Interactions : אינטראקציות

4.5. Interaction with other medicinal products and other forms of interaction

Concomitant treatment with monoamine oxidase inhibitors (MAO) is contraindicated (see section 4.3). Before commencing treatment with Timonil retard, any therapy with MAO inhibitors must have been discontinued at least two weeks earlier.


Concomitant treatment with Timonil may require dose adjustment or ceasing treatment with one of the medicines.

Effects of carbamazepine on the plasma concentrations of other drugs Carbamazepine induces the cytochrome-P450 system (predominantly isoenzyme CYP3A4) so that the plasma concentrations of substances that are metabolised by the cytochrome- P450 system may be diminished, and their dosage may need to be adjusted according to the clinical requirements. The inducing effect of carbamazepine may remain for about two weeks after cessation of treatment.

This applies, for example, to:
-     analgetics, anti-inflammatory agents: buprenorphine, fentanyl, methadone, paracetamole, phenazone, tramadol
-     anthelmintics: praziquantel, albendazole
-     anticoagulants: warfarin, phenprocoumon, dicumarole, acenocoumarole -     antidepressants: bupropion, citalopram, mianserin, mirtazapine, nefazodone, sertraline, trazodon, tricyclic antidepressants (e.g. imipramine, amitriptyline, nortriptyline, clomipramine)
-     antiemetics: aprepitant, ondansetron
-     other anticonvulsants (clonazepam, ethosuximide, felbamate, primidone, lamotrigine, oxcarbazepine, phenytoin, tiagabine, topiramate, valproic acid, zoniamide). To avoid phenytoin intoxication and subtherapeutic concentrations of carbamazepine, it is recommended that the plasma concentration of phenytoin be adjusted to 13 micrograms/mL before incorporating adjunctive treatment with carbamazepine.
-     Antifungal agents: caspofungin, azole-derivative antifungals (e.g. voriconazole, itraconazole, with the result that patients may fail to respond to the antimycotics). For patients treated with voriconazole or itraconazole, alternative anticonvulsants are to be recommended.
-     antiviral substances: protease-inhibitors for treatment of HIV, e.g. indinavir, ritonavir, saquinavir
-     benzodiazapines (alprazolam, clobazam, midazolam – with the result that patients may fail to respond to midazolam)
-     bronchodilators, antiasthmatics: theophylline
-     cardiovascular medications: calcium antagonists (of the dihydropyridine type, e.g.
felodipine, nimodipine), digoxin, simvastatin, atrovastatin, lovastatin, cerivastatin, ivabradin
-     hormonal contraceptives
-     immunosuppressives: ciclosporin, tacrolimus, sirolimus, everolimus -     corticosteroids (e.g. prednisolon, dexamethason)
-     typical neuroleptics (haloperidol, bromperidol) and atypical neuroleptics (clozapine, olanzapine, paliperidone, risperidone, quetiapine, aripiprazole, ziprasidone) -     thyroid hormones: levothyroxine
-     tetracyclines (e.g. doxycycline)
-     cytostatics: cyclophosphamide, imatinib, lapatinib, temsirolimus -     others: methylphenidate, quinidine, propranolol, flunarizine, rifabutin, tadalafil, toremifene, gestrinone, oestrogens, progesterone derivatives
When taking the “pill”, in addition to the reduction in activity of the hormones contained in the oral contraceptive pill, sudden breakthrough bleeding or spotting may occur. Therefore other, non-hormonal means of contraception should be recommended. Due to its enzyme-inducing character, carbamazepine may neutralize the effects of oestrogens and/or progesterone derivates which may lead e.g. to contraceptive failure..

The plasma concentration of phenytoin can be either reduced or increased by carbamazepine, which can lead in exceptional cases to states of confusion or even coma.
Carbamazepine can lower the plasma level of bupropion and increase that of its metabolite hydroxybupropion thus diminishing the clinical efficacy and safety of bupropion.


Although carbamazepine can lower the plasma level of trazodone, it appears to potentiate the antidepressive effect of trazodone.
Carbamazepine may possibly accelerate the metabolisation of zotepine.

Reduced plasma concentration of carbamazepine:
Carbamazepine is metabolised by the cytochrome-P450 system (predominantly by the isoenzyme CYP3A4). Inducers of CYP3A4 may increase the carbamazepine metabolism and with this may possibly lead to a decrease in the carbamazepine plasma concentration and in therapeutic efficacy. Vice versa, it may come to a decreased metabolism of carbamazepine after discontinuation of a CYP-3A4-inducer and consequently to an increased carbamazepine plasma concentration.
A decrease in the carbamazepine plasma concentration may be caused e.g. by: 
-     other anticonvulsants: methosuximide, oxcarbazepine, phenobarbital, phenytoin, primidone, progabide, valproic acid, valpromide and possibly clonazepam (data is in parts contradictory). To avoid phenytoin intoxication and subtherapeutic concentrations of carbamazepine, it is recommended that the plasma concentration of phenytoin be adjusted to 13 micrograms/mL before incorporating adjunctive treatment with carbamazepine.
-     bronchodilators, antiasthmatics: theophylline, aminophylline
-     dermatics: isotretinoin
-     antituberculotic drug: rifampicin
-     cytostatics: doxorubicin, cisplatin
-     others: St. John’s wort (Hypericum perforatum)

Alternatively, the plasma levels of the pharmacologically effective metabolite carbamazepine-10,11-epoxide may be increased by valproic acid and primidone.

The concomitant administration of felbamate can diminish the plasma level of carbamazepine and increase that of carbamazepine-10,11-epoxide; at the same time, that of felbamate can be diminished.

Due to these mutual interactions, it is recommended that the plasma levels are monitored especially during concomitant therapy with several antiepileptics, and the dosage of Timonil retard should be adjusted if necessary.

Too low carbamazepine plasma levels may cause an aggravation of the disease, e.g.
recurrence of epileptic seizures, seizures in multiple sclerosis or recurrence of facial pain or pain in the oropharyngeal space.

Increased plasma concentration of carbamazepine:
Carbamazepine is metabolised by the cytochrome-P450 system (predominantly by the isoenzyme CYP3A4) to the active metabolite carbamazepine-10,11-epoxid. Thus, the carbamazepine plasma concentration may also be increased by inhibitors of the cytochrome- P450 system, e.g. by:

-     analgetics, anti-inflammatory agents: ibuprofen, dextropropoxyphene/propoxyphene – combination with dextropropoxyphene may lead to carbamazepine toxicity -     androgens: danazol
-     antibiotics: ciprofloxacin, macrolide antibiotics (e.g. erythromycin, troleandomycin, josamycin, clarithromycin)
-     antidepressants: desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodon, viloxazine
-     antifungal agents: azole-derivative antifungal agents (e.g. itraconazole, ketoconazole, fluconazole, voriconazole). For patients treated with voriconazole or itraconazole, alternative anticonvulsants are to be recommended.
-     antihistaminics: terfenadine, loratadine

-    antiviral substances: protease inhibitors for the treatment of HIV, e.g. ritonavir -    calcium antagonists (e.g. verapamil, diltiazem)
-    carboanhydrase inhibitors (diuretics): acetazolamide
-    muscle relaxants: oxybutynine, dantrolene
-    neuroleptics: loxapine, olanazapine
-    antiplatelet drug: ticlopidine
-    antituberculotic: isoniazid
-    ulcer therapeutic agents: cimetidine, omeprazole
-    others: grapefruit juice, nicotinamide (in high doses)

Increased plasma levels of carbamazepine can lead to the symptoms described under undesirable effects (e.g. dizziness, tiredness, unsteadiness of gait, double vision). Therefore, if such symptoms occur, the carbamazepine plasma concentrations must be checked and the dose reduced if necessary.

Increased plasma concentration 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 human microsomal epoxide hydrolase may result in increased carbamazepine-10,11 epoxide plasma concentrations. Increased plasma levels of carbamazepine-10,11-epoxide can lead to the symptoms described in section 4.8 (e.g.
dizziness, fatigue, gait disturbance, diplopia). Therefore, if such symptoms occur, the plasma concentration must be checked and the dose reduced as necessary if any of the following substances are administered concomitantly: loxapine, quetiapine, oxcarbazepine, primidone, progabide, valproic acid, valnoctamide and valpromide.

Other interactions:
Concomitant use of carbamazepine and levetiracetam may increase carbamazepine toxicity.

Simultaneous use of carbamazepine and lithium, neuroleptics or metoclopramide can promote the occurrence of neurological side effects. In the case of patients who are being treated with neuroleptics it must be remembered that carbamazepine reduces the plasma levels of these medicinal products and thus may cause deterioration in the clinical picture. A dose adjustment of the respective neuroleptic drug may be necessary.

It is important to note that concomitant use of lithium and carbamazepine can, in particular, potentiate the neurotoxicity of each drug. It is therefore necessary to monitor plasma levels of the two drugs carefully. Treatment with neuroleptics should have been discontinued at least 8 weeks previously and not be given simultaneously. The following signs of neurotoxicity should be looked for: unsteady gait, ataxia, horizontal nystagmus, hyperreflexia, muscle twitches (muscle fasciculation).

The literature indicates that the additional administration of carbamazepine in patients already taking neuroleptic drugs increases the risk of onset of a malignant neuroleptic syndrome or a Stevens-Johnson syndrome.

The hepatoxicity of isoniazid can be increased by carbamazepine.

Combined administration of carbamazepine and some diuretics (hydrochlorothiazide, furosemide) can lead to symptomatic hyponatraemia.

The effectiveness of drugs used as muscle relaxants, e.g. pancuronium, can be impaired by carbamazepine. Because of this, a more rapid clearing of the neuromuscular blockade is possible.
Patients treated with muscle relaxants should therefore be carefully monitored and the dose of these drugs increased if necessary.


Carbamazepine plasma levels should be monitored during concomitant administration of carbamazepine and isotretinoin (active substance for the treatment of acne).

The concomitant administration of carbamazepine and paracetamol may reduce the bioavailability of paracetamol. Long-term use of carbamazepine and paracetamol (acetaminophen) can lead to hepatotoxicity.

Carbamazepine appears to enhance the elimination of thyroid hormones and to increase the requirement for these substances in patients with hypothyroidism. Therefore thyroid function parameters should be measured at the start and end of carbamazepine treatment in patients receiving substitution therapy. The dosage of the thyroid hormones should be modified if required. In particular, concomitant treatment with carbamazepine and other anticonvulsant drugs (e.g. phenobarbital) can alter thyroid function.

Simultaneous administration of antidepressants of the serotonin reuptake inhibitor type (e.g.
fluoxetine) can lead to a toxic serotonin syndrome.

It is recommended not to use carbamazepine in combination with nefazodone (agent that relieves depression) because carbamazepine leads to a pronounced reduction of the nefazodone plasma level or even a complete loss of action. Further, during concomitant administration of nefazodone and Timonil retard, the carbamazepine plasma level is increased and that of its active metabolite, carbamazepine-10,11-epoxide, reduced.

The concomitant administration of carbamazepine and antiarrhythmic agents, cyclic antidepressants or erythromycin increases the risk of cardiac conduction anomalies.

The concomitant administration of carbamazepine and eslicarbazepine acetate may increase eslicarbazepine acetate toxicity. Diplopia, coordination disturbances and dizziness occurred more commonly with the concomitant administration of eslicarbazepine acetate and carbamazepine than with the combination of eslicarbazepine acetate with other anticonvulsants.

With the concomitant administration of carbamazepine and oxcarbazepine. drops in carbamazepine plasma levels of 0-22% with a simultaneous increase in carbamazepine epoxide by 30% have occurred.

There have been reports of increased bioavailability and raised plasma levels of carbamazepine in connection with drinking grapefruit juice.

Like other psychoactive substances, carbamazepine can reduce the patients’ alcohol tolerance. Therefore, patients should not drink alcohol during treatment.

Interference with serological tests
Due to interference in HPLC analysis, carbamazepine can lead to false-positive perphenazine concentrations. Carbamazepine and its 10,11-epoxide metabolite can lead to false-positive concentrations of tricyclic antidepressants in fluorescence polarisation immunoassays.