WARNINGS
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 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.
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.
General
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 carbamazepine.
These reactions have been extremely rare. However, a few fatalities have been
reported.
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.
PRECAUTIONS
General
Before initiating therapy, a detailed history and physical
examination should be made.
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.
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.
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 non-prescription
medication or herbal products.
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.
Increases in total cholesterol, LDL and HDL have been observed in some
patients taking anticonvulsants. Therefore, periodic evaluation of these
parameters is also recommended.
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 being used.
Thyroid function tests have been reported to show decreased values with
carbamazepine administered alone.
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.
Drug Interactions
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 Carbatrol® 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 Carbatrol® 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 Carbatrol®, 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 Carbatrol® 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 Carbatrol® are the following:
Cisplatin, 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 Carbatrol®, and
then begins a course of treatment with one of these CYP3A4 inducers, it is
reasonable to expect that a dose increase for Carbatrol® 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 Carbatrol® 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, trazodone(5), valproate, warfarin(6), 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)Following co-administration of carbamazepine
400mg/day with trazodone 100mg to 300mg daily, carbamazepine reduced trough
plasma concentrations of trazodone (as well as meta-chlorophenylpiperazine
[mCPP]) by 76 and 60% respectively, compared to precarbamazepine values.
(6)Warfarin’s anticoagulant effect can be reduced in
the presence 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 Carbatrol®, it is
reasonable to expect that a dose increase for the concomitant agent may be
necessary.
Agents with Increased Levels in the
Presence of Carbamazepine:
Carbatrol® increases the plasma levels of the following
agents:
Clomipramine HCl, phenytoin(7),
and primidone
(7)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 Carbatrol®, it
is reasonable to expect that a dose decrease for the concomitant agent may be
necessary.
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, Carbatrol® 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 Carbatrol®, it is
reasonable to expect that a dose adjustment may be necessary.
Because of its primary CNS effect, caution should be used when Carbatrol® is
taken with other centrally acting drugs and alcohol.
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.
Nursing Mothers
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.
Pediatric Use
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 children.
Taken as a whole, this information supports a conclusion that the generally
acceptable therapeutic range of total carbamazepine in plasma (i.e., 4-12 μg/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.
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