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DEPRAZIN

DEPRAZİN coated tablets
DEPRAZIN

International non-patented name: Mirtazapine

Composition
Active substance: 1 tablet contains 30 mg of mirtazapine.
Excipients: lactose monohydrate, pregelatinized starch, magnesium stearate, pink opadri 02F24260 (hypromellose 5cP, titanium dioxide (E171), macrogol 8000, yellow iron oxide (E172), red iron oxide (E172)).

Description
pink, oval coated tablets.

Pharmacotherapeutic group
Antidepressant.

ATC code: N06AX11.

Pharmacological properties
Pharmacodynamics
Mirtazapine is a tetracyclic antidepressant with a sedative effect. The drug has a high effect in depressive states, which in its clinical manifestation reflect symptoms such as satisfaction, lack of feelings of joy, loss of interest (angedonia), psychomotor inhibition, sleep disorder (especially in the form of early awakening), weight loss, as well as suicidal thoughts and changes in mood during the day.

The antidepressant effect of the drug begins 1-2 weeks after starting the treatment.

Mirtazapine is an antagonist of presynaptic α2-adrenoreceptors located in the central nervous system and accelerates the central noradrenergic and serotoninergic transmission of nerve impulses.

Acceleration of impulse transmission occurs only due to 5-HT1-serotonin receptors, while 5-HT2- and 5-HT3-serotonin receptors are blocked by mirtazapine. Both enantiomers of mirtazapine have antidepressant activity, the S (+) enantiomer blocks α2-adrenoreceptors and 5-HT2-serotonin receptors, and the R (-) enantiomer blocks 5-HT3-serotonin receptors. The sedative effect of mirtazapine is due to its antagonistic effect with H1-histamine receptors. Mirtazapine is usually well tolerated by patients. In therapeutic doses, it practically does not block m-cholinoreceptors and does not affect the cardiovascular system.

Pharmacokinetics
It is rapidly absorbed when taken orally (bioabsorption is close to 50%), the maximum concentration in the blood (Cmax) occurs after 2 hours. 85% binds to blood plasma proteins. The average elimination half-life (T1/2) is 20-40 hours (rarely up to 65 hours). Relatively short elimination half-life is observed in young people. Equilibrium concentration is reached after 3-4 days and remains unchanged during the following period.

In the recommended dose range, the pharmacokinetic parameters of mirtazapine are linearly dependent on the dose of the drug. Food intake does not affect the pharmacokinetics of the drug.

Mirtazapine undergoes active metabolism and is excreted in urine and feces within a few days. Its main metabolic pathway in the body consists of oxidation with demethylation and conjugation.

Cytochrome P450 isoenzymes (CYP2D6 and CYP1A2) are involved in the formation of the 8-hydroxymetabolite of mirtazapine, while the CYP3A4 isoenzyme ensures the formation of N-demethylated and N-oxidized metabolites. Demethylmirtazapine has pharmacological activity. The clearance of mirtazapine is reduced in case of renal and hepatic insufficiency

Instructions for use
Treatment of major depressive states.

Contraindications
Hypersensitivity to mirtazapine or any component of the drug.

It should not be used in patients with rare hereditary problems such as lactose intolerance, lactase deficiency and glucose-galactose malabsorption. Since the effectiveness and safety of mirtazapine in children under 18 years of age have not been determined, the use of the drug in children is not recommended. The use of mirtazapine in combination with MAO inhibitors.

Special instructions and precautions
When taking Mirtazapine, the following should be taken into account:

  • the use of antidepressants during the treatment of patients with schizophrenia or other mental disorders may aggravate mental symptoms; paranoid thoughts may intensify.
  • against the background of treatment, the depressive phase of manic-depressive psychosis can change to the manic phase.
  • in young people (under 24 years) with depression and other mental disorders, antidepressants increase the risk of suicidal ideation and suicidal tendencies compared to placebo. Therefore, when prescribing mirtazapine to young people (under 24 years of age), it is necessary to consider the ratio of the risk of suicide and the benefit to be obtained from the use of the drug. In short-term studies, the risk of suicide did not increase in people over the age of 24, and it decreased slightly in people over the age of 65. Any depressive state in itself increases the risk of suicide. Therefore, patients should be closely monitored to detect behavioral changes and disorders, as well as suicidal tendencies during treatment.
  • although mirtazapine is not habit forming, sudden discontinuation of treatment after long-term treatment may rarely lead to a withdrawal syndrome. Most elimination reactions are weak and limited. Symptoms such as dizziness, agitation, restlessness, headache and nausea may be more common. Although these symptoms are reported as symptoms of withdrawal syndrome, they may actually be symptoms of an underlying disease. Gradual discontinuation of mirtazapine treatment is recommended.
  • elderly patients are more likely to have side effects.

During clinical studies with mirtazapine, side effects were more pronounced in elderly patients, but clinical data on this are limited.

  • if symptoms of jaundice appear, the treatment should be stopped.
  • alcohol should be avoided during treatment with mirtazapine.
  • rarely functional disorders of the bone marrow such as granulocytopenia or agranulocytosis may occur while taking mirtazapine. This usually occurs after 4-6 weeks of treatment and disappears when treatment is stopped. Physicians should be sensitive to elevated body temperature, sore throat, stomatitis, and other symptoms of flu-like syndrome (they should inform the patient about this). If such symptoms develop, the treatment should be stopped and a blood laboratory examination should be performed.
  • according to the results of post-registration experience, serotonin syndrome may occur very rarely only in patients treated with mirtazapine.

Dosage correction and regular medical supervision are important in the following categories of patients:

  • patients with epilepsy accompanied by organic damage to the brain (rarely, convulsions may develop against the background of drug treatment);
  • patients with kdney and liver failure;
  • patients with heart disease (conduction disorders, angina pectoris and recent myocardial infarction);
  • patients with cerebrovascular disease (also with a history of ischemic stroke);
  • patients with arterial hypotonia or prone to hypotonia (as well as dehydrated and hypovolemic patients);
  • patients taking too many drugs (especially those affecting the central nervous system).

Like other antidepressants, mirtazapine should be used with caution in the following situations:

  • difficulty urinating, as well as hyperplasia of the prostate gland;
  • acute closed glaucoma and high intraocular pressure;
  • diabetes;
  • combined use of mirtazapine with benzodiazepines.

Interaction with other medicines
Pharmacokinetic interaction

  • mirtazapine undergoes intensive metabolism with the participation of CYP2D6 and CYP3A4 isoenzymes and to a lesser extent CYP1A2 isoenzyme. During the interaction study on healthy volunteers, it was determined that paroxetine, an inhibitor of the CYP2D6 isoenzyme, did not affect the pharmacokinetics of mirtazapine. When co-administered with ketoconazole, a strong inhibitor of the CYP3A4 isoenzyme, the maximum plasma concentration and AUC of mirtazapine increased by 40% and 50%, respectively. Mirtazapine should be used with caution in combination with CYP3A4 isozyme inhibitors, erythromycin or nefazodone.
  • inhibitors of the CYP3A4 isoenzyme, such as carbamazepine and phenytoin, double the clearance of mirtazapine and reduce its concentration in the blood by 45-60%. When carbamazepine or other inducers of hepatic metabolism (for example, rifampicin) are added to treatment with mirtazapine, the dose of mirtazapine should be increased. When treatment with such drugs is stopped, it may be necessary to reduce the dose of mirtazapine.
  • the bioavailability of mirtazapine can increase by 50% when used together with cimetidine. It is recommended to reduce the dose of mirtazapine at the beginning of treatment with cimetidine and to increase it after stopping treatment with cimetidine.
  • during in vivo studies, the effect of mirtazapine on the pharmacokinetics of risperidone or paroxetine (CYP2D6 isoenzyme substrate), carbamazepine (CYP3A4 isoenzyme substrate), amitriptyline, cimetidine and phenytoin was not determined.
  • no significant clinical effect or pharmacokinetic change was observed during co-treatment with lithium.
  • Pharmacodynamic interaction
  • mirtazapine should not be taken together with MAO inhibitors or within two weeks after treatment with MAO inhibitors.
  • mirtazapine can enhance the sedative effect of benzodiazepines and other sedative drugs. Caution should be exercised when using this group of drugs together with mirtazapine.
  • mirtazapine can enhance the depressant effect of alcohol on the CNS. Therefore, patients should limit alcohol consumption during the treatment period.

There is a risk of serotonin syndrome when mirtazapine is co-administered with other serotonergic drugs (for example, selective serotonin reuptake inhibitors and venlafaxine). According to the results of post-registration experience, serotonin syndrome is very rare in patients receiving mirtazapine together with selective serotonin reuptake inhibitors and venlafaxine. If the combined use of these drugs is important, then it is advisable to change the dose with caution and monitor the symptoms of high serotonin stimulation.

  • mirtazapine at a daily dose of 30 mg caused a weak but statistically significant increase in INR (international normalized ratio) in warfarin-treated patients. It is not excluded that higher doses of mirtazapine will cause a more noticeable effect. When mirtazapine is taken together with warfarin, it is recommended to monitor BNM

Use during pregnancy and lactation
The safety of mirtazapine during pregnancy has not been established, but no teratogenic effects have been identified in animal studies. Therefore, the drug can be used during pregnancy only in cases where the benefit to the mother is higher than the potential risk to the fetus. It is not recommended to use the drug during lactation, as there is no information on the drug’s excretion in breast milk.

It should be used with caution in patients with liver failure. The clearance of mirtazapine may be reduced in patients with liver failure, this feature should be taken into account when using in such patients.

Use in case of functional impairment of the liver
It should be used with caution in patients with renal failure. The clearance of mirtazapine may decrease in patients with renal insufficiency, this feature should be taken into account when using in such patients..

Use in elderly patients
It should be used with caution in patients with renal failure. The clearance of mirtazapine may decrease in patients with renal insufficiency, this feature should be taken into account during use in such patients.

Use in pediatrics
Since the efficacy and safety of mirtazapine in children under 18 years of age have not been determined, the use of the drug in children is not recommended.

Effects on the ability to drive vehicles and other potentially dangerous mechanisms
Since mirtazapine can impair attention, during the treatment period it is necessary to avoid potentially dangerous activities that require a high psychomotor reaction, such as driving a vehicle and working with mechanisms.

 Method of use and dosage
Tablets are taken inside with liquid without chewing.
Adults: the effective daily dose ranges from 15 mg to 45 mg, the starting dose is 15 mg or 30 mg.
Elderly: The recommended dose is the same as for adults. In order to obtain satisfactory and safe treatment results in elderly patients, increasing the dose should be done only under the supervision of a doctor.
It should be used with caution in patients with liver and kidney failure. The clearance of mirtazapine may decrease in patients with renal insufficiency, this feature should be taken into account during use in such patients.

The drug is taken once a day, at about the same time, before going to bed in the evening. It can also be taken twice a day by dividing the daily dose into two parts (in the morning and in the evening before going to bed, the larger dose should be taken in the evening).

Treatment should be continued for 4-6 months, until the symptoms of the disease disappear completely. After that, the treatment can be gradually stopped. Mirtazapine usually begins to show its effect after 1-2 weeks of treatment. If an adequate response is not achieved within 2-4 weeks of treatment with an adequate dose, treatment should be discontinued.

Side effects
Because many symptoms related to the underlying disease are observed in depressed patients, it is difficult to determine whether these symptoms are due to the underlying disease or to the medication. The following classification is used to express the frequency of side effects: very often (>1/10), often (>1/100 and < 1/10), sometimes ((>1/1000 and < 1/100 ), rare (>1/10000 and < 1/1000), frequency not determined (< 1/10000).

To the blood and lymphatic system: the frequency is not determined – bone marrow depression (granulocytopenia, agranulocytosis, aplastic anemia, thrombocytopenia), eosinophilia.

To the nervous system: very often – drowsiness (which causes a decrease in attention), which usually occurs in the first week of treatment (note: reducing the dose usually does not lead to a decrease in the sedative effect, but the antidepressant effect weakens), headache; often – lethargy, dizziness, tremors; sometimes – paresthesia, “restless legs” syndrome, fainting; rare – myoclonus, very rare – convulsions (stroke), serotonin syndrome, paresthesia of the mucous membrane of the oral cavity.

Gastrointestinal tract: very often – dry mouth; often – nausea, vomiting, diarrhea; sometimes – decreased sensitivity of the mucous membrane of the oral cavity; frequency not determined – edema of the mucous membrane of the oral cavity.
Skin and subcutaneous tissue: often – skin rash.
Musculoskeletal and connective tissue: often – arthralgia, myalgia, back pain.
Endocrine system: frequency not determined – violation of antidiuretic hormone secretion.
Nutrition and metabolism: very often increased appetite.
From the veins: often – orthostatic hypotension; sometimes – arterial hypotension.
General and local disorders: often – local edema; sometimes – fatigue.
To the liver and biliary tract: rare – increased activity of serum transaminases.
Mental disorders: often – unusual dreams, agitation, insomnia; sometimes-nightmares, mania, excitement, hallucination, psychomotor wakefulness (including akathasia and hyperkinesia); frequency not determined – suicidal thoughts.
Laboratory-instrumental indicators (according to the results of post-registration studies): very often – an increase in body mass.
*- anxiety and insomnia (may be a symptom of depression) may increase and worsen during treatment with antidepressants.
Development or exacerbation of agitation and insomnia may occur very rarely during treatment with mirtazapine.

Overdose
Experiences with mirtazapine overdose show that symptoms are usually very mild. There have been reports of slowing down of the central nervous system accompanied by tachycardia, disorientation with a slight increase in arterial pressure, and a persistent sedative effect. At doses higher than the therapeutic dose, more severe consequences (including lethal consequences) are possible, especially if an overdose of several drugs taken at the same time occurs. In cases of overdose, it is important to carry out symptomatic treatment in order to support the vital functions of the body. At this time, it is recommended to wash the stomach and take activated charcoal.

Packing form
10 coated tablets, in a blister. 3 blisters are packed in a cardboard box together with a leaflet.

Store condition
It should be stored at a temperature not higher than 25ºС and out of the reach of children.

Shelf life
3 years.
Do not use after the expiration date.
By prescription

Manufacturer
Farmalabor-produtos Farmaceuticos, S.A., Portugal.
Zona İndutrial de Condeixa-a-Nova, Condeixa-Nova, 3150-194, Portugal.
ATLANTIC PHARMA S.A., Portugal.