Mirtazapine

Mirtazapine is an Antidepressant agent belonging to the Histamine H₁ and Serotonin 5-HT2 and 5-HT3 receptor antagonist class.

Mirtazapine is a tetracyclic antidepressant used in the treatment of major depression and is used off-label as a drug for insomnia and to increase appetite.

The absorption of this drug is rapid and complete. The absolute bioavailability is about 50%. The Peak blood concentrations are attained within about 2 hours after an oral dose. The volume of distribution after an oral steady-state dose was measured to be 107 ± 42L. Mirtazapine extensively hepatic metabolism via CYP1A2, 2D6, 3A4 and via demethylation and hydroxylation. The Excretion of Mirtazapine via Urine (75%) and feces (15%) as metabolites.

Mirtazapine shows side effects like Drowsiness, dizziness, anxiousness, confusion, increased weight and appetite, dry mouth, constipation, nausea, vomiting.

Mirtazapine is available in the form of Oral tablets.

Mirtazapine is available in India, Canada, US, Netherlands, Singapore, Japan, Italy, China, Germany and Australia.

Mirtazapine belongs to the Histamine H₁ and Serotonin 5-HT2 and 5-HT3 receptor antagonist to the class acts as Antidepressant Agent.

Mirtazapine, a tetracyclic antidepressant, blocks the central presynaptic α₂- adrenergic autoreceptors and heteroceptors resulting in an increased noradrenergic and serotonergic activity. It also has a potent blocking activity in 5-HT₂, 5-HT₃ serotonin receptor and H₁ histamine receptor while a moderate blocking activity in peripheral α₁-adrenergic and muscarinic antagonist.

Mirtazapine is available in the form of Oral Tablet.

Mirtazapine Tablet is taken orally, usually in divided dose.

Mirtazapine belongs to the class of tetracyclic antidepressant. It is used for the treatment of symptoms associated with severe/clinical depression.

Mirtazapine is an Antidepressant agent belonging to the Histamine H₁ and Serotonin 5-HT2 and 5-HT3 receptor antagonist class.

Mirtazapine is a tetracyclic antidepressant that works by its central presynaptic alpha₂-adrenergic antagonist effects, which results in increased release of norepinephrine and serotonin. It is also a potent antagonist of 5-HT₂ and 5-HT₃ serotonin receptors and H₁ histamine receptors and a moderate peripheral alpha₁-adrenergic and muscarinic antagonist; it does not inhibit the reuptake of norepinephrine or serotonin.

Mirtazapine is approved for use in the following clinical indications

• Headache, chronic tension-type, prophylaxis

Oral: Initial: 15 mg once daily at bedtime; may increase after 1 week to 30 mg/day based on response and tolerability.

• Major depressive disorder

Oral: Initial: 15 mg once daily at bedtime; may increase dose in 15 mg increments at intervals of ≥1 week based on response and tolerability. Maximum dose: 45 mg/day; however, doses up to 60 mg/day have been used in clinical trials.

• Panic disorder

Oral: Initial: 15 mg once daily at bedtime; may increase in increments of 15 mg at intervals of no less than 1 week based on response and tolerability, up to a usual maximum of 45 mg once daily.

Oral: Initial: 15 mg once daily at bedtime; may increase after 1 week to 30 mg/day based on response and tolerability.

Oral: Initial: 15 mg once daily at bedtime; may increase dose in 15 mg increments at intervals of ≥1 week based on response and tolerability. Maximum dose: 45 mg/day; however, doses up to 60 mg/day have been used in clinical trials.

Oral: Initial: 15 mg once daily at bedtime; may increase in increments of 15 mg at intervals of no less than 1 week based on response and tolerability, up to a usual maximum of 45 mg once daily.

Mirtazapine is available in various strengths as 7.5 mg, 15 mg, 30 mg, 45 mg.

Mirtazapine is available in the form of Oral Tablet.

1. Dosage Adjustment in Kidney Patient

eGFR ≥30 mL/minute/1.73 m²: No dosage adjustment necessary.

eGFR <30 mL/minute/1.73 m²: Initial: 7.5 to 15 mg once daily; titrate slowly with close monitoring for adverse effects.

2. Dosage Adjustment in Hepatic impairment Patient

There are no dosage adjustments provided.

Mirtazapine is contraindicated in patients with

• Hypersensitivity:

Mirtazapine Tablets are contraindicated in patients with a known hypersensitivity to mirtazapine or to any of the excipients.

• Monoamine Oxidase Inhibitors:

The concomitant use of Mirtazapine Tablets and a monoamine oxidase (MAO) inhibitor is contraindicated. Mirtazapine should not be used within 14 days of initiating or discontinuing therapy with a monoamine oxidase inhibitor (MAOI).

• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. The degree of anticholinergic blockade produced by this agent is low relative to other antidepressants.
• Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising.
• Ocular effects: May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.

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. Accordingly, patients should be advised to avoid alcohol while taking Mirtazapine.

It is not known whether mirtazapine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Mirtazapine Tablets are administered to nursing women.

Mirtazapine is not recommended for use in pregnant women unless clearly needed and the benefits outweigh the risks.

Common

· Drowsiness, Weight gain, Dry mouth, Increased appetite, Constipation, Lack of energy, Weakness, Dizziness, Serum triglycerides increased, Dream disorders, Disturbance in thinking, ALT increased, Swelling of extremities, Muscle pain, Confusion, Urinary frequency, Tremor, Back pain, Shortness of breath.

Rare

· Worsening depression, Status epilepticus, Suicidal thoughts, suicide, Agranulocytosis, Low white blood cell count.

• Amitriptyline: In healthy, CYP2D6 extensive metabolizer patients (n=32), amitriptyline (75 mg daily), at steady state, did not cause relevant changes in the pharmacokinetics of steady state mirtazapine (30 mg daily); mirtazapine also did not cause relevant changes to the pharmacokinetics of amitriptyline.
• Warfarin: In healthy male subjects (n=16), mirtazapine (30 mg daily), at steady state, caused a small (0.2) but statistically significant increase in the International Normalized Ratio (INR) in subjects treated with warfarin. As at a higher dose of mirtazapine, a more pronounced effect cannot be excluded. It is advisable to monitor the INR in case of concomitant treatment of warfarin with mirtazapine.
• Lithium: No relevant clinical effects or significant changes in pharmacokinetics have been observed in healthy male subjects on concurrent treatment with subtherapeutic levels of 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: In an in vivo, nonrandomized, interaction study, subjects (n=6) in need of treatment with an antipsychotic and antidepressant drug, showed that mirtazapine (30 mg daily) at steady state did not influence the pharmacokinetics of risperidone (up to 3 mg twice a day).

The common side effects of Mirtazapine include the following

Common side effects

· Drowsiness, dizziness, anxiousness, confusion, increased weight and appetite, dry mouth, constipation, nausea, vomiting.

Rare side effects

· Flu-like symptoms, fever, chills, sore throat, mouth sores, or other signs of infection, chest pain, fast heartbeat, seizures.

• Pregnancy

Pregnancy Category C

Teratogenic Effects: 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/m2 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/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

• Nursing Mothers

It is not known whether mirtazapine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Mirtazapine Tablets are administered to nursing women.

• Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

• Geriatric Use

Approximately 190 elderly individuals (≥65 years of age) participated in clinical studies with Mirtazapine Tablets. This drug 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. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Sedating drugs may cause confusion and over-sedation in the elderly. No unusual adverse age-related phenomena were identified in this group. Pharmacokinetic studies revealed a decreased clearance in the elderly. Caution is indicated in administering Mirtazapine to elderly patients.

Symptoms: Disorientation, prolonged sedation, impaired memory, tachycardia and mild hypertension or hypotension.

Management: Symptomatic treatment. May perform gastric lavage and administer activated charcoal.

• Pharmacodynamic

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. 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.

• Pharmacokinetics

Absorption

The absorption of this drug is rapid and complete. The absolute bioavailability is about 50%. The Peak blood concentrations are attained within about 2 hours after an oral dose.

Distribution

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

Metabolism and Excretion

Mirtazapine extensively hepatic metabolism via CYP1A2, 2D6, 3A4 and via demethylation and hydroxylation. The Excretion of Mirtazapine via Urine (75%) and feces (15%) as metabolites.

1. Fawcett J, Barkin RL. Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression. Journal of affective disorders. 1998 Dec 1;51(3):267-85.
2. Burrows GD, Kremer CM. Mirtazapine: clinical advantages in the treatment of depression. Journal of clinical psychopharmacology. 1997 Apr 1;17(2):34S-9S.
3. Posey DJ, Guenin KD, Kohn AE, Swiezy NB, McDougle CJ. A naturalistic open-label study of mirtazapine in autistic and other pervasive developmental disorders. Journal of child and adolescent psychopharmacology. 2001 Sep 1;11(3):267-77.

• https://www.uptodate.com/contents/mirtazapine-drug-information#F197073
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020415s023s024.pdf
• https://go.drugbank.com/drugs/DB00370
• https://www.drugs.com/mirtazapine.html
• https://medlineplus.gov/druginfo/meds/a697009.html
• https://www.rxlist.com/mirtazapine/generic-drug.htm