What are the significant drug interactions with carbamazepine?

From the Guidelines

Carbamazepine has numerous significant drug interactions due to its potent induction of cytochrome P450 enzymes, which can reduce the effectiveness of many medications, including oral contraceptives, warfarin, and certain antidepressants, and increase the risk of toxicity with drugs that inhibit CYP3A4, such as erythromycin and clarithromycin 1.

Significant Drug Interactions

The following are some of the significant drug interactions with carbamazepine:

• Oral contraceptives: reduced effectiveness due to increased metabolism 1
• Warfarin: reduced effectiveness due to increased metabolism, requiring a 50% increase in warfarin maintenance dose after initiation of carbamazepine 1
• Benzodiazepines: reduced effectiveness due to increased metabolism
• Antipsychotics: reduced effectiveness due to increased metabolism
• Certain antidepressants: reduced effectiveness due to increased metabolism
• Erythromycin and clarithromycin: increased carbamazepine levels, potentially causing toxicity due to CYP3A4 inhibition 1
• MAO inhibitors: increased risk of serotonin syndrome
• Sodium valproate: increased carbamazepine's active metabolite

Clinical Implications

When prescribing carbamazepine, dosage adjustments of concurrent medications are often necessary, and alternative medications should be considered when possible. Patients should be monitored for decreased efficacy of their other medications or signs of carbamazepine toxicity, such as dizziness, ataxia, and drowsiness. These interactions occur because carbamazepine strongly induces liver enzymes that metabolize many drugs, while being subject to inhibition of its own metabolism by other medications.

Management of Drug Interactions

To manage these interactions, healthcare providers should:

• Monitor patients closely for signs of toxicity or reduced efficacy
• Adjust dosages of concurrent medications as needed
• Consider alternative medications when possible
• Educate patients about the potential risks and benefits of carbamazepine therapy By taking a proactive approach to managing drug interactions, healthcare providers can minimize the risks associated with carbamazepine therapy and optimize patient outcomes.

From the FDA Drug Label

Clinically meaningful drug interactions have occurred with concomitant medications and include (but are not limited to) the following: 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

The significant drug interactions with carbamazepine include:

• Agents that increase carbamazepine levels: CYP3A4 inhibitors such as 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: CYP3A4 inducers such as cisplatin, doxorubicin HCl, felbamate, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, and aminophylline.
• Effect of carbamazepine on plasma levels of concomitant agents: Carbamazepine may reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C8/9/19, and 3A4.
• Specific interactions:

• Aripiprazole: dose should be doubled when carbamazepine is added, and reduced when carbamazepine is withdrawn.
• Tacrolimus: monitoring of blood concentrations and dosage adjustments are recommended.
• Temsirolimus: concomitant use should be avoided, or dosage adjustment should be considered.
• Lapatinib: concomitant use should be avoided, or dose should be gradually titrated up.
• Nefazodone: concomitant use is contraindicated.
• Valproate: concentrations should be monitored when carbamazepine is introduced or withdrawn. 2

From the Research

Significant Drug Interactions with Carbamazepine

The following are significant drug interactions with carbamazepine:

• Inducers of carbamazepine metabolism:
  • Phenytoin, phenobarbital, and primidone accelerate the elimination of carbamazepine, reducing plasma carbamazepine concentrations 3
  • Other drugs that may induce carbamazepine metabolism include macrolide antibiotics, isoniazid, metronidazole, and certain antidepressants 3, 4
• Inhibitors of carbamazepine metabolism:
  • Stiripentol, remacemide, acetazolamide, macrolide antibiotics, isoniazid, metronidazole, certain antidepressants, verapamil, diltiazem, cimetidine, danazol, and propoxyphene can inhibit carbamazepine metabolism, leading to elevated plasma carbamazepine concentrations 3
  • Valproic acid, valpromide, valnoctamide, and progabide can inhibit the metabolism of the active metabolite carbamazepine-10,11-epoxide, leading to elevated plasma concentrations 3
• Effects of carbamazepine on other drugs:
  • Carbamazepine is a potent inducer of CYP3A4 and other oxidative enzyme systems in the liver, leading to accelerated metabolism of concurrently prescribed anticonvulsants, such as valproic acid, clonazepam, ethosuximide, lamotrigine, topiramate, tiagabine, and remacemide 3
  • Carbamazepine can also induce the metabolism of other drugs, including tricyclic antidepressants, antipsychotics, steroid oral contraceptives, glucocorticoids, oral anticoagulants, cyclosporin, theophylline, chemotherapeutic agents, and cardiovascular drugs 3
• Interactions with oral contraceptives:
  • Carbamazepine can induce the metabolism of oral contraceptives, leading to increased risk of contraceptive failure 5
  • Estrogens in oral contraceptives can induce glucuronosyltransferase, reducing plasma levels of carbamazepine and other antiepileptic drugs cleared by glucuronidation 5

Prediction and Management of Drug Interactions

• Physiologically based pharmacokinetic modeling can be used to predict drug-drug interactions with carbamazepine 6
• Knowledge of the pharmacological properties of combined drugs, particularly their therapeutic index, site of metabolism, and ability to affect specific drug-metabolizing isoenzymes, can help predict interactions 3
• Avoidance of unnecessary polypharmacy, selection of alternative agents with lower interaction potential, and careful dosage adjustments based on serum drug concentration monitoring and clinical observation can minimize the risks associated with carbamazepine drug interactions 3, 4