Brintellix pills 10mg №28

INSTRUCTIONS

BRINTELLIX film-coated tablets, 10 mg each, number 28

full cycle production: H. Lundbeck A / S, Denmark;

primary and secondary packaging: Elayafarm, France; tests on the indicator "microbiological purity":

Eurofins Pharma A / S, Denmark

COMPOSITION

active ingredient: vortioxetine;

1 coated pill contains 5 mg or 10 mg of vortioxetine as vortioxetine hydrobromide;

excipients: mannitol (E 421), microcrystalline cellulose, hydroxypropylcellulose, sodium starch (type A), Magnesium stearate, hypromellose, macrogol 400, titanium dioxide (E 171); pills of 5 mg of iron oxide red (E172); pills 10 mg iron oxide yellow (E 172).

DOSAGE FORM

Tablets, film coated.

Main physical and chemical properties:

5 mg pills are pink, drop-shaped tablets, film-pills with “TL” symbols on one side and “5” on the other; 10 mg tablets: yellow, drop-shaped tablets, film-pills with “TL” symbols on one side and “10” on the other.

PHARMACOLOGICAL GROUP

Antidepressants. ATX code N06A X26.

PHARMACOLOGICAL PROPERTIES

Pharmacological.

Mechanism of action

The mechanism of action of vortioxetine is believed to be related to its multimodal activity, which is a combination of two pharmacological mechanisms: direct modulation of receptor activity and inhibition of the serotonin transporter (5-HT).Preclinical data show that vortioxetine is an antagonist of 5-HT 3, 5-HT 7 and 5-HT 1D receptors, a partial agonist of 5-HT 1B receptors, an agonist of 5-HT 1A receptors and an inhibitor of 5-HT transporter, causes modulation of neurotransmission in several systems, including serotonin, norepinephrine, dopamine, histamine, acetylcholine, GABA and glutamate. Such multimodal activity is believed to provide antidepressants and anxiolytic effects, as well as improved cognitive function, learning, and memory in preclinical studies of vortioxetine. In addition, preclinical studies indicate that vortioxetine does not cause sexual dysfunction. The exact contribution of each component of this mechanism to the observed pharmacodynamic profile remains unclear, so attention should be used when extrapolating preclinical data directly to a person.

It was established that the seizure of the serotonin transporter with various daily doses of vortioxetine was approximately 50% - a dose of 5 mg, 65% - at a dose of 10 mg, and more than 80% - a dose of 20 mg. Vortioxetine clinically showed an antidepressant effect on the seizure of the 5-HT conveyor by 50%.

Clinical efficacy and safety

The efficacy of vortioxetine increases with increasing dose. In addition, vortioxetine within doses of 5–20 mg demonstrated efficacy in a wide range of depressive (on the MADRS scale) and anxious (on the HAM-A scale) symptoms of depression.

Relapse prevention

The duration of the antidepressant effect was demonstrated in a relapse prevention study, in which the risk of relapse was twice as high in the placebo group than in the vortioxetine group.

In the range of doses of vortioxetine from 5 to 20 mg per day, the effectiveness and tolerability in the elderly responded to the results of studies in the adult population.

Patients with severe depression or high levels of anxiety symptoms

Antidepressant efficacy has also been demonstrated in patients with severe depression (≥ 30 MADRS scores) and in depressed patients with a high level of anxiety symptoms (≥ 20 HAM-A scores) in short-term studies, including studies in elderly patients, and long-term relapse prevention studies.

Patients with an inadequate response to treatment of SSRIs / PPEs

In a comparative study of flexible doses in patients with depression after an inadequate response to the treatment of an existing episode of SSRIs / VELOSIN vortiroxetine at a daily dose of 10-20 mg was statistically significantly more effective than agomelatine at a dose of 25-50 mg (according to the MADRS scale), clinical value was proved on CGI-I and SDS scales.

Cognitive dysfunction in depression

In the course of studies of the effect of the drug on cognitive processes, it turned out that the effect of vortioxetine is mainly due to a direct effect on cognitive function rather than an indirect effect through the improvement of symptoms of depression.

Quality of life and overall functioning

Vortioxetine was superior to placebo in terms of quality of life, clinically significantly improved overall health (EQ-5D) and overall functioning (SDS - work, social and family life) compared with placebo or active comparison agent (agomelatine). Moreover, the best effects compared with placebo in terms of quality of life persisted over the long-term study of relapse prevention.

Portability and safety

The safety and tolerability of vortioxetine were evaluated in short- and long-term studies for doses of 5–20 mg per day.

Vortioxetine did NOT increase the frequency of insomnia or drowsiness compared with placebo.

In a systematic assessment of potential withdrawal symptoms, there was no clinically significant difference between vortioxetine and placebo in terms of the frequency and nature of withdrawal symptoms after either a short-term (6-12 weeks) or a long-term (24-64 weeks) treatment period.

In clinical trials with vortioxetine, the incidence of unwanted sexual reactions was low and similar to placebo, the incidence rates of sexual dysfunction associated with therapy, and overall ASEX scores did not have clinically significant differences with placebo regarding the symptoms of sexual dysfunction when using the recommended dose of vortoxetine, but high doses were associated with a numerical increase in cases of dysfunction.

In clinical trials, similarly to placebo, vortioxetine did not affect body weight, heart rate, and blood pressure.

There were no clinically significant changes in the assessments of liver and kidney function during clinical trials.

Vortioxetine did not have any clinically significant effect on ECG parameters, including QT-, QTc-, PR-, and QRS-intervals, in patients with major depressive disorder. In a thorough study of QTc among healthy volunteers, when applying doses up to 40 mg per day, the potential for an increase in QTc interval was not observed.

Childhood

Clinical studies among pediatric patients have not been conducted, therefore, the safety and efficacy of Brinetelex for patients under the age of 18 years have not been established.

Pharmacokinetics. Absorption Vortioxetine is slowly but well absorbed after ingestion and the peak plasma concentration is reached within 7-11 hours. After repeated administration of 5, 10 or 20 mg per day, an average C max value of 9-33 ng / ml was observed. Bioavailability is 75%. The effect of food intake on pharmacokinetics was not observed.

Distribution The average volume of distribution (VSS) is 2,600 liters, which indicates volumetric extravascular distribution. Vortioxetine binds strongly to plasma proteins (98-99%) and binding does not seem to depend on plasma vortioxetine concentration.

Metabolism Vortioxetine is extensively metabolized in the liver, mainly through oxidation and subsequent conjugation with glucuronic acid.

In vitro isoenzymes of cytochrome P450 CYP2D6, CYP3A4 / 5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 are involved in the metabolism of vortoxetine. In vitro inhibitory or inducing effects of vortioxetine on CYP CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 / 5 isoenzymes were not observed. Vortioxetine is a weak P-gp substrate and inhibitor.

The main metabolite of vortioxetine is pharmacologically inactive.

Withdrawal The half-life is 66 hours. Approximately 2/3 of the inactive metabolite vortioxetine is excreted in the urine and about 1/3 in the feces. Only a small amount of vortioxetine is excreted in the feces. Permanent plasma concentration is reached after 2 weeks.

Linearity / nonlinearity Pharmacokinetics is linear and does not depend on time in the range of studied doses (2.5-60 mg per day). According to the half-life, the accumulation index ranges from 5 to 6 based on AUC 0-24 after several doses of doses from 5 to 20 mg per day.

In elderly healthy volunteers (aged ≥ 65 years, n = 20), the effect of vortioxetine increased by 27% (C Max and AUC) compared with young healthy volunteers from the control group (aged ≤ 45 years) after several doses of 10 mg per day. Dose adjustment is not required.

Renal failure

After a single dose of 10 mg of vortioxetine, renal failure (according to Cockroft-Gault formula, mild, moderate or severe, n = 8 in the group) caused a slight increase in exposure (up to 30%) compared with that in the control group of healthy volunteers. In patients with end-stage renal disease, only a small fraction of vortioxetine was lost during the dialysis process (AUC and C Max by 13% and 27% lower; n = 8) after a single dose of 10 mg of vortioxetine.Dose adjustment is not required.

Liver failure

After a single dose of 10 mg of vortioxetine, there was no effect of mild or moderate liver failure (Child-Pugh, criteria A and B; n = 8 in each group) on the pharmacokinetics of vortioxetine (no change in AUC was less than 10%). Dose adjustment is not required. Vortioxetine has not been studied in patients with severe hepatic insufficiency, and caution should be exercised in prescribing these patients.

Weak metabolizers of CYP2D6

In weak metabolizers of CYP2D6, plasma concentration of vortioxetine was approximately two times higher than in extensive metabolisers. In the presence of potent CYP3A4 / 2C9 inhibitors, the effect can potentially be higher. Dose adjustment may be required, as for all patients, depending on the individual response.

INDICATIONS

Treatment of major depressive disorder in adults.

CONTRAINDICATIONS

Hypersensitivity to the active substance or any component of the drug.

Concurrent use with non-selective MAO inhibitors (MAO) or selective MAO-A inhibitors.

INTERACTIONS WITH OTHER MEDICINES AND OTHER TYPES OF INTERACTIONS

Vortioxetine is metabolized in the liver mainly by oxidation and subsequent conjugation with glucuronic acid. The isoenzymes of cytochrome P450 CYP2D6, CYP3A4 / 5, CYP2C19, CYP2C9, CYP2A6, CYP2C8, and CYP2B6 are involved in vitro metabolism of vortioxetine.

Effect of other drugs on the action of vortioxetine

Irreversible non-selective MAO inhibitors

Because of the risk of serotonin syndrome, vortioxetine is contraindicated in any combination with irreversible non-selective MAO inhibitors. Treatment with vortioxetine should not be started earlier at least 14 days after discontinuation of treatment with irreversible non-selective MAO inhibitors. Reception of vortioxetine should be discontinued at least 14 days before the start of treatment with irreversible non-selective MAO inhibitors.

Revolving selective inhibitor of MAO-A (moclobemide)

The combination of vortioxetine with a reversible selective MAO-A inhibitor, such as moclobemide, is contraindicated. Careful monitoring of serotonin syndrome with simultaneous use is necessary.

Reverse non-selective inhibitor of MAO (linezolid)

The combination of vortioxetine with a weak reversible and non-selective MAO inhibitor, such as the antibiotic linezolid, is contraindicated. Careful monitoring of serotonin syndrome with simultaneous use is necessary.

Non-current selective inhibitors of MAO-B (selegilin, rasagiline)

Despite the lower (than with MAO-A inhibitors) expected risk of serotonin syndrome, the combination of vortioxetine with irreversible MAO-B inhibitors, such as selegiline or rasagiline, must be carried out with caution. Careful monitoring of serotonin syndrome with simultaneous use is necessary.

Serotonergic Medicines

Co-administration with serotonergic drugs (for example, with tramadol, Sumatriptan and other triptans) can lead to serotonin syndrome.St. John's wort Simultaneous use of serotonergic antidepressants and herbal remedies containing St. John's wort can increase the frequency of adverse reactions, including serotonin syndrome.

Drugs that reduce the convulsive threshold

Anti-depressants of serotonergic action can reduce the threshold of convulsive readiness. It is recommended to use other medicines that can reduce the threshold of convulsive readiness (as antidepressants (TCA, SIOZS, SIZD), neuroleptics (phenothiazines, thioxanthenes, butyrophenone, I), mefloxin,anti-depressants, melanchroma, neuroleptics (phenothiazines, tioksanteny, butyrophenones, IH), neuroleptics (phenothiazines, tioksanteny, butyrophenone, I), melephinos.

ECT (electroconvulsive therapy)

There is no clinical experience of simultaneous use of vortioxetine with ECT, so caution is advisable.

Inhibitors of cytochrome P450

When administered together with 150 mg of bupropion (a strong CYP2D6 inhibitor) twice a day for 14 days in healthy volunteers, the effect of vortioxetine increased 2.3 times for AUC. Co-administration more often resulted in an increase in the incidence of side effects when bupropion was added to vortioxetine than when vortioxetine was added to bupropion. Depending on the patient's individual sensitivity, when adding strong CYP2D6 inhibitors to therapy (for example, bupropion, quinidine, Fluoxetine , paroxetine), low-dose vortioxetine may be considered.

When co-administered with vortioxetine after 6 days of Ketoconazole use 400 mg per day (CYP3A4 / 5 inhibitor and P-glycoprotein) or Fluconazole 200 mg per day (CYP2C9 inhibitor,CYP2C19 and CYP3A4 / 5) in healthy volunteers, 1.3 and 1, 5-fold increase in AUC of vortioxetine was observed, respectively. Dose adjustment is not required.

The effect of a single dose of 40 mg of Omeprazole (an inhibitor of CYP2C19) on the pharmacokinetics of long-term use of vortioxetine in healthy volunteers was not observed.

The combination of potent inhibitors of CYP3A4 and CYP2C9 in patients with low CYP2D6 metabolism has not been studied, however, one should probably expect an increased effect of vortioxetine on such patients.

Inductors of cytochrome P450

After a single injection of 20 mg of vortioxetine together after 10 days of taking rifampicin 600 mg per day (inducer of CYP isoenzymes) in healthy volunteers, there was a decrease in AUC of vortioxetine by 72%. Depending on the patient's individual response, a dose adjustment may be required if cytochrome P450 inducer (for example, rifampicin, Carbamazepine , phenytoin) is added to the treatment with vortioxetine.

Acetylsalicylic acid

The effect of repeated administration of Acetylsalicylic acid 150 mg per day on the pharmacokinetics of vortioxetine in healthy volunteers was not observed.

Effect of Vortioxetine on the Effects of Other Medicines

Anticoagulants and antiplatelet agents

There were no significant effects on the international normalized ratio of prothrombin or plasma R- / S-warfarin compared with placebo when co-administered with a fixed dose of Warfarin vortioxetine in healthy volunteers was not observed.In addition, a significant inhibitory effect compared with placebo on platelet aggregation with co-administration of Aspirin at a dose of 150 mg per day after administration of vortioxetine in healthy volunteers was not observed. However, as with the use of other serotonergic drugs, caution should be exercised when using vortioxetine in combination with oral anticoagulants or antiplatelet agents due to the potential increase in the risk of bleeding from pharmacodynamic interactions.

Alcohol Effects on the pharmacokinetics of vortioxetine or ethanol, as well as significant impairment of cognitive function compared with placebo after administration of vortioxetine at doses of 20 mg or 40 mg with simultaneous single administration of ethanol 0.6 g / kg in healthy volunteers were not detected. However, like other drugs acting on the central nervous system, the use of vortioxetine in combination with alcohol is not recommended.

Cytochrome P450 Substrates

In vitro vortioxetine showed no potential for inhibition or induction of cytochrome P450 isoenzymes. The inhibitory effects of creepis on the isoenzymes of cytochrome P4 CYP2C19 cytochrome (omeprazole, diazepam), CYP3A4 / 5 (ethinylestradiol, midazolam), and kptotoxplotophlomectycid cells, as well as cptotocp cells; CYP1A2 (caffeine) or CYP2D6 (dextromethorphan) in healthy volunteers detected.

A significant impairment of cognitive function compared with placebo after administration of vortioxetine simultaneously with 10 mg of diazepam was not detected.

Significant effect onlevels of sex hormones compared with placebo after simultaneous use of vortioxetine with a combined oral contraceptive (ethinyl estradiol 30 µg / levonorgestrel 150 µg) was not detected.

Lithium, tryptophan

There was no clinically significant effect of stable concentrations of lithium after simultaneous use with vortioxetine in healthy volunteers. However, there have been reports of increased effects when using antidepressants of serotonergic action together with lithium or tryptophan, therefore, the simultaneous use of vortioxetine with these drugs should be carried out with caution.

FEATURES OF APPLICATION

Use in the pediatric patient population

Brinetelex is not recommended for the treatment of depression in patients under the age of 18 years, since safety and efficacy for this age group has not been established. In clinical trials, children who were given other antidepressants were suicidal (suicidal attempts and suicidal thoughts) and hostility (mainly aggression, oppositional behavior, anger) were observed more often than in patients who were given placebo.

Suicide / suicidal thoughts

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicidal events). This risk persists until significant remission is achieved. Since improvement may not occur during the first few weeks of treatment or more, the condition of the patients should be carefully monitored until improvement occurs.From general clinical experience it is known that the risk of suicide may increase in the early stages of recovery.

Patients with a history of suicide-related events or with significant signs of suicidal thoughts before treatment are known to be at greater risk of suicidal thoughts or suicide attempts and require careful observation during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with Mental disorders showed an increased risk of suicidal behavior compared with placebo in patients under the age of 25 years.

Strict supervision of patients and, in particular, of high-risk individuals should be accompanied by treatment, especially at the start of therapy and after a dose change. Patients (and their caregivers) should be warned about the need to monitor any clinical deterioration, suicidal behavior or thoughts and unusual changes in behavior, as well as the need to consult a doctor immediately if these symptoms occur.

Seizures Seizures are a potential risk with antidepressants. Therefore, treatment with vortioxetine should begin with caution in patients who have a history of convulsions, or in patients with unstable epilepsy. Treatment of any patient should be discontinued if seizures develop or their frequency increases.

Serotonin syndrome or neuroleptic malignant syndrome

Serotonin syndrome (SS) or neuroleptic malignant syndrome (NZS), a potentially life-threatening condition, can develop during treatment with Brintellix . The risk of developing SS and NZS increases with the simultaneous use of serotonergic drugs (including triptans), agents that affect the metabolism of serotonin (including MAO inhibitors), antipsychotics and other dopamine antagonists. The symptoms of SS or NZS should be closely monitored.

Symptoms of SS include changes in mental state (such as agitation, hallucinations and coma), autonomic instability (for example, tachycardia, labile blood pressure and hyperthermia), neuromuscular aberrations (such as hyperreflexia, lack of coordination) and / or gastrointestinal symptoms (for example nausea, vomiting and diarrhea). If such signs appear, you should immediately discontinue use of the drug Brinttelix and start symptomatic treatment.

Mania / hypomania

Brintellix should be administered with caution to patients with a history of mania / hypomania and discontinue use if a manic phase develops.

Bleeding As with the use of any other anti-depressant serotonergic action (SSRIs, PPE), abnormal hemorrhages are possible, such as bruises, purpura, and other hemorrhages, such as gastrointestinal or gynecological bleeding. Caution is advised on patientstaking anticoagulants and / or drugs that affect platelet function (for example, atypical antipsychotics and phenothiazines, most TCAs, nonsteroidal anti-inflammatory drugs, acetylsalicylic acid), as well as patients with a known bleeding tendency or blood clotting disorders.

Hyponatremia About hyponatremia, probably due to inadequate secretion of ADH, with the use of antidepressants of groups of SSRIs, PPE, was rarely reported. Caution should be exercised when patients are at risk of developing hyponatremia, such as elderly patients, with cirrhosis, or with the simultaneous use of drugs that cause hyponatremia. For patients with symptomatic hyponatremia, it is advisable to discontinue use of Brintellix and initiate appropriate medical intervention.

Renal failure

Data on the use of patients with severe deficiency is limited, therefore, caution should be exercised.

Liver failure

Vortioxetine has not been studied in patients with severe hepatic insufficiency; caution should be exercised in treating such patients.

Use during pregnancy or lactation.

Pregnancy Experience of using vortioxetine in pregnant women is limited.

In animal studies, the teratogenic effect has not been established, but there has been a decrease in body weight and a delay in ossification of the fetus.

After the use of serotonergic drugs in newborns in women at the late stages of pregnancy, the following symptoms may appear: respiratory distress, cyanosis, shortness of breath, convulsions, temperature instability, difficulty feeding, vomiting, hypoglycemia, hypertension, hypotension, hyperreflexia, tremor, nervousness, irritability, lethargy, constant crying, drowsiness and difficulty sleeping. These symptoms may be associated with withdrawal effects or excessive serotonergic activity. In most cases, such complications begin immediately or soon (<24 hours) after delivery.

Epidemiological data have shown that the use of SSRIs during pregnancy, especially at late periods, can lead to an increase in the risk of persistent pulmonary hypertension in the newborn (PLHN). Although the association of PLHN with vorioxetine treatment has not been studied, this potential risk cannot be ruled out, given the mechanism of action (increase in serotonin concentrations).

Brinetelex should not be used during pregnancy, if the clinical condition of the woman does not require treatment with vortioxetine.

Breast-feeding

The available preclinical data have shown that vortioxetine and metabolites are excreted into breast milk. It is expected that vortioxetine is secreted into breast milk. The risk to the infant cannot be excluded. The decision to discontinue / continue breastfeeding or discontinue / detain from treatment with Brinetelex should be made taking into account the benefits of breastfeeding for the baby and the benefits of therapy for the woman.

Fertility A study of fertility in males and females of animals showed no effect of vortioxetine on fertility, sperm quality, and mating performance.

The ability to influence the reaction rate when driving motor transport or other mechanisms.

No significant impairment to the ability to drive vehicles, cognitive functions, or other psychomotor skills compared with placebo was observed in healthy volunteers. However, patients should exercise caution when driving or operating dangerous machinery.

METHOD OF ADMINISTRATION AND DOSES

Mode of application

Brintellix is ingested with or without food.

The initial and maintenance doses are 10 mg once a day.

Depending on the individual sensitivity of the patient, the dose can be increased to a maximum of 20 mg per day or reduced to a minimum of 5 mg per day.

After eliminating the symptoms of depression, it is recommended to continue treatment for another 6 months to strengthen the anti-depressive effect.

Termination of treatment

Treatment with Brinetelex can be stopped abruptly, there is no need to gradually reduce the dose.

Special patient groups

Dose adjustment for elderly patients solely on the basis of age is not required.

Inhibitors of cytochrome P450

Depending on the individual patient's response, the use of low doses of vortioxetine should be considered if powerful CYP2D6 inhibitors are added to therapy (for example, bupropion, quinidine, fluoxetine, paroxetine).

Inductors of cytochrome P450

Depending on the patient's individual response, dose adjustment of vortioxetine should be considered if cytochrome P450 inducer is added to therapy (for example, rifampicin, carbamazepine, phenytoin).

Children.

The safety and efficacy of Brintellix for the treatment of depression in patients under the age of 18 years have not been established, therefore, the use is not recommended.

OVERDOSE

Experience is limited. Acceptance of vortioxetine in the dose range from 40 to 75 mg caused an exacerbation of such side effects: nausea, postural dizziness, diarrhea, abdominal discomfort, generalized itching, drowsiness, and blush.

Treatment should be symptomatic and include appropriate monitoring. Medical supervision in specialized conditions is recommended.

ADVERSE REACTIONS

The most frequent adverse reaction was nausea. Adverse reactions were usually mild or moderate and were observed during the first two weeks of treatment. Reactions, as a rule, were transient and usually did not lead to cessation of therapy. On the part of the digestive system (for example, nausea) was more often observed in women than in men. The adverse reactions listed below are defined as: very often (≥ 1/10), often (≥ 1/100 to <1/10), infrequent (≥ 1/1000 to <1/100), rare (≥ 1/10 000 to <1/1000), very rare (<1/10 000) and unknown (the frequency cannot be determined from the available data).