Mirzaten

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Mirzaten (Mirzaten®)

Composition:

Active substance: 1 film-coated tablet contains 30 mg or 45 mg of mirtazapine;

Excipients: lactose monohydrate, powdered cellulose, sodium starch glycolate (type A), pregelatinized starch, colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose, titanium dioxide (E 171), iron oxide red (E 172) – only in 30 mg tablets, iron oxide yellow (E 172) – only in 30 mg tablets, talc, macrogol 6000.

Medicinal form: Film-coated tablets.

Main physicochemical properties:

30 mg tablets: orange-brown, oval, biconvex, film-coated tablets with a score line on one side.

45 mg tablets: white, oval, biconvex, film-coated tablets.

Pharmacotherapeutic group. Antidepressants. ATC code: N06AX11.

Pharmacological Properties

Pharmacodynamics

Mirtazapine is a central nervous system α2-receptor antagonist that increases noradrenergic and serotonergic transmission. The enhancement of serotonergic transmission occurs via 5-HT1 receptors, as mirtazapine blocks 5-HT2 and 5-HT3 receptors. The antidepressant activity of the drug is mediated by both of its enantiomers: the S(+) enantiomer blocks α2 and 5-HT2 receptors, while the R(–) enantiomer blocks 5-HT3 receptors.

The sedative effect of mirtazapine results from its antagonistic action on histamine H1 receptors. At therapeutic doses, mirtazapine has virtually no anticholinergic activity and exerts minimal effects on the cardiovascular system.

The effect of mirtazapine on the QT interval was evaluated in a randomized, placebo- and moxifloxacin-controlled clinical trial involving 54 healthy volunteers who received a standard dose of 45 mg and a supratherapeutic dose of 75 mg. Linear modeling showed that QT interval prolongation remained below the threshold for clinically significant prolongation (see section "Special precautions for use***").

Children. In two randomized, double-blind, placebo-controlled trials involving children aged 7 to 18 years with major depressive disorder (n = 259), using a flexible dosing regimen during the first 4 weeks (15–45 mg of mirtazapine), followed by a fixed dose (15 mg, 30 mg, or 45 mg of mirtazapine) for an additional 4 weeks, no significant differences between mirtazapine and placebo were demonstrated on either primary or secondary endpoints. A significant increase in body weight (≥7%) was observed in 48.8% of patients in the mirtazapine treatment group compared to 5.7% in the placebo group. Urticaria (11.8% vs. 6.8%) and hypertriglyceridemia (2.9% vs. 0%) were also observed.

Pharmacokinetics

After oral administration, the active substance mirtazapine is rapidly and well absorbed (its bioavailability is approximately 50%), with peak plasma concentrations reached within about 2 hours.

Approximately 85% of mirtazapine is bound to plasma proteins.

The elimination half-life is approximately 20–40 hours; in young males, both prolonged (up to 65 hours) and shortened half-lives have been observed.

This long elimination half-life allows for once-daily dosing. Steady-state plasma concentrations are achieved within 3–4 days, after which no further accumulation occurs. When mirtazapine is administered at recommended doses, pharmacokinetic parameters change linearly. Food intake has no effect on the pharmacokinetics of mirtazapine.

Mirtazapine is extensively metabolized and excreted in urine and feces over several days. The main metabolic pathways are demethylation and oxidation followed by conjugation. In vitro data from human liver microsome analysis indicate that cytochrome P450 enzymes CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, while CYP3A4 is considered responsible for the formation of N-demethyl and N-oxide metabolites. The demethylated metabolite is pharmacologically active and has a pharmacokinetic profile similar to that of the parent compound.

Elimination of mirtazapine may be slowed in patients with renal or hepatic impairment.

Clinical characteristics.

Indications.

Treatment of episodes of major depression.

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 simultaneously with MAO inhibitors or within less than 2 weeks after discontinuation of MAO inhibitors. Likewise, MAO inhibitors may be administered approximately 2 weeks after stopping mirtazapine (see section "Contraindications").
• Concomitant use with other serotonergic agents [L-tryptophan, triptans, buprenorphine, tramadol, linezolid, selective serotonin reuptake inhibitors (SSRIs), venlafaxine, lithium, and St. John’s wort (Hypericum perforatum)] may lead to an increased frequency of serotonin-related effects (serotonin syndrome) (see section "Special precautions for use"). Patients should be cautious and closely monitored clinically when these agents are combined with mirtazapine.
• Mirtazapine may enhance the sedative effect of benzodiazepines and other sedative drugs (particularly neuroleptics, H1 antihistamine antagonists, and opioids). These medicinal products should be prescribed cautiously in combination with mirtazapine.
• Mirtazapine may potentiate the central nervous system depressant effect of alcohol; therefore, patients should avoid alcohol abuse during mirtazapine treatment.
• Mirtazapine at a dose of 30 mg once daily caused a small but statistically significant increase in the international normalized ratio (INR) in subjects taking warfarin. Since a more pronounced effect cannot be excluded at higher mirtazapine doses, INR should be monitored during concomitant use of warfarin and mirtazapine.

Pharmacokinetic interactions.

• Carbamazepine and phenytoin, CYP3A4 inducers, approximately double the clearance of mirtazapine, resulting in a 60% and 45% reduction in mean plasma concentration of mirtazapine, respectively. When carbamazepine or any other hepatic metabolism inducer (e.g., rifampicin) is co-administered during mirtazapine therapy, an increase in the mirtazapine dose may be required. After discontinuation of the concomitant drug, a reduction in mirtazapine dose may become necessary.
• Concomitant use of the strong CYP3A4 inhibitor ketoconazole increases peak plasma levels and AUC of mirtazapine by approximately 40% and 50%, respectively.
• Concomitant use of cimetidine (a weak inhibitor of CYP1A2, CYP2D6, and CYP3A4) with mirtazapine may increase the mean plasma concentration of mirtazapine by more than 50%. Caution is advised, and dose reduction should be considered when mirtazapine is used concomitantly with strong CYP3A4 inhibitors, HIV protease inhibitors, azole antifungal agents, erythromycin, cimetidine, or nefazodone.
• Interaction studies showed no clinically significant pharmacokinetic effects of concomitant administration of mirtazapine with paroxetine, amitriptyline, risperidone, or lithium.

Special precautions for use.

Use in children.

Mirtazapine should not be used in children and adolescents.

Suicidal behaviour (suicide attempts and suicidal thoughts) and hostility (mainly aggression, oppositional behaviour and anger) have been observed more frequently in clinical trials among children and adolescents treated with antidepressants compared to those receiving placebo. If, despite this, a decision to treat is made based on clinical necessity, patients should be closely monitored for the emergence of suicidal symptoms. Furthermore, there are no data available on the long-term safety in children and adolescents with regard to growth, maturation, and cognitive and behavioural development.

Suicide / suicidal thoughts or clinical worsening.

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related phenomena). 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. General clinical experience indicates that the risk of suicide may increase in the early stages of recovery.

It is known that patients with a history of suicide-related events or with a substantial number of suicidal ideations prior to treatment initiation, who are at increased risk of suicidal thoughts and suicide attempts, require close monitoring throughout treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of emergence of suicidal behaviour with antidepressants compared to placebo in patients under 25 years of age. Close monitoring of patients, particularly those at increased risk, should be implemented during antidepressant therapy, especially in the initial stages of treatment and following any dosage adjustments. Patients (and caregivers) should be warned to monitor for any clinical worsening, suicidal behaviour or thoughts, or unusual changes in behaviour, and to seek immediate medical advice if such symptoms occur.

Due to the possibility of suicide, particularly at the beginning of treatment, patients should be prescribed the smallest necessary amount of Mirtazapine, film-coated tablets.

Suppression of bone marrow function.

With the use of mirtazapine, as with all other antidepressants, suppression of bone marrow function may occur, manifesting as granulocytopenia or agranulocytosis. In most cases, these events are transient and usually resolve after discontinuation of treatment. During post-marketing use of mirtazapine, isolated cases of agranulocytosis have been reported, mostly reversible, but in some cases with fatal outcome. Fatal cases were predominantly reported in patients aged 65 years and older. Attention should be paid to symptoms such as fever, sore throat, stomatitis, and other signs of infection. If such symptoms occur, treatment should be discontinued and a blood test performed.

Jaundice.

If jaundice occurs, treatment should be discontinued.

Conditions requiring medical supervision.

Careful dose selection and regular medical monitoring are required for patients with:

• epilepsy and organic brain disorders: although clinical experience indicates that seizures are rare during mirtazapine treatment, as with other antidepressants, Mirtazapine should be initiated cautiously in patients with a history of seizures. Treatment should be discontinued in any patient who develops seizures or experiences an increase in seizure frequency;
• hepatic impairment: following a single oral 15 mg dose of mirtazapine, clearance of mirtazapine is reduced by approximately 35% in patients with mild to moderate hepatic impairment compared to subjects with normal liver function. The mean plasma concentration of mirtazapine increases by approximately 55%;
• renal impairment: following a single oral 15 mg dose of mirtazapine, clearance of mirtazapine decreased by approximately 30% and 50%, respectively, in patients with moderate (creatinine clearance < 40 ml/min) and severe (creatinine clearance ≤ 10 ml/min) renal impairment compared to healthy subjects. Mean plasma concentration of mirtazapine increased correspondingly by approximately 55% and 115%. No significant difference was observed in patients with mild renal impairment (creatinine clearance < 80 ml/min) compared to the control group;
• cardiac diseases associated with conduction disorders, in patients with angina pectoris and acute myocardial infarction – in such cases, standard precautions should be observed and concomitant therapy carefully followed;
• low blood pressure;
• diabetes mellitus: in patients with diabetes mellitus, antidepressants may affect blood glucose levels. Adjustment of insulin and/or oral hypoglycaemic agents may be necessary; close monitoring is recommended.

As with other antidepressants, the following should be considered:

• in patients with schizophrenia or other psychiatric disorders, psychotic symptoms and paranoid thoughts may be exacerbated during treatment with antidepressants.
• During treatment of the depressive phase of bipolar disorder, progression from depression to mania may occur. Patients with a history of mania/hypomania should be closely monitored. Mirtazapine should be discontinued in any patient who enters a manic phase.
• Although Mirtazapine does not cause dependence, post-marketing experience shows that abrupt discontinuation after prolonged use may occasionally lead to withdrawal symptoms. Most withdrawal reactions are mild and self-limiting. Among the various withdrawal symptoms, dizziness, agitation, anxiety, headache, and nausea are the most common. Although these have been reported as withdrawal symptoms, it should be understood that such symptoms may also relate to the underlying condition. Gradual discontinuation of mirtazapine treatment is recommended (see section "Special precautions for use").
• Caution is advised in patients with urinary disorders such as prostate hyperplasia, and in patients with acute angle-closure glaucoma and elevated intraocular pressure (although the likelihood of problems with Mirtazapine is low due to its very weak anticholinergic activity).
• Akathisia / psychomotor agitation: antidepressant use has been associated with the development of akathisia, characterised by subjectively unpleasant or pathological restlessness and an urge to move, often accompanied by inability to sit or stand still. This is most likely to occur during the first few weeks of treatment. Increasing the dose in patients with such symptoms may be harmful.
• During post-marketing surveillance, cases of QT interval prolongation, torsade de pointes, ventricular tachycardia, and sudden death have been reported. Most cases were associated with overdose or other risk factors for QT prolongation, particularly concomitant use of drugs that prolong the QT interval (see sections "Interaction with other medicinal products and other forms of interaction" and "Overdose"). Caution should be exercised when prescribing mirtazapine to patients with cardiovascular disorders or a family history of QT prolongation, as well as when used concomitantly with other medicinal products that may prolong the QT interval.

Hypnatremia.

Hypnatremia, possibly related to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), has been reported very rarely with mirtazapine. Caution is advised in patients at increased risk, for example, elderly patients or those taking concomitant medications that may cause hypnatremia.

Serotonin syndrome.

Interaction with serotonergic agents: serotonin syndrome may occur when selective serotonin reuptake inhibitors (SSRIs) are used concomitantly with other serotonergic agents (see section "Interaction with other medicinal products and other forms of interaction"). Symptoms of serotonin syndrome may include hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations in vital signs, and mental status changes including confusion, irritability, and extreme agitation progressing to delirium and coma. These agents should be used with caution in combination with mirtazapine. Treatment with mirtazapine should be discontinued if symptoms of serotonin syndrome occur, and symptomatic treatment should be initiated. Post-marketing experience has shown that serotonin syndrome is very rare in patients treated solely with mirtazapine.

Serious skin reactions.

Serious skin reactions have been reported with mirtazapine treatment, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), bullous dermatitis, and erythema multiforme, which may be life-threatening. If signs or symptoms of these reactions occur, mirtazapine should be discontinued immediately.

If a patient develops one of these reactions during mirtazapine treatment, the patient must never be re-exposed to mirtazapine.

Elderly patients.

Elderly patients are often more sensitive to the drug, particularly regarding adverse effects. During clinical trials of mirtazapine, adverse effects in elderly patients were not observed more frequently than in other age groups.

Special warnings regarding certain inactive ingredients.

Mirtazapine contains lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

Limited data on the use of mirtazapine in pregnant women do not indicate an increased risk of congenital anomalies. Animal studies have not shown any teratogenic effects of clinical significance, but toxic effects on intrauterine development were observed. The drug should be prescribed with caution to pregnant women. If Mirtazapine was used during pregnancy or immediately before delivery, postnatal monitoring of the newborn is recommended to account for possible withdrawal effects.

Epidemiological data have shown that the use of SSRIs during pregnancy, particularly in late pregnancy, increases the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have been conducted on the association between mirtazapine treatment and PPHN, the potential risk cannot be excluded, considering the related mechanism of action (increased serotonin concentration).

Animal studies and some human data have shown that mirtazapine passes into breast milk in very small amounts. The decision to continue or discontinue breastfeeding or to continue or discontinue Mirtazapine therapy should be made taking into account the benefits of breastfeeding for the child and the benefits of Mirtazapine treatment for the mother.

Fertility: no effect on reproductive capacity or fertility has been observed.

Ability to affect reaction speed when driving or operating machinery.

Mirtazapine has a minor or moderate effect on the ability to drive and use machinery. Mirtazapine may impair concentration and attention (especially in the initial phase of treatment). Patients should avoid performing potentially hazardous tasks requiring concentration and good attention, such as driving a car or operating machinery, while taking the medication.

Method of administration and dosage.

Adults.

The effective daily dose is generally 15–45 mg; the initial dose is 15 mg (½ of a 30 mg tablet) or 30 mg.

Mirtazapine usually starts to work within 1–2 weeks of treatment. A positive response to therapy can generally be expected within 2–4 weeks with an adequate dose. If the patient does not respond to treatment, the dose may be increased to the maximum recommended dose. If no response is observed within 2–4 weeks after this increase, treatment should be discontinued.

Elderly patients.

The recommended dose for elderly patients 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). This should be taken into account when prescribing Mirzaten to this patient group (see section "Special precautions for use").

Hepatic impairment.

Mirtazapine clearance may be reduced in patients with hepatic impairment. This should be considered when prescribing Mirzaten to such patients, especially those with severe hepatic impairment, as patients with severe hepatic dysfunction were not included in clinical trials (see section "Special precautions for use").

The drug should be initiated at the lowest dose with monitoring of mirtazapine clearance, particularly when increasing the dose.

Mirtazapine has a terminal half-life of 20–40 hours; therefore, Mirzaten is suitable for once-daily dosing. The drug should be taken once daily before bedtime. The daily dose of Mirzaten may also be divided into two doses (one in the morning and one in the evening).

Tablets should be swallowed whole, without chewing, and taken with a small amount of liquid.

Patients with depression should be treated for a sufficient duration, at least 6 months, until complete resolution of clinical symptoms.

It is recommended to discontinue mirtazapine treatment gradually to avoid withdrawal symptoms.

Children

Use in children is not recommended.

Overdose.

Current experience with overdose of mirtazapine alone suggests that symptoms are generally mild. Cases of central nervous system depression with confusion and prolonged sedation, accompanied by tachycardia and mild hypertension or hypotension, have been reported. However, more serious outcomes (including fatal outcomes) are possible with doses significantly higher than the therapeutic dose, particularly in cases of mixed overdose. In such cases, QT interval prolongation and ventricular tachycardia of the torsade de pointes type have also been observed.

In case of overdose, appropriate symptomatic and supportive treatment should be provided to maintain vital functions. ECG monitoring is required.

Administration of activated charcoal and gastric lavage are also recommended.

Children. In cases of overdose in children, the same immediate measures as for adults should be implemented.

Adverse Reactions

Patients with depression have a wide range of symptoms related to the disease itself. Therefore, it may sometimes be difficult to determine which symptoms are due to the underlying illness and which are due to treatment with Mirzaten.

Adverse reactions occurring in over 5% of patients: somnolence, sedation, dry mouth, weight gain, increased appetite, dizziness, and fatigue.

Severe cutaneous adverse reactions have been reported during treatment with mirtazapine, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), bullous dermatitis, and erythema multiforme (see section "Special Warnings and Precautions for Use").

All results from randomized, placebo-controlled trials in patients (including indications other than major depressive disorder) were evaluated for the presence of adverse reactions.

A meta-analysis evaluated 20 studies of 12-week treatment, in which 1501 patients (134 patients per year) received mirtazapine doses up to 60 mg and 850 patients (79 patients per year) received placebo. Extension phases of these studies were excluded to maintain the comparison with placebo treatment.

During clinical trials and post-marketing use of mirtazapine, the following adverse reactions have been observed, with frequencies defined as: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated based on available data).

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

Endocrine system disorders: Frequency not known — inappropriate antidiuretic hormone secretion, hyperprolactinemia (and associated symptoms: galactorrhea, gynecomastia).

Metabolism and nutrition disorders: Very common — weight gain\textsuperscript{1}, increased appetite\textsuperscript{1}; frequency not known — hyponatremia.

Psychiatric disorders: Common — sleep disorders, confusion, restlessness\textsuperscript{2,5}, insomnia\textsuperscript{3,5}; uncommon — night terrors\textsuperscript{2}, mania, agitation\textsuperscript{2}, hallucinations; psychomotor agitation including akathisia and hyperkinesia; rare — aggression; frequency not known — suicidal thoughts\textsuperscript{6}, suicidal behavior\textsuperscript{6}, somnambulism.

Nervous system disorders: Very common — somnolence\textsuperscript{1,4}, sedation\textsuperscript{1,4}, headache\textsuperscript{2}, common — lethargy\textsuperscript{1}, amnesia (in most cases resolved after discontinuation of the drug), dizziness, tremor; uncommon — paresthesia\textsuperscript{2}, restless legs syndrome, loss of consciousness; rare — myoclonus; frequency not known — seizures (including stroke), serotonin syndrome, perioral paresthesia, dysarthria.

Vascular disorders: Common — orthostatic hypotension; uncommon — hypotension\textsuperscript{2}.

Gastrointestinal disorders: Very common — dry mouth; common — nausea\textsuperscript{3}, diarrhea\textsuperscript{2}, vomiting\textsuperscript{2}, constipation\textsuperscript{1}; uncommon — perioral hypoaesthesia; rare — pancreatitis; frequency not known — oral cavity swelling, increased salivation.

Hepatobiliary disorders: Rare — increased serum transaminase activity.

Skin and subcutaneous tissue disorders: Common — exanthema\textsuperscript{2}; frequency not known — Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme, toxic epidermal necrolysis; frequency not known — drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders: Common — arthralgia, myalgia, back pain\textsuperscript{1}; frequency not known — rhabdomyolysis (acute skeletal muscle necrosis).

Renal and urinary disorders: Frequency not known — urinary retention.

Reproductive system and breast disorders: Frequency not known — priapism.

General disorders: Common — peripheral edema\textsuperscript{1}, fatigue, general edema, localized edema.

Investigations: Frequency not known — increased creatine kinase levels.

Adverse reactions commonly observed in clinical trials involving children: weight gain, urticaria, hypertriglyceridemia.

\textsuperscript{1} During clinical trials, these symptoms occurred more frequently in patients receiving mirtazapine compared to placebo.

\textsuperscript{2} During clinical trials, these symptoms occurred more frequently in the placebo group compared to the mirtazapine group.

\textsuperscript{3} During clinical trials, these symptoms occurred more frequently with placebo compared to mirtazapine.

\textsuperscript{4} Dose reduction usually does not reduce somnolence/sedation but may compromise the antidepressant efficacy.

\textsuperscript{5} Restlessness and insomnia may develop or worsen after treatment with antidepressants (which may be symptoms of depression). Development or worsening of restlessness and insomnia has been reported during mirtazapine treatment.

\textsuperscript{6} Cases of suicidal thoughts and suicidal behavior have been reported during or immediately after discontinuation of mirtazapine therapy (see section "Special Warnings and Precautions for Use").

In laboratory analyses during clinical trials, transient increases in transaminase and gamma-glutamyl transferase levels were observed; however, no statistically significant increase in related adverse events was reported with mirtazapine compared to placebo.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

5 years.

Storage conditions.

Store at temperatures not exceeding 30 °C.

Keep out of the reach and sight of children.

Packaging.

10 tablets per blister; 3, 6, or 9 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.