What drug-drug interactions should you be vigilant for when someone is prescribed carbamazepine?

Carbamazepine is approved by the US Food and Drug Administration for generalized tonic-clonic, focal seizures, mixed seizure patterns, and trigeminal neuralgia (DailyMed – US National Library of Medicine 2008). It is also considered a second-line treatment for the treatment of bipolar mania and has efficacy for bipolar depression (Yatham et al. 2018). However, its adverse effects, narrow therapeutic window, and drug-drug interactions make it a complicated medication to use. Carbamazepine is broken down into carbamazepine-10,11-epoxide (an active metabolite) by CYP3A4 and to a lesser extent CYP3A5 (Marino et al. 2012). It broadly induces the CYP450 system but specifically is a potent inducer of CYP3A4, and also induces CYP1A2, CYP2B6, CYP2C9, P-gp, and UGT. Carbamazepine induces its own metabolism, so its half-life is initially 25-65 hours, then after several weeks, shortens to 12-17 hours.

Carbamazepine may have relevant drug-drug interactions with commonly used psychotropic medications that sometimes are used concurrently for the treatment of bipolar disorder. What follows is not a comprehensive list, but some interactions to keep in mind. Relevant CYP3A4 inducers (which decrease carbamazepine levels) include phenytoin, rifampin, and St. John’s wort, and CYP3A4 inhibitors (which increase carbamazepine levels) include macrolide antibiotics, several antifungals (including ketoconazole and fluconazole), fluoxetine, and fluvoxamine. Valproate causes an increased level of carbamazepine-10,11-epoxide, and in the presence of carbamazepine, valproate levels may decrease. Carbamazepine may also decrease levels of corticosteroids, clonazepam, clozapine, lamotrigine, olanzapine, oral contraceptives, haloperidol, and risperidone.

Please see the related answer card on therapeutic drug monitoring for carbamazepine.

 

REFERENCES

  • DailyMed – US National Library of Medicine. (2008). “Carbamazepine drug label information.” from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c13bc0b8-7900-4ef4-98ed-e1315a08d95d.
  • Marino SE, Birnbaum AK, Leppik IE, et al: Steady-state carbamazepine pharmacokinetics following oral and stable-labeled intravenous administration in epilepsy patients: effects of race and sex. Clin Pharmacol Ther 91:483-488, 2012
  • Yatham LN, Kennedy SH, Parikh SV, et al: Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord 20:97-170, 2018
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