Carbamazepine
(BAN, USAN, rINN)

Synonyms: Carbamazepina; Carbamazépine; Carbamazepinum; G-32883; Karbamatsepiini; Karbamazepin; Karbamazepinas; Karbamazepinum. 5H-Dibenz[b,f]azepine-5-carboxamide.
Cyrillic synonym: Карбамазепин.
💊 Chemical information
Chemical formula: C15H12N2O = 236.3.
CAS — 298-46-4.
ATC — N03AF01.
ATC Vet — QN03AF01.
Pharmacopoeias.
In Chin., Eur., Int., Jpn, and US.Ph. Eur. 6.2
(Carbamazepine). A white or almost white crystalline powder. It exhibits polymorphism. Very slightly soluble in water; sparingly soluble in alcohol and in acetone; freely soluble in dichloromethane. Store in airtight containers.USP 31
(Carbamazepine). A white or off-white powder. Practically insoluble in water; soluble in alcohol and in acetone. Store in airtight containers.Incompatibility.
Carbamazepine suspension should be mixed with an equal volume of diluent before nasogastric use as undiluted suspension is adsorbed onto PVC nasogastric tubes. 1 The FDA have received a report of a patient who passed an orange rubbery mass in his faeces the day after taking a carbamazepine suspension (Tegretol; Novartis, USA) followed immediately by chlorpromazine solution (Thorazine; GSK, USA). Subsequent testing showed that mixing the same carbamazepine suspension with a thioridazine hydrochloride solution (Mellaril; Novartis, USA) also resulted in the precipitation of a rubbery orange mass. 1. Clark-Schmidt AL, et al. Loss of carbamazepine suspension through nasogastric feeding tubes. Am J Hosp Pharm 1990; 47: 2034–7.Stability.
FDA studies indicate that carbamazepine tablets could lose up to one-third of their effectiveness if stored in humid conditions. 1 This appears to be due to formation of a dihydrate form which leads to hardening of the tablet and poor dissolution and absorption. 2,3Antibacterials.
The antimycobacterial isoniazid1,2 and macrolides3 such as clarithromycin, erythromycin, and troleandomycin have been reported to cause substantial elevations of serum concentrations of carbamazepine and symptoms of carbamazepine toxicity. Clarithromycin has also been reported to have caused hyponatraemia when added to carbamazepine therapy in a 30-year-old epileptic woman.4 Rifampicin and isoniazid decreased the serum concentrations of carbamazepine in a 44year-old woman being treated for bipolar disorder and suspected tuberculosis, resulting in hypomania.5 Use of carbamazepine with isoniazid may increase the risk of isoniazid-induced hepatotoxicity.1. Valsalan VC, Cooper GL. Carbamazepine intoxication caused by interaction with isoniazid. BMJ 1982; 285: 261–2
2. Wright JM, et al. Isoniazid-induced carbamazepine toxicity and vice versa. N Engl J Med 1982; 307: 1325–7
3. Pauwels O. Factors contributing to carbamazepine-macrolide interactions. Pharmacol Res 2002; 45: 291–8
4. Kanbay M, et al. Hyponatremia due to an additive effect of carbamazepine and clarithromycin. South Med J 2007; 100: 222
5. Zolezzi M. Antituberculosis agents and carbamazepine. Am J Psychiatry 2002; 159: 874.
2. Wright JM, et al. Isoniazid-induced carbamazepine toxicity and vice versa. N Engl J Med 1982; 307: 1325–7
3. Pauwels O. Factors contributing to carbamazepine-macrolide interactions. Pharmacol Res 2002; 45: 291–8
4. Kanbay M, et al. Hyponatremia due to an additive effect of carbamazepine and clarithromycin. South Med J 2007; 100: 222
5. Zolezzi M. Antituberculosis agents and carbamazepine. Am J Psychiatry 2002; 159: 874.
Anticoagulants.
For the effect of carbamazepine on warfarin.Antidepressants.
As with all antiepileptics, antidepressants may antagonise the antiepileptic activity of carbamazepine by lowering the convulsive threshold. Antidepressants such as desipramine,1 fluoxetine,2 fluvoxamine,3nefazodone4 (and perhaps trazodone5), and viloxazine6 increase plasma concentrations of carbamazepine and may induce carbamazepine toxicity. A toxic serotonin syndrome has been reported in a patient who received fluoxetine with carbamazepine.7 Severe neurotoxicity reported during therapy with lithium and carbamazepine8,9 may be due to a synergistic effect as reports indicate that either drug was tolerated when not given with the other and measured plasma concentrations did not indicate overdosage.9 However, toxic serum concentrations of lithium have also been reported, due to carbamazepine-induced acute renal failure. Because of the structural similarity to tricyclic antidepressants licensed product information suggests that carbamazepine should not be given to patients taking an MAOI or within 14 days of stopping such treatment. St John’s wort has been shown to induce several drug metabolising enzymes and consequently it has been suggested that it might reduce the blood concentrations of carbamazepine leading to an increased risk of seizure.10 However, a multipledose study11 in healthy subjects reported that St John’s wort had no significant effect on the pharmacokinetics of carbamazepine or its active epoxide metabolite. For the effect of carbamazepine on antidepressants, see Bupropion, Fluoxetine, Mianserin, Nefazodone, and Amitriptyline.1. Lesser I. Carbamazepine and desipramine: a toxic reaction. J Clin Psychiatry 1984; 45: 360
2. Pearson HJ. Interaction of fluoxetine with carbamazepine. J Clin Psychiatry 1990; 51: 126
3. Fritze J, et al. Interaction between carbamazepine and fluvoxamine. Acta Psychiatr Scand 1991; 84: 583–4
4. Ashton AK, Wolin RE. Nefazodone-induced carbamazepine toxicity. Am J Psychiatry 1996; 153: 733
5. Sánchez Romero A, et al. Interaction between trazodone and carbamazepine. Ann Pharmacother 1999; 33: 1370
6. Scarpello JHB, Cottrell N. Overuse of monitoring of blood concentrations of antiepileptic drugs. BMJ 1987; 294: 1355
7. Dursun SM, et al. Toxic serotonin syndrome after fluoxetine plus carbamazepine. Lancet 1993; 342: 442–3
8. Andrus PF. Lithium and carbamazepine. J Clin Psychiatry 1984; 45: 525
9. Chaudhry RP, Waters BGH. Lithium and carbamazepine interaction: possible neurotoxicity. J Clin Psychiatry 1983; 44: 30–1
10. Committee on Safety of Medicines/Medicines Control Agency. Reminder: St John’s wort (Hypericum perforatum) interactions. Current Problems 2000; 26: 6–7. Also available at: http:// www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON007462&RevisionSelectionMethod= LatestReleased (accessed 09/06/08
11. Burstein AH, et al. Lack of effect of St John’s Wort on carbamazepine pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 2000; 68: 605–12.
2. Pearson HJ. Interaction of fluoxetine with carbamazepine. J Clin Psychiatry 1990; 51: 126
3. Fritze J, et al. Interaction between carbamazepine and fluvoxamine. Acta Psychiatr Scand 1991; 84: 583–4
4. Ashton AK, Wolin RE. Nefazodone-induced carbamazepine toxicity. Am J Psychiatry 1996; 153: 733
5. Sánchez Romero A, et al. Interaction between trazodone and carbamazepine. Ann Pharmacother 1999; 33: 1370
6. Scarpello JHB, Cottrell N. Overuse of monitoring of blood concentrations of antiepileptic drugs. BMJ 1987; 294: 1355
7. Dursun SM, et al. Toxic serotonin syndrome after fluoxetine plus carbamazepine. Lancet 1993; 342: 442–3
8. Andrus PF. Lithium and carbamazepine. J Clin Psychiatry 1984; 45: 525
9. Chaudhry RP, Waters BGH. Lithium and carbamazepine interaction: possible neurotoxicity. J Clin Psychiatry 1983; 44: 30–1
10. Committee on Safety of Medicines/Medicines Control Agency. Reminder: St John’s wort (Hypericum perforatum) interactions. Current Problems 2000; 26: 6–7. Also available at: http:// www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON007462&RevisionSelectionMethod= LatestReleased (accessed 09/06/08
11. Burstein AH, et al. Lack of effect of St John’s Wort on carbamazepine pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 2000; 68: 605–12.
Antiepileptics.
Interactions of varying degrees of clinical significance have been reported between carbamazepine and other antiepileptics. Serum concentrations of carbamazepine are reported to be reduced by phenobarbital, but without loss of seizure control;1,2this reduction is probably due to induction of carbamazepine metabolism. The interaction with phenytoin is somewhat more complex and the consequences vary. Again, these reports do not indicate a loss of seizure control or toxicity resulting from the interaction, although the possibility presumably exists. Gradually withdrawing phenytoin from 2 patients who had been receiving carbamazepine and phenytoin resulted in a dramatic increase in plasma-carbamazepine concentrations;4 one patient exhibited neurotoxic symptoms. The authors recommended that plasma-carbamazepine monitoring should be carried out whenever phenytoin is withdrawn in patients taking these two drugs together. Valproic acid produces an increase in serum concentrations of the active epoxide metabolite of carbamazepine. This is usually attributed to inhibition of its hydrolysis by epoxide hydrolase, although an additional proposed mechanism5 is inhibition of the glucuronidation of carbamazepine-10,11-trans-diol, the compound to which the epoxide is converted under normal circumstances. Adverse effects may be a problem if unusually high epoxide concentrations arise but, in general, this interaction is of limited clinical significance. However, valpromide, the amide derivative, is a much more powerful inhibitor of epoxide hydrolase than valproic acid,6-8 and therefore produces greater increases in epoxide plasma concentrations with clinical signs of toxicity.7 Switching from sodium valproate to valpromide has resulted in toxicity in patients also receiving carbamazepine.7 Neither valproic acid nor valpromide have any significant effect on plasma concentrations of the parent drug, carbamazepine. Va l no c t a mide, an isomer of valpromide, appears to be at least as potent as valpromide in inhibiting the elimination of the epoxide metabolite of carbamazepine.9 Valnoctamide has been used as an anxiolytic, although it does appear to possess some antiepileptic activity. For a report of acute psychosis associated with the combination of carbamazepine and sodium valproate, see Effects on Mental Function under Adverse Effects, above. For the effects of carbamazepine on valproate. Of the other antiepileptics stiripentol10,11 has been reported to inhibit carbamazepine metabolism, while felbamate causes a significant fall in plasma-carbamazepine concentrations which may require an increase in the dose of carbamazepine.12 However, another study13 has shown a significant increase in plasma-concentrations of the active epoxide metabolite, which may counteract the effect of the decrease in plasma concentrations of the parent compound. Neurotoxicity has been seen after use of carbamazepine with lamotrigine.14 The suggestion that this was due to raised concentrations of carbamazepine epoxide was not confirmed in a controlled study in which the 2 drugs were used together safely and effectively.15 Toxic epidermal necrolysis occurred16 when lamotrigine was added to carbamazepine therapy in a patient who had been taking carbamazepine for 3 years; symptoms resolved progressively when both drugs were stopped. Symptoms of carbamazepine toxicity have been reported17 when levetiracetam was added to carbamazepine therapy; this interaction appeared to be due to a pharmacodynamic mechanism as blood levels of carbamazepine and its epoxide metabolite were not altered. There have also been reports18 of carbamazepine toxicity when topiramate was added to carbamazepine therapy; symptoms resolved when the dose of carbamazepine was reduced. Fulminant liver failure has been reported19 after an increase in adjunctive topiramate dose in a patient maintained on carbamazepine for 2 years without any signs of hepatotoxicity. The GABA agonist progabide has increased plasma concentrations of the epoxide metabolite, probably due to inhibition of microsomal epoxide hydrolase.20 Vigabatrin is reported21 to increase the clearance of carbamazepine by about 35%. For the effects of carbamazepine on ethosuximide, on lamotrigine, on oxcarbazepine, on primidone, on tiagabine, and on topiramate. For interactions with benzodiazepines, see below.1. Cereghino JJ, et al. The efficacy of carbamazepine combinations in epilepsy. Clin Pharmacol Ther 1975; 18: 733–41
2. Rane A, et al. Kinetics of carbamazepine and its 10,11-epoxide metabolite in children. Clin Pharmacol Ther 1976; 19: 276–83
3. Christiansen J, Dam M. Influence of phenobarbital and diphenylhydantoin on plasma carbamazepine levels in patients with epilepsy. Acta Neurol Scand 1973; 49: 543–6
4. Chapron DJ, et al. Unmasking the significant enzyme-inducing effects of phenytoin on serum carbamazepine concentrations during phenytoin withdrawal. Ann Pharmacother 1993; 27: 708–11
5. Bernus I, et al. The mechanism of the carbamazepine-valproate interaction in humans. Br J Clin Pharmacol 1997; 44: 21–7
6. Levy RH, et al. Inhibition of carbamazepine epoxide elimination by valpromide and valproic acid. Epilepsia 1986; 27: 592
7. Meijer JWA, et al. Possible hazard of valpromide-carbamazepine combination therapy in epilepsy. Lancet 1984; i: 802
8. Pisani F, et al. Effect of valpromide on the pharmacokinetics of carbamazepine-10,11-epoxide. Br J Clin Pharmacol 1988; 25: 611–13
9. Pisani F, et al. Impairment of carbamazepine-10,11-epoxide elimination by valnoctamide, a valpromide isomer, in healthy subjects. Br J Clin Pharmacol 1992; 34: 85–7
10. Levy RH, et al. Stiripentol level-dose relationship and interaction with carbamazepine in epileptic patients. Epilepsia 1985; 26: 544–5
11. Cazali N, et al. Inhibitory effect of stiripentol on carbamazepine and saquinavir metabolism in human. Br J Clin Pharmacol 2003; 56: 526–36
12. Albani F, et al. Effect of felbamate on plasma levels of carbamazepine and its metabolites. Epilepsia 1991; 32: 130–2
13. Wagner ML, et al. Effect of felbamate on carbamazepine and its major metabolites. Clin Pharmacol Ther 1993; 53: 536–43
14. Warner T, et al. Lamotrigine-induced carbamazepine toxicity: an interaction with carbamazepine-10,11-epoxide. Epilepsy Res 1992; 11: 147–50
15. Stolarek I, et al. Vigabatrin and lamotrigine in refractory epilepsy. J Neurol Neurosurg Psychiatry 1994; 57: 921–4
16. Mansouri P, et al. Toxic epidermal necrolysis associated with concomitant use of lamotrigine and carbamazepine: a case report. Arch Dermatol 2005; 141: 788–9
17. Sisodiya SM, et al. Carbamazepine toxicity during combination therapy with levetiracetam: a pharmacodynamic interaction. Epilepsy Res 2002; 48: 217–19
18. Mack CJ, et al. Interaction of topiramate with carbamazepine: two case reports and a review of clinical experience. Seizure 2002; 11: 464–7
19. Bjøro K, et al. Topiramate and fulminant liver failure. Lancet 1998; 352: 1119
20. Kroetz DL, et al. In vivo and in vitro correlation of microsomal epoxide hydrolase inhibition by progabide. Clin Pharmacol Ther 1993; 54: 485–97
21. Sánchez-Alcaraz A, et al. Effect of vigabatrin on the pharmacokinetics of carbamazepine. J Clin Pharm Ther 2002; 27: 427–30.
2. Rane A, et al. Kinetics of carbamazepine and its 10,11-epoxide metabolite in children. Clin Pharmacol Ther 1976; 19: 276–83
3. Christiansen J, Dam M. Influence of phenobarbital and diphenylhydantoin on plasma carbamazepine levels in patients with epilepsy. Acta Neurol Scand 1973; 49: 543–6
4. Chapron DJ, et al. Unmasking the significant enzyme-inducing effects of phenytoin on serum carbamazepine concentrations during phenytoin withdrawal. Ann Pharmacother 1993; 27: 708–11
5. Bernus I, et al. The mechanism of the carbamazepine-valproate interaction in humans. Br J Clin Pharmacol 1997; 44: 21–7
6. Levy RH, et al. Inhibition of carbamazepine epoxide elimination by valpromide and valproic acid. Epilepsia 1986; 27: 592
7. Meijer JWA, et al. Possible hazard of valpromide-carbamazepine combination therapy in epilepsy. Lancet 1984; i: 802
8. Pisani F, et al. Effect of valpromide on the pharmacokinetics of carbamazepine-10,11-epoxide. Br J Clin Pharmacol 1988; 25: 611–13
9. Pisani F, et al. Impairment of carbamazepine-10,11-epoxide elimination by valnoctamide, a valpromide isomer, in healthy subjects. Br J Clin Pharmacol 1992; 34: 85–7
10. Levy RH, et al. Stiripentol level-dose relationship and interaction with carbamazepine in epileptic patients. Epilepsia 1985; 26: 544–5
11. Cazali N, et al. Inhibitory effect of stiripentol on carbamazepine and saquinavir metabolism in human. Br J Clin Pharmacol 2003; 56: 526–36
12. Albani F, et al. Effect of felbamate on plasma levels of carbamazepine and its metabolites. Epilepsia 1991; 32: 130–2
13. Wagner ML, et al. Effect of felbamate on carbamazepine and its major metabolites. Clin Pharmacol Ther 1993; 53: 536–43
14. Warner T, et al. Lamotrigine-induced carbamazepine toxicity: an interaction with carbamazepine-10,11-epoxide. Epilepsy Res 1992; 11: 147–50
15. Stolarek I, et al. Vigabatrin and lamotrigine in refractory epilepsy. J Neurol Neurosurg Psychiatry 1994; 57: 921–4
16. Mansouri P, et al. Toxic epidermal necrolysis associated with concomitant use of lamotrigine and carbamazepine: a case report. Arch Dermatol 2005; 141: 788–9
17. Sisodiya SM, et al. Carbamazepine toxicity during combination therapy with levetiracetam: a pharmacodynamic interaction. Epilepsy Res 2002; 48: 217–19
18. Mack CJ, et al. Interaction of topiramate with carbamazepine: two case reports and a review of clinical experience. Seizure 2002; 11: 464–7
19. Bjøro K, et al. Topiramate and fulminant liver failure. Lancet 1998; 352: 1119
20. Kroetz DL, et al. In vivo and in vitro correlation of microsomal epoxide hydrolase inhibition by progabide. Clin Pharmacol Ther 1993; 54: 485–97
21. Sánchez-Alcaraz A, et al. Effect of vigabatrin on the pharmacokinetics of carbamazepine. J Clin Pharm Ther 2002; 27: 427–30.
Antifungals.
Malaise, myoclonus, and trembling were reported1 to have developed in a patient receiving carbamazepine after the addition of miconazole to therapy. Ketoconazole was associated with a significant increase in plasma-carbamazepine concentrations in 8 epileptic patients stabilised on carbamazepine;2 plasma concentrations of the epoxide metabolite were unchanged. A threefold increase in serum-carbamazepine concentrations, reported3 in a patient after addition of fluconazole to carbamazepine therapy, was asymptomatic; however, carbamazepine toxicity has been reported4,5 in 2 patients stabilised on carbamazepine who were given fluconazole. Terbinafine has also been reported6 to cause possible carbamazepine toxicity. For the effect of carbamazepine on itraconazole.1. Loupi E, et al. Interactions médicamenteuses et miconazole. Therapie 1982; 37: 437–41
2. Spina E, et al. Elevation of plasma carbamazepine concentrations by ketoconazole in patients with epilepsy. Ther Drug Monit 1997; 19: 535–8
3. Finch CK, et al. Fluconazole-carbamazepine interaction. South Med J 2002; 95: 1099–1100
4. Nair DR, Morris HH. Potential fluconazole-induced carbamazepine toxicity. Ann Pharmacother 1999; 33: 790–2
5. Ulivelli M, et al. Clinical evidence of fluconazole-induced carbamazepine toxicity. J Neurol 2004; 251: 622–3
6. Baath NS, et al. Possible carbamazepine toxicity with terbinafine. Can J Clin Pharmacol 2006; 13: e228–e231.
2. Spina E, et al. Elevation of plasma carbamazepine concentrations by ketoconazole in patients with epilepsy. Ther Drug Monit 1997; 19: 535–8
3. Finch CK, et al. Fluconazole-carbamazepine interaction. South Med J 2002; 95: 1099–1100
4. Nair DR, Morris HH. Potential fluconazole-induced carbamazepine toxicity. Ann Pharmacother 1999; 33: 790–2
5. Ulivelli M, et al. Clinical evidence of fluconazole-induced carbamazepine toxicity. J Neurol 2004; 251: 622–3
6. Baath NS, et al. Possible carbamazepine toxicity with terbinafine. Can J Clin Pharmacol 2006; 13: e228–e231.
Antihistamines.
Te rfenadine and carbamazepine are both highly protein bound and therefore may compete for protein binding sites. An 18-year-old woman receiving carbamazepine as an antiepileptic experienced symptoms of neurotoxicity shortly after starting treatment with terfenadine for rhinitis.1 The concentration of free carbamazepine in the plasma was higher than normal and returned to normal on stopping terfenadine.1. Hirschfeld S, Jarosinski P. Drug interaction of terfenadine and carbamazepine. Ann Intern Med 1993; 118: 907–8.
Antimalarials.
Chloroquine and mefloquine may antagonise the antiepileptic activity of carbamazepine by lowering the convulsive threshold.Antiprotozoals.
A patient receiving carbamazepine for bipolar disorder developed dizziness, diplopia, and nausea 4 days after the addition of metronidazole for diverticulitis.11. Patterson BD. Possible interaction between metronidazole and carbamazepine. Ann Pharmacother 1994; 28: 1303–4.
Antipsychotics.
As with all antiepileptics, antipsychotics may antagonise the antiepileptic activity of carbamazepine by lowering the convulsive threshold. Increased plasma concentrations of carbamazepine epoxide have been reported to occur during therapy with carbamazepine and loxapine1 or quetiapine,2 possibly due to induction of carbamazepine metabolism or inhibition of metabolism of the epoxide. Raised serum concentrations of carbamazepine have also been reported in patients receiving haloperidol.3 For the effect of carbamazepine on antipsychotics, see under Chlorpromazine.1. Collins DM, et al. Potential interaction between carbamazepine and loxapine: case report and retrospective review. Ann Pharmacother 1993; 27: 1180–3
2. Fitzgerald BJ, Okos AJ. Elevation of carbamazepine-10,11epoxide by quetiapine. Pharmacotherapy 2002; 22: 1500–3
3. Iwahashi K, et al. The drug-drug interaction effects of haloperidol on plasma carbamazepine levels. Clin Neuropharmacol 1995; 18: 233–6.
2. Fitzgerald BJ, Okos AJ. Elevation of carbamazepine-10,11epoxide by quetiapine. Pharmacotherapy 2002; 22: 1500–3
3. Iwahashi K, et al. The drug-drug interaction effects of haloperidol on plasma carbamazepine levels. Clin Neuropharmacol 1995; 18: 233–6.
Antivirals.
Ritonavir inhibits several microsomal liver enzymes and therefore may potentially increase plasma concentrations of carbamazepine. Licensed product information for ritonavir advises that such combinations may require monitoring. Carbamazepine toxicity has been reported1,2 after interaction with ritonavir. In one report,2 the patient was also taking nelfinavir and lopinavir, both of which are substrates and inhibitors of CYP450 isoenzymes. For the effect of carbamazepine on HIV-protease inhibitors.1. Mateu-de Antonio J, Grau S. Ritonavir-induced carbamazepine toxicity. Ann Pharmacother 2001; 35: 125–6
2. Bates DE, Herman RJ. Carbamazepine toxicity induced by lopinavir/ritonavir and nelfinavir. Ann Pharmacother 2006; 40: 1190–5.
2. Bates DE, Herman RJ. Carbamazepine toxicity induced by lopinavir/ritonavir and nelfinavir. Ann Pharmacother 2006; 40: 1190–5.
Anxiolytics.
For a discussion of the potential interaction between carbamazepine and the anxiolytic valnoctamide, an isomer of the antiepileptic valpromide, see Antiepileptics, above. See also Benzodiazepines, below.Benzodiazepines.
The metabolism of benzodiazepines may be enhanced by induction of hepatic drug-metabolising enzymes in patients who have received long-term therapy with carbamazepine; benzodiazepine plasma concentrations are reduced, half-life is shorter, and clearance is increased1,2. Some benzodiazepines may also affect carbamazepine. One group of workers reported that after addition of clobazam to carbamazepine therapy a dose reduction for the latter was required due to increased blood concentrations.3 In a later study4 it appeared that clobazam could produce a moderate increase in the metabolism of carbamazepine. The plasma ratio of metabolites of carbamazepine, including carbamazepine-10,11-epoxide, to parent compound was increased in patients taking clobazam and carbamazepine.1. Dhillon S, Richens A. Pharmacokinetics of diazepam in epileptic patients and normal volunteers following intravenous administration. Br J Clin Pharmacol 1981; 12: 841–4
2. Lai AA, et al. Time-course of interaction between carbamazepine and clonazepam in normal man. Clin Pharmacol Ther 1978; 24: 316–23
3. Franceschi M, et al. Clobazam in drug-resistant and alcoholic withdrawal seizures. Clin Trials J 1983; 20: 119–25
4. Muñoz JJ, et al. The effect of clobazam on steady state plasma concentrations of carbamazepine and its metabolites. Br J Clin Pharmacol 1990; 29: 763–5.
2. Lai AA, et al. Time-course of interaction between carbamazepine and clonazepam in normal man. Clin Pharmacol Ther 1978; 24: 316–23
3. Franceschi M, et al. Clobazam in drug-resistant and alcoholic withdrawal seizures. Clin Trials J 1983; 20: 119–25
4. Muñoz JJ, et al. The effect of clobazam on steady state plasma concentrations of carbamazepine and its metabolites. Br J Clin Pharmacol 1990; 29: 763–5.
Calcium-channel blockers.
Six patients with steady-state carbamazepine concentrations had symptoms of neurotoxicity consistent with carbamazepine intoxication within 36 to 96 hours of the first dose of verapamil.1 In 5 patients, in whom plasma concentrations were measured, there was a mean increase of 46% in total carbamazepine and 33% in free carbamazepine; no effect on the plasma protein binding of carbamazepine was seen. The results suggested that verapamil inhibits the metabolism of carbamazepine to an extent likely to have important clinical repercussions. There has also been a report2 of a patient in whom diltiazem, but not nifedipine, precipitated carbamazepine neurotoxicity. For the effect of carbamazepine on dihydropyridine calciumchannel blockers, see under Nifedipine.1. Macphee GJA, et al. Verapamil potentiates carbamazepine neurotoxicity: a clinically important inhibitory interaction. Lancet 1986; i: 700–703
2. Brodie MJ, Macphee GJA. Carbamazepine neurotoxicity precipitated by diltiazem. BMJ 1986; 292: 1170–1.
2. Brodie MJ, Macphee GJA. Carbamazepine neurotoxicity precipitated by diltiazem. BMJ 1986; 292: 1170–1.
Ciclosporin.
For the effect of carbamazepine on ciclosporin.Corticosteroids.
For the effect of carbamazepine on corticosteroids.Danazol.
Use of danazol with carbamazepine has been reported to increase the half-life and decrease clearance of carbamazepine,1 resulting in increases in plasma-carbamazepine concentrations of up to 100%1,2 and resultant toxicity in a number of patients.21. Krämer G, et al. Carbamazepine-danazol drug interaction: its mechanism examined by a stable isotope technique. Ther Drug Monit 1986; 8: 387–92
2. Zielinski JJ, et al. Clinically significant danazol-carbamazepine interaction. Ther Drug Monit 1987; 9: 24–7.
2. Zielinski JJ, et al. Clinically significant danazol-carbamazepine interaction. Ther Drug Monit 1987; 9: 24–7.
Dermatological drugs.
Addition of isotretinoin to regular carbamazepine therapy appeared to reduce plasma concentrations of the latter and its active epoxide metabolite.1 However, no adverse events were noted during a 6-week period of treatment with isotretinoin. Nonetheless, licensed product information for carbamazepine recommends that the levels of carbamazepine are monitored if both are used together.1. Marsden JR. Effect of isotretinoin on carbamazepine pharmacokinetics. Br J Dermatol 1988; 119: 403–4.
Diuretics.
There has been a report of symptomatic hyponatraemia associated with use of carbamazepine and a diuretic. Carbamazepine serum concentrations are increased by acetazolamide.11. McBride MC. Serum carbamazepine levels are increased by acetazolamide. Ann Neurol 1984; 16: 393.
Gastrointestinal drugs.
Cimetidine is reported to produce a transient increase in plasma-carbamazepine concentrations, with a return to pre-cimetidine values within about a week;1 some increase in adverse effects was seen. Ranitidine does not appear to affect plasma-carbamazepine concentrations.2 Neurotoxicity has been seen in a patient receiving carbamazepine and metoclopramide.31. Dalton MJ, et al. Cimetidine and carbamazepine: a complex drug interaction. Epilepsia 1986; 27: 553–8
2. Dalton MJ, et al. Ranitidine does not alter single-dose carbamazepine pharmacokinetics in healthy adults. Drug Intell Clin Pharm 1985; 19: 941–4
3. Sandyk R. Carbamazepine and metoclopramide interaction: possible neurotoxicity. BMJ 1984; 288: 830.
2. Dalton MJ, et al. Ranitidine does not alter single-dose carbamazepine pharmacokinetics in healthy adults. Drug Intell Clin Pharm 1985; 19: 941–4
3. Sandyk R. Carbamazepine and metoclopramide interaction: possible neurotoxicity. BMJ 1984; 288: 830.
Grapefruit juice.
The bioavailability and plasma concentrations of carbamazepine have been reported1 to be increased by grapefruit juice.1. Garg SK, et al. Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy. Clin Pharmacol Ther 1998; 64: 286–8.
Levothyroxine.
For the effect of carbamazepine on levothyroxine.Neuromuscular blockers.
For the effect of carbamazepine on suxamethonium and on competitive neuromuscular blockers, see under Atracurium.Sex hormones.
For the effect of carbamazepine on oral contraceptives and for the possible effect on tibolone. See also Danazol, aboveTheophylline.
A decrease in serum-carbamazepine concentrations of about 50% was reported1 in an epileptic patient given theophylline. The patient experienced seizures and the proposed mechanism was that theophylline had increased the metabolism of carbamazepine. For the effect of carbamazepine on theophylline.1. Mitchell EA, et al. Interaction between carbamazepine and theophylline. N Z Med J 1986; 99: 69–70.