MONCITRA

Mirtazapine is a tetracyclic piperazino-azepine antidepressant agent that was initially approved for the treatment of major depressive disorder (MDD) in the Netherlands in 1994.

This drug was first n the off-label management of various other conditions.

It may improve the symptoms of neurological disorders, reverse weight loss caused by medical conditions, improve sleep, and prevent nausea and vomiting after surgery.

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. 9,

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. 2, 22, 29.

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.

Label 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. 14, 15 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. 16, 23 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. 8, 20, Label 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.

5-hydroxytryptamine receptor 2A Antagonist 5HT3 serotonin receptor Antagonist Alpha-2A adrenergic receptor Antagonist + 1 more target.

The absorption of this drug is rapid and complete. 12, Label Due to first pass metabolism in the liver and metabolism in the gut wall, absolute bioavailability is about 50%.

Label, 12 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.

Label, 12 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.

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

Mirtazapine is heavily metabolized in humans.

Demethylation and hydroxylation and subsequent glucuronide conjugation are the major pathways by which mirtazapine is metabolized. 12, Label 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.

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.

Label, 12 Hover over products below to view reaction partners Mirtazapine mirtazapine-N-oxide N-desmethylmirtazapine 8-hydroxymirtazapine.

This drug is mainly excreted by the kidney.

It is 75% eliminated in the urine and 15% eliminated in the feces.

20-40 hours Label, 12.

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 clearance is slower in the elderly than in younger subjects.

Exercise caution when this drug is given to elderly patients.

In a clinical trial, elderly males showed a marked decrease in mirtazapine clearance when compared to young males taking the same dose.

This difference was less significant when clearance was compared between elderly females and younger females taking mirtazapine.

Label Clearance in hepatic and renal impairment Patients with hepatic and renal impairment have decreased rates of clearance and dosage adjustments may be necessary for these patients.

Moderate renal impairment and hepatic impairment cause about a 30% decrease in mirtazapine clearance.

Severe renal impairment leads to a 50% decrease in mirtazapine clearance.

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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 Label.

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.

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 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.

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.

Label 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.

Label 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.

• Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome.

• With a known hypersensitivity to mirtazapine or to any of the excipients in mirtazapine tablets.

Severe skin reactions, including Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have been reported following the use of mirtazapine tablets.

• Concomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of stopping MAOIs.

• Known hypersensitivity to mirtazapine or any of the excipients in mirtazapine tablets.

• Starting dose: 15 mg once daily; may increase up to maximum recommended dose of 45 mg once daily.

• Administer orally once daily, preferably in the evening prior to sleep.

• Reduce dose gradually when discontinuing mirtazapine tablets. 2.1 Recommended Dosage The recommended starting dose of mirtazapine tablets is 15 mg once daily, administered orally, preferably in the evening prior to sleep.

If patients do not have an adequate response to the initial 15 mg dose, increase the dose up to a maximum of 45 mg per day. Dose changes should not be made in intervals of less than to 2 weeks to allow sufficient time for evaluation of response to a given dose. 2.3 Screen for Bipolar Disorder Prior to Starting Mirtazapine Tablets Prior to initiating treatment with mirtazapine tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania. 2.4 Switching Patients to or from a Monoamine Oxidase Inhibitor Antidepressant At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of mirtazapine tablets.

In addition, at least 14 days must elapse after stopping mirtazapine tablets before starting an MAOI antidepressant. 2.5 Dosage Modifications Due to Drug Interactions Strong CYP3A Inducers An increase in dosage of mirtazapine tablets may be needed with concomitant strong CYP3A inducer (e.g., carbamazepine, phenytoin, rifampin) use.

Conversely, a decrease in dosage of mirtazapine tablets may be needed if the CYP3A inducer is discontinued.

CYP3A Inhibitors A decrease in dosage of mirtazapine tablets may be needed with concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin).

Conversely, an increase in dosage of mirtazapine tablets may be needed if the CYP3A4 inhibitor is discontinued.

A decrease in dosage of mirtazapine tablets may be needed with concomitant use of cimetidine.

Conversely, an increase in dosage of mirtazapine tablets may be needed if cimetidine is discontinued. 2.6 Discontinuation of Mirtazapine Tablets Treatment Adverse reactions may occur upon discontinuation or dose reduction of mirtazapine tablets.

Gradually reduce the dosage of mirtazapine tablets rather than stopping abruptly whenever possible.

Mirtazapine tablets, USP are supplied as: 15 mg Tablets – Yellow, biconvex, capsule shaped film coated tablets with a score line in between “0” and “8” on one side and “A” debossed on the other side.

Bottles of 30 NDC 71205-481-30 Bottles of 60 NDC 71205-481-60 Bottles of 90 NDC 71205-481-90 Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Protect from light and moisture.

Reproduction studies in pregnant rats and rabbits at doses up to 100 mg/kg and 40 mg/kg, respectively [20 and 17 times the maximum recommended human dose (MRHD) on an mg/m 2 basis, respectively], have revealed no evidence of teratogenic effects.

However, in rats, there was an increase in post-implantation losses in dams treated with mirtazapine.

There was an increase in pup deaths during the first 3 days of lactation and a decrease in pup birth weights.

The cause of these deaths is not known.

The effects occurred at doses that were 20 times the MRHD, but not at 3 times the MRHD, on an mg/m 2 basis.

There are no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, mirtazapine should be used during pregnancy only if clearly needed.

Mirtazapine may be excreted in breast milk.

Exercise caution when administering mirtazapine to nursing women.

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.

In an 8-week-long clinical trial in pediatric patients receiving doses between 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.

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.

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.

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.