Mirtazapine (Page 5 of 7)

8.2 Lactation

Risk Summary

Data from published literature report the presence of mirtazapine in human milk at low levels with relative infant doses for mirtazapine ranging between 0.6 and 2.8% of the maternal weight-adjusted dose (see Data). No adverse effects on the breastfed infant have been reported in most cases of maternal use of mirtazapine. There are no data on the effects of mirtazapine on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mirtazapine and any potential adverse effects on the breastfed infant from mirtazapine or from the underlying maternal condition.

Data

In a published pooled analysis of 8 breastfeeding mother-infant pairs, the mean (min, max) total relative infant doses for mirtazapine and its desmethyl metabolite were 1.5% (0.6%, 2.8%) and 0.4% (0.1%, 0.7%) of the maternal weight-adjusted dose (median (min, max) dose of 38 mg (30 mg, 120 mg), respectively). No adverse drug effects were reported for any of the infants.

8.4 Pediatric Use

The safety and effectiveness of mirtazapine have not been established in pediatric patients with MDD. Two placebo-controlled trials in 258 pediatric patients with MDD have been conducted with mirtazapine, and the data were insufficient to establish the safety and effectiveness of mirtazapine in pediatric patients with MDD.

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning and Warnings and Precautions (5.1)].

In an 8-week-long clinical trial in pediatric patients receiving doses between 15 to 45 mg per day, 49% of mirtazapine-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients. The mean increase in weight was 4 kg (2 kg SD) for mirtazapine-treated patients versus 1 kg (2 kg SD) for placebo-treated patients [see Warnings and Precautions (5.7)].

8.5 Geriatric Use

Approximately 190 patients ≥65 years of age participated in clinical studies with mirtazapine. Mirtazapine is known to be substantially excreted by the kidney (75%), and the risk of decreased clearance of this drug is greater in patients with impaired renal function. Pharmacokinetic studies revealed a decreased clearance of mirtazapine in the elderly [see Clinical Pharmacology (12.3)].

Sedating drugs, including mirtazapine, may cause confusion and over-sedation in the elderly. Elderly patients may be at greater risk of developing hyponatremia. Caution is indicated when administering mirtazapine to elderly patients [see Warnings and Precautions (5.12), (5.15) and Clinical Pharmacology (12.3)] . In general, dose selection for an elderly patient should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal or Hepatic Impairment

The clearance of mirtazapine is reduced in patients with moderate to severe renal or hepatic impairment. Consequently, plasma mirtazapine levels may be increased in these patient groups, compared to levels observed in patients without renal or hepatic impairment. Dosage decrease may be necessary when administering mirtazapine to patients with moderate to severe renal or hepatic impairment [see Warnings and Precautions (5.13), Use in Specific Populations (8.5), and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Human Experience

In premarketing clinical studies, there were reports of mirtazapine overdose alone or in combination with other pharmacological agents. Signs and symptoms reported in association with overdose included disorientation, drowsiness, impaired memory, and tachycardia.

Based on postmarketing reports, serious outcomes (including fatalities) may occur at dosages higher than the recommended doses, especially with mixed overdoses. In these cases, QT prolongation and Torsades de Pointes have also been reported [see Warnings and Precautions (5.5), Adverse Reactions (6.2), and Drug Interactions (7)].

Overdose Management

No specific antidotes for mirtazapine are known.

Contact Poison Control (1-800-222-1222) for the latest recommendations.

11 DESCRIPTION

Mirtazapine tablets, USP contain mirtazapine USP. Mirtazapine has a tetracyclic chemical structure and belongs to the piperazino-azepine group of compounds. It is designated 1,2,3,4,10,14b-hexahydro-2-methylpyrazino [2,1-a] pyrido [2,3-c][2] benzazepine and has the molecular formula of C 17 H 19 N 3 . Its molecular weight is 265.35. The structural formula is the following and it is the racemic mixture:

Mirtazpine Structure

Mirtazapine is a white to creamy white crystalline powder which is practically insoluble in water.

Mirtazapine tablets, USP are available for oral administration as scored film-coated tablets containing 15 or 30 mg of mirtazapine USP, and unscored film-coated tablets containing 7.5 or 45 mg of mirtazapine USP. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, and titanium dioxide. In addition, the 15 mg contains iron oxide yellow and 30 mg contains iron oxide red, iron oxide black, and iron oxide yellow.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of mirtazapine for the treatment of major depressive disorder, is unclear. However, its efficacy could be mediated through its activity as an antagonist at central presynaptic α 2 -adrenergic inhibitory autoreceptors and heteroreceptors and enhancing central noradrenergic and serotonergic activity.

12.2 Pharmacodynamics

In preclinical studies, mirtazapine acts as an antagonist at α 2 -adrenergic inhibitory autoreceptors and heteroreceptors and as an antagonist at serotonin 5-HT 2 and 5-HT 3 receptors. Mirtazapine has no significant affinity for the 5-HT 1A and 5-HT 1B receptors.

Mirtazapine also acts as an antagonist of histamine (H 1 ) receptors, peripheral α 1 -adrenergic receptors, and muscarinic receptors. Actions at these receptors may explain some of the other clinical effects of mirtazapine (e.g., its prominent somnolent effects and orthostatic hypotension may be explained by its inhibition of histamine (H 1 ) receptors and peripheral α 1 -adrenergic receptors, respectively).

Cardiac Electrophysiology

The effect of mirtazapine on QTc interval was assessed in healthy subjects. At a dose of 75 mg (1.67 times the maximum recommended dosage), mirtazapine does not prolong the QTc interval to a clinically meaningful extent.

12.3 Pharmacokinetics

Plasma levels of mirtazapine are linearly related to dose over a dose range of 15 to 80 mg (1.78 times the maximum recommended dose). Steady state plasma levels of mirtazapine are attained within 5 days, with about 50% accumulation (accumulation ratio=1.5). The (–) enantiomer has an elimination half-life that is approximately twice as long as the (+) enantiomer and therefore achieves plasma levels that are about 3 times as high as that of the (+) enantiomer.

Absorption

Mirtazapine has an absolute bioavailability of about 50% following oral administration. Peak plasma concentrations of mirtazapine are reached within about 2 hours post dose.

Food Effect

The presence of food in the stomach has a minimal effect on both the rate and extent of absorption.

Distribution

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

Elimination

Mirtazapine has a half-life of about 20 to 40 hours following oral administration of mirtazapine.

Metabolism

Mirtazapine is extensively metabolized after oral administration. Major pathways of bio-transformation are demethylation and hydroxylation followed by glucuronide conjugation. In vitro data from human liver microsomes indicate that CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas CYP3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite. Several unconjugated metabolites possess pharmacological activity but are present in the plasma at very low levels.

Excretion

Mirtazapine and its metabolites are eliminated predominantly (75%) via urine with 15% in feces.

Specific Populations

Geriatric Patients

Following oral administration of mirtazapine tablets 20 mg/day for 7 days to subjects of varying ages (range 25 to 74 years old), oral clearance of mirtazapine was reduced in the elderly compared to the younger subjects. The clearance in elderly males was 40% lower compared to younger males, while the clearance was 10% lower in elderly females compared to younger females [see Warnings and Precautions (5.15), Use in Specific Populations (8.5)].

Male and Female Patients

The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20 to 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).

Race

There have been no clinical studies to evaluate the effect of race on the pharmacokinetics of mirtazapine.

Patients with Renal Impairment

When compared to subjects with normal renal function, total body clearance of mirtazapine was reduced approximately 30% in renal impaired patients with GFR=11 to 39 mL/min/1.73 m 2 and approximately 50% in renal impaired patients with GFR=<10 mL/min/1.73 m 2) [see Warnings and Precautions (5.15), Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

Following a single 15 mg oral dose of mirtazapine, the oral clearance of mirtazapine in patients with hepatic impairment was decreased by approximately 30%, compared to subjects with normal hepatic function [see Warnings and Precautions (5.13, 5.15), Use in Specific Populations (8.6)].

Drug Interactions Studies

Warfarin

Mirtazapine (30 mg daily) at steady state caused a statistically significant increase (0.2) in the International Normalized Ratio (INR) in subjects treated with warfarin [see Drug Interactions (7)].

QTc-Prolonging Drugs

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 mirtazapine overdose [see Warnings and Precautions (5.5), Adverse Reactions (6.1, 6.2), Drug Interactions (7), and Overdosage (10)].

Phenytoin

In healthy male subjects (n=18), phenytoin (200 mg daily, at steady state) increased mirtazapine (30 mg daily, at steady state) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 45% [see Drug Interactions (7)]. Mirtazapine did not significantly affect the pharmacokinetics of phenytoin.

Carbamazepine

In healthy male subjects (n=24), carbamazepine (400 mg twice a day, at steady state) increased mirtazapine (15 mg twice a day, at steady state) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 60% [see Drug Interactions (7)].

Cimetidine

In healthy male subjects (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% [see Drug Interactions (7)]. Mirtazapine did not cause relevant changes in the pharmacokinetics of cimetidine.

Ketoconazole

In healthy male Caucasian subjects (n=24), coadministration of the strong 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 [see Drug Interactions (7)].

Amitriptyline

In healthy, CYP2D6 extensive metabolizer patients (n=32), amitriptyline (75 mg daily), at steady state, did not cause relevant changes to the pharmacokinetics of steady state mirtazapine (30 mg daily); mirtazapine also did not cause relevant changes to the pharmacokinetics of amitriptyline.

Paroxetine

In healthy CYP2D6 extensive metabolizer subjects (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.

Lithium

No relevant clinical effects or significant changes in pharmacokinetics have been observed in healthy male subjects on concurrent treatment with 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.

Risperidone

Mirtazapine (30 mg daily) at steady state did not influence the pharmacokinetics of risperidone (up to 3 mg twice a day) in subjects (n=6) in need of treatment with an antipsychotic and antidepressant drug.

Alcohol

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 were shown to be additive with those produced by alcohol.

Diazepam

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 has been shown to be additive with those caused by diazepam.

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