Is there a risk of drug interaction if Tegretol Retard (carbamazepine) and Remeron (mirtazapine) ar

Fråga: Is there a risk of drug interaction if Tegretol Retard (carbamazepine) and Remeron (mirtazapine) are administered concomitantly? The question concerns an older woman with epilepsy and dementia, treated with Tegretol Retard 200 mg x2. Her physician now wants to start treatment with Remeron for depression. In addition to Tegretol Retard she also takes Furosemid, Kalium Retard, Seloken and Sobril.

Sammanfattning: Enzyme induction by carbamazepine has been shown to cause a considerable decrease in mirtazapine plasma concentrations that may require adjustment of the mirtazapine dosage. We recommend monitoring of the plasma levels of mirtazapine if the drugs are to be used concomitantly.

Svar: Mirtazapine is an antidepressant derivative of mianserine (1) and acts pharmacologically by increasing the noradrenergic and serotonergic (5-HT1-mediated) neurotransmission through a blockade of presynaptic alfa 2-adrenergic receptors (2). It is extensively metabolised. The percentage of the dose excreted unchanged is less than 5 percent (3). Approximately 40 percent is metabolised by CYP2D6 to an inactive metabolite (1). Mirtazapine also undergoes direct conjugation (approximately 25 percent), N-demethylation via CYP3A4 (approximately 25 percent) and N-oxidation via CYP3A4 (approximately 10 percent). The demethylmetabolite is pharmacologically active and is estimated to contribute to 5-10 percent of the total pharmacological activity of mirtazapine. In vitro results indicate that mirtazapine has little inhibitory effect on CYP isoenzymes (1). This seems to be the case also in humans since none of several drug-drug interaction studies so far have been indicative of a CYP-inhibitory effect of mirtazapine.

Carbamazepine, a common antiepileptic drug, is metabolised predominately by CYP3A4 (4). Carbamazepine induces CYP3A4 and CYP2C9. It also induces glucuronosyltransferase.

In a study of healthy male volunteers a 60 percent decrease in mirtazapine plasma concentrations was found when multiple doses of mirtazapine 30 mg were added to carbamazepine 400 mg x 2 at steady state for 3 weeks (1). This decrease in plasma concentrations was considered to be due to enzyme induction by carbamazepine. The pharmacokinetics of carbamazepine and its enzyme inducing properties were not affected by coadministration of multiple doses of mirtazapine.

Antidepressants, particularly tricyclic antidepressants are well known to reduce the seizure threshold (5). At therapeutic dosages seizures are a rare, but potentially serious complication of antidepressant therapy. Mirtazapine has been shown to have a very low seizure-inducing potential both in patients with and without previous history of seizure (5,6).

In this context it should also be noted that carbamazepine is commonly used in bipolar manic-depressive patients as a mood stabiliser. Moreover, carbamazepine has been shown to potentiate various antidepressants (both tricyclic antidepressants and SSRI) in patients with treatment resistant depression in the course of bipolar or unipolar affective disorder (7). It is thus possible that the concomitant use of carbamazepine and mirtazapine can have an additive antidepressant effect.