Darunavir / cobicistat

Mirtazapine

Dose adjustment and closer monitoring are required.

No pharmaceutical opinion available for this interaction.

Mechanism

Darunavir / cobicistat can inhibit the metabolism (CYP 3A4 and 2D6) and increase the plasma concentration of Mirtazapine.

Darunavir / cobicistat

Pharmacodynamic effects

Recommendations

Alternative solution(s)

Mirtazapine

Pharmacodynamic effects

Possible increase of adverse effects.

Increased risk of an extension of the QT interval.

Recommendations

Start with the lowest dose possible, or in patients already on treatment, a dose reduction may be necessary.

Monitor closely clinical efficacy and appearance of adverse effects.

In patients already being treated with this combination and tolerating it, if deemed appropriate, keep actual treatment and exercise close monitoring of adverse effects.

Alternative solution(s)

Monitor

Mirtazapine adverse effects: drowsiness, dry mouth, increased appetite, gain of weight, constipation, dizziness and headaches.

QT interval in patients with possible electrolyte disorders or other risk factors for QT prolongation.

Tests

Pharmacokinetic parameters

Comment

Mirtazapine product monograph recommends caution when co-administered with CYP2D6 inhibitors or strong CYP3A4 inhibitors.

In fact, the concomitant administration of mirtazapine (unique dosage of 30 mg) and ketoconazole, a powerful inhibitor of CYP3A4 (200 mg BID during 6.5 days) resulted in an increase of around 40% and 50%; of the Cmax and the AUC of mirtazapine, respectively. In a study with a pharmacokinetic modelling approach, an increase of 52% of the AUC of mirtazapine has been observed. During the concomitant use, two adverse events have been reported: a patient suffered from a circulatory collapse and another patient had syncope. Both patients have had a brief loss of consciousness.

Ritonavir, a powerful inhibitor of 2D6 could accentuate this increase of mirtazapine. In fact, during a pharmacokinetic study with mirtazapine (30 mg/day) and paroxetine, powerful inhibitor of CYP2D6 (40 mg/day), an increase of plasma concentrations of mirtazapine and its demethylated metabolite of around 18% and 25% has been observed. These increases have not been considered as having a clinical significance.

However, among side effects, an exanthema has been observed (1 patient over 24) which entailed the study withdrawal of the participant. Increases of AST and ALT rates have been reported for one participant so he had to stop the study. For this same participant, high rates of leukocytes and neutrophils have been noted, as well as decreases of lymphocytes and basophiles rates.

Reference
  • 2580
    Mirtazapine (Remeron), Merck, Quebec, Canada, 16 Mars 2015.
  • 2626
    Spina E, Trifirò G, Caraci F. Clinically significant drug interactions with newer antidepressants. CNS Drugs. 2012 Jan 1;26(1):39-67.
  • 2839
    Siccardi M, Marzolini C, Seden K et al. Prediction of drug-drug interactions between various antidepressants and efavirenz or boosted protease inhibitors using a physiologically based pharmacokinetic modelling approach. Clin Pharmacokit 2013; 52:582-592.