ratio-Mirtazapine

Uses

ratio-Mirtazapine Tablets are used for the treatment of major depressive disorder.

The efficacy of ratio-Mirtazapine in the treatment of major depressive disorder was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the Diagnostic and Statistical Manual of Mental Disorders- 3rd edition (DSM-III) category of major depressive disorder

A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt, or suicidal ideation.

The effectiveness of ratio-Mirtazapine in hospitalized depressed patients has not been adequately studied.

The efficacy of ratio-Mirtazapine in maintaining a response in patients with major depressive disorder for up to 40 weeks following 8 to 12 weeks of initial open-label treatment was demonstrated in a placebo-controlled trial. Nevertheless, the physician who elects to use ratio-Mirtazapine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient

ratio-Mirtazapine is also used to associated treatment for these conditions: Depression, Dysthymic Disorder, Fibromyalgia, Generalized Anxiety Disorder (GAD), Hot Flushes, Insomnia, Major Depressive Disorder (MDD), Nausea and vomiting, Neurological Disorders, Obsessive Compulsive Disorder (OCD), PTSD Symptoms, Pain, Cancer, Panic Disorder, Poststroke depression, Schizophrenia, Sleep disorders and disturbances, Social Phobia, Substance Abuse Disorders, Tension Headache, Low body weight, Weight restoration

How ratio-Mirtazapine works

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.

ratio-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. ratio-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.

Dosage

ratio-Mirtazapine dosage

Adult: Initially, 15 mg daily; may be increased gradually depending on clinical response. Change dose at intervals of at least 1-2 wk. Usual effective dose: 15-45 mg daily given as single dose, preferably at bedtime, or in 2 divided doses.

Children: Safety and efficacy not established.

Geriatric: Use with caution.

Side Effects

The most commonly reported adverse effects with mirtazapine are increase in appetite, weight gain, edema, drowsiness or sedation, dizziness, headache etc.

Toxicity

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

ratio-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. ratio-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.

Precaution

ratio-Mirtazapine should be used cautiously in patients with epilepsy or history of seizure, history of mania /hypomania, patients with hepatic or renal impairment; cardiac disorders e.g. conduction disturbances, angina pectoris, recent MI. Hypotension, DM, psychoses, history of bipolar disorder. Stop treatment if jaundice develops. Monitor patient for signs of bone marrow depression. Monitor patient for suicidal tendency. Avoid abrupt withdrawal. May impair ability to drive or operate machinery.

Interaction

ratio-Mirtazapine potentiates sedative effects with alcohol or benzodiazepines, increased plasma levels with potent CYP3A4 inhibitors (e.g. HIV-protease inhibitors, azole antifungals including ketoconazole, erythromycin, nefazodone), reduced plasma levels with carbamazepine and other inducers of CYP3A4 and increased bioavailability with cimetidine.

Food Interaction

• Avoid alcohol.
• Take with or without food. Food does not significantly affect absorption.

[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.

Use in combination may result in additive central nervous system depression and
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

ratio-Mirtazapine Cholesterol interaction

[Moderate] ratio-Mirtazapine may significantly elevate serum triglyceride and total cholesterol levels.

Patients with preexisting hyperlipidemia may require closer monitoring during mirtazapine therapy, and adjustments made accordingly in their lipid-lowering regimen.

ratio-Mirtazapine Drug Interaction

Major: duloxetine, escitalopram, sertralineModerate: aripiprazole, zolpidem, diphenhydramine, pregabalin, metoprolol, metoprolol, quetiapine, alprazolamUnknown: amphetamine / dextroamphetamine, aspirin, omega-3 polyunsaturated fatty acids, atorvastatin, levothyroxine, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol

ratio-Mirtazapine Disease Interaction

Major: renal/liver disease, pheochromocytoma, bipolar screening, depression, hypotension, neutropeniaModerate: mania, ALT elevations, hyperlipidemia, hyponatremia, mania/hypomania, seizures, glaucoma

Volume of Distribution

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

Elimination Route

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. ratio-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.

Half Life

20-40 hours

Clearance

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

Clearance in elderly patients

ratio-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.

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.

Elimination Route

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

Pregnancy & Breastfeeding use

ratio-Mirtazapine Should not be used during pregnancy and lactation.

Contraindication

ratio-Mirtazapine is contraindicated in patients with hypersensitivity. Do not use with or within 2 weeks of stopping an MAOI; at least 1 week should elapse between discontinuing mirtazapine and initiating any drug which may provoke a serious reaction (e.g. phenelzine)

Acute Overdose

Symptoms: Disorientation, drowsiness, impaired memory, tachycardia.

Management: Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac functions. General supportive and symptomatic measures are also recommended. Do not induce emesis. Gastric lavage may be used if done soon after ingestion, or in symptomatic patients. Administer activated charcoal. No specific antidotes are known.

Storage Condition

Store at 15-30° C . Protect from light and moisture.

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