Carbamazepine toxicity

Certain medications (e.g., cimetidine, diltiazem, erythromycin, fluoxetine, fluvoxamine, isoniazid, itraconazole, ketoconazole, nefazodone, propoxyphene, and verapamil) added to carbamazepine therapy may cause carbamazepine toxicity. 

Carbamazepine Increased plasma concentrations of carbamazepine symptoms of carbamazepine toxicity... 

Carbamazepine also can induce the enzymes that metabolize other anticonvulsant drugs, including phenytoin, primidone, phenobarbital, valproic acid, clonazepam, and ethosuximide, and metabolism of other drugs the patient may be taking. Similarly, other drugs may induce metabolism of carbamazepine the end result is the same as for autoinduction, and the dose of carbamazepine must be readjusted. A common drug-drug interaction is between carbamazepine and the macrolide antibiotics erythromycin and trolean-domycin. After a few days of antibiotic therapy, symptoms of carbamazepine toxicity develop this is readily reversible if either the antibiotic or carbamazepine is discontinued. 

Carbamazepine toxicity is manifested by drowsiness, nausea and vomiting, gait disturbance, nystagmus, confusion, neuromuscular excitability, and seizures (Menkes, 1999). Overdose with CBZ can be lethal (Arana et ah, 1986). In a retrospective study of 307 intoxicated patients, 41 (13%) had a fatal outcome (Schmidt and Schmitz-Buhl, 1995). Doses exceeding 24 g were important indicators of fatality. The management of CBZ overdose is primarily supportive, to prevent potential atrioventricular (AV) block (Arana et ah, 1986), possible respiratory depression (Schmidt and Schmitz-Buhl, 1995), stupor, and coma. 

Upregulates [ H]-NMDA binding Upregulates NMDA —> release [ H]aspartate Upregulates NMDA —> PI turnover NMDA protects against carbamazepine toxicity... 

Wright JM, Stokes EF, Sweeney VP. Isoniazid-induced carbamazepine toxicity and vice versa a double drug interaction. N EnglJ Med 1982 307 1325-1327. 

Holmes GL. Carbamazepine toxicity. In Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic Drugs. 4th ed. New York Raven Press, 1995 567-579. 

L. Durelli, et al., Carbamazepine toxicity and poisoning Incidence, clinical features and management. Med. Toxicol. Adv. Drug Exp. 4 95-107, 1989. 

In a controlled study in 12 healthy men the combination of carbamazepine and nefazodone led to increased plasma carbamazepine concentrations and substantially lowered plasma nefazodone concentrations (21). This interaction, which is due to inhibition of CYP3A4 by nefazodone, could lead to difficulties during treatment, since the risk of carbamazepine toxicity would have to be balanced against the loss of therapeutic effect of nefazodone. Except in special circumstances it is probably better to avoid the combination. 

Phenobarbital Phenytoin Primidone Carbamazepine Reduced effect of carbamazepine usually compensated by the action of the added drug risk of carbamazepine toxicity when interfering drug is withdrawn Induction of carbamazepine metabolism... 

Verapamil Carbamazepine Phenytoin High risk of carbamazepine toxicity interaction with phenytoin inconsistent Inhibition of metabolism of the object drugs... 

Loxapine Carbamazepine Risk of carbamazepine toxicity interaction poorly documented Unknown... 

Valnoctamide Carbamazepine Risk of carbamazepine toxicity Inhibition of epoxide hydrolase... 

Carbamazepine toxicity with lamotrigine pharmacokinetic or pharmacodynamic interaction Epilepsia... 

In a 33-year-old man stabilized on carbamazepine, the addition of fluconazole (150 mg/day) led to severe carbamazepine toxicity associated with high carbamazepine concentrations (104 pmol/l) (95). The condition cleared after withdrawal of both drugs, and carbamazepine was then re administered without recurrence of toxicity. This interaction is likely to be mediated by inhibition of the CYP3A4-mediated metabolism of carbamazepine by fluconazole. 

Macnab AJ, Robinson JL, Adderly RJ, D Orsogna L. Heart block secondary to erythromycin-induced carbamazepine toxicity. Pediatrics 1987 80(6) 951-3. 

Burman W, Orr L. Carbamazepine toxicity after starting combination antiretroviral therapy including ritonavir and efavirenz. AIDS 2000 14(17) 2793. ... 

Berbel Garcia A, Latorre Ibarra A, Porta Etessam J, Martinez Salio A, Perez Martinez D, Siaz Diaz R, Toledo Heras M. Protease inhibitor-induced carbamazepine toxicity. Clin Neuropharmacol 2000 23(4) 216-18. 

Nair DR, Morris HH. Potential fluconazole-induced carbamazepine toxicity. Ann Pharmacother 1999 33(7-8) 790-2. 

Severe carbamazepine toxicity can occur if dextropropoxyphene is taken concurrently (19). 

Fluconazole can cause carbamazepine toxicity, presumably by inhibition of CYP3A4 (82). 

A 33-year-old man on stable therapy with carbamazepine (400 mg tds) for a seizure disorder became stupor-ose due to carbamazepine toxicity after taking fluconazole 150 mg/day for 3 days. Withdrawal of both drugs resulted in a fall in carbamazepine concentrations (maximum concentration 25 pg/ml) and return of the... 

Four patients with refractory epilepsy taking carbamaze-pine were given added levetiracetam and developed central nervons system effects (ataxia, diplopia, nystagmns) suggestive of carbamazepine toxicity (18). Rednction in the dose of carbamazepine resolved the symptoms in three cases. Carbamazepine and carbamazepine-epoxide blood concentrations were not altered dnring levetiracetam co-medication. Thns, a pharmacodjmamic interaction between carbamazepine and levetiracetam is likely. 

Sisodiya SM, Sander JW, Patsalos PN. Carbamazepine toxicity during combination therapy with levetiracetam a pharmacodynamic interaction. Epilepsy Res 2002 48(3) 217-19. 

Carbamazepine toxicity, with dizziness, lethargy, and nystagmus, developed in a 17-year-old boy two days after he started to take clarithromycin 500 mg/day (129). His serum carbamazepine concentration (previously acceptable) rose, but returned to within the target range after withdrawal of clarithromycin. 

Berrettini WH. A case of erythromycin-induced carbamazepine toxicity. J Chn Psychiatry 1986 47(3) 147. 

Carranco E, Karens J, Co S, Peak V, Al-Rajeh S. Carbamazepine toxicity induced by concurrent erythromycin therapy. Arch Neurol 1985 42(2) 187-8. 

Stafstrom CE, Nohria V, Loganbill H, Nahouraii R, Boustany RM, DeLong GR. Erythromycin-induced carbamazepine toxicity a continuing problem. Arch Pediatr Adolesc Med 1995 149(1) 99-101. 

Troleandomycin can cause carbamazepine toxicity by inhibiting CYP3A4 (8). 

The primary and common toxic event involves the CNS. Cardiac conduction delays and ventricular arrhythmias can be seen but are infrequent. Sinus tachycardia and hypotension are more commonly seen. In the few deaths directly attributable to carbamazepine toxicity ventricular dysrhythmias have been the terminal event. Coma, seizures, and respiratory depression are commonly seen in adults at levels greater than 40 rgmH (170 mmol H ). Status epilepticus has been reported. The incidence of serious toxicity is similar in adults and children. However, serum levels are less predictive in children. 

Carbamazepine Possible carbamazepine toxicity, although a controlled study did not support this... 

Acute overdoses of carbamazepine are potentially lethal, and serum levels above 15 mcg/mL are associated with ataxia, choreiform movements, diplopia, nystagmus, cardiac conduction changes, seizures, and coma. Gastric lavage, hemoperfusion, and symptomatic treatment are recommended for the management of carbamazepine toxicity. 

Carbamazepine is metabolized to an active 10,11-epoxide metabolite, thus medications that inhibit 3A4 isoenzymes may result in carbamazepine toxicity (e.g., cimetidine, dUtiazem, erythromycin, fluoxetine, fluvoxamine, isoniazid, itraconazole, ketoconazole, nefa-zodone, propoxyphene, and verapamil). " When carbamazepine is combined with valproate, the carbamazepine dose should be reduced because valproate displaces carbamazepine from protein binding sites, thus increasing free levels." Combining clozapine and carbamazepine is not recommended because of the possibdity of bone marrow suppression with both agents. ... 

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