Carbamazepine

Brand Names: Tegretol, Epitol, Atretol

outside U.S., Brand Names also known as: Apo-Carbamazepine; Camapine; Carbadac; Carbagamma; Carbatol; Carbazene; Carbazep; Carbazina; Carbazine; Carmaz; Carmine; Carmine CR; Carpaz; Carzepin; Carzepine; Convuline; Degranol; Eleptin; Epileptol; Epileptol CR; Foxalepsin; Foxalepsin Retard; Hermolepsin; Karbamazepin; Kodapan; Lexin; Macrepan; Mazepine; Mazetol; Neugeron; Neurotol; Neurotop; Neurotop Retard; Nordotol; Panitol; Sirtal; Tardotol; Taver; Tegol; Tegretal; Tegretol CR; Tegretol-S; Telesmin; Temporol; Temporal Slow; Teril; Timonil; Timonil Retard; Zeptol

Description

Carbamazepine (Epitol, Tegretol, Atretol) given as a monotherapy or in combination with lithium or neuroleptics has been found useful in the treatment of acute mania and the prophylactic treatment of bipolar (manic-depressive) disorders.

Carbamazepine is an anticonvulsant and specific analgesic for trigeminal neuralgia.

Pharmacology

In controlled clinical trials, carbamazepine (Tegretol, Epitol, Atretol) has been shown to be effective in the treatment of psychomotor and grand mal seizures, as well as trigeminal neuralgia.

Carbamazepine relieves or diminishes the pain associated with trigeminal neuralgia often within 24 to 48 hours.

Like other tricyclic compounds, carbamazepine has a moderate anticholinergic action which is responsible for some of its adverse effects. A tolerance may develop to the action of carbamazepine after a few months of treatment and should be watched for.

Carbamazepine may suppress ventricular automaticity due to its membrane-depressant effect. A number of investigators have reported a deterioration of EEG abnormalities during carbamazepine-combined treatment.

When taken in a single oral dose, the carbamazepine tablets and chewable tablets yield peak plasma concentrations within 4 to 24 hours.

Indications and Usage

Trigeminal Neuralgia: Carbamazepine 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.

Treatment of Acute Mania and Prophylaxis in Bipolar (Manic-Depressive) Disorders: Carbamazepine may be used as a monotherapy or as an adjunct to lithium in the treatment of acute mania or prophylaxis of bipolar (manic-depressive) disorders in patients who are resistant to or are intolerant of conventional antimanic drugs. Carbamazepine may be a useful alternative to neuroleptics in such patients. Patients with severe mania, dysphoric mania or rapid cycling who are non-responsive to lithium may show a positive response when treated with carbamazepine.

It is important to note that these recommendations are based on extensive clinical experience and some clinical trials versus active comparison agents.

Epilepsy: Carbamazepine 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:

Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement than those with other types.
Generalized tonic-clonic seizures (grand mal).
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.

Contraindications

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, nortriptyline, etc. 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 fourteen days, or longer if the clinical situation permits.

Carbamazepine should not be administered to patients with known hypersensitivity to carbamazepine or to any of the tricyclic compounds, such as amitriptyline, trimipramine, imipramine, or their analogues or metabolites, because of the similarity in chemical structure.

Warnings

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 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 carbamazepine. These reactions have been extremely rare. However, a few fatalities have been reported.

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 borne in mind.

Usage in Pregnancy & Nursing

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. Carbamazepine 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.

Carbamazepine passes into breast milk in concentrations of about 25 to 60% of the plasma level. No reports are available on the long-term effect of breast-feeding. The benefits of breast-feeding should be weighed against the possible risks to the infant. Should the mother taking carbamazepine nurse her infant, the infant must be observed for possible adverse reactions, e.g. somnolence.

Precautions

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.

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.

Since a given dose of carbamazepine 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.

Long-term toxicity studies in rats indicated a potential carcinogenic risk. Therefore, the possible risk of drug use must be weighed against the potential benefits before prescribing carbamazepine to individual patients.

Information for the Patient
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.

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.

Pediatric Use
Safety and effectiveness in children below the age of 6 years have not been established.

Drug Interactions

The simultaneous administration of phenobarbital, phenytoin, or primidone, or a combination of two, produces a marked lowering of serum levels, of carbamazepine. The effect of valproic acid on carbamazepine blood levels is not clearly established, although an increase in the ratio of active 10, 11-epoxide metabolite to parent compound is a consistent finding.

The half-lives of phenytoin, warfarin, doxycycline, and theophylline were significantly shortened when administered concurrently with carbamazepine. Haloperidol and valproic acid serum levels may be reduced when these drugs are administered with carbamazepine. The doses of these drugs may therefore have to be increased when carbamazepine is added to the therapeutic regimen.

Concomitant administration of carbamazepine with erythromycin, cimetidine, propoxyphene, isoniazid, fluoxetine or calcium channel blockers has been reported to result in elevated plasma levels of carbamazepine resulting in toxicity in some cases. Also 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.

Taking carbamazepine while you are taking birth control pills may decrease the effectiveness of your birth control pills. To prevent pregnancy, use an additional form of birth control.

BEFORE USING THIS MEDICINE: INFORM YOUR DOCTOR OR PHARMACIST of all prescription and over-the-counter medicine that you are taking. This includes diltiazem, lamotrigine, anticoagulants, clozapine, cyclosporine, haloperidol, male hormones, isoniazid, lithium, propoxyphene, antibiotics, corticosteroids, fluoxetine, verapamil, and medicines used to treat seizures and depression. Inform your doctor of any other medical conditions including heart conditions, anemia or blood disorders, allergies, pregnancy, or breast-feeding.

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 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.

This medicine may cause increased sensitivity to the sun. Avoid exposure to the sun, sunlamps, or tanning booths until you know how you react to this medicine. Use a sunscreen or protective clothing if you must be outside for a prolonged period.

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), Stevens-Johnson syndrome, 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, primary thrombophlebitis, recurrence of thrombophlebitis, 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.

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, elevated BUN and microscopic deposits in the urine have also been reported. Testicular atrophy occurred in rats receiving carbamazepine orally from 4 to 52 weeks at dosage levels of 50 to 400 mg/kg/day. Additionally, rats receiving carbamazepine in the diet for two 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.

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.

Other: Isolated cases of 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.

Drug Abuse & Dependence
No evidence of abuse potential has been associated with carbamazepine, nor is there evidence of psychological or physical dependence in humans.

Overdose

Signs and Symptoms

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).

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 (>60g) 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 carbamazepine 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 on 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.

Dosage

HOW TO USE THIS MEDICINE:

DO NOT EXCEED THE RECOMMENDED DOSE or take this medicine for longer than prescribed. Exceeding the recommended dose or taking this medicine for longer than prescribed may be habit forming.

Follow the directions for using this medicine provided by your doctor.
Take this medicine with food or milk.
Store this medicine at room temperature, away from heat and light.
If you miss a dose of this medicine, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.
Do not stop taking this medicine without first checking with your doctor.

Additional Information: Do not share this medicine with others for whom it was not prescribed. Do not use this medicine for other health conditions. Keep this medicine out of the reach of children.

Epilepsy

Adults And Children Over 12 Years Of Age

Initial: Either 200 mg twice a day for tablets and extended release tablets or 1 teaspoon four times a day for suspension (400 mg per day). Increase at weekly intervals by adding up to 200 mg per day using a twice a day regimen of extened release or three times a day or four times a day regimen until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily in children 12 to 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 twice a day for tablets or 1/2 teaspoon four times a day for suspension (200 mg per day). Increase at weekly intervals by adding up to 100 mg per day using a three times a day or four times a day regimen until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily.

Maintenance: Adjust dosage to the minimum effective level, usually 400-800 mg daily.

Combination Therapy: Carbamazepine 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.

Trigeminal Neuralgia

Initial: On the first day, either 100 mg twice a day for tablets or 1/2 teaspoon four times a day for suspension for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg a day using increments of 100 mg every 12 hours for tablets or 50 mg (1/2 teaspoon) four times a day 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 mg to 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.

Mania and Bipolar (Manic-Depressive) Disorders:
The initial daily dosage should be low, 200 to 400 mg/day, administered in divided doses, although higher starting doses of 400 to 600 mg/day may be used in acute mania. This dose may be gradually increased until patient symptomatology is controlled or a total daily dose of 1600 mg is achieved. Increments in dosage should be adjusted to provide optimal patient tolerability. The usual dose range is 400 to 1200 mg/day administered in divided doses. Doses used to achieve optimal acute responses and tolerability should be continued during maintenance treatment. When given in combination with lithium and neuroleptics, the initial dosage should be low, 100 to 200 mg daily, and then increased gradually. A dose higher than 800 mg/day is rarely required when given in combination with neuroleptics and lithium, or with other psychotropic drugs such as benzodiazepines. Plasma levels are probably not helpful for guiding therapy in bipolar disorders.

IF USING THIS MEDICINE FOR AN EXTENDED PERIOD OF TIME, obtain refills before your supply runs out.

How Supplied

200 mg tablet, chewable tablets 200 mg, CR 200 mg & 400 mg

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The information in this monograph is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects. This information is generalized and is not intended as specific medical advice. If you have questions about the medicines you are taking or would like more information, check with your doctor, pharmacist, or nurse.