Mirazep

I N S T R U C T I O N for medical use of the medicinal product MIRAZEP (MIRAZEP)

Composition:

Active substance: mirtazapine;

1 film-coated tablet contains 15 mg or 30 mg of mirtazapine;

Excipients: microcrystalline cellulose, sodium croscarmellose, pregelatinized starch, talc, magnesium stearate, hypromellose, titanium dioxide (E 171), propylene glycol, yellow iron oxide (E 172) (15 mg tablets), red iron oxide (E 172) (30 mg tablets).

Dosage form. Film-coated tablets.

Main physicochemical properties:

15 mg tablets: yellow, round, biconvex, film-coated tablets.

30 mg tablets: light brown, round, biconvex, film-coated tablets.

Pharmacotherapeutic group. Antidepressants.

ATC code N06AX11.

Pharmacological properties.

Pharmacodynamics.

Mirtazapine is an antagonist of presynaptic α-receptors, which enhances central noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission occurs selectively via 5-HT1 receptors, since mirtazapine blocks 5-HT2 and 5-HT3 receptors. Both enantiomers of mirtazapine possess antidepressant activity: the S(+) enantiomer blocks α2- and 5-HT2 receptors, while the R(-) enantiomer blocks 5-HT3 receptors. Mirtazapine blocks

H1-receptors, which accounts for its sedative properties. At therapeutic doses, mirtazapine has virtually no anticholinergic activity and does not affect the cardiovascular system.

Pharmacokinetics.

After oral administration, Mirzep is rapidly and well absorbed (bioavailability is approximately 50%), reaching maximum plasma concentration within about

2 hours. Approximately 85% of mirtazapine is bound to plasma proteins. The mean elimination half-life ranges from 20 to 40 hours; cases with half-life up to 65 hours have been reported. A shorter half-life is usually observed in younger patients. The prolonged elimination half-life allows once-daily dosing. Steady-state concentration is reached within 3–4 days, after which accumulation ceases. Within the recommended dose range, the pharmacokinetic parameters of mirtazapine exhibit linear dependence on the administered dose. Food intake does not affect the pharmacokinetics of mirtazapine.

Mirtazapine is extensively metabolized and eliminated from the body via urine and feces over several days. The main biotransformation pathways are demethylation and oxidation, followed by conjugation. The demethylated metabolite is pharmacologically active and likely exerts the same pharmacological effect as the parent compound.

Clearance of mirtazapine may be reduced in patients with renal or hepatic impairment.

Clinical characteristics.

Indications.

Treatment of major depressive episode.

Contraindications.

Hypersensitivity to the active substance or to any component of the medicinal product. Concomitant use of mirtazapine with monoamine oxidase inhibitors (MAOIs).

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

• Mirtazapine must not be used concomitantly with MAO inhibitors or within 2 weeks after
  discontinuation of such therapy. Conversely, approximately 2 weeks should elapse before
  patients receiving mirtazapine start using MAO inhibitors.

Furthermore, as with selective serotonin reuptake inhibitors, concomitant use of mirtazapine with other serotonergic agents (L-tryptophan, triptans, tramadol, linezolid, selective serotonin reuptake inhibitors, venlafaxine, lithium, and St John's wort (Hypericum perforatum)) may lead to serotonin-related effects. Caution is recommended and close clinical monitoring is advised when these agents are used in combination with mirtazapine;

• mirtazapine may enhance the sedative effects of benzodiazepines and other sedative medicinal products (particularly most antipsychotics, H1 antihistamine antagonists, and opioids). Caution should be exercised when prescribing these medicinal products concomitantly with mirtazapine;
• Mirazep may enhance the CNS-depressant effect of alcohol; therefore, patients should refrain from consuming alcohol during treatment with mirtazapine;
• mirtazapine at a dose of 30 mg once daily caused a small but statistically significant increase in INR (International Normalized Ratio) in patients treated with warfarin. Monitoring of INR is recommended during concomitant treatment with warfarin and mirtazapine due to the potential for increased INR.

Pharmacokinetic interactions

• Carbamazepine and phenytoin, CYP3A4 inducers, increase the clearance of mirtazapine by approximately 2-fold, resulting in a reduction of the mean plasma concentration of mirtazapine by 60% and 45%, respectively. When carbamazepine or any other hepatic metabolism inducer (such as rifampicin) is added to mirtazapine therapy, the dose of mirtazapine should be increased. If treatment with such a medicinal product is discontinued, a reduction in the dose of mirtazapine may become necessary;
• concomitant administration of the potent CYP3A4 inhibitor ketoconazole increased peak plasma levels and AUC (area under the concentration-time curve) of mirtazapine by approximately 40% and 50%, respectively;
• when cimetidine (a weak inhibitor of CYP1A2, CYP2D6, and CYP3A4) is co-administered with mirtazapine, mean plasma concentrations of mirtazapine may increase by more than 50%. Precautionary measures should be taken and dose reduction considered when mirtazapine is used concomitantly with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin, cimetidine, or nefazodone;
• interaction studies did not reveal any relevant pharmacokinetic effects with concomitant administration of mirtazapine with paroxetine, amitriptyline, risperidone, or lithium.

Special precautions for use.

Suicide/suicidal thoughts or clinical worsening.

Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicide-related events). This risk persists until significant remission occurs. Since improvement may not occur during the first few weeks of treatment or longer, patients should be closely monitored until such improvement takes place. The risk of suicide may increase in the early stages of recovery.

Patients with a history of suicide attempts or those exhibiting pronounced suicidal ideation prior to treatment initiation are at higher risk of developing suicidal thoughts or suicide attempts and should be closely monitored throughout the entire treatment period. Analysis of clinical trials of antidepressants used in adults with psychiatric disorders has shown an increased risk of developing suicidal behavior in patients under 25 years of age taking antidepressants compared to those receiving placebo.

Close monitoring of patients, especially those at high risk of suicidal behavior, should accompany antidepressant therapy, particularly during initial treatment and after dosage adjustments. Patients (and caregivers) should be warned to watch for any clinical symptoms, suicidal behavior or thoughts, and unusual changes in behavior, and to seek immediate medical advice if such symptoms occur. Considering the possibility of suicide, particularly at the beginning of treatment, patients should be prescribed the minimal necessary amount of Mirazep tablets.

Myelosuppression.

During treatment with Mirazep, suppression of bone marrow activity has been reported, typically manifesting as granulocytopenia or agranulocytosis.

Isolated cases of agranulocytosis have been reported, mostly reversible, but in some cases with fatal outcomes. Fatal outcomes were predominantly observed in patients aged 65 years and older. Physicians should pay attention to symptoms such as fever, sore throat, stomatitis, or other signs of infection. If such symptoms occur, treatment should be discontinued and a blood test performed.

Jaundice.

Treatment should be discontinued if jaundice occurs.

Conditions requiring medical supervision. Careful dosing and regular, close monitoring are necessary for patients with the following conditions:

• Epilepsy and organic brain damage: although clinical experience shows that seizures occur rarely during treatment with mirtazapine, as with other antidepressants, Mirazep should be used with particular caution in patients with a history of seizures. Treatment should be discontinued in patients who develop seizures or experience an increase in seizure frequency;
• Hepatic impairment: after oral administration of 15 mg mirtazapine, mirtazapine clearance decreased by approximately 35% in patients with mild to moderate hepatic impairment compared to patients with normal liver function. The average plasma concentration of mirtazapine increased by approximately 55%. When prescribing 30 mg mirtazapine, the benefit/possible risk ratio for the patient should be considered;
• Renal impairment: after single oral administration of 15 mg mirtazapine to patients with moderate (10 ml/min < creatinine clearance < 40 ml/min) or severe (creatinine clearance < 10 ml/min) renal impairment, mirtazapine clearance decreased by approximately 30% and 50%, respectively, compared to healthy subjects. The average plasma concentration of mirtazapine increased by 55% and 115%, respectively. No significant differences were observed in patients with mild renal impairment (40 ml/min < creatinine clearance < 80 ml/min). When prescribing 30 mg mirtazapine, the benefit/possible risk ratio for the patient should be considered, and creatinine clearance should be monitored;
• Heart disease, such as conduction disorders, angina pectoris, and recent myocardial infarction. Such cases require standard precautionary measures and concomitant therapy should be prescribed cautiously;
• Arterial hypotension;
• Diabetes mellitus: in patients with diabetes mellitus, antidepressants may affect blood glucose levels. Adjustment of insulin and/or oral hypoglycemic agents may be necessary, and close monitoring is recommended. As with other antidepressants, the following should be considered:
• In patients with schizophrenia or other psychiatric disorders, psychotic symptoms may worsen during antidepressant treatment; paranoid thoughts may become more intense;
• During treatment of the depressive phase of bipolar disorder, a switch into manic phase may occur. Close monitoring is required in patients with a history of manic or hypomanic episodes. Mirtazapine treatment should be discontinued if the patient enters a manic phase;
• Abrupt discontinuation of treatment after prolonged use may occasionally lead to withdrawal symptoms. Most withdrawal reactions are mild and resolve spontaneously. The most common withdrawal symptoms include dizziness, agitation, restlessness, headache, and nausea. Although these have been reported as withdrawal symptoms, it should be recognized that these symptoms may also be related to the course of the underlying illness. Gradual discontinuation of mirtazapine is recommended;
• Caution is required when treating patients with urinary retention, including due to prostate hyperplasia, and patients with acute angle-closure glaucoma and elevated intraocular pressure (however, the effect of Mirazep is unlikely due to its very low anticholinergic activity);
• Akathisia/psychomotor agitation: antidepressant use has been associated with akathisia, characterized by subjectively unpleasant or anxiety-inducing restlessness, a need to move frequently, and inability to sit or stand still. These symptoms are most likely to occur during the first few weeks of treatment; therefore, dose increases may be harmful.
  • Cases of QT interval prolongation, torsade de pointes, ventricular tachycardia, and sudden death have been reported. Most reports are associated with overdose or involve patients with other risk factors for QT interval prolongation, particularly when co-administered with drugs known to prolong the QT interval.

Mirtazapine should be prescribed cautiously in patients with known cardiovascular disorders or a family history of QT interval prolongation, as well as when used concomitantly with other medicinal products that may prolong the QT interval.

Hypotonic hyponatremia.

Very rare cases of hyponatremia associated with inappropriate secretion of antidiuretic hormone (ADH) have been reported during mirtazapine use. Elderly patients or patients receiving concomitant therapy that may cause hyponatremia require precautionary measures.

Serotonin syndrome.

Interaction with serotonergic agents: serotonin syndrome may occur when selective serotonin reuptake inhibitors are used concomitantly with other serotonergic agents. Symptoms of serotonin syndrome may include hyperthermia, muscle rigidity, myoclonus, autonomic instability with possible rapid fluctuations in vital signs, and mental status changes ranging from confusion and agitation to extreme excitement progressing to delirium and coma. Serotonin syndrome is very rare in patients treated solely with mirtazapine.

Elderly patients.

When prescribing mirtazapine to elderly patients, the potential for adverse effects associated with antidepressant use should be considered. The incidence of adverse reactions in elderly patients was not higher than in other age groups.

Use during pregnancy or breastfeeding.

Limited data on the use of mirtazapine in pregnant women do not indicate an increased risk of congenital malformations. Animal studies did not show any teratogenic effects manifested by clinical symptoms; however, an adverse effect on fetal development was observed.

Epidemiological data suggest that the use of SSRIs during pregnancy, especially in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated the association between PPHN and mirtazapine treatment, this potential risk cannot be excluded, considering the similar mechanism of action (increased serotonin concentrations).

The drug should be prescribed to pregnant women with particular caution, taking into account the benefit/possible risk ratio for the fetus. If Mirazep is used up to childbirth or immediately before delivery, postnatal monitoring of the newborn is recommended to account for possible withdrawal effects.

Mirtazapine is excreted in breast milk in very small amounts. The decision whether to continue/stop breastfeeding or to continue/stop treatment with Mirazep should be made by the physician, considering the benefits of Mirazep therapy for the woman and the potential risk for the infant.

Ability to affect reaction speed when driving vehicles or operating machinery.

Mirtazapine has a minor or moderate influence on the ability to drive cars and operate machinery. The drug may impair concentration and attention (especially during the initial stage of treatment). Patients taking mirtazapine should avoid engaging in potentially hazardous activities requiring concentration and attention.

Method of administration and dosage.

The tablet should be swallowed whole with a small amount of liquid.

This medication should be taken once daily in the evening before bedtime. Mirtazapine may also be administered in lower doses, evenly divided throughout the day (in the morning and evening).

Treatment should be continued until symptoms have completely disappeared—typically for at least 6 months. Thereafter, discontinuation of the medication should be gradual to avoid withdrawal symptoms.

Adults

The effective daily dose is usually between 15 mg and 45 mg; the initial dose is 15 mg or 30 mg. If the initial dose is 15 mg and the daily dose is either 15 mg or 45 mg, tablets of the corresponding strength should be used. Mirtazapine generally begins to show effect after 1–2 weeks of treatment. Treatment with an appropriate dose should lead to a positive response within 2–4 weeks. If the response is inadequate, the dose may be increased. If no effect is observed within the following 2–4 weeks, the medication should be discontinued.

Elderly patients

The recommended dose is the same as for adults. To achieve an optimal and safe outcome, dose escalation in elderly patients should be performed under strict medical supervision.

Renal impairment

Mirtazapine clearance may be reduced in patients with moderate to severe renal impairment (creatinine clearance < 40 mL/min). When prescribing Mirezap to this patient group, creatinine clearance should be monitored.

Hepatic impairment

Mirtazapine clearance may be reduced in patients with hepatic impairment. This should be taken into account when prescribing Mirezap to such patients, particularly those with severe hepatic impairment. Mirezap should be initiated at the lowest dose, with monitoring of mirtazapine clearance, especially when increasing the dose.

Children.

Mirezap is not recommended for use in children. Behaviour related to suicide (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour, and anger) have been observed more frequently in children treated with antidepressants compared to children treated with placebo. Long-term safety data in children regarding growth, maturation, cognitive and behavioural development are lacking.

Overdose.

Symptoms observed are usually of mild severity. Central nervous system depression with confusion and prolonged sedation has been reported, accompanied by tachycardia and mild arterial hypotension/hypertension. However, more serious outcomes (including fatal cases) are possible when doses significantly exceeding the therapeutic dose are taken, especially in cases of mixed overdoses.

In such cases, prolongation of the QT interval and ventricular tachycardia of the torsade de pointes type have also been reported.

In cases of overdose, patients should receive appropriate symptomatic treatment and supportive care for vital functions. Activated charcoal may be administered or gastric lavage performed.

Children. In cases of overdose, measures described for adults should be applied.

Adverse reactions.

Symptoms observed in patients with depression may be related to the disease itself. However, it is sometimes difficult to determine whether specific symptoms are manifestations of the underlying illness or are caused by treatment with the drug.

The most commonly reported adverse reactions are somnolence, sedation, dry mouth, weight gain, increased appetite, dizziness, and fatigue.

Undesirable effects are classified by frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), frequency not known (adverse reactions from spontaneous reports).

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

Metabolism and nutrition disorders: very common – weight gain, increased appetite; frequency not known – hyponatremia.

Psychiatric disorders: common – unusual dreams, confusion, restlessness, insomnia; uncommon – nightmares, mania, agitation, hallucinations, psychomotor hyperactivity (including akathisia, hyperkinesia); rare – aggression; frequency not known – suicidal ideation, suicidal behavior.

Nervous system disorders: very common – somnolence, sedation, headache; common – lethargy, dizziness, tremor; uncommon – paraesthesia, restless legs syndrome, syncope; rare – myoclonus; frequency not known – seizures (haemorrhages), serotonin syndrome, oral paraesthesia, dysarthria.

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

Gastrointestinal disorders: very common – dry mouth; common – nausea, diarrhoea, vomiting, constipation; uncommon – oral hypoaesthesia; rare – pancreatitis; frequency not known – swelling of oral mucosa, increased salivation.

Hepatobiliary disorders: rare – increased serum transaminase activity.

Skin and subcutaneous tissue disorders: common – exanthema; frequency not known – Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: common – arthralgia, myalgia, back pain; frequency not known – rhabdomyolysis.

Renal and urinary disorders: frequency not known – urinary retention.

General disorders: common – peripheral oedema, fatigue; frequency not known – somnambulism, generalized oedema, localized oedema.

Investigations: frequency not known – increased creatine kinase levels.

Reduction in dose usually does not reduce somnolence/sedation, but may compromise the efficacy of the antidepressant.

Agitation and insomnia (which may be symptoms of depression) may develop or worsen during treatment with antidepressants. Cases of development or worsening of agitation and insomnia have been reported during treatment with mirtazapine.

Cases of suicidal thoughts and suicidal behavior have been reported during mirtazapine therapy or immediately after discontinuation of treatment. Transient increases in levels of transaminases and γ-glutamyltransferase have been observed.

Pediatric population.

In clinical studies in children, the following adverse events were observed: weight gain, urticaria, and hypertriglyceridemia.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C in a dry place, out of reach of children.

Packaging. 10 tablets per blister; 3 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer. Micro Labs Limited.

Manufacturer's address and place of business.
92, SIPCOT Industrial Complex, Hosur, Tamil Nadu, IN–635 126, India.