and
the time to reach the peak was 14 ± 8 hours.
The plasma half-life of carbamazepine-10, 11-epoxide following administration
of carbamazepine is 34 ± 9 hours. Following
a single oral dose of extended-release carbamazepine (200-800 mg) the AUC and
Cmax of carbamazepine-10, 11-epoxide were less than 10% of carbamazepine.
Following multiple dosing of extended-release carbamazepine (800-1600 mg daily
for 14 days), the AUC and Cmax of carbamazepine-10, 11-epoxide were
dose related, ranging from 15.7 mg·
hr/mL and 1.5 mg/mL at 800 mg/day to 32.6 mg·
hr/mL and 3.2 mg/mL at 1600 mg/day, respectively,
and were less than 30% of carbamazepine. Carbamazepine-10, 11-epoxide is 50%
bound to plasma proteins.
Food Effect: A high fat meal diet increased the rate of absorption of
a single 400 mg dose (mean Tmax was reduced from 24 hours, in the
fasting state, to 14 hours and Cmax increased from 3.2 to 4.3 mg/mL)
but not the extent (AUC) of absorption. The elimination half-life remains unchanged
between fed and fasting state. The multiple dose study conducted in the fed
state showed that the steady-state Cmax values were within the therapeutic
concentration range. The pharmacokinetic profile of extended-release carbamazepine
was similar when given by sprinkling the beads over applesauce compared to the
intact capsule administered in the fasted state.
Hepatic Dysfunction: The effect of hepatic impairment on the pharmacokinetics
of carbamazepine is not known. However, given that carbamazepine is primarily
metabolized in the liver, it is prudent to proceed with caution in patients
with hepatic dysfunction.
Renal Dysfunction: The effect of renal impairment on the pharmacokinetics
of carbamazepine is not known.
Gender: No difference in the mean AUC and Cmax of carbamazepine
and carbamazepine-10, 11-epoxide was found between males and females.
Age: Carbamazepine is more rapidly metabolized to carbamazepine-10,
11-epoxide in young children than adults. In children below the age of 15, there
is an inverse relationship between CBZ-E/CBZ ratio and increasing age.
Race: No information is available on the effect of race on the pharmacokinetics
General: 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 patient with epilepsy may lead to seizures
or even status epilepticus with its life-threatening hazards.
The most severe adverse reactions previously observed with carbamazepine were
reported in the hemopoietic system (see BOX 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 lowest dosage recommended.
The following additional adverse reactions were previously reported with carbamazepine:
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
(Lyells 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
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
Testicular atrophy occurred in rats receiving carbamazepine orally from 4-52
weeks at dosage levels of 50-400 mg/kg/day. Additionally, rats receiving carbamazepine
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/day 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 carbamazepine 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 carbamazepine, nor
is there evidence of psychological or physical dependence in humans.
Clinically meaningful drug interactions have occurred with concomitant medications
and include, but are not limited to the following:
Agents Highly Bound to Plasma Protein
Carbamazepine is not highly bound to plasma proteins; therefore, administration
of CarbatrolÒ to a patient taking another drug
that is highly protein bound should not cause increased free concentrations
of the other drug.
Agents that Inhibits Cytochrome P450 Isoenzymes and/or Epoxide Hydrolase
Carbamazepine is metabolized mainly by cytochrome P450 (CYP) 3A4 to the active
carbamazepine 10, 11-epoxide, which is further metabolized to the trans-diol
by epoxide hydrolase. Therefore, the potential exists for interaction between
carbamazepine and any agent that inhibits CYP3A4 and/or epoxide hydrolase. Agents
that are CYP3A4 inhibitors that have been found, or are expected, to increase
plasma levels of CarbatrolÒ are the following:
Acetazolamide, azole antifungals, cimetidine, clarithromycin(1),
dalfopristin, danazol, delavirdine, diltiazem, erythromycin(1), fluoxetine,
fluvoxamine, grapefruit juice, isoniazid, itraconazole, ketoconazole, loratadine,
nefazadone, niacinamide, nicotinamide, protease inhibitors, propoxyphene, quinine,
quinupristin, troleandomycin, valproate(1), verapamil, zileuton.
(1)also inhibits epoxide hydrolase resulting in increased levels
of the active metabolite carbamazepine 10, 11- epoxide
Thus, if a patient has been titrated to a stable dosage of CarbatrolÒ,
and then begins a course of treatment with one of these CYP3A4 or epoxide hydrolase
inhibitors, it is reasonable to expect that a dose reduction for CarbatrolÒ
may be necessary.
Agents that Induce Cytochrome P450 Isoenzymes
Carbamazepine is metabolized by CYP3A4. Therefore, the potential exists for
interaction between carbamazepine and any agent that induces CYP3A4. Agents
that are CYP inducers that have been found, or are expected, to decrease plasma
levels of CarbatrolÒ are the following:
Cisplastin, doxorubicin HCL, felbamate, rifampin, phenobarbital, phenytoin(2),
primidone, methsuximide, and theophylline
(2)Phenytoin plasma levels have also been reported to increase
and decrease in the presence of carbamazepine, see below.
Thus, if a patient has been titrated to a stable dosage on CarbatrolÒ,
and then begins a course of treatment with one of these CYP3A4 inducers, it
is reasonable to expect that a dose increase for CarbatrolÒ
may be necessary.
Agents with Decreased Levels in the Presence of Carbamazepine due to Induction
of Cytochrome P450 Enzymes
Carbamazepine is known to induce CYP1A2 and CYP3A4. Therefore, the potential
exists for interaction between carbamazepine and any agent metabolized by one
(or more) of these enzymes. Agents that have been found, or are expected to
have decreased plasma levels in the presence of CarbatrolÒ
due to induction of CYP enzymes are the following:
Acetaminophen, alprazolam, amitriptyline, bupropion, buspirone, citalopram,
clobazam, clonazepam, clozapine, cyclosporin, delavirdine, desipramine, diazepam,
dicumarol, doxycycline, ethosuximide, felbamate, felodipine, glucocorticoids,
haloperidol, itraconazole, lamotrigine, levothyroxine, lorazepam, methadone,
midazolam, mirtazapine, nortriptyline, olanzapine, oral contraceptives(3),
oxcarbazepine, phenytoin(4), praziquantel, protease inhibitors, quetiapine,
risperidone, theophylline, topiramate, tiagabine, tramadol, triazolam, valproate,
warfarin(5), ziprasidone, and zonisamide.
(3)Break through bleeding has been reported among patients receiving
concomitant oral contraceptives and their reliability may be adversely affected.
(4)Phenytoin has also been reported to increase in the presence
of carbamazepine. Careful monitoring of phenytoin plasma levels following
co-medication with carbamazepine is advised.
(5)Warfarins anticoagulant effect can be reduced in the presence
Thus, if a patient has been titrated to a stable dosage on one of the agents
in this category, and then begins a course of treatment with CarbatrolÒ,
it is reasonable to expect that a dose increase for the concomitant agent may
Agents with Increased Levels in the Presence of Carbamazepine
CarbatrolÒ increases the plasma levels of the
Clomipramine HCl, phenytoin(6), and primidone
(6)Phenytoin has also been reported to decrease in the presence
of carbamazepine. Careful monitoring of phenytoin plasma levels following
co-medication with carbamazepine is advised.
Thus, if a patient has been titrated to a stable dosage on one of the agents
in this category, and then begins a course of the treatment with CarbatrolÒ,
it is reasonable to expect that a dose decrease for the concomitant agent may
Pharmacological/Pharmacodynamic Interactions with Carbamazepine
Concomitant administration of carbamazepine and lithium may increase the risk
of neurotoxic side effects.
Given the anticonvulsant properties of carbamazepine, CarbatrolÒ
may reduce the thyroid function as has been reported with other anticonvulsants.
Additionally, anti-malarial drugs, such as chloroquine and mefloquine, may antagonize
the activity of carbamazepine.
Thus if a patient has been titrated to a stable dosage on one of the agents
in this category, and then begins a course of treatment with CarbatrolÒ,
it is reasonable to expect that a dose adjustment may be necessary.
Because of its primary CNS effect, caution should be used when CarbatrolÒ
is taken with other centrally acting drugs and alcohol.
Patients should be made aware that Carbatrol contains carbamazepine and should
not be used in combination with any other medications containing carbamazepine.
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. The prescribing physician will wish to weigh the benefits of therapy
against the risks in treating or counseling women of childbearing potential.
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
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.
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/m2 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 current accepted procedures should be considered
a part of routine prenatal care in childbearing women receiving carbamazepine.
Patients with a history of adverse hematologic reaction to any drug may be
particularly at risk.
Severe dermatologic reactions, including toxic epidermal necrolysis (Lyells
syndrome) and Stevens-Johnson syndrome have been reported with carbamazepine.
These reactions have been extremely rare. However, a few fatalities have been
In patients with seizure disorder, carbamazepine should not be discontinued
abruptly because of the strong possibility of precipitating status epilepticus
with attendant hypoxia and threat to life.
Carbamazepine 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 considered.
Co-administration of carbamazepine and delavirdine may lead to loss of virologic
response and possible resistance to PRESCRIPTOR or to the class of non-nucleoside
reverse transcriptase inhibitors.
Before initiating therapy, a detailed history and physical examination should
Carbamazepine should be used with caution in patients with a mixed seizure
disorder that includes atypical absence seizures, since in these patients carbamazepine
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 carbamazepine.
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.
Increases in total cholesterol, LDL and HDL have been observed in some patients
taking anticonvulsants. Therefore, periodic evaluation of these parameters is
Monitoring of blood levels (see 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
Thyroid function tests have been reported to show decreased values with carbamazepine
Hyponatremia has been reported in association with carbamazepine use, either
alone or in combination with other drugs.
Interference with some pregnancy tests has been reported.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Administration of carbamazepine to Sprague-Dawley rats for two years in the
diet at doses of 25, 75, and 250 mg/kg/day (low dose approximately 0.2 times
the maximum human daily dose of 1200 mg on a mg/m2 basis), 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)
Labor and Delivery
The effect of carbamazepine on human labor and delivery is unknown.
Carbamazepine and its epoxide metabolite are transferred to breast milk and
during lactation. The concentrations of carbamazepine and its epoxide metabolite
are approximately 50% of the maternal plasma concentration. 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.
Substantial evidence of carbamazepine 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 pathogenic 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
Taken as a whole, this information supports a conclusion that the generally
acceptable therapeutic range of total carbamazepine in plasma (i.e., 4-12 mg/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.
No systematic studies in geriatric patients have been conducted.
Lowest known lethal dose: adults, >60 g (39-year-old man). 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,
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
Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates,
or hydantoins are taken at the same time, the signs and symptoms of acute poisoning
with carbamazepine may be aggravated or modified.
For the most up to date information on management of carbamazepine overdose,
please contact the poison center for your area by calling 1-800-222-1222. The
prognosis in cases of carbamazepine poisoning is generally favorable. Of 5,645
cases of carbamazepine exposures reported to US poison centers in 2002, a total
of 8 deaths (0.14% mortality rate) occurred. Over 39% of the cases reported
to these poison centers were managed safely at home with conservative care.
Successful management of large or intentional carbamazepine exposures requires
implementation of supportive care, frequent monitoring of serum drug concentrations,
as well as aggressive but appropriate gastric decontamination.
Elimination of the Drug: The primary method for gastric decontamination
of carbamazepine overdose is use of activated charcoal. For substantial recent
ingestions, gastric lavage may also be considered. Administration of activated
charcoal prior to hospital assessment has the potential to significantly reduce
drug absorption. There is no specific antidote. In overdose, absorption of carbamazepine
may be prolonged and delayed. More than one dose of activated charcoal may be
beneficial in patients that have evidence of continued absorption (e.g., rising
serum carbamazepine levels).
Measures to Accelerate Elimination
The data on use of dialysis to enhance elimination in carbamazepine is scarce.
Dialysis, particularly high flux or high efficiency hemodialysis, may be considered
in patients with severe carbamazepine poisoning associated with renal failure
or in cases of status epilepticus, or where there are rising serum drug levels
and worsening clinical status despite appropriate supportive care and gastric
decontamination. For severe cases of carbamazepine overdose unresponsive to
other measures, charcoal hemoperfusion may be used to enhance drug clearance.
Respiratory Depression: Keep the airways free; resort, if necessary,
to endotracheal intubation, artificial respiration, and administration of oxygen.
Hypotension, Shock: Keep the patients 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.
Carbamazepine 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 and nortriptyline. Likewise, on theoretical grounds its use with
monoamine oxidase inhibitors is not recommended. Before administration of carbamazepine,
MAO inhibitors should be discontinued for a minimum of 14 days, or longer if
the clinical situation permits.