Mirtazapine

DEA NFLIS-Drug Category -> Antidepressants

Pharmaceuticals

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Tetracyclic Antidepressants (TeCAs)

2.9

2.82

slightly soluble in water

1.10e+00 g/L

Breast Feeding; Lactation; Milk, Human; Antidepressive Agents; Antidepressive Agents, Second-Generation; Adrenergic alpha-2 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin 5-HT3 Receptor Antagonists

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

EMA approved medicines: Veterinary medicine

Active Ingredients (Mirtazapine) -> FDA Greenbook

114-116 °C

114 - 116 °C

7.3

7.7

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P261, P264, P270, P271, P273, P280, P301+P317, P304+P340, P318, P319, P330, P391, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 60 reports by companies from 7 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

Acute Tox. 4 (100%)

Acute Tox. 4 (100%)

Treatment should consist of those general measures employed in the management of overdose with any drug effective in the treatment of major depressive disorder. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. There is no experience with the use of forced diuresis, dialysis, hemoperfusion or exchange transfusion in the treatment of mirtazapine overdosage. No specific antidotes for mirtazapine are known. (L1712)

Liver test abnormalities have been reported to occur in up to 10% of patients on mirtazapine, but elevations are usually modest and rarely require dose modification or discontinuation. Rare instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on mirtazapine. The onset of injury has varied greatly from several months to several years. The pattern of serum enzyme elevations is usually hepatocellular, but mixed forms have also been described. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon.

Mirtazapine is a relatively safe drug, although it is slightly more toxic than most SSRIs (except citalopram). Few fatalities have been attributed to an overdose of mirtazapine. The reported fatal toxicity index for mirtazapine is 3.1 deaths per million prescriptions (95% CI), which is relatively similar to that observed with SSRIs. One study involving mirtazapine overdose in 267 patients reported that tachycardia, mild hypertension, and mild CNS depression are associated with overdose, and patients ingesting other substances with mirtazapine experienced more severe toxicity.

Mirtazapine acts as an antagonist at central pre-synaptic alpha(2)-receptors, inhibiting negative feedback to the presynaptic nerve and causing an increase in NE release. Blockade of heteroreceptors, alpha(2)-receptors contained in serotenergic neurons, enhances the release of 5-HT, increasing the interactions between 5-HT and 5-HT₁ receptors and contributing to the anxiolytic effects of mirtazapine. Mirtazapine also acts as a weak antagonist at 5-HT₁ receptors and as a potent antagonist at 5-HT₂ (particularly subtypes 2A and 2C) and 5-HT₃ receptors. Blockade of these receptors may explain the lower incidence of adverse effects such as anxiety, insomnia, and nausea. Mirtazapine also exhibits significant antagonism at H1-receptors, resulting in sedation. Mirtazapine has no effects on the reuptake of either NE or 5-HT and has only minimal activity at dopaminergic and muscarinic receptors.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Mirtazapine

vLess-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

◉ Summary of Use during Lactation

◈ What is mirtazapine?

N06AX11

N - Nervous system

QN - Nervous system

**General effects and a note on suicidality** Mirtazapine is effective in treating moderate to severe depression and treats many symptoms normally associated with this condition. These symptoms may include disturbed sleep, lack of appetite, and anhedonia, in addition to anxiety.. It is important to note that suicidal ideation and behavior may emerge or increase during treatment with mirtazapine, as with any other antidepressant. This risk is especially pronounced in younger individuals. Patients, medical professionals, and families should monitor for suicidal thoughts, worsening depression, anxiety, agitation, sleep changes, irritable behavior, aggression, impulsivity, restlessness, and other unusual behavior when this drug is taken or the dose is adjusted. Do not administer mirtazapine to children. When deciding to prescribe this drug, carefully consider the increased risk of suicidal thoughts and behavior, especially in young adults. **Effects on appetite and weight gain** In addition to the above effects, mirtazapine exerts stimulating effects on appetite, and has been used for increasing appetite and decreasing nausea in cancer patients. Some studies and case reports have shown that this drug improves eating habits and weight gain in patients suffering from anorexia nervosa when administered in conjunction with psychotherapy and/or other psychotropic drugs. In a clinical trial, women with depression experienced a clinically significant mean increase in body weight, fat mass, and concentrations of leptin when treated with mirtazapine for a 6-week period, with a lack of effect on glucose homeostasis. **Effects on sleep** The use of mirtazapine to treat disordered sleep has been leveraged from its tendency to cause somnolence, which is a frequently experienced adverse effect by patients taking this drug. Mirtazapine has been shown to exert beneficial effects on sleep latency, duration, and quality due to its sedating properties. Insomnia is a common occurrence in patients with depression, and mirtazapine has been found to be efficacious in treating this condition.

**Summary** The mechanism of action of mirtazapine is not fully understood but may be explained by its effects on central adrenergic and serotonergic activity. This drug exhibits a fast onset of action, a high level of response, a manageable side-effect profile, and dual noradrenergic and serotonergic effects that are unique from the effects of other antidepressants. **Effects on various receptors** It has been shown that both noradrenergic and serotonergic activity increase following mirtazapine administration. The results of these studies demonstrate mirtazapine exerts antagonist activity at presynaptic α2-adrenergic inhibitory autoreceptors and heteroreceptors in the central nervous system. This is thought to lead to enhanced noradrenergic and serotonergic activity, which are known to improve the symptoms of depression and form the basis of antidepressant therapy. Mirtazapine is a strong antagonist of serotonin 5-HT2 and 5-HT3 receptors. It has not been found to bind significantly to the serotonin 5-HT1A and 5-HT1B receptors but indirectly increases 5-HT1A transmission. In addition to the above effects, mirtazapine is a peripheral α1-adrenergic antagonist. This action may explain episodes of orthostatic hypotension that have been reported after mirtazapine use. Mirtazapine is a potent histamine (H1) receptor antagonist, which may contribute to its powerful sedating effects. The pain-relieving effects of mirtazapine may be explained by its effects on opioid receptors.

Mirtazapine is heavily metabolized in humans. Demethylation and hydroxylation and subsequent glucuronide conjugation are the major pathways by which mirtazapine is metabolized. Data from in vitro studies on human liver microsomes show that cytochrome 2D6 and 1A2 lead to the formation of the _8-hydroxy metabolite_ of mirtazapine. The CYP3A enzyme metabolizes this drug into its _N-desmethyl and N-oxide_ metabolites. There are various other unconjugated metabolites of this drug that are pharmacologically active, but are measured in the blood at limited concentrations.

Mirtazapine has known human metabolites that include N-Desmethylmirtazapine, Mirtazapine N-oxide, and 8-hydroxy-mirtazapine.

Mirtazapine is extensively metabolized by demethylation and hydroxylation followed by glucuronide conjugation. Cytochrome P450 2D6 and cytochrome P450 1A2 are involved in formation of the 8-hydroxy metabolite of mirtazapine, and cytochrome P450 3A4 is responsible for the formation of the N-desmethyl and N-oxide metabolites. Several metabolites possess pharmacological activity, but plasma levels are very low. Route of Elimination: This drug is known to be substantially excreted by the kidney (75%). Half Life: 20-40 hours

Mood-stimulating drugs used primarily in the treatment of affective disorders and related conditions. Several MONOAMINE OXIDASE INHIBITORS are useful as antidepressants apparently as a long-term consequence of their modulation of catecholamine levels. The tricyclic compounds useful as antidepressive agents (ANTIDEPRESSIVE AGENTS, TRICYCLIC) also appear to act through brain catecholamine systems. A third group (ANTIDEPRESSIVE AGENTS, SECOND-GENERATION) is a diverse group of drugs including some that act specifically on serotonergic systems.

Drugs that selectively bind to but do not activate histamine H1 receptors, thereby blocking the actions of endogenous histamine. Included here are the classical antihistaminics that antagonize or prevent the action of histamine mainly in immediate hypersensitivity. They act in the bronchi, capillaries, and some other smooth muscles, and are used to prevent or allay motion sickness, seasonal rhinitis, and allergic dermatitis and to induce somnolence. The effects of blocking central nervous system H1 receptors are not as well understood.

Agents that alleviate ANXIETY, tension, and ANXIETY DISORDERS, promote sedation, and have a calming effect without affecting clarity of consciousness or neurologic conditions. ADRENERGIC BETA-ANTAGONISTS are commonly used in the symptomatic treatment of anxiety but are not included here.

Drugs that bind to and block the activation of ADRENERGIC ALPHA-2 RECEPTORS.

Drugs that bind to but do not activate SEROTONIN 5-HT2 RECEPTORS, thereby blocking the actions of SEROTONIN or SEROTONIN 5-HT2 RECEPTOR AGONISTS. Included under this heading are antagonists for one or more specific 5-HT2 receptor subtypes.

Drugs that bind to but do not activate SEROTONIN 5-HT3 RECEPTORS, thereby blocking the actions of SEROTONIN or SEROTONIN 5-HT3 RECEPTOR AGONISTS.

The absorption of this drug is rapid and complete. Due to first pass metabolism in the liver and metabolism in the gut wall, absolute bioavailability is about 50%. Peak blood concentrations are attained within about 2 hours after an oral dose. Food has little effect on the absorption of mirtazapine, and no dose adjustment is required if it is taken with food. Steady-state levels are achieved by about 5 days after the initial dose. Mirtazapine pharmacokinetics vary across gender and age range. Females and the elderly population have been shown to have higher blood concentrations in comparison to males and younger adults.

This drug is mainly excreted by the kidney. It is 75% eliminated in the urine and 15% eliminated in the feces.

The volume of distribution after an oral steady-state dose was measured to be 107 ± 42L in a pharmacokinetic study.

Total body clearance in males was found to be 31 L/h in a clinical pharmacokinetics study after intravenous administration. **Clearance in elderly patients*

Use (kg; approx.) in Germany (2009): >2500

For the treatment of major depressive disorder.

Animal Drugs -> FDA Approved Animal Drug Products (Green Book) -> Active Ingredients

Pharmaceuticals -> Nervous System -> Antidepressants

Pharmaceuticals