Carbamazepine

Brand names: Carbamazepine (Chewable), CarbamazepineER, Carbatrol, EQUETRO, Epitol, Tegretol, TegretolXR, Carbamazepine, CARBAMAZEPINE, carbamazepine, CARBAMAZEPINE ER, Carbamazepine ER, Tegretol XR, Carbamazepin

Boxed warning

WARNINGS SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENT WITH CARBAMAZEPINE. THESE REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH CARBAMAZEPINE. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH CARBAMAZEPINE UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS, LABORATORY TESTS ). APLASTIC ANEMIA AND AGRANULOCYTOSIS 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 TO 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 carbamazepine, 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.

Warnings

BOXED WARNING: Serious dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), occurring at an estimated rate of 1-6 per 10,000 new users in Caucasian populations but about 10 times higher in some Asian countries, particularly linked to the HLA-B*1502 allele; and aplastic anemia and agranulocytosis, with risk "5 to 8 times greater than in the general population," though overall incidence remains low. Other major warnings/contraindications: history of bone marrow depression; hypersensitivity to carbamazepine or tricyclic compounds; concurrent use with MAO inhibitors (discontinue ≥14 days before starting) or nefazodone; increased suicidal ideation risk with antiepileptic drugs; hepatic porphyria history; and Pregnancy Category D fetal risk.

Contraindications

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 (MAO) 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. Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated.

Overdose

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). Oral LD 50 in animals (mg/kg): mice, 1,100 to 3,750; rats, 3,850 to 4,025; rabbits, 1,500 to 2,680; guinea pigs, 920. Signs and Symptoms The first signs and symptoms appear after 1 to 3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (greater than 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 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. Convulsion: 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) 59 Fe-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 A 2 and F hemoglobin, and (7) serum folic acid and B 12 levels. A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultation should be sought.

Drug interactions

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 ® * solution. Subsequent testing has shown that mixing tegretol suspension and chlorpromazine solution (both generic and brand name) as well as carbamazepine suspension and liquid Mellaril ® , 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:

Uses

Indicated for: - Epilepsy, including partial seizures with complex symptomatology, generalized tonic-clonic seizures, and mixed seizure patterns ("absence seizures (petit mal) do not appear to be controlled by carbamazepine") - Trigeminal neuralgia and glossopharyngeal neuralgia pain, with the label stating the drug "is not a simple analgesic and should not be used for the relief of trivial aches or pains."

Dosage forms & strengths

Capsule, Extended Release Tablet Tablet, Chewable Tablet, Extended Release POWDER TABLET TABLET, EXTENDED RELEASE SUSPENSION CAPSULE, EXTENDED RELEASE TABLET, FILM COATED, EXTENDED RELEASE TABLET, CHEWABLE

CARBAMAZEPINE 100 mg CARBAMAZEPINE 200 mg CARBAMAZEPINE 300 mg CARBAMAZEPINE 400 mg Carbamazepine 100 mg Carbamazepine 200 mg Carbamazepine 300 mg Carbamazepine 400 mg CARBAMAZEPINE 1 kg/kg CARBAMAZEPINE 200 mg/1 CARBAMAZEPINE 100 mg/1 CARBAMAZEPINE 100 mg/5mL CARBAMAZEPINE 400 mg/1 CARBAMAZEPINE 300 mg/1 CARBAMAZEPINE 1 g/g CARBAMAZEPINE 150 kg/150kg CARBAMAZEPINE 25 kg/25kg CARBAMAZEPINE 200 mg/10mL

DOSAGE AND ADMINISTRATION (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. Epilepsy (see INDICATIONS AND USAGE ) Adults and children over 12 years of age-Initial: 200 mg twice a day for tablets (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a three times a day or four times a day regimen of carbamazepine tablets until the optimal response is obtained. Dosage generally should not exceed 1,000 mg daily in children 12 to 15 years of age, and 1,200 mg daily in patients above 15 years of age. Doses up to 1,600 mg daily have been used in adults in rare instances. Maintenance : Adjust dosage to the minimum effective level, usually 800 to 1,200 mg daily. Children 6 to 12 years of age-Initial: 100 mg twice a day for tablets (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a three times a day or four times a day regimen of carbamazepine tablets until the optimal response is obtained. Dosage generally should not exceed 1,000 mg daily. Maintenance : Adjust dosage to the minimum effective level, usually 400 to 800 mg daily. Children under 6 years of age-Initial: 10 to 20 mg/kg/day twice a day or three times a day as tablets. Increase weekly to achieve optimal clinical response administered three times a day or four times a day. 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: 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 (see PRECAUTIONS , Drug Interactions , and Pregnancy ). Trigeminal Neuralgia (see INDICATIONS AND USAGE ) Initial: On the first day, 100 mg twice a day for tablets 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, only as needed to achieve freedom from pain. Do not exceed 1,200 mg daily. Maintenance: Control of pain can be maintained in most patients with 400 to 800 mg daily. However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 1,200 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. Dosage Information for Tablets Indication Initial Dose Subsequent Dose Maximum Daily Dose Epilepsy Under 6 yr 10 to 20 mg/kg/day twice a day or 3 times a day Increase weekly to achieve optimal clinical response, 3 times a day or 4 times a day 35 mg/kg/24 hr (see Dosage and Administration section above) 6 to 12 yr 100 mg twice a day (200 mg/day) Add up to 100 mg/day at weekly intervals, 3 times a day or 4 times a day 1,000 mg/24 hr Over 12 yr 200 mg twice a day (400 mg/day) Add up to 200 mg/day at weekly intervals, 3 times a day or 4 times a day 1,000 mg/24 hr (12 to 15 yr) 1,200 mg/24 hr (>15 yr) 1,600 mg /24 hr (adults, in rare instances) Trigeminal Neuralgia 100 mg twice a day (200 mg/day) Add up to 200 mg/day in increments of 100 mg every 12 hr 1,200 mg/24 hr

All identified pills

109 TEVA

WHITE ROUND · Carbamazepine

8 manufacturers

143