Apo-Carbamazepine

Apo-Carbamazepine

carbamazepine

Manufacturer:

Apotex

Distributor:

Pharmaforte
Full Prescribing Info
Contents
Carbamazepine.
Description
Each tablet contains: Carbamazepine USP 200mg. Energy <1 kJ (0.18 kcal)/tablet. Gluten and Tartrazine-free.
Action
Pharmacology: Carbamazepine has anticonvulsant properties which are useful in the treatment of psychomotor and other partial epilepsies when administered in conjunction with other anticonvulsant drugs to prevent the possible generalization of the epileptic discharge. A mild psychotropic effect has been observed in some patients. It seems related to the effect of carbamazepine in psychomotor or temporal lobe epilepsy.
Carbamazepine relieves or diminishes the pain associated with trigeminal neuralgia, often within 24 or 48 hours.
Like other tricyclic compounds, carbamazepine has a moderate anticholinergic action responsible for some of its side effects.
Watch for a tolerance to the action of carbamazepine which may develop after a few months of treatment.
A number of investigators have reported a deterioration of EEG abnormalities with regard to local alteration and higher incidence of records with nil beta activity during carbamazepine-combined treatment.
Ventricular automaticity may be suppressed by carbamazepine because of its membrane depressant effect associated with suppression of phase 4 depolarization of the heart muscle fibre.
The absorption and elimination of carbamazepine in humans in relatively slow. After a single-dose, oral administration of 400mg carbamazepine, peak plasma levels of 35 to 55 kg/ml were obtained in about 6 hours. Plasma levels were virtually unchanged for a further 6 hours (12 hours after administration). The acute biological half of carbamazepine is 37 hours.
Pharmacogenomics: There is growing evidence of the role of different HLA alleles in predisposing patients to immune-mediated adverse reactions.
Association with HLA-B*1502: Retrospective studies in patients of Han Chinese ancestry and Thai origin found a strong correlation between Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) skin reactions associated with carbamazepine and the presence in these patients of the Human Leukocyte Antigen (HLA)-B*1502 allele. The frequency of HLA-B*1502 allele ranges from 2 to 12% in Han Chinese populations and is about 8% in Thai populations. Higher reporting rates of SJS (rare rather than very rare) are reported in some countries in Asia (e.g. Taiwan, Malaysia and the Philippines) in which there is a higher frequency of the HLA-B*1502 allele in the population (e.g. above 15% in the Philippines and some Malaysian populations). Allele frequencies up to about 2%, 6% and 12% have been reported in Korea, India and Singapore, respectively. The frequency of the HLA-B*1502 allele is negligible in persons of European descent, several African populations, indigenous peoples of the Americas, Hispanic populations sampled and in Japanese (<1%).
The allele frequencies listed here represent the percentage of chromosomes in the specified population that carry the allele of interest, meaning that the percentage of patients who carry a copy of the allele on at least one of their two chromosomes (i.e., the "carrier frequency") is nearly twice as high as the allele frequency. Therefore, the percentage of patients who may be at risk is nearly twice the allele frequency.
Testing for the presence of HLA-B*1502 allele is highly recommended prior to the initiation of carbamazepine therapy in new patients of Asian ancestry (see Information for the healthcare professionals as follows). The use of carbamazepine should be avoided in tested patients who are found to be positive for HLA-B*1502 unless the benefits clearly outweigh the risks. HLA-B*1502 may be a risk factor for the development of SJS/TEN in Chinese patients taking other anti-epileptic drugs (AED) associated with SJS/TEN. Consideration should therefore be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable. Screening is not generally recommended in patients from populations in which the prevalence of HLA-B*1502 is low, e.g. in Caucasian. Screening is generally not recommended for any current carbamazepine users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLAB* 1502 status.
The identification of subjects carrying the HLA-B*1502 allele and the avoidance of carbamazepine therapy in these subjects has been shown to decrease the incidence of carbamazepine-induced SJS/TEN.
Association with HLA-A*3101: Human Leukocyte Antigen (HLA)-A*3101 may be a risk factor for the development of cutaneous adverse drug reactions such as SJS, TEN, DRESS, AGEP and maculopapular rash. Retrospective genome-wide studies in Japanese and Northern European populations reported association between severe skin reactions (SJS, TEN, DRESS, AGEP and maculopapular rash) associated with carbamazepine use and the presence of the HLA-A*3101 allele in these patients.
The frequency of the HLA-A*3101 allele varies widely between ethnic populations and its frequency is about 2 to 5% in European populations and about 10% in the Japanese population. The frequency of this allele is estimated to be less than 5% in the majority of Australian, Asian, African and North American populations with some exceptions within 5-12%. Prevalence above 15% has been estimated in some ethnic groups in South America (Argentina and Brazil), North America (US Navajo and Sioux, and Mexico Sonora Seri) and Southern India (Tamil Nadu) and between 10%-15% in other native ethnicities in these same regions.
The allele frequencies listed here represent the percentage of chromosomes in the specified population that carry the allele of interest, meaning that the percentage of patients who carry a copy of the allele on at least one of their two chromosomes (i.e., the "carrier frequency") is nearly twice as high as the allele frequency. Therefore, the percentage of patients who may be at risk is nearly twice the allele frequency.
Testing for the presence of HLA-A*3101 allele should be considered in patients with ancestry in genetically at-risk populations (for example, patients of the Japanese and Caucasian populations, patients who belong to the indigenous populations of the Americas, Hispanic populations, people of southern India, and people of Arabic descent), prior to initiating treatment with carbamazepine (see Information for the healthcare professionals as follows). The use of carbamazepine should be avoided in patients who are found to be positive for HLA-A*3101, unless the benefits clearly outweigh the risks. Screening is generally not recommended for any current carbamazepine users, as the risk of SJS/TEN, AGEP, DRESS and maculopapular rash is largely confined to the first few months of therapy, regardless of HLA-A*3101 status.
Limitation of genetic screening: Genetic screening results must never substitute for appropriate clinical vigilance and patient management. Many patients positive for HLA-B*1502 and treated with carbamazepine will not develop SJS/TEN. In populations in which HLA-B*1502 is common, these reactions rarely occur in HLA-B*1502-negative patients. Many patients positive for HLA-A*3101 and treated with carbamazepine will not develop SJS, TEN, DRESS, AGEP or maculopapular rash and patients negative for HLA-A*3101 of any ethnicity can still develop these severe cutaneous adverse reactions. The role of other possible factors in the development of, and morbidity from, these severe cutaneous adverse reactions, such as AED dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.
Information for the healthcare professionals: If testing for the presence of the HLA-B*1502 allele is performed, high-resolution "HLA-B*1502 genotyping" is recommended. The test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are detected. Similarly if testing for the presence of the HLA-A*3101 allele is performed, high-resolution "HLA-A*3101 genotyping" respectively is recommended. The test is positive if either one or two HLA-A*3101 alleles are detected and negative if no HLA-A*3101 alleles are detected.
Indications/Uses
Trigeminal Neuralgia: For the symptomatic relief of pain only during periods of exacerbation of true or primary trigeminal neuralgia (tic douloureux). It should not be used preventively during period of remission in some patients carbamazepine has relieved glossopharyngeal neuralgia. For patients who fail to respond to carbamazepine or who are sensitive to the drug, recourse to other accepted measures must be considered.
Carbamazepine is not a simple analgesic and should not be used to relieve trivial facial pain or headache.
Epilepsy: For the management of psychomotor (temporal lobe) epilepsy and as an adjunct in some patients with secondary or partial epilepsy with complex symptomatology or secondarily generalized seizures when administered in combination with other anti-epileptic medication.
Carbamazepine is essentially ineffective in controlling petit mal, minor motor, myoclonic and predominantly unilateral seizures. It does not prevent the generalization of epileptic discharge.
Dosage/Direction for Use
Epilepsy: A low initial daily dosage with a gradual increase in dosage is advised. Adjust dosage to the needs of the individual patient.
Initially, adults: 100 to 200mg once or twice a day depending upon the severity of the case and previous therapeutic history. The initial dosage is progressively increased until the best response is obtained, up to a maximum of 600mg daily. The usual optimal dosage is 600mg daily, but occasionally dosages up to 800 to 1000mg have been used for short periods. As soon as seizures disappear, reduce dosage very gradually until a minimum effective dose is reached.
Trigeminal Neuralgia: The initial daily dosage should be small 200mg, taken in two doses of 100mg each, is recommended. The total daily dosage can be increased by 200mg per day until relief of pain is obtained. This is usually achieved at a dosage between 200 and 800mg daily; occasionally up to 1200mg per day may be necessary. As soon as relief of pain has been obtained and maintained, attempt a progressive reduction in dosage until a minimum effective dosage is reached. Because trigeminal neuralgia is characterized by periods of remission, reduce or discontinue the use of carbamazepine at intervals of not more than 3 months depending upon the individual clinical course.
Prophylactic use of the drug in trigeminal neuralgia is not recommended. Administer carbamazepine in 2 or 3 divided doses daily, with meals whenever possible.
Overdosage
Symptoms: Dizziness, ataxia, drowsiness, stupor, nausea, vomiting, restlessness, agitation, disorientation, tremor, involuntary movements, opisthotones, abnormal reflexes (slowed or hyperactive): mydriasis, nystagmus, flushing, cyanosis and urinary retention.
Hypotension or hypertension may develop. Coma may ensue. The EEG may show dysthythmias. Laboratory findings in isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria and acetonuria.
Treatment: There is no known specific antidote to carbamazepine. Experience with accidental carbamazepine overdosage is limited. Since carbamazepine is chemically related to tricyclic antidepressant imipramine, reference to treatment of imipramine overdosage is relevant. Induce emesis and perform gastric lavage. Observe vital signs and administer symptomatic treatment as required. Hyperirritability may be controlled by the administration of parenteral barbiturates; however, barbiturates should not be used if drugs that inhibit MAO have also been taken by the patient, either overdosage or in recent therapy (within two weeks).
Barbiturates may also induce respiratory depression, particularly in children. Have equipment available for artificial ventilation and resuscitation when barbiturates are employed. Paraldehyde may be used to counteract muscular hypertonus without producing respiratory depression. Treat shock (circulatory collapse) with supportive measures including IV fluid, oxygen and corticosteroids. Monitor the EGG to detect any cardiac arrhythmias or conduction defects, particularly in children.
Contraindications
Should not be administered to patients with a history of hepatic disease or serious blood disorder.
Should not be administered immediately before in conjunction with, or immediately after administering a MAO inhibitor. When it seems desirable to administer carbamazepine to a patient who has been receiving a MAO Inhibitor, there should be as long a drug-free interval as the clinical condition will allow. In no case should this be less than 14 days. The dosage of Apo-Carbamazepine should be low initially and increases very gradually.
Patients presenting atrio-ventricular heart block should not be given carbamazepine.
Because of similarity of chemical structure, carbamazepine should not be administered to patients with a known hypersensitivity to any of the tricyclic compounds such as amitriptyline, trimipramine, imipramine, or their analogue or metabolites.
Warnings
Although reported infrequently, serious adverse effects have been observed during the use of carbamazepine. Agranulocytosis and aplastic anemia have occurred in a few instances with fatal outcome. Leukopenia thrombocytopenia and hepatocellular and cholestatic jaundice have also been reported. It is, therefore, important that carbamazepine be used carefully and close clinical and frequent laboratory supervision should be maintained throughout treatment in order to detect as early as possible signs and symptoms of a possible blood dyscrasia.
Carcinogenicity studies conducted in rats indicated a potential carcinogenic risk. Keep in mind the possible risks as well as the potential benefits before prescribing carbamazepine.
Special Precautions
Hematological and Other Adverse Reactions: Conduct complete blood studies, including platelet counts, and evaluation of hepatic and renal function and urinalysis before instituting treatment. Maintain careful clinical and laboratory supervision throughout treatment, including frequent performance of complete blood counts, in order to detect any early signs or symptoms of blood dyscrasia. Should any signs or symptoms or abnormal laboratory findings suggestive of blood dyscrasia or liver disorder occur, immediately discontinue use of carbamazepine until the case is carefully reassessed.
Urinary Retention and Increased Intraocular Pressure: Because of its anticholinergic action, give carbamazepine cautiously. If at all, to patients with increased intraocular pressure or urinary retention, follow such patients closely.
Behavioral Disorders: Because it is closely related to the other tricyclic drugs, there is some possibility that carbamazepine might activate a latent psychosis, or in elderly patients, produce agitation or confusion, especially when combined with other drugs. Exercise caution in use with alcoholics.
Cardiovascular Disorders: Use carbamazepine cautiously in patients with a history of coronary artery disease, organic heart disease, or congestive failure.
Perform an ECG before administering carbamazepine to exclude the possibility that the patient has an atrio-ventricular block whenever a defect in the conductive system is suspected.
Occupational hazards: Dizziness and drowsiness are possible side effects. Warn patients about possible hazards.
Oral Contraceptive Use: Efficacy of oral contraceptives may be diminished for patients being treated with carbamazepine. Advise patients to use an alternative non-steroidal contraceptive method.
Use In Pregnancy & Lactation
Safe use in pregnancy has not been established. Therefore, carbamazepine should not be administered during the first three months of pregnancy. Do not give to women of child-bearing potential unless, in the opinion of the physician, the expected benefits to the patients outweigh the possible risk to the fetus. Carbamazepine should not be administered to nursing mothers because of demonstrated toxicity in nursing animals.
Adverse Reactions
The most frequently reported are drowsiness, unsteadiness on the feet, vertigo/dizziness, gastrointestinal disturbance, and nausea. These reactions usually occur only during the initial phase of therapy. They rarely necessitate discontinuing carbamazepine therapy. Minimize reactions by initiating treatment at a low dosage.
Hematologic, hepatic, cardiovascular and dermatologic reactions are more serious and require discontinuance of therapy.
Hematological Reactions: Transitory leukopenia, eosinophilia, leukocytosis, thrombocytopenic purpura, agranulocytosis, macrocytic anemia and aplastic anemia. In a few instances, deaths have occurred.
Hepatic Disturbances: Abnormalities in liver function tests and cholestatic or hepatocellular jaundice during long term administration of carbamazepine.
Dermatological Reactions: Skin sensitivity reactions and rashes, erythematous rashes, pruritic eruptions, urticaria, photosensitivity, pigmentary changes, neurodermatitis and, in rare cases, Steven-Johnson syndrome, exfoliative dermatitis, alopecia, diaphoresis, erythema multiforms, erythema nodosum, and aggravation of disseminated lupus erythematosus.
Neurological Reactions: Reported reactions occurring during treatment with carbamazepine include vertigo, somnolence, disturbances of coordination, confusion, headache, fatigue, blurred vision, transient diplopia and oculomotor disturbances, speech disturbances, abnormal involuntary movements and increase in motor seizures. In addition, peripheral neuritis and paresthesia, depression with agitation, talkativeness, nystagmus, and tinnitus have been reported but only very rarely. There have been some reports of paralysis and other symptoms of cerebral arterial insufficiency, but no conclusive relationship to the administration of carbamazepine could be established.
Cardiovascular System: Recurrence of thrombophlebitis in patients with a prior history of thrombophlebitis, congestive heart failure, aggravation of hypertension. Stock's Adams in patients with AV block, hypotension, syncope and collapse, edema, aggravation of coronary artery disease. Some of these complications have resulted in fatalities. Other cardiovascular complication (including myocardial infarction and arrhythmia) have been associated with other tricyclic compounds. Whether all these complications are drug-related is not known at this time.
Genitourinary Reactions: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, and impotence, elevation of BUN, albuminuria, and glycosuria have also been observed.
Digestive Tract: Nausea, vomiting, gastric or abdominal discomfort, diarrhea, anorexia, dryness of mouth and throat, glossitis and stomatitis.
Eyes: No conclusive evidence that carbamazepine produced pathological changes in the cornea, lens or retina. However, many phenothiazines and related drugs have been shown to cause eye changes. Periodic eye examinations, including slit lamp fundoscopy and tonometry are recommended.
Other Reported Reactions: Fever and chills, lymphadenopathy, aching joints and muscles, leg cramps and conjunctivitis.
Drug Interactions
The following drug interactions and / or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parenthesis where appropriate) - not necessarily inclusive: Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Acetaminophen: Risk of hepatotoxicity with single toxic dose or prolonged use of high doses of acetaminophen may be increased, and therapeutic effects of acetaminophen may be decreased in patients taking hepatic enzyme-inducing agents such as carbamazepine.
Adrenocorticoids, glucocorticoid, and mineralocorticoid: Concurrent use may decrease the adrenocorticoid effect because of increased adrenocorticoid metabolism resulting from induction of hepatic microsomal enzymes.
Aminophylline or Oxtriphylline or Theophylline: Concurrent use with carbamazepine may stimulate hepatic metabolism of the xanthines (except dyphylline), resulting in increased theophylline clearance.
Anticoagulants, coumarin or indandione-derivative: Anticoagulant effects may be decreased because of induction of hepatic microsomal enzyme activity, resulting in increased anticoagulant metabolism leading to decreased anticoagulant serum concentration and elimination half-life; dosage adjustments based on monitoring of prothrombin time may be necessary during and after carbamazepine therapy.
Anticonvulsant, hydantoin or Anticonvulsant, succinimide or Barbiturate or Benzodiazepine metabolized via hepatic microsomal enzymes especially clonazepam or Primidone or Valproic acid: Concurrent use with carbamazepine may result in increased metabolism, leading to decreased serum concentrations and reduced elimination half-lives of these medications because of induction of hepatic microsomal enzyme activity; monitoring of blood concentrations as a guide to dosage is recommended, especially when any of these medications or carbamazepine is added to or withdrawn from existing regimen.
Valproic acid causes an increase in the active 10,11-epoxide metabolite of carbamazepine by inhibition of its breakdown product.
In addition, use of carbamazepine in combination with other anticonvulsant has been reported to be associated with an increased risk of congenital defects.
Antidepressants tricyclic or Haloperidol or Loxapine or Maprotiline or Molindone or Phenothiazide or Pimozide or Thioxanthenes: Concurrent use of these agents with carbamazepine may enhance the CNS depressant effects of Carbamazepine, lower the seizure threshold and decrease the anticonvulsant effect of carbamazepine; dosage adjustment may be necessary to control seizures; anticholinergic effects may be potentiated, leading to confusion and delirium.
Also, concurrent use of haloperidol, and possibly other neuroleptics with carbamazepine may decrease plasma concentration of the neuroleptic by about 60% with or without adverse clinical effects; close observation of patient for clinical signs of ineffectiveness of the neuroleptic is recommended; dosage adjustment may be necessary.
Carbonic anhydrase inhibitors: Concurrent use may increase the risk of carbamazepine-induced osteopenia; it is recommended that patients receiving concurrent therapy be monitored for early signs or osteopenia and that the carbonic anhydrase inhibitor be discontinued and appropriate treatment initiated is necessary.
Chlorpropamide or Clofibrate or Desmopressin or Lypressin or Posterior pituitary or Thiazide diuretics (when used for their paradoxical antidiuretic activity in the treatment of diabetes insipidus) or Vasopressin: Concurrent use with carbamazepine may potentiate the antidiuretic effect, leading to a lower sodium concentration and causing adverse effects that include increased seizure activity; a reduction in dosage of either or both medication may be necessary for optimal therapeutic effect in the treatment of diabetes insipidus.
Cimetidine: Concurrent use may result in increased plasma concentration of carbamazepine by delaying its clearance, leading to carbamazepine toxicity.
Contraceptive, estrogen-containing oral, or Cyclosporine, or Decarbazine, or Digitalis glycosides with the possible exception of digoxin, or Disopyramide, or Estrogen including estramustine, or Levothyroxine, or Maxiletine, or Quinitine: Concurrent use may decrease the effects of these medications because of increased metabolism resulting from induction of hepatic microsomal enzyme activity; dosage adjustment may be necessary.
Patients should be advised to use a non-hormonal method of birth control or an oral contraceptive containing only a progestin.
Danazol, or Diltiazem, or Verapamil: Concurrent use of these agents with carbamazepine may inhibit carbamazepine metabolism, resulting in increased plasma concentration and toxicity.
Carbamazepine toxicity may be delayed for several weeks after initiation of danazol therapy; carbamazepine dosage may need to be reduced.
It is recommended that nifedipine be used as an alternative to verapamil or diltiazem.
Doxycycline: Concurrent use may decrease plasma concentration and elimination half-life of doxycycline because of induction of hepatic microsomal enzyme activity; if concurrent use cannot be avoided, doxycycline plasma concentration or the therapeutic response to doxycycline should be closely monitored and dosage adjustments made as necessary.
Enflurane, or Malothane, or Methoxyflurane: Chronic use of a hepatic enzyme-inducing agent such as carbamazepine prior to anesthesia, leading to an increased risk of hepatotoxicity.
Formation of nephrotoxic metabolites of methoxyflurane may be increased by chronic use of a hepatic enzyme-inducing agent such as carbamazepine prior to anesthesia, leading to increased risk of nephrotoxicity.
Erythromycin or Troleandomycin: Concurrent use of these agents with carbamazepine may inhibit carbamazepine metabolism, resulting in increased plasma concentration and toxicity; it is recommended that an alternative antibiotic to erythromycin or troleandomycin be used.
Influenza virus vaccine: Concurrent use with carbamazepine may inhibit carbamazepine metabolism, resulting in increased plasma concentrations and toxicity; carbamazepine serum concentrations may be increased on days 7 to 14 after influenza virus vaccination; dosage adjustment of carbamazepine based on the patient’s clinical status and serum concentration may be necessary.
Isoniazid: Carbamazepine may induce microsomal metabolism of isoniazid, increasing formation of a reactive intermediate and leading to hepatotoxicity; also, isoniazid administration may result in elevated plasma concentration of carbamazepine and possible toxicity.
Lithium: Concurrent use may decrease the antidiuretic effect of carbamazepine and increase the neurotoxic side effects even at nontoxic blood concentration of both lithium and carbamazepine; however, the concurrent use of lithium with carbamazepine may be synergistic in the treatment of patients with manic-depressive illness who fail to respond to either drug alone.
Mebendazole: In patients receiving high oral doses of mebendazole for treatment of tissue-dwelling organisms such as Echinococcus mulyocularis or granulosus [Hydatid disease], carbamazepine has been shown to lower plasma mebendazole concentration by induction of hepatic microsomal enzymes and to impair the therapeutic response; if carbamazepine is being used for seizures, replacement with another anticonvulsant is recommended; treatment of intestinal helminthes such as whipworms or hookworms does not appear to be affected by the rate of hepatic metabolism of mebendazole
Monoamine oxidase (MAO) inhibitor, including furazolidone, pargyline and procarbazine: Concurrent use with carbamazepine has resulted hyperpyretic crises, hypertensive crises, severe convulsions, and death; a medication-free interval of at least 14 days is recommended between discontinuing MAO inhibitor therapy and initiating carbamazepine therapy, or vice versa.
MAO inhibitors may also cause a change in the pattern of epileptiform seizures in patients receiving carbamazepine as an anticonvulsant.
Propoxyphene: Concurrent use with carbamazepine may inhibit carbamazepine metabolism, resulting in increased plasma concentration and toxicity; it is recommended that an alternative analgesic to propoxyphene be used.
Storage
Store between 15 and 30°C in a well-closed container.
ATC Classification
N03AF01 - carbamazepine ; Belongs to the class of carboxamide derivatives antiepileptic.
Presentation/Packing
Tab 200 mg (round, white, double-scored, flat, beveled-edge, identified APO 200) x 100's, 500's.
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