Tegretol Drug Interactions

Cytochrome P450 3A4 (CYP3A4) is the main enzyme catalysing the formation of the active metabolite carbamazepine-10,11 epoxide. Coadministration of CYP3A4 inhibitors may result in increased plasma levels of carbamazepine, which could induce adverse effects. Coadministration of CYP3A4 inducers may increase Tegretol metabolism, leading to a decrease in serum carbamazepine and, possibly, a reduction in the therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may decrease the metabolism of carbamazepine, leading to an increase in carbamazepine serum levels.
Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II enzymes in the liver, and may therefore reduce plasma concentrations of comedications mainly metabolized by CYP3A4.
Human microsomal epoxide hydrolase is considered the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide. Coadministration of inhibitors of human microsomal epoxide hydrolase (e.g. valproate) may result in elevated blood levels of carbamazepine-10,11 epoxide.
Agents that may raise plasma levels of carbamazepine: Elevated plasma levels of carbamazepine may result in adverse effects (e.g. dizziness, drowsiness, ataxia, diplopia), and the dosage of Tegretol should therefore be adjusted accordingly, and/or plasma levels monitored, if Tegretol is used concomitantly with the following agents: Antitubercular agents: isoniazid.
Cardiovascular agents: verapamil, diltiazem.
Analgesics, anti-inflammatory agents: dextropropoxyphene, ibuprofen.
Antidepressants: possibly desipramine, viloxazine, fluoxetine, fluvoxamine, trazodone, paroxetine.
Gastrointestinal agents: possibly cimetidine, omeprazole.
Carbonic anhydrase inhibitors: acetazolamide.
Androgens: danazol.
Antibiotics: macrolide antibiotics (e.g. erythromycin, troleandomycin, josamycin, clarithromycin, ciprofloxacin).
Antifungals: azole derivatives (e.g. itraconazole, ketoconazole, fluconazole, voriconazole). Alternative anticonvulsants may be recommended in patients treated with voriconazole or itraconazole.
Antihistamines: terfenadine, loratadine.
Antivirals: protease inhibitors for HIV treatment (e.g. ritonavir).
Antiepileptics: stiripentol, vigabatrin.
Antipsychotic agents: loxapine, olanzapine, quetiapine.
Muscle relaxants: oxybutynin, dantrolene.
Platelet aggregation inhibitors: ticlopidine.
Other: grapefruit juice, nicotinamide (only at high doses).
Agents that may raise plasma levels of carbamazepine-10,11-epoxide: Elevated plasma levels of carbamazepine-10,11-epoxide may cause adverse effects (e.g. dizziness, drowsiness, ataxia, diplopia), and the dosage of Tegretol should therefore be closely monitored, and adjusted where required, if Tegretol is given concomitantly with any of the following agents: loxapine, quetiapine, primidone, progabide, valproate, valnoctamide and valpromide.
Agents that may lower plasma levels of carbamazepine: The dose of Tegretol may have to be adjusted if Tegretol is used concomitantly with the following agents: Antiepileptics: phenobarbital, primidone, methsuximide, felbamate, oxcarbazepine, phensuximide, phenytoin (to avoid phenytoin intoxication and subtherapeutic concentrations of carbamazepine, it is recommended to adjust the plasma concentration of phenytoin to 13 μg/ml before commencing carbamazepine treatment) fosphenytoin, clonazepam.
Cytostatics: cisplatin, doxorubicin.
Antitubercular agents: rifampicin.
Bronchodilators or antiasthmatics: theophylline, aminophylline.
Dermatological drugs: isotretinoin.
Other: herbal preparations containing St John's wort (Hypericum perforatum).
Effect of Tegretol on plasma levels of concomitantly administered agents: Carbamazepine may lower plasma levels of certain drugs, and diminish - or even abolish - their activity. The dosage of the following drugs may have to be adjusted to meet clinical requirements: Analgesics, anti-inflammatory agents: buprenorphine, methadone, fentanyl, paracetamol (long-term administration of carbamazepine and paracetamol (acetaminophen) may lead to hepatotoxicity), phenazone (antipyrine), tramadol.
Antibiotics: doxycycline, rifabutin.
Anticoagulants: oral anticoagulants (warfarin, phenprocoumon, dicoumarol, acenocoumarol, rivaroxaban, dabigatran, apixaban, edoxaban).
Antidepressants: tricyclic antidepressants (e.g. imipramine, amitriptyline, nortriptyline, clomipramine), bupropion (carbamazepine may lower plasma levels of bupropion and raise those of its metabolite hydroxybupropion, thereby reducing the clinical efficacy and safety of bupropion), citalopram, mianserin, nefazodone, sertraline, trazodone. Tegretol should not be used in combination with MAO inhibitors. Before administering Tegretol, MAO inhibitors should be discontinued for a minimum of 2 weeks, or even longer if the clinical situation permits (see Contraindications).
Antiemetics: aprepitant.
Antiepileptics: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, eslicarbazepine, oxcarbazepine, primidone, tiagabine, topiramate, valproate, zonisamide. To avoid phenytoin intoxication and subtherapeutic concentrations of carbamazepine, it is recommended to adjust the plasma concentration of phenytoin to 13 μg/ml before commencing carbamazepine treatment. There have been rare reports of an increase in plasma mephenytoin levels, which may - in exceptional cases - cause confusional states and even coma.
Antifungals: itraconazole, ketoconazole, voriconazole. Alternative anti-convulsants may be recommended in patients treated with voriconazole or itraconazole.
Anthelmintics: praziquantel, albendazole.
Cytostatics: imatinib, cyclophosphamide, lapatinib, temsirolimus.
Antipsychotic agents: clozapine, haloperidol, bromperidol, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, paliperidone.
Antivirals: protease inhibitors for HIV treatment (e.g. indinavir, ritonavir, saquinavir).
Anxiolytics: alprazolam, midazolam.
Bronchodilators or antiasthmatics: theophylline.
Cardiovascular agents: calcium channel blockers (dihydropyridine group), e.g. felodipine, digoxin, quinidine, propranolol, simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine.
Corticosteroids: e.g. prednisolone, dexamethasone.
Immunosuppressants: ciclosporin, tacrolimus, everolimus, sirolimus.
Thyroid hormones: levothyroxine: Carbamazepine seems to promote the elimination of thyroid hormones and to increase the need for them in patients with hypothyroidism. Thyroid parameters must therefore be determined in patients receiving replacement therapy both at the start and at the end of treatment with Tegretol.
If necessary, the dosage of the thyroid hormone products should be adjusted. Thyroid function may be altered in particular by concomitant use of carbamazepine and other anticonvulsants (e.g. phenobarbital).
Contraceptives: hormonal contraceptives (sudden breakthrough bleeding may occur when the "pill" is taken, in addition to attenuation of the effect of hormonal contraceptives. Therefore, either the oral contraceptive should contain more than 50 μg oestrogen, or other, non-hormonal methods of contraception should be recommended.)
Drugs for the treatment of erectile dysfunction: tadalafil.
Points to consider in connection with combination therapy: There is evidence that concomitant use of carbamazepine and levetiracetam increases the toxicity of carbamazepine.
Concomitant administration of carbamazepine and isoniazid has been reported to increase the hepatotoxicity of isoniazid.
Please note that concomitant use, in particular of lithium or metoclopramide and carbamazepine, may potentiate the neurotoxic effects of both active substances. Therefore, close monitoring of clinical symptoms is necessary. Over 8 weeks should elapse following termination of prior treatment with neuroleptics, and concurrent treatment should also be avoided. Patients should be monitored for the following signs of neurotoxic symptoms: unsteady gait, ataxia, horizontal nystagmus, increased muscle proprioceptive reflexes, muscle twitching (fasciculations).
The literature indicates that the addition of carbamazepine to ongoing neuroleptic therapy may increase the risk of neuroleptic malignant syndrome or Stevens-Johnson syndrome.
Concomitant administration of Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatraemia.
Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g. pancuronium), the dosage of which may therefore need to be raised. Patients should be monitored closely for unexpectedly rapid recovery from neuromuscular blockade.
Like other psychoactive drugs, carbamazepine may reduce alcohol tolerance. Abstention from alcohol is therefore advised.
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 and thus increase the risk of thrombosis. Therefore, if concomitant use is necessary, close monitoring for possible signs and symptoms of thrombosis is recommended.
Considerations for 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 concentrations in fluorescence polarized immunoassays.