Carbamazepine

(BAN, USAN, rINN)
Carbamazepine Chemical formula
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. 2,3

Antibacterials.

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.

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.

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.

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.

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.1
1. 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.

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.

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.

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.

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.2
1. 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.

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.1
1. 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.3
1. 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.

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, above

Theophylline.

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.

Vitamins.

The plasma concentration of carbamazepine was increased in 2 patients given nicotinamide.1 For the effect of antiepileptics, including carbamazepine, on vitamin D concentrations, see Effects on Bone under the Adverse Effects of Phenytoin.
1. Bourgeois BFD, et al. Interactions between primidone, carbamazepine, and nicotinamide. Neurology 1982; 32: 1122–6.

💊 Pharmacokinetics

Carbamazepine is slowly and irregularly absorbed from the gastrointestinal tract and has a bioavailability of 85 to 100%. It is extensively metabolised in the liver, notably by the cytochrome P450 isoenzymes CYP3A4 and CYP2C8. One of its primary metabolites, carbamazepine-10,11-epoxide, is also active. Carbamazepine is excreted in the urine almost entirely in the form of its metabolites; some are also excreted in faeces. Elimination of carbamazepine is reported to be more rapid in children and accumulation of the active metabolite may often be higher than in adults. Carbamazepine is widely distributed throughout the body and is about 70 to 80% bound to plasma proteins. It induces its own metabolism so that the plasma halflife may be considerably reduced after repeated dosage. The mean plasma half-life of carbamazepine on repeated dosage is about 12 to 24 hours; it appears to be considerably shorter in children than in adults. Moreover, the metabolism of carbamazepine is readily induced by drugs that induce hepatic microsomal enzymes (see Interactions, above). Monitoring of plasma concentrations may be performed when clinically indicated and the therapeutic range of total plasma-carbamazepine is usually quoted as being about 4 to 12 micrograms/mL (17 to 50 micromoles/litre), although this is subject to considerable variation. It has been suggested by some, but not all investigators, that measurement of free carbamazepine concentrations in plasma may prove more reliable, and concentrations in saliva or tears, which contain only free carbamazepine, have also been measured. Carbamazepine crosses the placental barrier and is distributed into breast milk. The pharmacokinetics of carbamazepine are affected by use with other antiepileptics (see under Interactions, above).
1. Schmidt D, Haenel F. Therapeutic plasma levels of phenytoin, phenobarbital, and carbamazepine: individual variation in relation to seizure frequency and type. Neurology 1984; 34: 1252–5
2. Bertilsson L, Tomson T. Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11epoxide: an update. Clin Pharmacokinet 1986; 11: 177–98
3. Gilman JT. Carbamazepine dosing for pediatric seizure disorders: the highs and lows. DICP Ann Pharmacother 1991; 25: 1109–12
4. Kodama Y, et al. In vivo binding characteristics of carbamazepine and carbamazepine-10,11-epoxide to serum proteins in paediatric patients with epilepsy. Eur J Clin Pharmacol 1993; 44: 291–3
5. Bernus I, et al. Early stage autoinduction of carbamazepine metabolism in humans. Eur J Clin Pharmacol 1994; 47: 355–60
6. Caraco Y, et al. Carbamazepine pharmacokinetics in obese and lean subjects. Ann Pharmacother 1995; 29: 843–7
7. Mahmood I, Chamberlin N. A limited sampling method for the estimation of AUC and C of carbamazepine and carbamazepine epoxide following a single and multiple dose of a sustained-release product. Br J Clin Pharmacol 1998; 45: 241–6
8. Cohen H, et al. Feasibility and pharmacokinetics of carbamazepine oral loading doses. Am J Health-Syst Pharm 1998; 55: 1134–40
9. Bondareva IB, et al. Population pharmacokinetic modelling of carbamazepine in epileptic elderly patients: implications for dosage. J Clin Pharm Ther 2006; 31: 211–21.

💊 Uses and Administration

Carbamazepine is a dibenzazepine derivative with antiepileptic and psychotropic properties. It is used to control secondarily generalised tonic-clonic seizures and partial seizures, and in some primary generalised seizures. Carbamazepine is also used in the treatment of trigeminal neuralgia and has been tried with variable success in glossopharyngeal neuralgia and other severe pain syndromes associated with neurological disorders such as tabes dorsalis and multiple sclerosis. Another use of carbamazepine is in the management of bipolar disorder unresponsive to lithium. In the treatment of epilepsy, the dose of carbamazepine should be adjusted to the needs of the individual patient to achieve adequate control of seizures; this usually requires total plasma-carbamazepine concentrations of about 4 to 12 micrograms/mL, and increased gradually as needed to maintain freedom from pain. This is usually at maintenance doses of 400 to 800 mg in divided doses; up to 1.2 g daily is considered standard maintenance in the USA, while UK licensed product information considers that up to 1.6 g daily may be needed in some patients. When pain relief has been obtained attempts should be made to reduce, and if possible stop, therapy, until another attack occurs. For the management of bipolar disorder, carbamazepine is given in an initial oral dose of 400 mg daily in divided doses, increased gradually as necessary up to a maximum of 1.6 g daily; the usual maintenance dose range is 400 to 600 mg daily.

Administration.

A modified-release formulation of carbamazepine can reduce fluctuations in carbamazepine concentrations,1 and tolerability and seizure control in patients with epilepsy may be improved.2,3 Such formulations should be considered in patients receiving high doses who suffer intermittent adverse effects, and might also permit a reduction to twiceor even, in some patients, once-daily dosage.2,4 However, bioavailability appears to be slightly less than conventional preparations and dosage adjustments may be required when changing between formulations.1
1. McKee PJW, et al. Monotherapy with conventional and controlled-release carbamazepine: a double-blind, double-dummy comparison in epileptic patients. Br J Clin Pharmacol 1991; 32: 99–104
2. Anonymous. Carbamazepine update. Lancet 1989; ii: 595–7
3. Ryan SW, et al. Slow release carbamazepine in treatment of poorly controlled seizures. Arch Dis Child 1990; 65: 930–5
4. McKee PJW, et al. Double dummy comparison between once and twice daily dosing with modified-release carbamazepine in epileptic patients. Br J Clin Pharmacol 1993; 36: 257–61.

Administration in children.

In the UK, the usual recommended oral dose of carbamazepine for generalised tonic-clonic and partial seizures in children is 10 to 20 mg/kg daily in divided doses. Alternatively the daily dose may be given according to age as follows:
■ up to 1 year: 100 to 200 mg
■ 1 to 5 years: 200 to 400 mg
■ 5 to 10 years: 400 to 600 mg
■ 10 to 15 years: 0.6 to 1 g As with adults, children should be started on a low initial dose of carbamazepine to minimise adverse effects; the BNFC suggests that those aged 1 month to 12 years may initially be given 5 mg/kg at night or 2.5 mg/kg twice daily, increasing by 2.5 to 5 mg/kg every 3 to 7 days as necessary to a usual maintenance dose of 5 mg/kg 2 or 3 times daily. Older children may be given the usual adult dose (see above) although a maximum of 1.8 g daily has been suggested. The BNFC also states that these doses may be used for the treatment of neuropathic pain and some movement disorders, and for mood stabilisation. Carbamazepine may be given rectally to children in whom oral treatment is temporarily not possible; the BNFC suggests this route may be used from 1 month of age. Doses should be about 25% greater than the corresponding oral dose, to a maximum of 250 mg, and given up to 4 times daily.

Bipolar disorder.

Carbamazepine may be given as an alternative to lithium or valproate in patients with bipolar disorder. Studies of its efficacy have been conflicting; although clearly effective in some patients, at least one early study suggested that short-term benefit was not sustained in the longer term.1 More recent results2,3 have suggested that lithium or valproate are generally more effective, but that carbamazepine may conceivably have a role in patients with nonclassical features. Carbamazepine has also been used with lithium, particularly in patients unresponsive to either drug alone; although there are suggestions that the combination may be more effective than monotherapy, particularly in patients with a history of rapid cycling,4 it is associated with a potential risk of serious neurotoxicity—see Antidepressants, under Interactions, above. While some commentators have suggested that carbamazepine is falling out of favour with specialists prescribing for bipolar disorder,5 a more recent literature review6 concluded that it was still a feasible treatment option.
1. Frankenburg FR, et al. Long-term response to carbamazepine: a retrospective study. J Clin Psychopharmacol 1988; 8: 130–2
2. Kleindienst N, Greil W. Differential efficacy of lithium and carbamazepine in the prophylaxis of bipolar disorder: results of the MAP study. Neuropsychobiology 2000; 42 (suppl 1): 2–10
3. Vasudev K, et al. Carbamazepine and valproate monotherapy: feasibility, relative safety and efficacy, and therapeutic drug monitoring in manic disorder. Psychopharmacology (Berl) 2000; 150: 15–23
4. Denicoff KD, et al. Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. J Clin Psychiatry 1997; 58: 470–8
5. Ferrier IN. Developments in mood stabilisers. Br Med Bull 2001; 57: 179–92
6. Stoner SC, et al. Historical review of carbamazepine for the treatment of bipolar disorder. Pharmacotherapy 2007; 27: 68–88.

Depression.

Carbamazepine has been tried1-3 for the augmentation of antidepressant therapy in the treatment of resistant depression. However, such combined therapy may lead to interactions—see also Antidepressants under Interactions, above.
1. De la Fuente JM, Mendlewicz J. Carbamazepine addition in tricyclic antidepressant-resistant unipolar depression. Biol Psychiatry 1992; 32: 369–74
2. Otani K, et al. Carbamazepine augmentation therapy in three patients with trazodone-resistant depression. Int Clin Psychopharmacol 1996; 11: 55–7
3. Ciusani E, et al. Combination therapy with venlafaxine and carbamazepine in depressive patients not responding to venlafaxine: pharmacokinetic and clinical aspects. J Psychopharmacol 2004; 18: 559–66.

Diabetes insipidus.

Cranial diabetes insipidus is usually treated by replacement therapy with antidiuretic hormone (ADH) in the form of desmopressin. Carbamazepine is one of a variety of other drugs that have been tried to promote ADH secretion, although some consider that it is usually ineffective and has unwanted effects.1,2 Doses of 200 to 400 mg daily by mouth have been given. See also Effects on Electrolytes under Adverse Effects, above.
1. Seckl J, Dunger D. Postoperative diabetes insipidus. BMJ 1989; 298: 2–3
2. Singer I, et al. The management of diabetes insipidus in adults. Arch Intern Med 1997; 157: 1293–1301.

Epilepsy.

Carbamazepine is one of the drugs of choice for partial seizures with or without secondary generalisation. It has been used for generalised tonic-clonic seizures (although valproate is the drug of choice where these occur in primary generalised epilepsy), but it may exacerbate absence and myoclonic seizures.

Hemifacial spasm.

Carbamazepine has been reported to have been of help in the treatment of hemifacial spasm.

Hiccup.

For the management of intractable hiccups see under Chlorpromazine. Carbamazepine may be of value for the treatment of neurogenic hiccups such as those that occur in multiple sclerosis.1 Carbamazepine has also been reported to have been of benefit in 3 patients with diaphragmatic flutter,2 a rare disorder associated with involuntary contractions of the diaphragm.
1. McFarling DA, Susac JO. Hoquet diabolique: intractable hiccups as a manifestation of multiple sclerosis. Neurology 1979; 29: 797–801
2. Vantrappen G, et al. High-frequency diaphragmatic flutter: symptoms and treatment by carbamazepine. Lancet 1992; 339: 265–7.

Hyperactivity.

When drugs are indicated for attention deficit hyperactivity disorder initial treatment is usually with a central stimulant but meta-analysis of a small number of trials has provided evidence that carbamazepine may be effective.1
1. Silva RR, et al. Carbamazepine use in children and adolescents with features of attention-deficit hyperactivity disorder: a metaanalysis. J Am Acad Child Adolesc Psychiatry 1996; 35: 352–8.

Lesch-Nyhan syndrome.

The severe self-mutilation that occurs in patients with Lesch-Nyhan syndrome has been reported to improve in those given antiepileptics such as carbamazepine.1
1. Roach ES, et al. Carbamazepine trial for Lesch-Nyhan self-mutilation. J Child Neurol 1996; 11: 476–8.

Movement disorders.

Carbamazepine is one of many drugs that have been tried in the symptomatic treatment of chorea; there have been anecdotal reports of benefit in both nonhereditary1,2 and hereditary choreas.3 Carbamazepine is also among the drugs that have been tried in the treatment of dystonias that have not responded to levodopa or antimuscarinics. Although some patients may benefit from carbamazepine, it is not generally recommended because of a relatively low success rate and the possibility of adverse effects.4Carbamazepine therapy has also been associated with movement disorders—see Effects on the Nervous System: Extrapyramidal Effects under Adverse Effects, above. Carbamazepine has also been used in resistant cases of tardive dyskinesia. Although not licensed in the UK for movement disorders in children, the BNFC suggests that carbamazepine may be tried in disorders such as paroxysmal kinesigenic choreoathetosis in doses similar to those used for the treatment of epilepsy (see Administration in Children, above).
1. Roig M, et al. Carbamazepine: an alternative drug for the treatment of nonhereditary chorea. Pediatrics 1988; 82: 492–5
2. García González MM, et al. Corea de Sydenham: presentación de un caso tratado con carbamazepina con excelente respuesta clínica. An Pediatr (Barc) 2007; 66: 80–3
3. Roulet E, Deonna T. Successful treatment of hereditary dominant chorea with carbamazepine. Pediatrics 1989; 83: 1077
4. Anonymous. Dystonia: underdiagnosed and undertreated? Drug Ther Bull 1988; 26: 33–6.

Neonatal seizures.

Carbamazepine has been tried in the management of neonatal seizures.

Neuropathic pain.

As well as being used to ease the pain of trigeminal neuralgia (see below) carbamazepine may be of use in other neuropathic pain including that associated with diabetic neuropathy. A systematic review1 concluded that about two-fifths of patients who take carbamazepine for neuropathic pain will achieve moderate pain relief, but this was based on small studies. The authors found no evidence that carbamazepine was effective for acute pain. Carbamazepine has also been tried in an attempt to prevent the painful sensory neuropathy associated with oxaliplatin treatment; results of preliminary studies have been conflicting.2,3 Although not licensed in the UK for neuropathic pain in children, the BNFC suggests that carbamazepine may be tried in doses similar to those used for the treatment of epilepsy (see Administration in Children, above).
1. Wiffen PJ, et al. Carbamazepine for acute and chronic pain. Available in the Cochrane Database of Systematic Reviews; Issu
3. Chichester: John Wiley; 2005 (accessed 09/06/08)
2. Eckel F, et al. Prophylaxe der Oxaliplatin-induzierten Neuropathie mit Carbamazepin: eine Pilotstudie. Dtsch Med Wochenschr 2002; 127: 78–82
3. Wilson RH, et al. Acute oxaliplatin-induced peripheral nerve hyperexcitability. J Clin Oncol 2002; 20: 1767–74.

Nocturnal enuresis.

Carbamazepine has been reported to be of benefit in the treatment of primary nocturnal enuresis; a dose of 200 mg at night for 15 nights markedly decreased the frequency of bed-wetting episodes in 8 children.1 For the conventional management of nocturnal enuresis.
1. Al-Waili NS, et al. Effect of carbamazepine on urinary volume and osmolality, water clearance, and serum osmolality in patients with primary enuresis. Eur Urol 2006; 50: 844–9.

Psychiatric disorders.

Carbamazepine has psychotropic properties and has been tried in the management of several psychiatric disorders, particularly in patients with bipolar disorder (see above). Carbamazepine has also been used with mixed results in various disorders for the control of symptoms such as agitation, aggression, and rage1-4. It may produce modest benefit when used as an adjunct to antipsychotics in the management of refractory schizophrenia but any improvement appears to be related to its mood stabilising effect.5 However, a more recent systematic review,6 albeit based on small studies, found carbamazepine to have no significant benefit either as monotherapy or as an adjunct to antipsychotics; the authors considered that further randomised studies may be warranted. Carbamazepine also has the potential to reduce serum concentrations of antipsychotics, resulting in clinical deterioration. Carbamazepine has also been tried7 in post-traumatic stress disorder.
1. Mattes JA. Comparative effectiveness of carbamazepine and propranolol for rage outbursts. J Neuropsychiatr Clin Neurosci 1990; 2: 159–64
2. Gleason RP, Schneider LS. Carbamazepine treatment of agitation in Alzheimer’s outpatients refractory to neuroleptics. J Clin Psychiatry 1990; 51: 115–18
3. Tariot PN, et al. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry 1998; 155: 54–61
4. Cueva JE, et al. Carbamazepine in aggressive children with conduct disorder: a double-blind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry 1996; 35: 480–90
5. Okuma T. Use of antiepileptic drugs in schizophrenia: a review of efficacy and tolerability. CNS Drugs 1994; 1: 269–84
6. Leucht S, et al. Carbamazepine for schizophrenia. Available in The Cochrane Database of Systematic Reviews; Issu
3. Chichester: John Wiley; 2007 (accessed 09/06/08)
7. Wolf ME, et al. Posttraumatic stress disorder in Vietnam veterans: clinical and EEG findings; possible therapeutic effects of carbamazepine. Biol Psychiatry 1988; 23: 642–4.

Restless legs syndrome.

The aetiology of restless legs syndrome is obscure and treatment has been largely empirical. In a double-blind study involving 174 patients carbamazepine appeared to be more effective than placebo.1 Oxcarbazepine has been reported2 to be of benefit in restless legs syndrome induced by paroxetine.
1. Telstad W, et al. Treatment of the restless legs syndrome with carbamazepine: a double blind study. BMJ 1984; 288: 444–6
2. Öztürk Ö, et al. Oxcarbazepine treatment for paroxetine-induced restless leg syndrome. Gen Hosp Psychiatry 2006; 28: 264–5.

Tinnitus.

Treatment of tinnitus is difficult, and many drugs have been tried. Although carbamazepine has been reported to be effective in some patients, it is rarely used because of its adverse effects.

Trigeminal neuralgia.

Carbamazepine is the drug of choice in the treatment of the acute stages of trigeminal neuralgia. Satisfactory pain relief may be achieved in 70% or more of patients, although increasingly larger doses may be required and adverse effects can be troublesome.

Withdrawal syndromes.

Carbamazepine has been tried in the prophylaxis and treatment of various withdrawal syndromes. Reduction in cocaine use associated with carbamazepine treatment was found in one short-term controlled study,1 although a systematic review2 of data from later studies concluded that there was no evidence to support the use of carbamazepine in the treatment of cocaine dependence. It has been reported3,4 to be of benefit in some patients during benzodiazepine withdrawal but such adjunct therapy is not usually indicated. Carbamazepine has been shown5,6 to be effective in the treatment of symptoms of the alcohol withdrawal syndrome but as there are limited data on its efficacy in preventing associated delirium tremens and seizures it is usually recommended that it should only be used as an adjunct to benzodiazepine therapy. Carbamazepine has also been studied7 as an aid in the treatment of alcohol dependence.
1. Halikas JA, et al. Cocaine reduction in unmotivated crack users using carbamazepine versus placebo in a short-term, doubleblind crossover design. Clin Pharmacol Ther 1991; 50: 81–95
2. Lima Reisser A, et al. Carbamazepine for cocaine dependence. Available in The Cochrane Database of Systematic Reviews; Issu
2. Chichester: John Wiley; 2002 (accessed 01/09/08)
3. Schweizer E, et al. Carbamazepine treatment in patients discontinuing long-term benzodiazepine therapy: effects on withdrawal severity and outcome. Arch Gen Psychiatry 1991; 48: 448–52
4. Klein E, et al. Alprazolam withdrawal in patients with panic disorder and generalized anxiety disorder: vulnerability and effect of carbamazepine. Am J Psychiatry 1994; 151: 1760–6
5. Malcolm R, et al. Double-blind controlled trial comparing carbamazepine to oxazepam treatment of alcohol withdrawal. Am J Psychiatry 1989; 146: 617–21
6. Stuppaeck CH, et al. Carbamazepine versus oxazepam in the treatment of alcohol withdrawal: a double-blind study. Alcohol Alcohol 1992; 27: 153–8
7. Mueller TI, et al. A double-blind, placebo-controlled pilot study of carbamazepine for the treatment of alcohol dependence. Alcohol Clin Exp Res 1997; 21: 86–92.

💊 Preparations

BP 2008: Carbamazepine Tablets; USP 31: Carbamazepine Extended-Release Tablets; Carbamazepine Oral Suspension; Carbamazepine Tablets.

Proprietary Preparations

Arg.: Actinerval; Carbagramon; Carbamat; CMP†; Conformal; Elebe; Tegretol; Austral.: Tegretol; Teril; Austria: Deleptin; Neurotop; Sirtal; Tegretol; Belg.: Tegretol; Braz.: Carmazin; Convulsan; Tegretard; Tegretol; Tegrex; Tegrezin; Uni Carbamaz; Canad.: Novo-Carbamaz; Tegretol; Chile: Carbactol Retard†; Eposal; Tegretal; Cz.: Biston; Neurotop; Tegretol; Timonil; Denm.: Nordotol†; Tegretol; Trimonil; Fin.: Neurotol; Tegretol; Fr.: Te g r e tol; Ger.: Carba; Carbabeta; Carbadura; Carbaflux; Carbagamma; Carbium†; espa-lepsin; Finlepsin; Fokalepsin; Sirtal; Tegretal; Timonil; Gr.: Te g r e tol; Hong Kong: Carzepin; CP-Carba; Tegretol; Teril; Hung.: Azepal†; Finlepsin†; Neurotop; Stazepine; Tegretol; Timonil; India: Carbacontin; Cizetol; Mazetol; Tegrital; Indon.: Bamgetol; Tegretol; Teril; Irl.: Gericarb; Tegretol; Temporol†; Israel: Carbi; Tegretol; Teril; Timonil; Ital.: Te gr et o l ; Malaysia: Tave r ; Te g re to l; Mex.: Adepril†; Apobace†; Bioneuril; Bioreunil†; Carbalan; Carbasal; Carbaval; Carbazep; Carbazina; Carpin; Clostedal; Dateril; Neugeron; Neurolep; Sepibest; Tegretol; Trepina; Ultrepyl; Volutol†; Zepiken; Neth.: Tegretol; Norw.: Tegretol; Trimonil; NZ: Tegretol; Teril; Philipp.: Carbilepp; Epazin; Epikor; Tegretol; Pol.: Amizepin; Finlepsin; Neurotop; Tegretol; Timonil; Port.: Tegretol; Rus.: Carbalepsin (Карбалепсин); Carbapin (Карбапин); Finlepsin (Финлепсин); Tegretol (Тегретол); Zeptol (Зептол); S.Afr.: Degranol; Tegretol; Singapore: Carbatol; Neurotop; Tegretol; Spain: Tegretol; Swed.: Hermolepsin; Tegretol; Trimonil; Switz.: Carsol; Neurotop; Tegretol; Timonil; Thai.: Antafit; Carbatol†; Carbazene; Carmapine; Carpine; Carzepine; Mapezine; Panitol; Taver; Tegretol; Zeptol; Turk.: Karazepin; Karbalex; Karbasif; Karberol; Kazepin; Tegretol; UAE: Fitzecalm; UK: Arbil; Carbagen; Epimaz; Tegretol; Teril†; Timonil†; USA: Atretol†; Carbatrol; Epitol; Equetro; Tegretol; Teril; Venez.: Convulex; Gabox†; Tanfedin; Tegretol.
Published October 15, 2018.