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Oxcarbazepine is an antiepileptic drug from the group of carboxamide derivatives, effective for the treatment of partial epileptic seizures and generalized tonic-clonic epileptic seizures in children and adults.

Synonyms Russian

Trileptal, monohydroxycarbamazepine.

English synonyms

Oxcarbazepine, Trileptal, Apydan, Monohydroxy carbamazepine, MHC, Oxcarbazepine metabolite.

Research method

Gas chromatography-mass spectrometry (GC-MS).

Units

µg/ml (micrograms per milliliter).

What biomaterial can be used for research?

Venous blood.

How to properly prepare for research?

Do not eat for 2-3 hours before the test; you can drink clean still water.
Do not smoke for 30 minutes before the test.

General information about the study

Oxcarbazepine (commonly called Trileptal) is an antiepileptic drug, a derivative of carbamazepine, which is included in the list of vital and essential drugs. It is used as a “drug of first choice” both in monotherapy and in combined treatment of partial epileptic seizures and generalized tonic-clonic epileptic seizures in children and adults.

The oxcarbazepine molecule differs from carbamazepine in the presence of an additional oxygen atom at the benzylcarboxamide group. This structural feature reduces the toxic effects of drug metabolites on the liver and prevents the development of severe forms of anemia, which sometimes occur while taking carbamazepine. The drug has a mechanism of action similar to carbamazepine, associated with blocking sodium channels and stabilizing the membranes of overexcited neurons, suppressing serial neuronal discharges and reducing synaptic conduction of impulses.

Oxcarbazepine is completely absorbed from the intestine and is rapidly metabolized to form a pharmacologically active metabolite, a monohydroxy derivative (MHD). Eating does not affect the absorption of the medicine. In the blood, the drug's metabolites are 40% protein bound, and the degree of binding does not depend on the concentration of the drug in the serum. Oxcarbazepine is excreted from the body primarily by the kidneys (95%) in the form of metabolites, 1% is excreted unchanged. About 4% of the dose is excreted through the intestines. In renal failure, excretion of the drug is impaired and its concentration in the blood increases. Concomitant use of certain drugs also affects blood levels of oxcarbazepine, which in some cases requires laboratory monitoring of serum drug concentrations.

Testing for oxcarbazepine is not necessary in all cases of taking the drug; it is recommended if there are factors affecting its metabolism and excretion, or if the previously prescribed dose of the drug is insufficiently effective.

What is the research used for?

To monitor the concentration of the drug in the blood;
to optimize seizure control by adjusting the dose of the drug;
to assess drug interactions;
to identify violations of the drug regimen.

When is the study scheduled?

When prescribing oxcarbazepine in combination with other drugs (including those associated with concomitant diseases and conditions);
when monitoring pediatric or elderly patients with renal failure, as well as pregnant women taking oxcarbazepine;
if the drug used is insufficiently effective and the issue of dose adjustment is decided;
if the patient is suspected of non-compliance with the oxcarbazepine regimen.

What do the results mean?

Reference values: 15 - 35 mcg/ml.

The results of the study are analyzed by the attending physician, taking into account the dose of oxcarbazepine, its regimen, the patient’s age, clinical picture of the disease and concomitant pathology.

What can influence the result?

Medicines that reduce the concentration of oxcarbazepine in the blood: phenytoin, phenobarbital, carbamazepine, valproic acid, verapamil.

Oxcarbazepine in the treatment of focal epilepsy

In the last decade, a number of new generation AEDs have entered clinical practice. On the one hand, this made it possible to improve the quality of medical care for patients with epilepsy, on the other hand, it acutely confronted doctors with the problem of choosing a drug in different situations: with newly diagnosed epilepsy, if it is necessary to switch to a second monotherapy, when selecting a rational combination therapy. According to the proposals of the Working Group on the draft new classification of 2001, the following forms of symptomatic and probably symptomatic (cryptogenic) focal epilepsy are identified: Limbic epilepsies: – mesial temporal lobe epilepsy with hippocampal sclerosis; – mesial temporal lobe epilepsy caused by a specific etiology; – other types of specific localization and etiology. Neocortical epilepsies: – Rasmussen syndrome; – hemiconvulsion-hemiplegia syndrome; – other types of specific localization and etiology; – migratory partial seizures of early infancy. Focal epilepsy is the most common form of the disease in adults (up to 60–70%), of which approximately half of the cases are temporal lobe epilepsy. Focal epilepsy is characterized by simple focal, complex focal and secondary generalized seizures, gelastic, hemiclonic seizures. Diagnosis of focal epilepsy is based on determining the focal onset of seizures based on descriptions of seizures, routine EEG data, video-EEG monitoring data, testing the patient during a seizure, and analysis of seizure EEG [18]. Long-term administration of AEDs is the mainstay of treatment for epilepsy. For newly diagnosed focal epilepsy in adults, priority is given to monotherapy. But only in 50–70% of cases is it possible to achieve remission on one drug. Moreover, the first monotherapy is only 50% successful. In addition, despite the introduction of new AEDs into practice, the problem of drug resistance remains acute [18]. In this regard, individual selection of AEDs is of great importance, ensuring a reduction in the frequency of seizures, minimizing the side effects of AEDs, preventing iatrogenic resistance, and improving the quality of life of patients. Since the 1960s, carbamazepine (CMZ) has been the main drug in the treatment of focal epilepsy in adults and a model for comparison in studies of new AEDs. Oxcarbazepine is a 10-keto analogue of carbamazepine. Oxcarbazepine was first licensed in Denmark as an antiepileptic drug in 1990 and registered in Russia in 2004. The antiepileptic effect of oxcarbazepine is exerted by its main metabolite, hydroxy-10,11-dihydro-5H-dibenzazepine-5-carboxamide (MHD - monohydroxy derivative). The main mechanism of action of MHD is the blockade of sodium channels, but others include effects on calcium and potassium channels. Unlike CMH, oxcarbazepine (OZ) is metabolized via cytochrome P450-dependent reductases and therefore lacks inducing effects on hepatic oxidase metabolism [20]. Also, during the biotransformation of OKZ, the formation of the epoxide metabolite, which is responsible for most of the side effects of ACM, does not occur [27]. OKZ does not cause autoinduction [10,13,20] and is characterized by high bioavailability (>95%) [13]. Monohydroxy derivative (MHD) has linear pharmacokinetics and a lower level of binding to plasma proteins compared to CMH [23]. The fact that it is MHD, and not OKZ, that is not an independent active agent is the basis for the relatively low toxicity in overdose. Thus, a tenfold increase in the OKZ content led to only a twofold increase in the MHD concentration [30]. When prescribing oxcarbazepine both in monotherapy and in combination therapy, the initial dose is 600 mg per day in two doses, with weekly titration of no more than 600 mg until the effect is achieved. But in a hospital setting, if necessary, it is possible to achieve a therapeutic dose within 24 hours [23]. Data from a number of controlled clinical studies show that oxcarbazepine is not inferior in effectiveness to carbamazepine, diphenine, valproate with better tolerability. The effectiveness of replacing other AEDs with oxcarbazepine monotherapy has also been confirmed. Currently, the drug is the first-line drug of choice for monotherapy, adjunctive therapy, and treatment of drug-resistant focal epilepsy in adults and children [4,23,26,31]. In addition, oxcarbazepine is the first of the new generation of drugs approved by the FDA for monotherapy of focal seizures, and the first drug in 25 years, approved in 2003 for use as monotherapy in children from 4 years of age [18]. In 2005, the journal Epilepsy & Behavior published the results of a survey of experts regarding the treatment of symptomatic localization-related epilepsy in adults [12]. Some recommendations based on this survey are presented below in Tables 1, 2, 3, which clearly demonstrate the modern view on the choice of AEDs. Thus, according to experts, of the new drugs, only oxcarbazepine is the most suitable for the treatment of focal epilepsy in simple and secondary generalized seizures. Oxcarbazepine is also recommended as a second monotherapy when switching from gabapentin, lamotrigine, levetiracetam, phenytoin, topiramate, valproate. Combinations of oxcarbazepine with levetiracetam, lamotrigine, topiramate, and valproate are considered rational. Transfer to monotherapy with oxcarbazepine in case of insufficient effectiveness and poor tolerability of other AEDs was accompanied by a statistically significant improvement in quality of life [22]. Transferring from CMH to monotherapy with oxcarbazepine is well tolerated by patients, leads to a decrease in the frequency or elimination of attacks and a decrease in side effects. It should be remembered that 200 mg of KMZ corresponds to 300 mg of OKZ. The transition from CMH to oxcarbazepine is also accompanied by normalization of neurophysiological parameters [6]. A decrease in side effects occurs in 3/4 of cases [23]. It is important that the transition from CMH to oxcarbazepine can be either gradual or almost instantaneous [2,3]. But a one-stage transition is most successful at doses of KMZ up to 800 mg/day. in other cases, slower titration is recommended [26]. Switching from CMH to oxcarbazepine is not justified when a rash appears due to the presence of cross-sensitivity, which is observed in 25% of cases [18,26]. In many cases, the interaction of OKZ with other drugs is not clinically significant, although OKZ can increase the concentration of phenytoin and reduce the concentrations of lamotrigine and topiramate [13]. The minimal activation potential of the cytochrome P450 system determines, on the one hand, the greater effectiveness of OKZ in duotherapy (for example, with valproate) compared to CMH [25], on the other hand, it may cause side effects due to increased blood concentrations of other drugs [ 13.28]. In such cases, monitoring of blood levels and dose adjustment of AEDs is necessary. Side effects are often transient and noted at the beginning of treatment [4,5]. The most important of them: headache, dizziness, weakness, nausea, drowsiness, ataxia, diplopia, hyponatremia. Among the side effects, hyponatremia should be noted, which occurs more often during treatment with oxcarbazepine than against the background of CMH. Thus, a decrease in sodium to a level of 128 mmol/l and below was observed in 12.4% of those treated with oxcarbazepine and in 2.8% of those treated with CMZ. In patients of older age groups and when taking oxcarbazepine in daily doses >30 mg/kg, the likelihood of developing hyponatremia is higher [8,17]. Hyponatremia is asymptomatic in most cases and is clinically manifested primarily by dysfunction of the central nervous system. The first signs are malaise, nausea, drowsiness, and later psychosis, epileptic seizures, and coma may develop. However, the need to monitor sodium levels only arises in the presence of kidney disease, concomitant use of drugs that cause hyponatremia (diuretics, oral contraceptives, NSAIDs), or when clinical signs occur [24]. Serious side effects include very rarely hypersensitivity syndrome to anticonvulsants and hematological disorders [18]. Activation of the group of isoenzymes CYP3A OKZ causes increased metabolism of oral contraceptives and a decrease in the concentration of ethinyl estradiol and levonorgestrel, so it is necessary to take contraceptives with a high estrogen content (50 mg) [27]. According to the literature, oxcarbazepine does not cause an increased risk of malformations when used alone during pregnancy (248 women) compared with population data, although further studies are needed to clarify the safety profile [16]. At the same time, there is evidence of an increase in MHD clearance during pregnancy, which can lead to a decrease in blood concentrations and disruption of drug remission, which necessitates the need to monitor MHD levels [14]. The effect of oxcarbazepine on reproductive endocrine function in men is dose-dependent: in doses up to 900 mg/day. The concentration of male sex hormones in the blood does not change; at higher doses, there is an increase in the level of testosterone, gonadotropins, and binding globulin. But unlike CMH, oxcarbazepine does not cause a decrease in the bioactivity of androgens [21]. Oxcarbazepine, like CMH, is contraindicated in absence seizures, myoclonic seizures, can cause their occurrence in case of erroneous prescription in idiopathic generalized epilepsy, and also cause the phenomenon of secondary bilateral synchronization in focal epilepsies. At the same time, the effect of OKZ on generalized tonic–clonic seizures is less dramatic than that of CMH [9,11]. Thus, oxcarbazepine is a new generation drug for the treatment of focal epilepsy, characterized by good efficacy, tolerability and a favorable pharmacokinetic profile.

Literature 1. Washington University Therapeutic Handbook, ed. M. Woodley, A. Whelan. Practice. Moscow, 1995. 2. Albani F, Baruzzi A; "PRIMO" Study Group Oxcarbazepine long-term treatment retention in patients switched over from carbamazepine. Neurol Sci. 2006 Jul;27(3):173–5. 3. Albani F, Grassi B, Ferrara R, Turrini R, Baruzzi A; PRIMO Study Group. Immediate (overnight) switching from carbamazepine to oxcarbazepine monotherapy is equivalent to a progressive switch. Seizure. 2004 Jun;13(4):254–63. 4. Bang LM, Goa KL. Spotlight on oxcarbazepine in epilepsy. CNS Drugs. 2004;18(1):57–61. 5. Beydoun A, Sachdeo RC, Kutluay E, McCague K, D'Souza J. Sustained efficacy and long-term safety of oxcarbazepine: one-year open-label extension of a study in refractory partial epilepsy. Epilepsy. 2003 Sep;44(9):1160–5. 6. Clemens B, Menes A, Nagy Z. Objective assessment of neurotoxicity while shifting from carbamazepine to oxcarbazepine. Acta Neurol Scand. 2004 May;109(5):324–9. 7. Dam M, Ekberg R, Loyning Y, Waltimo O, Jakobsen K. A double–blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res. 1989 Jan–Feb;3(1):70–6 8. Dong X, Leppik IE, White J, Rarick J. Hyponatremia from oxcarbazepine and carbamazepine. Neurology. 2005 Dec 27;65(12):1976–8. 9. Gelisse P, Genton P, Kuate C, Pesenti A, Baldy–Moulinier M, Crespel A. Worsening of seizures by oxcarbazepine in juvenile idiopathic generalized epilepsies. Epilepsy. 2004 Oct;45(10):1282–6. 10. Glauser T.A. Oxcarbazepine in the treatment of epilepsy. Pharmacotherapy. 2001 Aug;21(8):904–19. 11. Kaddurah AK, Holmes GL. Possible precipitation of myoclonic seizures with oxcarbazepine. Epilepsy Behav. 2006 Feb;8(1):289–93. 12. Karcerski S., Morrell MJ, Carpenter D. Treatment of epilepsy in adults: expert opinion, 2005. Epilepsy & Behavior 7 (2005)S1–S64 13. May TW, Korn-Merker E, Rambeck B. Clinical pharmacokinetics of oxcarbazepine . Clin Pharmacokinet. 2003;42(12):1023–42. 14. Mazzucchelli I., Onat FY, Ozkara C., Ataki D., Speccho LM, La Neve A., Gatti G., Perucca E. Changes in the disposition of carbamazepine and its metabolites during pregnancy and the puerperium. Epilepsia, 2006, v.47, n.3, p. 504–509. 15. McKee PJ, Blacklaw J, Forrest G, Gillham RA, Walker SM, Connelly D, Brodie MJ. A double–blind, placebo–controlled interaction study between oxcarbazepine and carbamazepine, sodium valproate and phenytoin in epileptic patients. Br J Clin Pharmacol. 1994 Jan;37(1):27–32. 16. Montouris G. Safety of the new antiepileptic drug oxcarbazepine during pregnancy. Curr Med Res Opin. 2005 May;21(5):693–701. 17. Nielsen OA, Johannessen AC, Bardrum B. Oxcarbazepine–induced hyponatremia, a cross-sectional study. Epilepsy Res. 1988 Jul-Aug;2(4):269–71. 18. Panayiotopoulos CP THE EPILEPSIES: Seizures, Syndromes and Management. 2005. Bladon. Medical Publishing.541p. 19. Pauletto G, Bergonzi P; Triveneto Epilepsy Study Group. Oxcarbazepine reduces seizure frequency in a high proportion of patients with both newly diagnosed and refractory partial seizures in clinical practice.Seizure. 2006 Apr;15(3):150–5. 20. Rabasseda X. Oxcarbapezine: anticonvulsant profile and safety. Drugs Today (Barc). 2001 May;37(5):333–355. 21. Rattya J, Turkka J, Pakarinen AJ, Knip M, Kotila MA, Lukkarinen O, Myllyla VV, Isojarvi JI. Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy. Neurology. 2001 Jan 9;56(1):31–6. 22. Sachdeo RC, Gates JR, Bazil CW, Barkley GL, Tatum W, D'Souza J, McCague K. Improved quality of life in patients with partial seizures after conversion to oxcarbazepine monotherapy. Epilepsy Behav. 2006 Aug 23. Schachter SC. Oxcarbazepine: current status and clinical applications. Expert Opin Investig Drugs. 1999 Jul;8(7):1103–12. 24. Schmidt D, Arroyo S, Baulac M, Dam M, Dulac O, Friis ML, Kalviainen R, Kramer G, van Parys J, Pedersen B, Sachdeo R. Recommendations on the clinical use of oxcarbazepine in the treatment of epilepsy: a consensus view. Acta Neurol Scand. 2001 Sep;104(3):167–70. 25. Schmidt D, Elger CE. What is the evidence that oxcarbazepine and carbamazepine are distinctly different antiepileptic drugs? Epilepsy Behav. 2004 Oct;5(5):627–35. 26. Smith PE; UK Oxcarbazepine Advisory Board. Clinical recommendations for oxcarbazepine. Seizure. 2002 Jan;11(1):73. 27. Shorvon SD Handbook of epilepsy treatment Blackwell Science Ltd, 2000, 248p. 28. Theis JG, Sidhu J, Palmer J, Job S, Bullman J, Ascher J. Lack of pharmacokinetic interaction between oxcarbazepine and lamotrigine. Neuropsychopharmacology. 2005 Dec;30(12):2269–74. 29. Tomson T. Drug selection for the newly diagnosed patient: when is a new generation antiepileptic drug indicated? J Neurol. 2004 Sep;251(9):1043–9. 30. van Opstal JM, Janknegt R, Cilissen J, L'Ortije WH, Nel JE, De Heer F. Severe overdosage with the antiepileptic drug oxcarbazepine. Br J Clin Pharmacol. 2004 Sep;58(3):329–31. 31. Vazquez B. Monotherapy in epilepsy: role of the newer antiepileptic drugs. Arch Neurol. 2004 Sep;61(9):1361–5.

Oxcarbazepine

special instructions

Use with caution in patients with known hypersensitivity to carbamazepine, as in this group of patients, approximately 25-30% of cases may develop hypersensitivity reactions to oxcarbazepine. Patients who do not have a history of hypersensitivity to carbamazepine may also develop hypersensitivity reactions to oxcarbazepine, including multiple organ dysfunction. If immediate hypersensitivity reactions occur, oxcarbazepine should be discontinued immediately and alternative therapy should be prescribed.

Use with caution in patients with severe liver dysfunction.

In patients with impaired renal function and who have a low serum sodium concentration, or in patients receiving concomitant treatment with drugs that promote sodium excretion from the body (diuretics, drugs that affect the secretion of ADH), the sodium concentration in the blood serum should be determined before initiating therapy with oxcarbazepine. blood serum. Subsequently, serum sodium concentrations should be monitored 2 weeks after initiation of therapy and then monthly for 3 months or as needed. Particular attention should be paid to these risk factors in elderly patients. If it is necessary to prescribe diuretics and other drugs that reduce the concentration of sodium in the blood serum, patients receiving oxcarbazepine should follow the same recommendations. If clinical symptoms suggestive of hyponatremia occur, serum sodium concentrations should be measured. For other patients, serum sodium concentrations can be measured during routine blood tests.

If symptoms of severe suppression of bone marrow hematopoiesis develop, it is necessary to consider discontinuing oxcarbazepine.

Episodes of suicidal behavior and ideation were rarely reported in patients receiving anticonvulsants. The mechanism for increasing the risk of suicide in this category of patients has not been established. Therefore, careful monitoring of patients receiving oxcarbazepine is necessary at all stages of treatment.

It is necessary to monitor body weight in all patients with heart failure to promptly detect fluid retention. If fluid retention occurs or as symptoms of heart failure progress, serum sodium concentrations should be determined. If hyponatremia occurs, the amount of fluid consumed should be limited. When using oxcarbazepine, in very rare cases, cardiac conduction disturbances are possible, therefore, during the treatment period, careful monitoring of patients with previous conduction disturbances (AV block, arrhythmia) is necessary.

When using oxcarbazepine, dermatological reactions were observed in both children and adults, and developed on average 19 days after the start of treatment. There are isolated reports of cases of recurrence of skin reactions when taking oxcarbazepine again. If skin reactions develop while using oxcarbazepine, you should consider discontinuing it and prescribing another antiepileptic drug.

If hepatitis is suspected, discontinuation of oxcarbazepine should be considered.

As with any other antiepileptic drugs, oxcarbazepine should be discontinued gradually due to the risk of increased seizure frequency.

Impact on the ability to drive vehicles and operate machinery

Patients who experience dizziness, drowsiness or other central nervous system disorders while taking oxcarbazepine should not drive vehicles or operate machinery during the treatment period.

Carbamazepine

Concomitant use with inhibitors of the CYP 3A4 isoenzyme may lead to increased plasma concentrations of carbamazepine. The combined use of inducers of the CYP 3 A 4 isoenzyme may lead to an acceleration of the metabolism of carbamazepine and a possible decrease in its plasma concentration. Withdrawal of concomitantly taken inducers of the CYP 3A4 isoenzyme may reduce the rate of biotransformation of carbamazepine and lead to an increase in the level of carbamazepine in the blood plasma. When used simultaneously with drugs metabolized by the CYP 3A4 isoenzyme, induction of metabolism and a decrease in their concentration in plasma is possible.

Drugs that may increase plasma concentrations of carbamazepine or carbamazepine-10,11-epoxide:

dextropropoxyphene, ibuprofen, danazol, macrolide antibiotics (eg, erythromycin, troleandomycin, josamycin, clarithromycin), fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine, stiripentol, vigabatrin, azoles (eg, itraconazole, ketoconazole, fluconazole, voriconazole ), loratadine , terfenadine, loxapine, olanzapine, quetiapine, isoniazid, viral protease inhibitors for the treatment of HIV infection (for example, ritonavir), acetazolamide, verapamil, diltiazem, omeprazole, oxybutynin, dantrolene, ticlopidine, nicotinamide (in adults, only in high doses), possibly - cimetidine, desipramine, primidone, valproic acid.

Drugs that may reduce plasma concentrations of carbamazepine:

felbamate, methsuximide, oxcarbazepine, phenobarbital, fensuximide, phenytoin, fosphenytoin, primidone, progabide, theophylline, aminophylline, isotretinoin, rifampicin, cisplatin, doxorubicin; herbal preparations containing St. John's wort and, although data are conflicting, possibly also clonazepam, valproic acid or valpromide.

The effect of carbamazepine on plasma concentrations of drugs used as concomitant therapy:

Carbamazepine may reduce plasma concentrations or reduce or even completely eliminate the effects of the following drugs: methadone, paracetamol, antipyrine, tramadol, doxycycline, oral anticoagulants (warfarin, phenprocoumon, dicumarol, acenocoumarol), bupropion, citalopram, trazodone, tricyclic antidepressants (imipramine, amitriptyline, nortriptyline, clomipramine), clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide, itraconazole, praziquantel, imatinib, clozapine, haloperidol, bromperidol, olanzapine, quetiapine , risperidone, ziprasidone, used in the treatment of HIV infection (indinavir, ritonavir, saquinavir), alprazolam; midazolam, theophylline, calcium channel blockers of the dihydropyridine group (for example, felodipine), digoxin, oral contraceptives (selection of alternative methods of contraception is necessary), glucocorticosteroids (for example, prednisolone, dexamethasone); cyclosporine, everolimus, levothyroxine sodium, estrogens and/or progesterone.

There are reports that while taking carbamazepine, the level of phenytoin in the blood plasma may either increase or decrease, and the level of mephenytoin may increase (in rare cases).

Combinations to consider:

Increased hepatotoxicity caused by isoniazid is possible when used simultaneously with carbamazepine.

In the case of co-administration with levetiracetam, the toxic effect of carbamazepine may be enhanced.

The combined use of carbamazepine and lithium or metoclopramide, as well as carbamazepine and antipsychotic drugs (haloperidol, thioridazine) can lead to an increase in the frequency of adverse neurological reactions (in the case of the latter combination, even with therapeutic concentrations of active substances in the blood plasma).

The simultaneous use of carbamazepine with some diuretics (hydrochlorothiazide, furosemide) can lead to hyponatremia, accompanied by clinical manifestations.

Carbamazepine may antagonize the action of non-depolarizing muscle relaxants (eg, pancuronium bromide). If such a combination of drugs is used, it may be necessary to increase the dose of these muscle relaxants; Patients should be closely monitored as the effects of muscle relaxants may cease more quickly than expected.

Coadministration with grapefruit juice may increase plasma levels of carbamazepine.