Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Cytochrome P450 3A4 (CYP3A4) is the main enzyme catalyzing formation of the active metabolite carbamazepine-10,11-epoxide. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide.

Co-administration of inhibitors of CYP3A4 or inhibitors of epoxide hydrolase with carbamazepine can which could induce adverse reactions (increase of carbamazepine or carbamazepine-10,11-epoxide plasma concentrations respectively). The dosage of Tegretol should be adjusted accordingly and/or the plasma levels monitored.

Co-administration of CYP3A4 inducers might increase the rate of carbamazepine metabolism, thus leading to potential decreases in the carbamazepine serum level and therapeutic effect.
Similarly, discontinuation of a CYP3A4 inducer may decrease the rate of metabolism of carbamazepine, leading to an increase in carbamazepine plasma levels. The dose of Tegretol may have to be adjusted.

Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II enzyme systems in the liver, and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP3A4 by induction of their metabolism.

Female patients of childbearing potential should be warned that the concurrent use of Tegretol with hormonal contraceptives may render this type of contraceptive ineffective (see Endocrinological effects). Alternative non-hormonal forms of contraception are recommended when using Tegretol (see Women of child-bearing potential, pregnancy, breast-feeding and fertility).

Interactions resulting in a contraindication
The use of Tegretol is contraindicated in combination with monoamine-oxidase inhibitors (MAOIs); before administering Tegretol MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical situation permits (see Effect of Tegretol on plasma levels of concomitant agents).

Agents that may raise carbamazepine plasma levels
Since raised plasma carbamazepine levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of Tegretol should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances described below.

Analgesics, anti-inflammatory drugs:    dextropropoxyphene, ibuprofen Androgens                               danazol
Antibiotics                             macrolide        antibiotics    (e.g.     erythromycin, troleandomycin,         josamycin,     clarithromycin),
ciprofloxacin
Antidepressants                         possibly desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine.
Antiepileptics                          stiripentol, vigabatrin
Antifungals                             azoles (e.g. itraconazole, ketoconazole, fluconazole, voriconazole). Alternative anticonvulsants may be recommended in patients treated with voriconazole or itraconazole
Antihistamines                          terfenadine
Antipsychotics                          olanzapine
Antituberculosis                        isoniazid
Antivirals                              protease inhibitors for HIV treatment (e.g. ritonavir) Carbonic anhydrase inhibitors           acetazolamide
Cardiovascular drugs:                   diltiazem, verapamil
Gastrointestinal drugs:                 possibly cimetidine, omeprazole Muscle relaxants                        oxybutynin, dantrolene
Platelet aggregation inhibitors         ticlopidine
Other interactions:                     grapefruit juice, nicotinamide (only in high dosage) 
Agents that may raise the active metabolite carbamazepine-10,11-epoxide plasma levels Since raised plasma carbamazepine-10,11-epoxide levels may result in adverse reactions (e.g.
dizziness, drowsiness, ataxia, diplopia), the dosage of Tegretol should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances described below:
Antipsychotics          Loxapine, quetiapine
Antiepileptics          Primidone, progabide, valproic acid, valpromide, brivaracetam
Hypnotics and           valnoctamide sedatives

Agents that may decrease carbamazepine plasma levels
The dose of Tegretol may have to be adjusted when used concomitantly with the substances described below.
Antiepileptics             felbamate,      methsuximide,     oxcarbazepine,      phenobarbital, phensuximide, phenytoin (to avoid phenytoin intoxication and subtherapeutic concentrations of carbamazepine it is recommended to adjust the plasma concentration of phenytoin to 13 micrograms
/mL before adding carbamazepine to the treatment) and fosphenytoin,
primidone, and, although the data are partly contradictory, possibly also clonazepam.
Antineoplastics            cisplatin or doxorubicin
Antituberculosis           rifampicin
Bronchodilatators or       theophylline, aminophylline anti-asthma drugs
Antimalarials:             mefloquine may antagonise the anticonvulsant effect of carbamazepine.
Dermatological drugs:      isotretinoin
Other interactions         herbal preparations containing St John's wort (Hypericum perforatum).

Effect of Tegretol on plasma levels of concomitant agents
Carbamazepine may lower the plasma level, or diminish - or even abolish - the activity of certain drugs. Dose adjustments may be required for several medicines. Examples of such medicines are listed below. Note that the list does not include all affected medicines. For more information regarding how individual medicines are affected by induction, see also the product information of the co-administered medicine:
Analgesics, anti-       buprenorphine, methadone, paracetamol (long-term administration of inflammatory agents carbamazepine and paracetamol may be associated with hepatotoxicity), phenazone (antipyrine), tramadol

Antibiotics            doxycycline, rifabutin.
Anticoagulants:        oral anticoagulants (e.g. warfarin, phenprocoumon, dicoumarol, acenocoumarol , rivaroxaban, dabigatran, apixaban, edoxaban)
Antidepressants:       bupropion, citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic    antidepressants     (e.g.   imipramine,   amitriptyline, nortriptyline, clomipramine).
Antiemetics:           Aprepitant
Antiepileptics:        clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, eslicarbazepine, oxcarbazepine, primidone, tiagabine, topiramate,
valproic acid, zonisamide. To avoid phenytoin intoxication and subtherapeutic concentrations of carbamazepine it is recommended to adjust the plasma concentration of phenytoin to 13 micrograms
/mL before adding carbamazepine to the treatment. There have been rare reports of an increase in plasma mephenytoin levels
Antifungals            itraconazole, voriconazole. Alternative anti-convulsants may be recommended in patients treated with voriconazole or itraconazole
Antihelmintics         praziquantel, albendazole
Antineoplastics        imatinib, cyclophosphamide, lapatinib, temsirolimus Antiplatelet           ticagrelor
Antipsychotics         clozapine, haloperidol and bromperidol, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, paliperidone
Antivirals             protease inhibitors for HIV treatment (e.g. indinavir, ritonavir, saquinavir)
Anxiolytics            alprazolam, midazolam
Bronchodilatators or   theophylline anti-asthma drugs
Contraceptives:        hormonal contraceptives (alternative contraceptive methods should be considered)
Cardiovascular         calcium channel blockers (dihydropyridine group) e.g. felodipine, drugs                  digoxin, simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine Corticosteroids        corticosteroids (e.g. prednisolone, dexamethasone) Drugs used in          tadalafil erectile dysfunction
Immunosuppressants cyclosporin, everolimus, tacrolimus, sirolimus
Thyroid agents       levothyroxine

Other drug             products containing oestrogens and/or progesterones interactions

Combinations that require specific consideration
Concomitant use of carbamazepine and levetiracetam has been reported to increase carbamazepine-induced toxicity.

Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid- induced hepatotoxicity.


Combined use of carbamazepine and lithium or metoclopramide on the one hand, and carbamazepine and neuroleptics (haloperidol, thioridazine) on the other, may lead to increased neurological adverse reactions (with the latter combination even in the presence of ‘therapeutic plasma levels’).

Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatraemia.

Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g.
pancuronium). Their dosage may need to be raised, and patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected.

Carbamazepine, like other psychoactive drugs, may reduce alcohol tolerance. It is therefore advisable for the patient to abstain from alcohol.

Concomitant use of carbamazepine with direct acting oral anti-coagulants (rivaroxaban, dabigatran, apixaban, and edoxaban) may lead to reduced plasma concentrations of direct acting oral anti-coagulants, which carries the risk of thrombosis. Therefore, if a concomitant use is necessary, close monitoring of signs and symptoms of thrombosis is recommended.

Interference with serological testing
Carbamazepine may result in false positive perphenazine concentrations in HPLC analysis due to interference.

Carbamazepine and the 10,11-epoxide metabolite may result in false positive tricyclic antidepressant concentration in fluorescence polarized immunoassay method.