Instructions Mirtazapine Sandoz film-coated tablets 30 mg blister No. 20
Composition
active ingredient: mirtazapine;
1 tablet contains mirtazapine 15 mg or 30 mg;
excipients: tablet core – lactose monohydrate, corn starch, hydroxypropylcellulose, colloidal anhydrous silicon dioxide, magnesium stearate;
15 mg tablets: shell (opadri yellow) – hydroxypropylmethylcellulose, titanium dioxide (E 171), polyethylene glycol 8000, iron oxide yellow (E 172), quinoline yellow (E 104), sunset yellow FCF (E 110);
30 mg tablets: shell (opadri beige) – hydroxypropylmethylcellulose, titanium dioxide (E 171), polyethylene glycol 8000, red iron oxide (E 172), yellow iron oxide (E 172), black iron oxide (E 172);
Dosage form
Film-coated tablets.
Main physicochemical properties:
15 mg tablets: yellow, round, biconvex, film-coated tablets, with a score on one side;
30 mg tablets: beige, round, biconvex, film-coated tablets, scored on one side.
Pharmacotherapeutic group
Antidepressants. ATX code N06A X11.
Pharmacological properties
Pharmacodynamics
Mirtazapine is a presynaptic α2 receptor antagonist that enhances central noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission occurs exclusively through 5-HT1 receptors, as mirtazapine blocks 5-HT2 and 5-HT3 receptors. Both enantiomers of mirtazapine have antidepressant activity, with the S(+) enantiomer blocking α2 and 5-HT2 receptors, and the R(–) enantiomer blocking 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.
Paediatric population: Two randomised, double-blind, placebo-controlled trials in children aged 7-18 years with major depressive disorder (n = 259) using a flexible dosing schedule for the first 4 weeks (15-45 mg mirtazapine) followed by a fixed dose (15 mg, 30 mg or 45 mg mirtazapine) for an additional 4 weeks showed no significant differences between mirtazapine and placebo on either the primary or all secondary endpoints. Significant weight gain (≥7%) was observed in 48.8% of patients in the mirtazapine group compared to 5.7% in the placebo group. Urticaria (11.8% vs. 6.8%) and hypertriglyceridaemia (2.9% vs. 0%) were also observed.
Pharmacokinetics
After oral administration, mirtazapine is rapidly and well absorbed (bioavailability is approximately 50%), reaching maximum plasma concentrations after approximately 2 hours. Almost 85% of mirtazapine is bound to plasma proteins. The mean half-life is 20–40 hours; cases of half-life of 65 hours have been reported; a shorter half-life is usually observed in young patients. The long half-life allows the drug to be taken once daily. Steady-state concentrations are reached after 3–4 days, after which accumulation disappears. At recommended doses, the pharmacokinetics of mirtazapine are linear. Food intake does not affect the pharmacokinetics of mirtazapine.
Mirtazapine is extensively metabolized and excreted in the urine and feces within a few days. The main biotransformation pathways are demethylation and oxidation followed by conjugation. In vitro data from liver microsomes indicate that the cytochrome P450 enzymes CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite.
+ mirtazapine, and CYP3A4 is considered responsible for the formation of the N-desmethyl and N-oxide metabolites. The N-desmethyl metabolite is pharmacologically active and probably exhibits the same pharmacological effects as the parent compound.
Mirtazapine clearance may be reduced in renal or hepatic insufficiency.
Indication
Treatment of deep depression.
Contraindication
Hypersensitivity to mirtazapine or to any other component of the drug.
Concomitant use of mirtazapine with monoamine oxidase inhibitors (MAO).
Interaction with other medicinal products and other types of interactions
Pharmacodynamic interactions.
Mirtazapine should not be taken concomitantly with MAO inhibitors or within 2 weeks of stopping treatment. After stopping treatment with mirtazapine, approximately 2 weeks should elapse before patients can take MAO inhibitors.
In addition, concomitant use of mirtazapine with selective serotonin reuptake inhibitors and other serotonergic active substances (L-tryptophan, triptans, tramadol, linezolid, venlafaxine, lithium and preparations containing St. John's wort (Hypericum perforatum) may lead to serotonin-mediated effects. Caution and close medical supervision are recommended when these active substances are combined with mirtazapine.
Mirtazapine may enhance the depressant effects of alcohol on the central nervous system, so patients should refrain from drinking alcohol during treatment with the drug.
Mirtazapine 30 mg once daily caused a small but statistically significant increase in INR (International Normalized Ratio) in patients treated with warfarin. It is recommended to monitor INR when warfarin is co-administered with mirtazapine due to the possibility of an increase.
The risk of QT prolongation and/or ventricular arrhythmias (e.g. torsade de pointes) is increased with concomitant use of drugs that prolong the QT interval (e.g. some antipsychotics and antibiotics).
Pharmacokinetic interactions.
Carbamazepine and phenytoin, inducers of CYP3A4, increase the clearance of mirtazapine by approximately 2-fold and, as a result, the mean plasma concentration of mirtazapine is reduced by 60% and 45%, respectively. When carbamazepine or any other inducer of hepatic metabolism (e.g. rifampicin) is added to mirtazapine therapy, the dose of mirtazapine should be increased. If treatment with such a drug is discontinued, a dose reduction of mirtazapine may be necessary.
Concomitant use 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 used with mirtazapine, the mean plasma concentrations of mirtazapine may increase by more than 50%. Caution should be exercised and the dose should be reduced when mirtazapine is used concomitantly with strong CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin, cimetidine or nefazodone.
No clinically significant pharmacokinetic interaction was found when mirtazapine was co-administered with paroxetine, amitriptyline, risperidone or lithium.
Application features
Severe skin reactions. Severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), bullous dermatitis and erythema multiforme, which can be fatal, have been reported in association with mirtazapine treatment. If signs and symptoms suggestive of these reactions appear, mirtazapine should be discontinued immediately. If a patient develops one of these reactions while taking Mirtazapine Sandoz®, he or she should never be treated with this medicine again.
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 exists until significant remission occurs. As improvement may not occur within the first few weeks or more of treatment, patients should be closely monitored until improvement occurs. It is general clinical experience that the risk of suicide may be increased in the early stages of recovery.
Patients with a history of suicidal ideation or who exhibit a significant degree of suicidal ideation prior to initiation of treatment are known to be at greater risk of suicidal thoughts or suicide attempts and should receive careful monitoring throughout treatment. An analysis of clinical trials of antidepressants in adults with psychiatric disorders has shown an increased risk of suicidal behaviour when taking antidepressants compared with patients under 25 years of age who received placebo.
During antidepressant therapy, close monitoring of patients at high risk of suicidal behavior is necessary, especially at the beginning of therapy and after dose changes. Patients (and caregivers of patients) should be warned about the need to pay attention to any clinical manifestations, suicidal behavior or thoughts and unusual changes in behavior and to seek medical advice immediately if such symptoms present.
Taking into account the possibility of suicide, especially at the beginning of treatment, the patient should be given the minimum necessary number of mirtazapine tablets.
Bone marrow depression: Bone marrow depression, usually manifested by granulocytopenia or agranulocytosis, has been reported with mirtazapine treatment.
Isolated cases of agranulocytosis have been reported, usually reversible but occasionally fatal (predominantly in patients over 65 years of age). The physician should be alert for symptoms such as fever, sore throat, stomatitis or other signs of infection. If such symptoms occur, treatment should be discontinued and a blood test should be performed.
Jaundice: Treatment should be discontinued if jaundice occurs.
epilepsy and organic brain lesions. Mirtazapine should be used with particular caution in patients with a history of epileptic seizures. Treatment should be discontinued in patients who develop epileptic seizures or when an increase in the frequency of epileptic seizures is observed; hepatic insufficiency: after oral administration of 15 mg of mirtazapine, its clearance was reduced by approximately 35% in patients with mild or moderate hepatic insufficiency compared to patients with normal liver function. The average plasma concentration of mirtazapine increased by approximately 55%. When prescribing 30 mg of mirtazapine, the benefit/potential risk ratio for the patient should be considered; Renal impairment: After a single oral dose of 15 mg mirtazapine in patients with moderate renal impairment (10 ml/min ≤ creatinine clearance < 40 ml/min) or severe renal impairment (creatinine clearance < 10 ml/min), the clearance of mirtazapine was reduced by approximately 30% and 50%, respectively, compared to healthy subjects. The mean plasma concentrations of mirtazapine increased by 55% and 115%, respectively. There were no significant differences in patients with mild renal impairment (40 ml/min ≤ creatinine clearance < 80 ml/min) compared to controls.
When prescribing 30 mg of mirtazapine, the benefit/potential 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 the usual precautions and concomitant therapy should be administered with caution; 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.
When using antidepressants, the following precautions should be taken into account:
When antidepressants are used in patients with schizophrenia or other psychiatric disorders, psychotic symptoms may be exacerbated; paranoid thoughts may become more intense; when treating the depressive phase of bipolar disorder, it may progress to a manic phase. Patients with a history of manic or hypomanic episodes should be carefully monitored. Mirtazapine should be discontinued if the patient enters a manic phase; although mirtazapine is not habit-forming, post-marketing experience suggests that abrupt discontinuation of treatment after prolonged use may occasionally lead to withdrawal symptoms. Most withdrawal reactions are mild and self-limiting. Among the various withdrawal symptoms reported, the most common were dizziness, agitation, restlessness, headache and nausea. Although these have been reported as withdrawal symptoms, it should be understood that they may be related to the underlying disease. It is recommended to gradually discontinue treatment with mirtazapine; caution should be exercised when treating patients with urinary disorders, including those resulting from prostatic hypertrophy, patients with acute angle-closure glaucoma and increased intraocular pressure (however, the effect of mirtazapine is unlikely due to its very low anticholinergic activity); akathisia/psychomotor agitation: the use of antidepressants has been associated with the development of akathisia, characterized by a subjectively unpleasant or anxious agitation and a frequent need to move, accompanied by an inability to sit or stand still. These symptoms are most likely to occur within the first few weeks of treatment, so increasing the dose may be harmful to health; cases of QT 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 prolongation, particularly when receiving concomitant medications that prolong the QT interval.
Mirtazapine should be prescribed with caution to patients with known cardiovascular disease or a family history of QT prolongation, as well as when used concomitantly with other drugs that may prolong the QT interval.
Hyponatremia: There have been isolated reports of hyponatremia with mirtazapine, which is associated with inappropriate antidiuretic hormone (ADH) secretion. Caution should be exercised in elderly patients or in patients receiving concomitant medications that may cause hyponatremia.
Elderly patients. When prescribing mirtazapine to elderly patients, the undesirable effects of antidepressants should be taken into account. The occurrence of adverse reactions in elderly patients was not observed more often than in patients of other age categories.
Lactose. The drug contains lactose, so it should not be prescribed to patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.
Mirtazapine Sandoz® 15 mg film-coated tablets contain sunset yellow FCF (E 110), which may cause allergic reactions.
Ability to influence reaction speed when driving vehicles or other mechanisms
Mirtazapine has minor or moderate influence on the ability to drive and use machines. The drug may impair concentration and attention (especially at the initial stage of treatment). Patients taking mirtazapine should avoid potentially hazardous activities that require concentration and attention.
Use during pregnancy or breastfeeding
Pregnancy: Limited data on the use of mirtazapine in pregnant women do not indicate an increased risk of birth defects. Animal studies have not shown any teratogenic effects manifested by clinical signs, but adverse effects on intrauterine development have been observed.
Epidemiological data suggest that the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy, especially in late pregnancy, increases the risk of persistent hypertension in the newborn (PPHN). Although no studies have investigated the association of PPHN with mirtazapine treatment, this potential risk cannot be excluded, given the relevant mechanism of action (increased serotonin concentrations).
Special caution should be exercised when prescribing the drug to pregnant women, taking into account the benefit/potential risk ratio for the fetus. If mirtazapine is used before or immediately before delivery, postnatal monitoring of the newborn is recommended to take into account possible withdrawal effects.
Breast-feeding: Animal studies and limited human data have shown excretion of mirtazapine in breast milk in very small amounts. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with mirtazapine should be made taking into account the benefit of breast-feeding for the child and the benefit of mirtazapine therapy for the woman.
Fertility: Preclinical data from animal reproductive toxicity studies indicate no effect on fertility with mirtazapine.
Method of administration and doses
Adults. The effective daily dose is usually 15 to 45 mg; the initial dose is 15 or 30 mg. Mirtazapine generally begins to show its effect after 1–2 weeks of treatment. Treatment with an adequate dose should produce a positive response within 2–4 weeks. If the response is insufficient, the dose can be increased. If no effect is observed within a further 2–4 weeks, the drug should be discontinued.
Elderly patients. The recommended dose is the same as for adults. In order to achieve a satisfactory and safe result, increasing the dose for elderly patients is carried out under close medical supervision.
Dosage in renal impairment: Mirtazapine clearance may be reduced in patients with moderate or severe renal impairment (creatinine clearance < 40 ml/min). When prescribing the drug to this category of patients, creatinine clearance should be monitored.
Dosage in hepatic insufficiency. Mirtazapine clearance may be reduced in patients with hepatic insufficiency. This fact should be taken into account when prescribing the drug to this category of patients, especially with severe hepatic insufficiency. Treatment should be started with the lowest dose, monitoring the clearance of mirtazapine, especially in the case of increasing the dose.
Mirtazapine has a half-life of 20–40 hours, so it can be used once a day. It is advisable to use the drug once at night before going to bed. The daily dose of the drug can also be divided into 2 doses (morning and evening; the larger dose should be taken at night).
Tablets should be taken orally, swallowed without chewing; if necessary, washed down with water.
Patients with depression should be treated for a long time, at least 6 months, until symptoms completely disappear.
It is recommended to discontinue treatment with mirtazapine gradually to avoid withdrawal symptoms.
Children
The drug should not be used in the treatment of children. Suicide-related behavior (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behavior, and anger) have been observed most frequently in children and adolescents treated with antidepressants. If treatment is initiated based on clinical need, the patient should be closely monitored for the emergence of suicidal symptoms. In addition, long-term safety data in children and adolescents regarding growth, maturation, cognitive and behavioral development are not available.
Overdose
Experience suggests that symptoms of mirtazapine overdose are usually mild. Central nervous system depression with disorientation and prolonged sedation, accompanied by tachycardia and mild hypotension or hypertension, has been reported. However, more severe consequences (including death) are possible with doses much higher than the therapeutic dose, especially in mixed overdoses.
In these cases, cases of QT prolongation and torsade de pointes-type ventricular tachycardia have also been reported.
In case of overdose, patients should receive appropriate symptomatic therapy to support vital functions. ECG monitoring should be performed. Activated charcoal or gastric lavage may be considered.
Children: In case of overdose, the measures described for adults should be taken.
Adverse reactions
Patients with depression have numerous symptoms that may be related to the illness itself. However, it is sometimes difficult to determine which symptoms are a manifestation of the illness and which are a result of mirtazapine treatment.
The most common adverse reactions occurring in more than 5% of patients treated with the drug are drowsiness, sedation, dry mouth, weight gain, increased appetite, dizziness and fatigue. Severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), bullous dermatitis and erythema multiforme, have been reported in association with mirtazapine treatment (see section 4.4).
Adverse reactions are classified according to frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency unknown (adverse reactions from spontaneous reports).
Blood and lymphatic system disorders: frequency unknown - bone marrow depression (granulocytopenia, agranulocytosis, aplastic anemia, thrombocytopenia), eosinophilia.
On the part of the endocrine system: frequency unknown - impaired secretion of antidiuretic hormone,
hyperprolactinemia (including associated symptoms - galactorrhea and gynecomastia).
Metabolism and nutrition disorders: very common - weight gain, increased appetite; frequency unknown - hyponatremia.
Psychiatric disorders: often - unusual dreams, confusion, restlessness, insomnia, amnesia*; infrequently - nightmares, mania, agitation, hallucinations, psychomotor agitation (including akathisia, hyperkinesia); rarely - aggression; frequency unknown - suicidal thoughts, suicidal behavior.
Nervous system: very often - drowsiness, sedation, headache; often - inhibition, dizziness, tremor; infrequently - paresthesia, restless legs syndrome, syncope; rarely - myoclonus; frequency unknown - convulsions (hemorrhages), serotonin syndrome, paresthesia of the oral cavity, dysarthria.
From the vascular system: often - orthostatic hypotension; infrequently - arterial hypotension.
From the gastrointestinal tract: very often - dry mouth; often - nausea, diarrhea, vomiting, constipation; infrequently - oral hypoesthesia; rarely - pancreatitis; frequency unknown - swelling of the oral mucosa, increased salivation.
On the part of the hepatobiliary system: rarely - increased activity of transaminases in the blood serum.
Skin and subcutaneous tissue disorders: common: exanthema; frequency unknown: Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS).
Musculoskeletal and connective tissue disorders: common: arthralgia, myalgia, back pain, frequency unknown: rhabdomyolysis.
Renal and urinary disorders: frequency unknown - urinary retention.
General disorders: often - peripheral edema, increased fatigue; frequency unknown - somnambulism, generalized edema, localized edema.
Laboratory indicators: frequency unknown - increased creatine kinase levels.
* In most cases, patients recovered after discontinuation of the drug.
Reducing the dose usually does not result in a decrease in drowsiness/sedation, but may reduce the effectiveness of the antidepressant.
Agitation and insomnia, which can be symptoms of depression, may develop or worsen as a result of treatment with antidepressants, including mirtazapine.
Cases of suicidal ideation and suicidal behaviour have been reported during mirtazapine therapy or early after treatment discontinuation.
Laboratory evaluation in clinical trials showed transient increases in transaminases and gamma-glutamyltransferase (however, no mirtazapine-related adverse reactions were reported that occurred at a higher frequency during treatment with mirtazapine than with placebo).
Pediatric population.
In clinical studies in children, the following adverse events were observed: weight gain, urticaria, and hypertriglyceridemia (see section "Pharmacological properties").
Expiration date
3 years.
Storage conditions
No special storage conditions are required.
Keep out of reach of children.
Packaging
10 tablets in a blister; 2 (10 × 2) blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Salutas Pharma GmbH, Germany.
Location of the manufacturer and its business address
Otto-von-Güricke-Allee 1, 39179, Barleben, Germany.
