Brintellix, 10 mg 28 pcs.

Pharmacodynamics

Mechanism of Action

The mechanism of action of vortioxetine is thought 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-NT).

. Preclinical data show that vortioxetine is a 5-HT 3, 5-HT 7 and 5-HT 1D receptor antagonist, partial 5-HT 1B receptor agonist, 5-HT 1A receptor agonist and 5-HT transporter inhibitor, causing modulation of neurotransmission in several systems, including serotonin, noradrenaline, dopamine, histamine, acetylcholine, GABA and glutamate.

This multimodal activity is thought to provide antidepressant 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 applied when extrapolating preclinical data directly to humans.

The serotonin transporter uptake by different daily doses of vortioxetine was found to be approximately 50% at the 5 mg dose, 65% at the 10 mg dose, and over 80% at the 20 mg dose. Vortioxetine clinically showed an antidepressant effect with a 50% capture of the 5-HT transporter.

Clinical efficacy and safety.

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

Prevention of relapse.

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

Elderly patients.

In the vortioxetine dose range of 5 to 20 mg per day, efficacy and tolerability in the elderly were consistent with results of studies in adults.

Patients with severe depression or high levels of anxiety symptoms.

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

Patients with inadequate response to SSRI/SRI treatment.

In a flexible dose comparison study in depressed patients after an inadequate treatment response to an existing SSRI/SIZZN episode, vortioxetine at a daily dose of 10-20 mg was statistically significantly more effective than agomelatine at 25-50 mg (MADRS scale), clinical significance was proven by the CGI-I and SDS scales.

Cognitive dysfunction in depression.

In studies of the drug’s effects on cognitive processes, it appears that the effects of vortioxetine are mainly due to direct effects on cognitive function rather than indirect effects through improvement of depression symptoms.

Quality of life and overall functioning.

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

Tolerability and safety.

The safety and tolerability of vortioxetine have been evaluated in short- and long-term studies for doses of 5-20 mg daily.

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

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

In clinical trials with vortioxetine, the frequency of reported adverse sexual reactions was low and similar to placebo, the rates of therapy-related sexual dysfunction and overall ASEX scores had no clinically significant differences with placebo for sexual dysfunction symptoms at the recommended dose of vortioxetine, but high doses were associated with numerical increases in dysfunction.

In clinical trials similar to placebo, vortioxetine had no effect on body weight, heart rate or blood pressure.

There were no clinically significant changes in liver or kidney function scores in clinical studies.

Vortioxetine had no clinically significant effect on ECG parameters, including QT-, QTc-, PR-, and QRS-intervals, in patients with major depressive disorder. In a careful study of QTc among healthy volunteers, no potential for increased QTc interval was observed with doses up to 40 mg per day.

Childhood.

The clinical studies in pediatric patients have not been conducted, therefore, the safety and efficacy of the drug. Brintellix for patients under the age of 18 years have not been established.

Pharmacokinetics

Absorption

Vortioxetine is slowly but well absorbed after oral administration and peak plasma concentrations are reached within 7-11 hours. An average C Max of 9-33 ng/ml has been observed after multiple doses of 5, 10, or 20 mg per day. The bioavailability is 75%. No effect of food intake on pharmacokinetics was observed.

Distribution

The mean volume of distribution (V SS) is 2600 L, indicating volumetric extravascular distribution. Vortioxetine binds strongly to plasma proteins (98-99%) and binding appears to be independent of plasma vortioxetine concentration.

Metabolism

Vortioxetine is extensively metabolized in the liver, primarily by oxidation and subsequent conjugation by glucuronic acid.

In vitro the cytochrome P450 isoenzymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 are involved in the metabolism of vortioxetine. No inhibitory or inducing effects of vortioxetine in vitro on the CYP CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 / 5 isoenzymes were observed. Vortioxetine is a weak P-gp substrate and inhibitor.

The main metabolite of vortioxetine is pharmacologically inactive.

Elimation

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

Linearity/nonlinearity

The pharmacokinetics are linear and time-independent over the range of doses studied (2.5-60 mg daily). According to the half-life, the accumulation index is 5 to 6 based on an AUC of 0-24 after multiple doses of 5 to 20 mg per day.

Elderly Patients

In elderly healthy volunteers (aged ≥65 years, n = 20), vortioxetine effects were increased by 27% (C max and AUC) compared with young healthy control volunteers (aged ≤45 years) after several doses of 10 mg daily. No dose adjustment is required.

Renal Impairment

After a single dose of 10 mg vortioxetine, renal impairment (Cockroft-Gault formula, mild, moderate or severe, n = 8 per group) caused a slight increase in exposure (up to 30%) compared with that in control healthy volunteers. In patients with end-stage renal failure, only a small fraction of vortioxetine was lost during the dialysis process (AUC and C Max 13% and 27% lower; n = 8) after a single dose of 10 mg vortioxetine. No dose adjustment was required.

Hepatic Impairment

After a single dose of 10 mg vortioxetine, the effects of mild to moderate hepatic impairment (Child-Pugh, criteria A and B; n=8 in each group) on the pharmacokinetics of vortioxetine was not observed (AUC changes were less than 10%). No dose adjustment was required. Vortioxetine has not been studied in patients with severe hepatic impairment, and caution should be exercised when prescribing in these patients.

Weak CYP2D6 metabolizers

In weak CYP2D6 metabolizers, vortioxetine had about twice the plasma concentration of extensive metabolizers. In the presence of potent CYP3A4/2C9 inhibitors, the effect could potentially be higher.

Dose adjustment may be required, as in all patients, depending on individual response.

Indications

The treatment of major depressive disorder in adults.

Active ingredient

How to take, the dosage

Brintellix is taken orally with or without food. The starting and maintenance doses are 10 mg once daily.

Depending on individual patient sensitivity, the dose may be increased to a maximum of 20 mg daily or decreased to a minimum of 5 mg daily.

After symptoms of depression have resolved, it is recommended that treatment be continued for another 6 months to strengthen the antidepressant effect.

The discontinuation of treatment. Treatment with Brintellix can be discontinued abruptly, there is no need to gradually reduce the dose.

Special patient groups. Elderly patients. Dose adjustment for elderly patients based solely on age is not necessary.

Cytochrome P450 inhibitors. Depending on the patient’s individual response, low-dose vortioxetine should be considered if potent CYP2D6 inhibitors (e.g., bupropion, quinidine, fluoxetine, paroxetine) are added to therapy.

Cytochrome P450 inducers. Depending on the patient’s individual response, dose adjustment to vortioxetine should be considered if a cytochrome P450 inducer (e.g., rifampicin, carbamazepine, phenytoin) is added to therapy.

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

Interaction

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

The effect of other drugs on the effects 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 than at least 14 days after stopping treatment with non-reversible non-selective MAO inhibitors. Vortioxetine should be discontinued at least 14 days before starting treatment with irreversible non-selective MAO inhibitors.

Overdose selective MAOA inhibitor (moclobemide). Combination of vortioxetine with a reversible selective MAOA inhibitor, such as moclobemide, is contraindicated. Close monitoring of serotonin syndrome during concomitant use is necessary.

Combination of vortioxetine with a weak reversible and nonselective MAOA inhibitor such as linezolid.The combination of vortioxetine with a weak reversible and nonselective MAOA inhibitor such as linezolid antibiotic is contraindicated. Close monitoring of serotonin syndrome during concomitant use is necessary.

Brain selective MAO-B inhibitors (selegiline, rasagiline). Despite the lower (than with MAO-A inhibitors) expected risk of serotonin syndrome, combining vortioxetine with nonreversible MAO-B inhibitors such as selegiline or rasagiline should be done with caution. Close monitoring of serotonin syndrome during concomitant use is necessary.

Serotonergic drugs.

Simultaneous administration with serotonergic drugs (e.g., tramadol, sumatriptan, and other triptans) may lead to serotonin syndrome.

Wort.

The concomitant use of serotonergic antidepressants and herbal remedies containing St. John’s Wort may increase the frequency of adverse reactions, including serotonin syndrome.

Drugs that decrease seizure threshold.

Serotoninergic antidepressants may decrease seizure threshold.Caution is recommended with concomitant use of other medications that can lower the seizure threshold (like antidepressants (TCAs, SSRIs, SSRIs), neuroleptics (phenothiazines, thioxanthenes, butyrophenones), mefloquine, bupropion and tramadol).

ECT (electroconvulsive therapy).

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

Cytochrome P450 inhibitors.

When administered together with 150 mg bupropion (a strong CYP2D6 inhibitor) twice daily for 14 days in healthy volunteers, the effect of vortioxetine increased 2.3-fold for AUC. Co-administration was more likely to result in an increased incidence of side effects when bupropion was added to vortioxetine than when vortioxetine was added to bupropion. Depending on individual patient sensitivity, low-dose vortioxetine may be considered when strong CYP2D6 inhibitors (e.g., bupropion, quinidine, fluoxetine, paroxetine) are added to therapy.

When vortioxetine was co-administered after 6 days of ketoconazole 400 mg daily (CYP3A4/5 and P-glycoprotein inhibitor) or fluconazole 200 mg daily (CYP2C9, CYP2C19 and CYP3A4/5 inhibitor) in healthy volunteers, 1.3 and 1 , 5-fold increased AUC of vortioxetine were observed respectively. No dose adjustment is required.

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

The combination of potent CYP3A4 and CYP2C9 inhibitors in patients with low CYP2D6 metabolism has not been studied, but increased effects of vortioxetine in such patients should probably be expected.

Cytochrome P450 inducers.

A single administration of 20 mg vortioxetine together after 10 days of administration of 600 mg daily rifampicin (a CYP isoenzyme inducer) in healthy volunteers showed a 72% reduction in the AUC of vortioxetine. Depending on individual patient response, dose adjustment may be required if a cytochrome P450 inducer (e.g., rifampicin, carbamazepine, phenytoin) is added to vortioxetine treatment.

Acetylsalicylic acid.

The effect of repeated administration of 150 mg acetylsalicylic acid daily on the pharmacokinetics of vortioxetine in healthy volunteers was not observed.

The effect of vortioxetine on the effects of other drugs. Anticoagulants and antiaggregants. There were no significant effects on international normalized ratio, prothrombin, or plasma R-/S-warfarin compared to placebo when vortioxetine was coadministered with fixed-dose warfarin in healthy volunteers.

In addition, no significant inhibitory effect on platelet aggregation was observed when coadministering aspirin at a dose of 150 mg daily after vortioxetine in healthy volunteers compared to placebo. However, as with other serotonergic agents, caution should be exercised when using vortioxetine in combination with oral anticoagulants or antiaggregants due to the potential increased risk of bleeding from pharmacodynamic interactions.

Alcohol.

The effects on the pharmacokinetics of vortioxetine or ethanol and no significant impairment of cognitive function compared to placebo after administration of vortioxetine at doses of 20 mg or 40 mg with a simultaneous single administration of 0.6 g/kg ethanol in healthy volunteers were found. However, like other CNS-acting agents, the use of vortioxetine in combination with alcohol is not recommended.

Cytochrome P450 Substrates.

In vitro vortioxetine showed no potential to inhibit or induce cytochrome P450 isoenzymes. Inhibitory effects of vortioxetine on the CYP2C19 (omeprazole, diazepam), CYP3A4/5 (ethinylestradiol, midazolam), CYP2B6 (bupropion), CYP2C9 (tolbutamide, S-warfarin), CYP1A2 (caffeine) or CYP2D6 (dextromethorphan) cytochrome P450 isoenzymes in healthy volunteers were found.

There was no significant impairment of cognitive function compared to placebo after vortioxetine concomitantly with 10 mg diazepam.

There were no significant effects on sex hormone levels compared to placebo after concomitant use of vortioxetine with the combined oral contraceptive (ethinylestradiol 30 µg/levonorgestrel 150 µg).

Lithium, tryptophan.

There have been no clinically significant effects of stable concentrations of lithium after concomitant use with vortioxetine in healthy volunteers. However, there have been reports of enhanced effects when serotonergic antidepressants are used together with lithium or tryptophan, so concomitant use of vortioxetine with these drugs should be used with caution.

Synopsis

Active ingredient: 5 mg or 10 mg vortioxetine in the form of vortioxetine hydrochloride.

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

Contraindications

Hypersensitivity to the active ingredient or any part of the drug.

Simultaneous use with nonselective MAOI inhibitors (MAOIs) or selective MAO-A inhibitors.

Side effects

The most common adverse reaction was nausea. Adverse reactions were usually mild to moderate and were observed within the first two weeks of treatment. The reactions were usually transient and usually did not lead to discontinuation of therapy. Digestive system reactions (e.g., nausea) were more common 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)

unknown (frequency cannot be determined from available data).

Food and metabolic side:

Often: Decreased appetite

Mental side:

Often: Abnormal dreams

Infrequent:Bruxism

Nervous System Side:

Often: Dizziness

Cardiovascular system side:

Infrequent: Blush

Digestive system side:

Very common: Nausea

Often: Diarrhea, constipation, vomiting

Skin and subcutaneous tissue:

Often: Generalized itching

Infrequent: Sweating at night

Overdose

Experience is limited. Taking vortioxetine in a dose range of 40 to 75 mg caused an exacerbation of such side effects:

Nausea

Postural dizziness

Diarrhea

Abdominal discomfort

Generalized itching

Sleepiness and blushing

Treatment should be symptomatic and include appropriate monitoring. Medical follow-up in a specialized setting is recommended.