Mirtazapine

265.35

265.35

288-060-6

DTXSID0023325

QN06AX11|N06AX11|N - Nervous system

2933990090

19.4

3.3

white solid

1.2±0.1 g/cm3

114-116 °C

432.4ºC at 760 mmHg

215.3±28.7 °C

1.668

H2O: Slight soluble ;DMSO: ~8 mg/mL, soluble

Store at RT

7.7

161 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

NONH for all modes of transport

3

22

22-24/25

UQ4410250

Xn

P301 + P312 + P330

H302-H336

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P261, P264, P270, P271, P273, P281, P301+P312, P304+P340, P308+P313, P312, P314, P330, P391, P403+P233, P405, and P501|Aggregated GHS information provided by 58 companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|P201, P202, P261, P264, P270, P271, P273, P280, P281, P301+P312, P302+P352, P304+P312, P304+P340, P308+P313, P312, P322, P330, P363, P391, P405, and P501|Aggregated GHS information provided by 12 companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

**LD50** Oral LD50 was 830 mg/kg in male Swiss mice 24 hours after being administered mirtazapine. **Overdose information** Activated charcoal should be administered during an overdose to absorb excess mirtazapine. General supportive therapy should be employed, including maintenance of an adequate airway, oxygen therapy, and ventilation therapy. Vital signs and cardiac rhythm must be monitored. It is not advisable to induce vomiting. Gastric lavage with a large-bore orogastric tube with proper protection of the airway is recommended. There is no antidote for mirtazapine available currently. Consider the possibility of mirtazapine combined with other drugs in an overdose and ensure to contact the local poison control center for guidance on management. **Carcinogenesis** At higher than normal doses, mirtazapine increased the incidence of hepatocellular adenomas and carcinomas in male mice. The highest doses administered to the mice were about 20 and 12 times the maximum recommended human dose (MRHD). Hepatocellular tumors and thyroid follicular adenoma/cystadenomas in male rats occurred at an increased rate at a higher mirtazapine dose (60 mg/kg/day). In female rats, both the medium (20 mg/kg/day) and higher (60 mg/kg/day) doses of mirtazapine increased the rate of hepatocellular adenomas. The relevance of these findings in humans is not known at this time. **Impairment of Fertility** Mirtazapine was administered to rats at doses reaching 100 mg/kg (equivalent to 20 times the maximum recommended human dose) in a fertility study. There was no impact on mating and conception, however, there was a disturbance of reproductive (estrous) cycling at higher doses. These doses were measured to be at least 3 times the maximum recommended human dose. Loss of fetus before implantation in the uterus occurred when doses equivalent to 20 times the maximum recommended dose were administered. **Use in pregnancy** This drug is categorized as a pregnancy category C drug. No adequate studies in pregnant women have been conducted. In rats, an increased rate of post-implantation demise occurred with mirtazapine administration. Additionally, an increase in deaths of rat pups during the first 3 days of lactation with a decrease in pup birth weight was noted. Studies on animals are not always relevant to human response. Mirtazapine should be used during pregnancy only if the clinical need outweighs the possible risks to the fetus. **Use in nursing** Whether this drug is excreted in human milk is unknown. Many drugs are found excreted in human breast milk, therefore caution is advised if this drug is used during nursing.

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 about 85% bound to plasma proteins.

This drug is indicated for the treatment of major depressive disorder and its associated symptoms. Mirtazapine has been used off-label for a variety of conditions including panic disorder, generalized anxiety disorder, dysthymia, tension headaches, hot flushes, post-traumatic stress disorder (PTSD), sleep disorders, substance abuse disorders, and sexual disorders, among others.|FDA Label|For bodyweight gain in cats experiencing poor appetite and weight loss resulting from chronic medical conditions.

Mirtazapine is a tetracyclic antidepressant with a somewhat unique mechanism of action. Mirtazapine therapy can be associated with transient asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of clinically apparent acute liver injury.

Antidepressant Agents

Mirtazapine has known transformation products that include 8-Hydroxymirtazapine.

**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.

Drugs that bind to and block the activation of ADRENERGIC ALPHA-2 RECEPTORS. (See all compounds classified as Adrenergic alpha-2 Receptor Antagonists.)|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. (See all compounds classified as Histamine H1 Antagonists.)|Drugs that bind to but do not activate SEROTONIN 5-HT3 RECEPTORS, thereby blocking the actions of SEROTONIN or SEROTONIN 5-HT3 RECEPTOR AGONISTS. (See all compounds classified as Serotonin 5-HT3 Receptor Antagonists.)|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. (See all compounds classified as Anti-Anxiety Agents.)|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. (See all compounds classified as Serotonin 5-HT2 Receptor Antagonists.)|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. (See all compounds classified as Antidepressive Agents.)

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*

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 8-hydroxy-mirtazapine, Mirtazapine N-oxide, and N-Desmethylmirtazapine.

20-40 hours

**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.

(N-methyl-11C)mirtazapine

Veterinary drugs -> Mirataz -> EMA Drug Category|Psychoanaleptics, Antidepressants in combination with psycholeptics -> Veterinary pharmacotherapeutic group|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Animal Drugs -> FDA Approved Animal Drug Products (Green Book) -> Active Ingredients|Pharmaceuticals|Pharmaceuticals -> Nervous System -> Antidepressants