Pharmacodynamics

The mechanism of action of REMERON® (mirtazapine) Tablets, as with other drugs effective in the treatment of major depressive disorder, is unknown.

Evidence gathered in preclinical studies suggests that mirtazapine enhances central noradrenergic and serotonergic activity. These studies have shown that mirtazapine acts as an antagonist at central presynaptic α₂ adrenergic inhibitory autoreceptors and heteroreceptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity.

Mirtazapine is a potent antagonist of 5-HT₂ and 5-HT₃ receptors. Mirtazapine has no significant affinity for the 5-HT_1A and 5-HT_1B receptors.

Mirtazapine is a potent antagonist of histamine (H₁) receptors, a property that may explain its prominent sedative effects.

Mirtazapine is a moderate peripheral α₁ adrenergic antagonist, a property that may explain the occasional orthostatic hypotension reported in association with its use.

Mirtazapine is a moderate antagonist at muscarinic receptors, a property that may explain the relatively low incidence of anticholinergic side effects associated with its use.

Pharmacokinetics

REMERON® (mirtazapine) Tablets are rapidly and completely absorbed following oral administration and have a half-life of about 20–40 hours. Peak plasma concentrations are reached within about 2 hours following an oral dose. The presence of food in the stomach has a minimal effect on both the rate and extent of absorption and does not require a dosage adjustment.

Mirtazapine is extensively metabolized after oral administration. Major pathways of biotransformation are demethylation and hydroxylation followed by glucuronide conjugation. In vitro data from human liver microsomes indicate that cytochrome 2D6 and 1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas cytochrome 3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite. Mirtazapine has an absolute bioavailability of about 50%. It is eliminated predominantly via urine (75%) with 15% in feces. Several unconjugated metabolites possess pharmacological activity but are present in the plasma at very low levels. The (–) enantiomer has an elimination half-life that is approximately twice as long as the (+) enantiomer and therefore achieves plasma levels that are about three times as high as that of the (+) enantiomer.

Plasma levels are linearly related to dose over a dose range of 15–80 mg. The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20–40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males). Steady state plasma levels of mirtazapine are attained within 5 days, with about 50% accumulation (accumulation ratio = 1.5).

Mirtazapine is approximately 85% bound to plasma proteins over a concentration range of 0.01 - 10µg/mL.

Special Populations

Geriatric

Following oral administration of REMERON® (mirtazapine) Tablets 20 mg/day for 7 days to subjects of varying ages (range, 25–74), oral clearance of mirtazapine was reduced in the elderly compared to the younger subjects. The differences were most striking in males, with a 40% lower clearance in elderly males compared to younger males, while the clearance in elderly females was only 10% lower compared to younger females. Caution is indicated in administering REMERON® to elderly patients (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Pediatrics

Safety and effectiveness of mirtazapine in the pediatric population have not been established (see PRECAUTIONS).

Gender

The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20–40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males) (see Pharmacokinetics).

Race

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