From the Guidelines
Carbamazepine has numerous significant drug interactions due to its strong enzyme-inducing properties, and it is essential to carefully monitor and adjust medications when co-administered with carbamazepine to minimize potential adverse effects and ensure optimal therapeutic outcomes.
Key Interactions
- Carbamazepine interacts with warfarin, oral contraceptives, and other anticonvulsants like valproate, lamotrigine, and phenytoin, reducing their effectiveness 1.
- Carbamazepine levels can be increased by erythromycin, clarithromycin, fluoxetine, and grapefruit juice, potentially causing toxicity.
- It can decrease the effectiveness of doxycycline, itraconazole, and HIV medications like protease inhibitors.
- Combining carbamazepine with MAO inhibitors or lithium may cause dangerous reactions.
- Calcium channel blockers like verapamil and diltiazem can increase carbamazepine levels.
Mechanism of Interactions
These interactions occur because carbamazepine induces cytochrome P450 enzymes, particularly CYP3A4, accelerating the metabolism of many medications. It also undergoes autoinduction, metabolizing itself more quickly over time.
Clinical Implications
Patients should always inform healthcare providers about all medications they're taking, and dosage adjustments may be necessary when starting or stopping carbamazepine or interacting medications.
Specific Considerations
- Concomitant use with medicinal products that are strong P-gp and/or strong CYP inducers, such as rifampicin, rifabutin, St John’s wort, carbamazepine, phenobarbital or phenytoin, are contraindicated due to the decrease in sofosbuvir, velpatasvir and/or voxilaprevir exposure with the potential loss in efficacy 1.
- Apremilast may be associated with the emergence or worsening of depression, and its use with strong inducers of cytochrome P450, such as carbamazepine, may result in decreased efficacy and is not recommended 1.
From the FDA Drug Label
Agents That May Affect Carbamazepine Plasma Levels When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required Agents That Increase Carbamazepine Levels CYP3A4 inhibitors inhibit carbamazepine metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include aprepitant, cimetidine, ciprofloxacin, danazol, diltiazem, macrolides (e.g., erythromycin, clarithromycin), fluoxetine, fluvoxamine, trazodone, omeprazole, oxybutynin, isoniazid, niacinamide (nicotinamide), azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil, ticlopidine, grapefruit juice, and protease inhibitors. Agents That Decrease Carbamazepine Levels CYP3A4 inducers can increase the rate of carbamazepine metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include cisplatin, doxorubicin HCl, felbamate, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline Effect of Carbamazepine on Plasma Levels of Concomitant Agents Decreased Levels of Concomitant Medications Carbamazepine is a potent inducer of hepatic 3A4 and is also known to be an inducer of CYP1A2, 2B6, 2C8/9/19 and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C8/9/19 and 3A4, through induction of their metabolism When used concomitantly with carbamazepine, monitoring of concentrations or dosage adjustment of these agents may be necessary: When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. If carbamazepine is later withdrawn, the aripiprazole dose should be reduced When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are recommended. The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus. If patients must be coadministered carbamazepine with temsirolimus, an adjustment of temsirolimus dosage should be considered The use of carbamazepine with lapatinib should generally be avoided. If carbamazepine is started in a patient already taking lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine is discontinued, the lapatinib dose should be reduced Concomitant use of carbamazepine with nefazodone results in plasma concentrations of nefazodone and its active metabolite insufficient to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated ( see CONTRAINDICATIONS). Monitor concentrations of valproate when carbamazepine is introduced or withdrawn in patients using valproic acid In addition, carbamazepine causes, or would be expected to cause, decreased levels of the following drugs, for which monitoring of concentrations or dosage adjustment may be necessary: acetaminophen, albendazole, alprazolam, aprepitant, buprenorphone, bupropion, citalopram, clonazepam, clozapine, corticosteroids (e.g., prednisolone, dexamethasone), cyclosporine, dicumarol, dihydropyridine calcium channel blockers (e.g., felodipine), doxycycline, eslicarbazepine, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, mianserin, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, sertraline, sirolimus, tadalafil, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.
The carbamazepine drug interaction list includes:
- Agents that increase carbamazepine levels: aprepitant, cimetidine, ciprofloxacin, danazol, diltiazem, macrolides, fluoxetine, fluvoxamine, trazodone, omeprazole, oxybutynin, isoniazid, niacinamide, azoles, acetazolamide, verapamil, ticlopidine, grapefruit juice, and protease inhibitors.
- Agents that decrease carbamazepine levels: cisplatin, doxorubicin HCl, felbamate, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline.
- Agents with decreased levels due to carbamazepine: aripiprazole, tacrolimus, temsirolimus, lapatinib, nefazodone, valproate, acetaminophen, albendazole, alprazolam, aprepitant, buprenorphone, bupropion, citalopram, clonazepam, clozapine, corticosteroids, cyclosporine, dicumarol, dihydropyridine calcium channel blockers, doxycycline, eslicarbazepine, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, mianserin, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, sertraline, sirolimus, tadalafil, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants, valproate, warfarin, ziprasidone, zonisamide. 2 2
From the Research
Carbamazepine Drug Interactions
- Carbamazepine is known to interact with various drugs, affecting its pharmacokinetics and potentially leading to toxic concentrations or reduced efficacy 3.
- The most significant interactions are those that induce or inhibit the metabolism of carbamazepine, particularly through the cytochrome P450 (CYP) 3A4 enzyme system.
- Drugs that accelerate the elimination of carbamazepine include:
- Phenytoin
- Phenobarbital (phenobarbitone)
- Primidone
- Drugs that inhibit carbamazepine metabolism and may lead to toxic concentrations include:
- Stiripentol
- Remacemide
- Acetazolamide
- Macrolide antibiotics
- Isoniazid
- Metronidazole
- Certain antidepressants
- Verapamil
- Diltiazem
- Cimetidine
- Danazol
- (Dextropropoxyphene) propoxyphene
- Carbamazepine is also a potent inducer of CYP3A4 and other oxidative enzyme systems, which can lead to increased metabolism of concurrently prescribed drugs, including:
- Valproic acid
- Clonazepam
- Ethosuximide
- Lamotrigine
- Topiramate
- Tiagabine
- Remacemide
- Tricyclic antidepressants
- Antipsychotics
- Steroid oral contraceptives
- Glucocorticoids
- Oral anticoagulants
- Cyclosporin
- Theophylline
- Chemotherapeutic agents
- Cardiovascular drugs
- Interactions with oral contraceptives can also occur, with carbamazepine inducing the metabolism of oral contraceptive steroids and potentially reducing their efficacy 4, 5.
- A physiologically based pharmacokinetic (PBPK) model of carbamazepine has been developed to predict drug-drug interactions, including interactions with alprazolam, bupropion, erythromycin, efavirenz, and simvastatin 6.
- The clinical significance of carbamazepine drug interactions depends on the magnitude of the change in concentration of active species and the therapeutic index of the drug 7.