Antiepileptic Drugs Affected by Azithromycin
Azithromycin does not have clinically significant pharmacokinetic interactions with antiepileptic drugs, unlike other macrolides such as erythromycin and clarithromycin that substantially interact with carbamazepine. 1, 2
Key Distinction Between Macrolides
The critical difference lies in the mechanism of interaction:
- Azithromycin primarily inhibits P-glycoprotein (P-gp) efflux transporters but does not significantly inhibit cytochrome P450 enzymes 1
- Erythromycin and clarithromycin are potent inhibitors of CYP3A4, the primary enzyme responsible for metabolizing several antiepileptic drugs 1, 3, 4
Antiepileptics NOT Significantly Affected by Azithromycin
Carbamazepine
- Carbamazepine is extensively metabolized by CYP3A4 and shows clinically significant interactions with erythromycin and clarithromycin, leading to toxic carbamazepine levels 4, 5
- Azithromycin does not inhibit CYP3A4 and therefore does not cause this interaction 1
- Erythromycin and clarithromycin can increase carbamazepine levels by 50-100%, causing ataxia, diplopia, nausea, and drowsiness 5
Phenytoin
- Phenytoin is metabolized by CYP2C9 and CYP2C19 6
- Erythromycin can interact with phenytoin through CYP450 inhibition 1
- Azithromycin lacks this CYP450 inhibitory effect 1
Other Antiepileptics
- Valproic acid, lamotrigine, levetiracetam, and other newer antiepileptics are not significantly affected by azithromycin due to its lack of CYP450 enzyme inhibition 6, 7
Important Clinical Caveat: QT Prolongation
While azithromycin does not cause pharmacokinetic interactions with antiepileptics, there is a pharmacodynamic concern regarding QT prolongation 1:
- Azithromycin can prolong the QT interval and increase risk of torsades de pointes 1
- This cardiac risk is additive with other QT-prolonging medications 1
- Monitor ECG if combining azithromycin with medications that lower seizure threshold or prolong QT interval 1
Practical Recommendation
Azithromycin is the preferred macrolide when antibiotic therapy is needed in patients taking antiepileptic drugs, particularly those on carbamazepine, phenytoin, or other CYP3A4-metabolized antiepileptics 2, 5. If erythromycin or clarithromycin must be used with carbamazepine, expect a 50-100% increase in carbamazepine levels and reduce the carbamazepine dose preemptively or monitor levels closely 4, 5.