WARNINGS
Patients should be made aware that EQUETROTM 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 a human daily dosage of 1200 mg on a mg/kg basis or 1.5-4 times the human daily dosage 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.
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 RESCRIPTOR or to the class of non-nucleoside reverse transcriptase inhibitors.
PRECAUTIONS
General
Before initiating therapy, a detailed history and physical examination should be made.
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.
Suicide: The possibility of suicide attempt is inherent in Bipolar Disorder and close supervision of high risk patients should accompany drug therapy. Prescriptions for EQUETROTM should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose.
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 EQUETROTM capsules can be opened and the contents sprinkled over food, such as a teaspoon of applesauce or other similar food products. EQUETROTM capsules or their contents should not be crushed or chewed.
EQUETROTM 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 ) may be useful for verification of drug compliance, assessing safety and determining the cause of toxicity including 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 EQUETROTM to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.
Agents that Inhibit 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 EQUETROTM are the following:
Acetazolamide, azole antifungals, cimetidine, clarithromycin(1), dalfopristin, danazol, delavirdine, diltiazem, erythromycin(1), fluoxetine, fluvoxamine, grapefruit juice, isoniazid, itraconazole, ketoconazole, loratadine, nefazodone, 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 EQUETROTM, 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 EQUETROTM 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 EQUETROTM 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 EQUETROTM, and then begins a course of treatment with one of these CYP3A4 inducers, it is reasonable to expect that a dose increase for EQUETROTM 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 EQUETROTM 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 400 mg/day with trazodone 100 mg to 300 mg daily, carbamazepine reduced the plasma concentration of trazodone (as well as meta-chlorophenylpiperazine [mCPP]) by 76 and 60% respectively, compared to pre-carbamazepine 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 EQUETROTM, 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:
EQUETROTM 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 EQUETROTM, 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, EQUETROTM 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 EQUETROTM, it is reasonable to expect that a dose adjustment may be necessary.
Because of its primary CNS effect, caution should be used when EQUETROTM 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 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. 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:
The safety and effectiveness of EQUETROTM in pediatric and adolescent patients have not been established.
Geriatric Use:
No systematic studies in geriatric patients have been conducted.
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