The impairment of cognitive and motor skills produced by mirtazapine tablets has been shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking mirtazapine.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during mirtazapine tablets therapy.
Patients should be advised to notify their physician if they are breastfeeding an infant.
There are no routine laboratory tests recommended.
As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility (see CLINICAL PHARMACOLOGY).
The metabolism and pharmacokinetics of mirtazapine tablets may be affected by the induction or inhibition of drug-metabolizing enzymes.
CYP Enzyme Inducers (these studies used both drugs at steady state)
Phenytoin: In healthy male patients (n=18), phenytoin (200 mg daily) increased mirtazapine (30 mg daily) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 45%. Mirtazapine did not significantly affect the pharmacokinetics of phenytoin.
Carbamazepine: In healthy male patients (n=24), carbamazepine (400 mg b.i.d.) increased mirtazapine (15 mg b.i.d.) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 60%.
When phenytoin, carbamazepine, or another inducer of hepatic metabolism (such as rifampicin) is added to mirtazapine therapy, the mirtazapine dose may have to be increased. If treatment with such a medicinal product is discontinued, it may be necessary to reduce the mirtazapine dose.
CYP Enzyme Inhibitors
Cimetidine: In healthy male patients (n=12), when cimetidine, a weak inhibitor of CYP1A2, CYP2D6, and CYP3A4, given at 800 mg b.i.d. at steady state was coadministered with mirtazapine (30 mg daily) at steady state, the Area Under the Curve (AUC) of mirtazapine increased more than 50%. Mirtazapine did not cause relevant changes in the pharmacokinetics of cimetidine. The mirtazapine dose may have to be decreased when concomitant treatment with cimetidine is started, or increased when cimetidine treatment is discontinued.
Ketoconazole: In healthy, male, Caucasian patients (n=24), coadministration of the potent CYP3A4 inhibitor ketoconazole (200 mg b.i.d. for 6.5 days) increased the peak plasma levels and the AUC of a single 30-mg dose of mirtazapine by approximately 40% and 50%, respectively.
Caution should be exercised when coadministering mirtazapine with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin, or nefazodone.
Paroxetine: In an in vivo interaction study in healthy, CYP2D6 extensive metabolizer patients (n=24), mirtazapine (30 mg/day), at steady state, did not cause relevant changes in the pharmacokinetics of steady state paroxetine (40 mg/day), a CYP2D6 inhibitor.
In healthy, CYP2D6 extensive metabolizer patients (n=32), amitriptyline (75 mg daily), at steady state, did not cause relevant changes in the pharmacokinetics of steady state mirtazapine (30 mg daily); mirtazapine also did not cause relevant changes to the pharmacokinetics of amitriptyline.
In healthy male subjects (n=16), mirtazapine (30 mg daily), at steady state, caused a small (0.2) but statistically significant increase in the International Normalized Ratio (INR) in subjects treated with warfarin. As at a higher dose of mirtazapine, a more pronounced effect can not be excluded, it is advisable to monitor the INR in case of concomitant treatment of warfarin with mirtazapine.
No relevant clinical effects or significant changes in pharmacokinetics have been observed in healthy male subjects on concurrent treatment with subtherapeutic levels of lithium (600 mg/day for 10 days) at steady state and a single 30-mg dose of mirtazapine. The effects of higher doses of lithium on the pharmacokinetics of mirtazapine are unknown.
In an in vivo , nonrandomized, interaction study, subjects (n=6) in need of treatment with an antipsychotic and antidepressant drug, showed that mirtazapine (30 mg daily) at steady state did not influence the pharmacokinetics of risperidone (up to 3 mg b.i.d.).
Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by mirtazapine tablets were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking mirtazapine tablets.
Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by mirtazapine tablets has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking mirtazapine tablets.
The risk of QT prolongation and/or ventricular arrhythmias (e.g., Torsades de Pointes) may be increased with concomitant use of medicines which prolong the QTc interval (e.g., some antipsychotics and antibiotics) and in case of mirtazapine overdose (see ADVERSE REACTIONS and OVERDOSAGE sections).
Carcinogenicity studies were conducted with mirtazapine given in the diet at doses of 2, 20, and 200 mg/kg/day to mice and 2, 20, and 60 mg/kg/day to rats. The highest doses used are approximately 20 and 12 times the maximum recommended human dose (MRHD) of 45 mg/day on an mg/m 2 basis in mice and rats, respectively. There was an increased incidence of hepatocellular adenoma and carcinoma in male mice at the high dose. In rats, there was an increase in hepatocellular adenoma in females at the mid and high doses and in hepatocellular tumors and thyroid follicular adenoma/cystadenoma and carcinoma in males at the high dose. The data suggest that the above effects could possibly be mediated by non-genotoxic mechanisms, the relevance of which to humans is not known.
The doses used in the mouse study may not have been high enough to fully characterize the carcinogenic potential of mirtazapine tablets.
Mirtazapine was not mutagenic or clastogenic and did not induce general DNA damage as determined in several genotoxicity tests: Ames test, in vitro gene mutation assay in Chinese hamster V 79 cells, in vitro sister chromatid exchange assay in cultured rabbit lymphocytes, in vivo bone marrow micronucleus test in rats, and unscheduled DNA synthesis assay in HeLa cells.
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