Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to, the following:
Agents That May Affect Carbamazepine Plasma Levels
CYP 3A4 inhibitors inhibit carbamazepine metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected to increase plasma carbamazepine levels include:
cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, nefazodone, loratadine, terfenadine, isoniazid, niacinamide, nicotinamide, propoxyphene, azoles (e.g., ketaconazole, itraconazole, fluconazole), acetazolamide, verapamil, grapefruit juice, protease inhibitors, valproate.*
CYP 3A4 inducers can increase the rate of carbamazepine metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include:
cisplatin, doxorubicin HCl, felbamate,† rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline.
When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.
*increased levels of the active 10,11-epoxide
†decreased levels of carbamazepine and increased levels of the 10,11-epoxide
Effect Of Carbamazepine On Plasma Levels Of Concomitant Agents
Increased levels: clomipramine HCl, phenytoin, primidone
Carbamazepine induces hepatic CYP activity. Carbamazepine causes, or would be expected to cause, decreased levels of the following:
acetaminophen, alprazolam, dihydropyridine calcium channel blockers (e.g., felodipine), cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine, dicumarol, doxycycline, ethosuximide, haloperidol, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, theophylline, tiagabine, topiramate, tramadol, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin,ziprasidone, zonisamide.
In concomitant use with carbamazepine, dosage adjustment of the above agents may be necessary.
Co-administration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect.
Co-administration of carbamazepine with nefazodone is contraindicated. (See CONTRAINDICATIONS).
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.
Concomitant use of carbamazepine with hormonal contraceptive products (e.g. oral, and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported. Alternative or back-up methods of contraception should be considered.
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 LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.
Signs And Symptoms: 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 (>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.
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 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) 59Fe-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 A2 and F hemoglobin, and (7) serum folic acid and B12 levels.
A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultation should be sought.
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 14 days, or longer if the clinical situation permits.
Co-administration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Co-administration of carbamazepine with nefazodone is contraindicated.
DRUG ABUSE AND DEPENDENCE
No evidence of abuse potential has been associated with carbamazepine, nor is there evidence of psychological or physical dependence in humans.
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