Carbamazepine with phenytoin

About 14 days after starting carbamazepine 400 mg daily, a patient taking itraconazole 200 mg daily was noted to have low itraconazole levels (0.15 mg/L), and about 2 months later they were undetectable. About 3 weeks after stopping the carbamazepine, itraconazole levels had reached the therapeutic range (0.36 mg/L). For mention of 2 patients taking carbamazepine with phenytoin, who had undetectable or very low itraconazole levels, and who relapsed or did not respond to itraconazole therapy, see Phenytoin + Azoles , p.552. 

After taking felodipine 10 mg daily for 4 days, 10 epileptics (ineluding 4 taking carbamazepine alone and 3 taking carbamazepine with phenytoin) had markedly reduced plasma felodipine levels (peak levels of 1.6 nanomol/L compared with 8.9 nanomol/L in 12 control subjects). The felodipine bioavailability was reduced to 6.6%. A study in 8 subjects found that the AUC of felodipine was reduced by only 28% by oxcar-bazepine 600 to 900 mg daily for a week. ... 

Fig. 1 Reflectance scan of a blank (A) and of a mixture of antiepileptics with 500 ng substance per chromatogram zone (B). Start (1), primidone (2), carbamazepine (3), phenytoin (4), phenobarbital (5), ethosuximide (6), hexobarbital (7) and solvent front (8).

Phenobarbital, carbamazepine, and phenytoin potentially reduce efficacy of OCs, and many anticonvulsants are known teratogens. The use of condoms in conjunction with high-estrogen OCs or intrauterine devices (IUDs) may be considered for women taking these drugs. 

Studies suggest that as monotherapy for partial seizures, lamotrigine is as effective as carbamazepine and phenytoin lamotrigine may be better tolerated. Clinical data suggest that oxcarbazepine is as effective as phenytoin, valproic acid, and immediate-release carbamazepine, with perhaps fewer side effects. 

Carbamazepine and phenytoin Reduced efficacy (pregnancy) has occurred. Warn users of the possibility of decreased efficacy with use of any related drugs. 

Conversion from adjunctive therapy with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate to monotherapy with lamothgine No specific dosing guidelines can be provided for conversion to monotherapy with lamothgine with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate. 

Baclofen, labeled as a skeletal muscle relaxant binds to GABA receptors and depresses excitation. It is also useful in the treatment of paroxysms of trigeminal neuralgia. Baclofen is effective in patients with carbamazepine-resistant pain and has been used successfully to relieve attacks in patients previously unresponsive to carbamazepine or phenytoin. 

Only a few well-documented drug combinations with phenytoin may necessitate dosage adjustment. Coadministration of the following drugs can result in elevations of plasma phenytoin levels in most patients cimetidine, chloramphenicol, disulfiram, sulthiame, and isoniazid (in slow acetylators). Phenytoin often causes a decline in plasma carbamazepine levels if these two drugs are given concomitantly. 

Approximately doubles widi valproate and decreases by approximately half with carbamazepine/primidone/phenytoin/phenobar-bital/rifampin therefore, initial doses may vary depending on concomitant medications. 

Backman JT, Olkkola KT, Ojala M, Laaksovirta H, Neuvonen PJ. Concentrations and effects of oral midazolam are greatly reduced in patients treated with carbamazepine or phenytoin. Epilepsia 1996 37(3) 253-257. 

Cardiac depressant effects may occur when verapamil or diltiazem is combined with a (p-adrenoceptor antagonoist or a cardiac glycoside. Nifedipine and verapamil are metabolised by cytochrome P-450 3A4. Inhibitors of this enzyme, e.g. HIV-protease inhibitors, cimetidine, fluoxetine, ketoconazole, erythromycin, will increase plasma levels and the dose should be carefully monitored. Conversely, enzyme inducers, e.g. carbamazepine, rifampicin, phenytoin, will decrease their plasma concentrations. 

The mechanism of action of carbamazepine appears to be similar to that of phenytoin. Like phenytoin, carbamazepine shows activity against maximal electroshock seizures. Carbamazepine, like phenytoin, blocks sodium channels at therapeutic concentrations and inhibits high-frequency repetitive firing in neurons in culture (Figure 24-4). It also acts presynaptically to decrease synaptic transmission. These effects probably account for the anticonvulsant action of carbamazepine. Binding studies show that carbamazepine interacts with adenosine receptors, but the functional significance of this observation is not known. 

Mebendazole is teratogenic in animals and therefore contraindicated in pregnancy. It should be used with caution in children younger than 2 years of age because of limited experience and rare reports of convulsions in this age group. Plasma levels may be decreased by concomitant use of carbamazepine or phenytoin and increased by cimetidine. Mebendazole should be used with caution in patients with cirrhosis. 

Crawford P, Chadwick DJ, Martin C, Tjia J, Back DJ, Orme M. The interaction of phenytoin and carbamazepine with combined oral contraceptive steroids. Br J Clin Pharmacol 1990 30(6) 892-6. 

Carbamazepine, phenobarbital, phenytoin, and anticonvulsant polytherapy increased both basal and stimulated concentrations of prolactin, whereas valproate did not (95). However, in other studies, prolactin was unchanged (94). In boys, phenobarbital lowered baseline LH and FSH concentrations and their response to releasing hormone baseline prolactin concentration was raised in comparison with healthy children, and the response of prolactin concentrations to stimulation was impaired (99). 

Total and free (unbound) thyroxine can be reduced by phenytoin and carbamazepine, but free triiodothyronine is normal or only slightly reduced. Thyroid-stimulating hormone is normal or only slightly altered and patients remain clinically euthyroid (94,108). Reductions in the concentrations of some thyroid hormones are probably related to enzyme induction the concentrations return to normal after substituting carbamazepine with oxcarbaze-pine, a less potent enzyme inducer (109). Hypothyroidism has been rarely described in patients taking phenytoin or carbamazepine (110). In contrast to earlier reports, there were no changes in thyroid hormones during treatment with valproate in a later study (111). 

Concentrations of lipoprotein(a) were measured in 51 patients taking long-term carbamazepine, phenobarbital, phenytoin, or valproate and 51 age- and sex-matched controls (133). Lipoprotein(a) concentrations were above 450 pg/ml in 11 patients compared with only 4 controls, and the mean serum lipoprotein(a) concentrations were 330 and 169 pg/ml respectively. The epileptic patients also had a thicker intima media of the common carotid artery. These results suggest that patients taking antiepileptic drugs may be at a higher risk of atherosclerosis. 

Hogan RE, Bertrand ME, Deaton RL, Sommerville KW. Total percentage body weight changes during add-on therapy with tiagabine, carbamazepine and phenytoin. Epilepsy Res 2000 41(l) 23-8. 

Zonisamide (ZonegranJ. Zonisamide is used primarily as an adjunct to other medications in adults with partial seizures. This drug stabilizes sodium channels in a manner similar to carbamazepine and phenytoin, and may also exert some of its antiseizure effects by inhibiting calcium entry into rapidly firing neurons. Zonisamide is fairly well tolerated, although side effects may include sedation, ataxia, loss of appetite, and fatigue. 

Mebendazole Accidental mebendazole poisoning in infants is associated with convulsions, respiratory arrest, and tachyarrhythmia.181 If administered concomitantly, mebendazole interacts with phenytoin, carbamazepine, and cimetidine. 

---