Remeron (Tablets) Instructions for Use

Marketing Authorization Holder

MSD Pharmaceuticals, LLC (Russia)

Manufactured By

N.V. Organon (Netherlands)

ATC Code

N06AX11 (Mirtazapine)

Active Substance

Mirtazapine (Rec.INN registered by WHO)

Dosage Forms

	Remeron	Film-coated tablets, 15 mg: 10 or 30 pcs.
		Film-coated tablets, 30 mg: 10 or 30 pcs.
		Film-coated tablets, 45 mg: 10 or 30 pcs.

Dosage Form, Packaging, and Composition

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Antidepressant

Pharmacological Action

The drug Remeron (Mirtazapine) is a tetracyclic antidepressant with a predominantly sedative effect.

The drug is most effective in depressive states with symptoms such as inability to experience pleasure and joy, loss of interest (anhedonia), psychomotor retardation, sleep disorders (especially early awakenings) and weight loss, as well as other symptoms: suicidal thoughts and diurnal mood swings.

The antidepressant effect of Remeron usually occurs after 1-2 weeks of treatment.

Mirtazapine is an antagonist of presynaptic α₂-adrenoreceptors in the central nervous system and enhances central noradrenergic and serotonergic neurotransmission.

In this case, the enhancement of serotonergic transmission is realized only through serotonin 5-HT₁ receptors, since Mirtazapine blocks serotonin 5-HT₂ and 5-HT₃ receptors.

It is believed that both enantiomers of mirtazapine have antidepressant activity, the S(+) enantiomer by blocking α₂-adreno- and serotonin 5-HT₂ receptors, and the R(-) enantiomer by blocking serotonin 5-HT₃ receptors.

The sedative properties of mirtazapine are due to its antagonistic activity against H₁-histamine receptors.

Mirtazapine is usually well tolerated. In therapeutic doses, it has practically no m-anticholinergic blocking effect and practically does not affect the cardiovascular system.

Pharmacokinetics

After oral administration, Mirtazapine is rapidly absorbed (bioavailability about 50%), reaching C_max in plasma in approximately 2 hours.

About 85% of mirtazapine is bound to plasma proteins.

The average T_1/2 is from 20 to 40 hours (rarely up to 65 hours). A shorter T_1/2 is observed in young people.

The equilibrium concentration of the substance is reached in 3-4 days and does not change thereafter.

In the recommended dose range, the pharmacokinetic parameters of mirtazapine have a linear dependence on the administered dose of the drug.

Food intake does not affect the pharmacokinetics of the drug.

Mirtazapine is actively metabolized and excreted in urine and feces over several days.

The main pathways of its metabolism in the body are demethylation and oxidation followed by conjugation.

Cytochrome P450 isoenzymes (CYP2D6 and CYP1A2) are involved in the formation of the 8-hydroxy metabolite of mirtazapine, while CYP3A4 presumably determines the formation of N-demethylated and N-oxidized metabolites.

Demethylmirtazapine is pharmacologically active.

The clearance of mirtazapine is reduced in renal or hepatic insufficiency.

Indications

• Depression.

ICD codes

Dosage Regimen

The tablets should be taken orally, if necessary with liquid, and swallowed without chewing.

Adults The effective daily dose is usually between 15 and 45 mg; the initial dose is 15 or 30 mg.

Elderly The recommended dose is the same as for adults. In elderly patients, to achieve a satisfactory and safe response to treatment, the dose increase should be carried out under direct medical supervision.

In patients with renal or hepatic impairment, the clearance of mirtazapine may be reduced. This should be taken into account when prescribing Remeron to this category of patients.

Remeron can be taken once a day, preferably at the same time, before bedtime. Remeron can also be prescribed for administration twice a day, dividing the daily dose in half (once in the morning and once at night, the higher dose should be taken at night).

Treatment should be continued for 4-6 months, if possible, until the patient’s symptoms completely disappear. After that, treatment can be gradually discontinued. Mirtazapine usually begins to take effect after 1-2 weeks of treatment. Treatment with an adequate dose should lead to a positive response within 2-4 weeks. If the response to treatment is insufficient, the dose can be increased to the maximum dose (up to 45 mg). If there is no response to treatment after another 2-4 weeks, treatment should be discontinued.

Adverse Reactions

Patients with depression have a number of symptoms caused by the disease, so it is sometimes difficult to distinguish between symptoms associated with the disease and symptoms caused by the use of the drug. The following classification is used to indicate the frequency of side effects: very common (≥1/10), common (≥1/100 and ≤1/10), uncommon (>1/1000 and ≤1/100), rare (>1/10000 and ≤1/1000), frequency not known (≤1/10000).

Blood and lymphatic system disorders frequency not known – bone marrow depression (granulocytopenia, agranulocytosis, aplastic anemia and thrombocytopenia), eosinophilia.

Nervous system disorders very common – drowsiness (which may lead to impaired concentration of attention), usually occurring during the first weeks of treatment. (N.B. dose reduction usually does not lead to a lesser sedative effect, but may reduce the effectiveness of the antidepressant), sedation, headache; common — lethargy, dizziness, tremor; uncommon – paresthesia, restless legs syndrome, syncope; rare – myoclonus, very rare – seizures (stroke), serotonin syndrome, paresthesia of the oral mucosa.

Gastrointestinal disorders very common – dry mouth; common – nausea, diarrhea, vomiting; uncommon – decreased sensitivity of the oral mucosa; frequency not known – edema of the oral mucosa.

Skin and subcutaneous tissue disorders common – skin rash.

Musculoskeletal and connective tissue disorders common – arthralgia, myalgia, back pain.

Endocrine disorders frequency not known – impaired secretion of antidiuretic hormone;

Metabolism and nutrition disorders very common – increased appetite.

Vascular disorders common – orthostatic hypotension; uncommon – arterial hypotension.

General disorders and administration site conditions common — peripheral edema; uncommon – fatigue.

Hepatobiliary disorders rare — increased serum transaminase activity.

Psychiatric disorders common — unusual dreams, confusion, anxiety*, insomnia*; uncommon – nightmares, mania, agitation, hallucinations, psychomotor agitation (including akathisia and hyperkinesia); frequency not known – suicidal ideation, suicidal behavior.

Laboratory and instrumental data (based on post-registration studies) very common – weight gain.

* – usually during treatment with antidepressants, anxiety and insomnia (which may be symptoms of depression) may develop or worsen. During treatment with Remeron, the development or worsening of anxiety and insomnia was reported very rarely.

Contraindications

• Hypersensitivity to mirtazapine or to any of the excipients.

Remeron should not be prescribed to patients with rare hereditary problems such as lactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Since the safety and efficacy of Remeron for children under 18 years of age have not been established, the use of Remeron for the treatment of children is not recommended.

With caution

Dosage adjustment and regular medical supervision are necessary for the following categories of patients

• Patients with epilepsy and organic brain lesions (during therapy with Remeron, seizures may rarely develop);
• Patients with hepatic or renal impairment;
• Patients with heart disease (conduction disorders, angina pectoris or recent myocardial infarction);
• Patients with cerebrovascular diseases (including a history of ischemic stroke);
• Patients with arterial hypotension and conditions predisposing to hypotension (including dehydration and hypovolemia);
  • Patients who abuse drugs, with dependence on drugs that affect the central nervous system, with manias, hypomanias.

Like other antidepressants, Remeron should be used with caution in the following cases

• Impaired urination, including with prostatic hyperplasia;
• Acute angle-closure glaucoma and increased intraocular pressure;
• Diabetes mellitus;
• With simultaneous prescription of benzodiazepines with Remeron.

Use in Pregnancy and Lactation

The safety of using Remeron during human pregnancy has not been established, however, no teratogenic effect was detected in animals, so it can be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.

The use of Remeron during lactation is not recommended due to the lack of data on its excretion in human breast milk.

Use in Hepatic Impairment

Use with caution in patients with hepatic impairment.

In patients with hepatic impairment, the clearance of mirtazapine may be reduced. This should be taken into account when prescribing Remeron to this category of patients.

Use in Renal Impairment

Use with caution in patients with renal impairment.

In patients with renal impairment, the clearance of mirtazapine may be reduced. This should be taken into account when prescribing Remeron to this category of patients.

Pediatric Use

Since the safety and efficacy of Remeron for children under 18 years of age have not been established, the use of Remeron for the treatment of children is not recommended.

Geriatric Use

Elderly: The recommended dose is the same as for adults. In elderly patients, to achieve a satisfactory and safe response to treatment, the dose increase should be carried out under direct medical supervision.

Elderly patients are usually more sensitive to side effects. In clinical studies of Remeron, it was not noted that side effects occurred more frequently in elderly patients than in other age groups, but they may be more pronounced; however, data are still limited.

Special Precautions

When using Remeron, it should be borne in mind that worsening of psychotic symptoms may occur when using antidepressants to treat patients with schizophrenia or other psychotic disorders; paranoid ideas may intensify; the depressive phase of manic-depressive psychosis during treatment may transform into a manic phase.

In young people (under 24 years of age) with depression and other mental disorders, antidepressants, compared with placebo, increase the risk of suicidal thoughts and suicidal behavior. Therefore, when prescribing Remeron to young people (under 24 years of age), the risk of suicide and the benefit of using the drug should be weighed. In short-term studies in people over 24 years of age, the risk of suicide was not increased, and in people over 65 years of age, it was somewhat reduced. Any depressive disorder itself increases the risk of suicide. Therefore, during treatment, the patient should be monitored to identify behavioral disorders or changes, as well as suicidal tendencies.

Although Remeron is not addictive, based on post-registration experience, it turned out that abrupt discontinuation of treatment after prolonged use can sometimes cause withdrawal symptoms. Most withdrawal reactions are mild and self-limiting. The following withdrawal symptoms were most frequently reported: dizziness, agitation, anxiety, headache and nausea. Although they were reported as withdrawal symptoms, it should be understood that these symptoms may be related to the underlying disease. It is recommended to discontinue mirtazapine treatment gradually.

Elderly patients are usually more sensitive, especially to side effects. In clinical studies of Remeron, it was not noted that side effects occurred more frequently in elderly patients than in other age groups, but they may be more pronounced; however, data are still limited.

If signs of jaundice appear, treatment should be interrupted.

Patients are advised to avoid alcohol consumption during treatment with Remeron.

Bone marrow depression, usually manifested as granulocytopenia or agranulocytosis, is rarely observed with the use of Remeron. It appears mostly after 4-6 weeks of treatment and is reversible after discontinuation of treatment. The doctor should pay close attention (and inform the patient) to symptoms such as fever, sore throat, stomatitis, and other signs of flu-like syndrome; if such symptoms appear, treatment should be stopped and a blood test should be performed.

Based on post-registration experience, it turned out that serotonin syndrome occurs very rarely in patients receiving treatment only with Remeron.

Effect on ability to drive vehicles and operate machinery.Remeron^® may reduce concentration. During treatment with antidepressants, patients should avoid performing potentially hazardous activities that require high speed of psychomotor reactions, such as driving a car or operating machinery.

Overdose

Available experience regarding overdose with Remeron alone indicates that symptoms are usually mild. CNS depression accompanied by disorientation and prolonged sedation in combination with tachycardia and a slight increase or decrease in blood pressure has been reported. However, there is a possibility of more severe outcomes (including fatal) at doses much higher than the therapeutic dose, especially in overdoses of several drugs taken simultaneously. In case of overdose, symptomatic therapy should be carried out to maintain vital body functions. Activated charcoal should be administered or gastric lavage should be performed.

Drug Interactions

Pharmacokinetic interaction

• Mirtazapine is intensively metabolized with the participation of CYP2D6 and CYP3A4 isoenzymes, and to a lesser extent with the participation of CYP1A2 isoenzyme. An interaction study in healthy volunteers showed that paroxetine, an inhibitor of the CYP2D6 isoenzyme, does not affect the pharmacokinetics of mirtazapine at steady state. Coadministration with a potent inhibitor of the CYP3A4 isoenzyme, ketoconazole, increased the maximum plasma concentration and AUC of mirtazapine by approximately 40% and 50%, respectively. Caution should be exercised when using mirtazapine in combination with potent inhibitors of the CYP3A4 isoenzyme, HIV protease inhibitors, azole antifungal drugs, erythromycin or nefazodone.
• Carbamazepine and phenytoin, inducers of the CYP3A4 isoenzyme, increased the clearance of mirtazapine approximately twofold, leading to a 45-60% decrease in mirtazapine plasma concentrations. When carbamazepine or another inducer of hepatic metabolism (e.g., rifampicin) is added to mirtazapine therapy, the dose of mirtazapine should be increased if necessary. When discontinuing treatment with such a drug, it may be necessary to reduce the dose of mirtazapine.
• When used in combination with cimetidine, the bioavailability of mirtazapine may increase by more than 50%. The dose of mirtazapine should be reduced if necessary at the beginning of treatment in combination with cimetidine or increased when discontinuing treatment with cimetidine.
• In interaction studies conducted in vivo, Mirtazapine did not affect the pharmacokinetics of risperidone or paroxetine (substrate of the CYP2D6 isoenzyme), carbamazepine (substrate of the CYP3A4 isoenzyme), amitriptyline, cimetidine or phenytoin.
• No significant clinical effects or changes in pharmacokinetics in humans were observed during treatment with mirtazapine in combination with lithium.

Pharmacodynamic interaction

• Mirtazapine should not be used in combination with MAO inhibitors or within two weeks after discontinuation of treatment with an MAO inhibitor.
• Mirtazapine may enhance the sedative properties of benzodiazepines and other sedatives. Caution should be exercised when prescribing these drugs together with mirtazapine.
• Mirtazapine may enhance the depressive effect of alcohol on the CNS. Therefore, patients should be warned to avoid consuming alcoholic beverages.
• In case of using other serotonergic medicinal products (e.g., selective serotonin reuptake inhibitors and venlafaxine) in combination with mirtazapine, there is a risk of interaction that may lead to the development of serotonin syndrome. Based on post-registration experience with the drug, it has been found that serotonin syndrome occurs very rarely in patients receiving treatment with mirtazapine in combination with selective serotonin reuptake inhibitors or venlafaxine. If such a combination is considered therapeutically necessary, then the dose should be carefully adjusted and signs of the onset of sustained serotonergic overstimulation should be directly monitored.
• Mirtazapine at a dose of 30 mg once daily caused a small but statistically significant increase in INR (International Normalized Ratio) in subjects receiving warfarin treatment. A more pronounced effect at a higher dose of mirtazapine cannot be excluded. It is recommended to monitor INR in case of warfarin treatment in combination with mirtazapine.

Storage Conditions

At a temperature of 2-30°C (-22°F), in a place protected from light and moisture, out of the reach of children.

Shelf Life

Shelf life – 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.