AVERTID

INSTRUCTIONS for medical use of the drug Quetiapine^®(Kventiax^®)

Composition:

Active substance: quetiapine;

1 film-coated tablet contains 25 mg or 100 mg, or 200 mg, or 300 mg of quetiapine (in the form of quetiapine fumarate);

Excipients: lactose monohydrate, calcium hydrophosphate dihydrate, microcrystalline cellulose, magnesium stearate, povidone, sodium croscarmellose (type A), hypromellose, titanium dioxide (E 171), macrogol 4000, yellow iron oxide (E 172) - contained in 25 mg and 100 mg tablets, red iron oxide (E 172) - contained in 25 mg tablets.

Pharmaceutical form.

Film-coated tablets.

Main physico-chemical properties:

• film-coated tablets of 25 mg: round, pale red, film-coated tablets with a beveled edge;
• film-coated tablets of 100 mg: round, yellow-brown, film-coated tablets;
• film-coated tablets of 200 mg: round, white, film-coated tablets;
• film-coated tablets of 300 mg: white, film-coated tablets in the shape of a capsule.

Pharmacotherapeutic group.

Antipsychotic drugs. Quetiapine.

ATC code N05A H04.

Pharmacological properties.

Pharmacodynamics.

Quetiapine is a derivative of dibenzothiazepine, which has a neuroleptic effect. Quetiapine and its active metabolite N-desalkylquetiapine interact with a number of neurotransmitter receptors. It remains unclear what contribution the N-desalkylated metabolite makes to the pharmacological effect of the drug.

Quetiapine exhibits affinity for serotonin receptors in the brain 5HT2 and 5HT1A (in vitro Ki is 288 and 557 nM, respectively) and dopamine receptors D1 and D2 (in vitro Ki is 558 and 531 nM, respectively). It is believed that this combination of receptor antagonism with relative selectivity of interaction with 5HT2 receptors compared to D2 is the basis for the clinical antipsychotic properties of the drug, as well as the relatively low frequency of development of extrapyramidal symptoms. Quetiapine also exhibits high affinity for histamine receptors H1 (in vitro Ki is 10 nM) and adrenergic receptors alpha 1 (in vitro Ki is 13 nM) with lower affinity for adrenergic receptors alpha 2 (in vitro Ki is 782 nM). Quetiapine does not bind to cholinergic muscarinic and benzodiazepine receptors.

N-desalkylquetiapine, similarly to quetiapine, exhibits affinity for serotonin receptors in the brain 5HT2 and dopamine receptors D1 and D2.

In addition, similar to quetiapine, N-desalkylquetiapine exhibits high affinity for serotonin receptors 5HT1 and histaminergic and adrenergic receptors alpha 1 with lower affinity for adrenergic receptors alpha 2.

Pharmacokinetics.

In the clinically significant dose range, the pharmacokinetics of quetiapine and N-desalkylquetiapine are linear. The kinetics of quetiapine in men and women, smokers and non-smokers, do not differ.

Absorption. Quetiapine is well absorbed in the gastrointestinal tract when taken orally. The bioavailability of quetiapine is practically unchanged when taken with food, while the values of Cmax and AUC increase by 25% and 15%, respectively. The maximum content of the drug in plasma is reached 2 hours after oral administration. The molar concentration of the active metabolite N-desalkylquetiapine in the steady state is 35% of that of quetiapine.

Distribution. The volume of distribution of quetiapine is 10 ± 4 l/kg, and the binding to plasma proteins is 83%.

Elimination and metabolism. The half-life of quetiapine is approximately 6-7 hours when taking the drug in clinically recommended doses. This indicator for N-desalkylquetiapine is approximately 12 hours. On average, the molar fraction of free quetiapine and its active metabolite excreted in the urine is less than 5%.

A study of the drug with radioactive isotopes showed that approximately 73% is excreted in the urine and 21% in the feces within one week.

Quetiapine is intensively metabolized in the liver, and the fraction of the original compound in the urine and feces within a week after taking the labeled quetiapine is less than 5% of the dose. Given the intensive metabolism of quetiapine in the liver, it should be expected that in patients with impaired liver function, the content of the drug in the plasma will be higher, so dose adjustment may be necessary.

The main reactions of quetiapine metabolism involve the oxidation of the side alkyl chain, hydroxylation of the dibenzothiazepine ring, sulfoxidation, and conjugation (phase 2). The main metabolites of quetiapine in human plasma are oxidation and sulfoxidation products, none of which have pharmacological activity.

The main enzyme of the cytochrome P450 system responsible for the metabolism of quetiapine is P450 3A4. The formation of N-desalkylated metabolite and the elimination of quetiapine occur mainly under the influence of this enzyme.

In vitro studies have shown that quetiapine and some of its metabolites (including N-desalkylquetiapine) are weak inhibitors of cytochrome P450 enzymes 1A2, 2C9, 2C19, 2D6, and 3A4. However, such inhibition in vitro is observed only at concentrations that are 5-50 times higher than the concentrations in the human body when taking the drug in doses of 300-800 mg/day.

Clinical characteristics.

Indications.

• Treatment of schizophrenia.
• Treatment of bipolar disorder, in particular:
• treatment of moderate and severe manic episodes in bipolar disorder;
• treatment of severe depressive episodes in bipolar disorder;
• prevention of relapse of the disease in patients with bipolar disorder, in patients with manic or depressive episodes, in which treatment with quetiapine is effective.

Contraindications.

Increased sensitivity to the active substance or to any component of the drug.

Contraindicated in combination with cytochrome P450 3A4 inhibitors, such as HIV protease inhibitors, azole antifungal agents, erythromycin, clarithromycin, and nefazodone.

Interaction with other medicinal products and other interactions.

Given that quetiapine primarily acts on the central nervous system, Kventiax^®should be used with caution in combination with other drugs that have a similar effect, as well as with alcohol.

Care should be taken when administering the drug to patients who are taking drugs with anticholinergic (muscarinic) effects (see "Special instructions").

Cytochrome P450 (CYP) 3A4 is the enzyme that is primarily responsible for the metabolism of quetiapine. During a study of the interaction in healthy volunteers, the simultaneous administration of quetiapine (25 mg) with ketoconazole (a CYP 3A4 inhibitor) caused an increase in the AUC of quetiapine by 5-8 times. Therefore, the simultaneous administration of quetiapine with CYP 3A4 inhibitors is contraindicated. It is also not recommended to consume grapefruit juice during the treatment with quetiapine.

During a study of multiple-dose administration with the aim of evaluating the pharmacokinetics of quetiapine, which was prescribed before and during treatment with carbamazepine (an inducer of liver enzymes), the simultaneous administration of carbamazepine significantly increased the clearance of quetiapine. This increase in clearance reduced the systemic exposure to quetiapine (measured by the AUC) to a level that was, on average, 13% of the exposure when quetiapine was administered alone, although in some patients, a greater effect was observed. As a result of this interaction, lower plasma concentrations may occur, which may affect the effectiveness of therapy with Kventiax^®.

The simultaneous administration of quetiapine and phenytoin (another inducer of microsomal enzymes) caused an increase in the clearance of quetiapine by approximately 450%. It is possible to start therapy with Kventiax^®in patients who are taking an inducer of liver enzymes only if the doctor believes that the benefit of using Kventiax^®outweighs the risks associated with the withdrawal of the inducer of liver enzymes. It is important that any changes in the administration of the inducer occur gradually. If necessary, it should be replaced with a non-inducer (e.g., sodium valproate) (see "Special instructions").

The pharmacokinetics of quetiapine is not significantly altered when co-administered with such antidepressants as imipramine (a known inhibitor of CYP 2D6) or fluoxetine (a known inhibitor of CYP 3A4 and CYP 2D6).

The simultaneous administration of such antipsychotics as risperidone or haloperidol did not cause significant changes in the pharmacokinetics of quetiapine. The simultaneous administration of quetiapine and thioridazine caused an increase in the clearance of quetiapine by approximately 70%.

When co-administered with cimetidine, the pharmacokinetics of quetiapine did not change.

The pharmacokinetics of lithium did not change when co-administered with quetiapine.

In a randomized study lasting 6 weeks, comparing the combination of lithium with Kventiax^®and placebo, and Kventiax^®in adult patients suffering from acute mania, an increase in the frequency of extrapyramidal phenomena (especially tremors), drowsiness, and weight gain was observed in the group with the addition of lithium compared to the group with the addition of placebo (see "Pharmacological properties").

In the pharmacokinetics of sodium valproate and quetiapine, no clinically significant changes were observed when they were co-administered. In a retrospective study involving children and adolescents who received sodium valproate, quetiapine, or a combination of these drugs, an increase in the number of cases of leukopenia and neutropenia was observed in the group that took both drugs compared to the groups that received these medications separately.

No studies on the interaction with cardiovascular drugs have been conducted.

Care should be taken when co-administering quetiapine with drugs that disrupt electrolyte balance or prolong the QT interval.

In patients who have taken quetiapine, there have been cases of false-positive results of enzyme immunoassay for the presence of methadone and tricyclic antidepressants. It is recommended to verify suspicious results of screening immunoassay using an appropriate chromatographic method.

Quetiapine should be used with caution in combination with serotonergic drugs, such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, as there is a risk of developing serotonin syndrome, a potentially life-threatening condition (see "Special instructions").

Special instructions.

Since Kventiax^®is indicated for the treatment of schizophrenia, bipolar disorder, and concomitant treatment of depressive episodes in patients with severe depressive disorders (SDD), the safety profile of the drug should be carefully considered in relation to the specific diagnosis and dose that the patient is taking.

The long-term efficacy and safety of concomitant therapy for patients with SDD have not been evaluated, but the long-term efficacy and safety of monotherapy with the drug have been studied in adult patients.

Children.

Kventiax^®is not recommended for use in children due to the lack of data supporting its use in this age group. Clinical studies of quetiapine have shown that, in addition to the known safety profile established for adults, the frequency of some adverse events is higher in children than in adults (increased appetite, increased prolactin levels in serum, vomiting, rhinitis, and syncope), or may have different consequences for children and adolescents (extrapyramidal symptoms and irritability), and one event that was not previously observed in adult patient studies (increased blood pressure) has been detected. In addition, changes in thyroid function tests have been observed in children and adolescents.

The delayed effect of treatment with Kventiax^®on growth and sexual maturation has not been studied for a period of more than 26 weeks. The long-term effect on cognitive and behavioral development is unknown.

During placebo-controlled clinical trials of Kventiax^®in pediatric and adolescent patients, treatment with quetiapine was associated with an increased frequency of extrapyramidal symptoms (EPS) in patients being treated for schizophrenia, bipolar mania, and depression (see "Adverse reactions").

Suicidal/suicidal thoughts or clinical worsening.

Depression in bipolar disorder is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicide-related events). This risk persists until significant improvement is achieved. Since improvement may not be observed during the first weeks of treatment or longer, patients should be closely monitored until such improvement is observed. According to general clinical experience, the risk of suicide may increase during the early stages of improvement.

In addition, it is necessary to consider the potential risk of suicidal-related events after abrupt discontinuation of quetiapine treatment.

Other mental disorders for which Kventiax^®should be prescribed may also be associated with an increased risk of suicidal-related events. Moreover, these disorders may occur simultaneously with depressive episodes.

When treating patients with other mental disorders, the same precautions should be taken as when treating patients with severe depressive episodes.

Patients who have a history of suicidal-related events or who demonstrate a high level of suicidal thinking before starting therapy have a higher risk of developing suicidal thoughts or attempting suicide and should be under close supervision 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 in patients under the age of 25.

Close monitoring of patients, particularly those at high risk, should be accompanied by medication therapy, especially at the beginning of treatment and during subsequent dose changes. Patients (and their caregivers) should be informed about the need to monitor for clinical worsening, suicidal behavior, or unusual changes in behavior and to seek medical help immediately if symptoms appear.

In short-term placebo-controlled trials in patients with severe depressive episodes in bipolar disorders, an increased risk of suicidal-related events was observed in young patients (under the age of 25) who were treated with quetiapine compared to those treated with placebo (3.0% versus 0%, respectively). In clinical trials involving patients with SDD, the frequency of suicidal-related events in young patients (under the age of 25) was 2.1% (3/144) in the quetiapine group and 1.3% (1/75) in the placebo group. A population-based retrospective study of quetiapine use in patients with major depressive disorder (MDD) showed an increased risk of self-harm and suicide in patients aged 25-64 years without a history of self-harm when quetiapine was co-administered with other antidepressants.

Somnolence and dizziness.

Treatment with quetiapine is associated with somnolence and similar symptoms, such as sedation (see "Adverse reactions"). During clinical trials, treatment of patients with bipolar depression, such symptoms occurred, as a rule, within the first 3 days of treatment and were predominantly mild to moderate in intensity. Patients with bipolar depression and patients with depressive episodes in SDD who experience somnolence may require monitoring for 2 weeks after the onset of somnolence or until symptoms resolve, or discontinuation of treatment.

Orthostatic hypotension.

Treatment with quetiapine was accompanied by orthostatic hypotension and associated dizziness (see "Adverse reactions"), which, like somnolence, usually occur during the period of dose titration. These phenomena may contribute to an increased frequency of accidental injuries (falls), especially among elderly patients. Therefore, patients should be advised to be careful while they are getting used to the possible effects of the drug.

Cardiovascular diseases.

Kventiax^®should be used with caution in patients with cardiovascular and cerebrovascular diseases or other conditions that may lead to arterial hypotension. Quetiapine may cause orthostatic hypotension, especially at the beginning of dose titration, so in such cases, dose reduction or longer titration may be necessary.

Sleep apnea syndrome.

There have been reports of sleep apnea syndrome in patients taking quetiapine. Patients should be treated with caution with quetiapine who are taking central nervous system depressants and who have a history of or are at risk of developing sleep apnea. This includes patients who are overweight/obese or male patients.

Seizures.

During controlled clinical trials, there was no difference in the frequency of seizures in patients taking quetiapine and patients in the placebo group. As with the treatment of other antipsychotic drugs, it is recommended to prescribe the drug with caution to patients with a history of seizures (see "Adverse reactions").

Extrapyramidal symptoms.

During placebo-controlled studies, quetiapine was associated with an increased frequency of extrapyramidal symptoms (EPS) compared to placebo in patients receiving treatment for episodes of major depression associated with bipolar disorder and severe depressive disorder.

The use of quetiapine was associated with the development of akathisia, which was characterized by subjective unpleasant or distressing restlessness and a need to move, often accompanied by an inability to sit or stand still. These phenomena are more likely to occur during the first few weeks of treatment. Increasing the dose in patients who develop such symptoms may harm them.

Tardive dyskinesia.

If symptoms of tardive dyskinesia appear, it is necessary to consider the need to reduce the dose or discontinue the use of Kventiax^®. Symptoms of tardive dyskinesia may worsen and even occur after discontinuation of therapy (see "Adverse reactions").

Malignant neuroleptic syndrome.

Malignant neuroleptic syndrome may be associated with the treatment of antipsychotics, including quetiapine. Clinical manifestations include hyperthermia, changes in mental status, muscle rigidity, vegetative instability, and increased creatine phosphokinase levels. In such a case, the use of Kventiax^®should be discontinued, and appropriate treatment should be initiated.

Severe neutropenia and agranulocytosis.

Severe neutropenia (neutrophil count <0.5 × 10⁹/L) was observed in clinical trials of quetiapine. Most cases of severe neutropenia occurred within two months of starting treatment with quetiapine. No clear relationship with dose was established. During the post-marketing period, some cases were fatal. Possible risk factors for neutropenia include pre-existing decreased white blood cell count and drug-induced neutropenia in history. There have been cases of agranulocytosis in patients without pre-existing risk factors. The possibility of neutropenia should be considered in patients with infection, especially in the absence of obvious favorable factors, as well as in patients with fever of unknown origin, and appropriate clinical measures should be taken.

It is necessary to advise patients to immediately report signs/symptoms indicating agranulocytosis or infection (such as fever, weakness, fatigue, or sore throat) at any time during treatment with Kventiax^®SR. Such patients should have a white blood cell count and absolute neutrophil count (ANC) performed promptly, especially in the absence of favorable factors.

Treatment with quetiapine should be discontinued if the neutrophil count in the blood is <1.0 × 10⁹/L. Patients should be monitored for signs of infection and changes in neutrophil levels (until the level exceeds 1.5 × 10⁹/L) (see "Pharmacodynamic properties").

Anticholinergic (muscarinic) effects.

Norquetiapine, an active metabolite of quetiapine, has moderate or high affinity for several subtypes of muscarinic receptors. This contributes to the occurrence of side effects that reflect anticholinergic effects when quetiapine is used in recommended doses and other drugs with anticholinergic effects in case of overdose. Quetiapine should be used with caution in patients who are taking drugs with anticholinergic (muscarinic) effects.

Quetiapine should be used with caution in patients with a current diagnosis or history of urinary retention, clinically significant prostatic hyperplasia, intestinal obstruction, or related conditions, increased intraocular pressure, or closed-angle glaucoma (see "Pharmacodynamics", "Interaction with other medicinal products and other interactions", "Overdose", and "Adverse reactions").

Interactions.

See also "Interaction with other medicinal products and other interactions".

The simultaneous administration of quetiapine with a potent inducer of liver enzymes, such as carbamazepine or phenytoin, significantly reduces the plasma concentration of quetiapine, which may harm the effectiveness of quetiapine therapy. Treatment with Kventiax^®in patients who are taking an inducer of liver enzymes can only be started if the doctor believes that the benefit of using Kventiax^®outweighs the risks associated with the withdrawal of the inducer of liver enzymes. It is important that any changes in the administration of the inducer occur gradually. If necessary, it should be replaced with a non-inducer (e.g., sodium valproate).

Effect on body weight.

Weight gain has been reported in patients treated with quetiapine, which should be monitored and adjusted according to clinical judgment and in accordance with recommendations for the use of antipsychotic drugs (see "Pharmacodynamics" and "Adverse reactions").

Hyperglycemia.

The development of hyperglycemia or exacerbation of diabetes mellitus has sometimes been associated with quetiapine, occasionally with ketoacidosis or coma, which has rarely been fatal, including several cases with a lethal outcome (see "Adverse reactions"). In several cases, patients had increased body weight, which may be a risk factor. Appropriate clinical monitoring should be performed in accordance with existing guidelines for the use of antipsychotic drugs. Patients who are treated with any antipsychotic drugs, including quetiapine, need to be monitored for the occurrence of symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes or risk factors for diabetes should be regularly checked for worsening glucose control. Body weight should be constantly monitored.

Lipids.

Increases in triglyceride levels, low-density lipoproteins (LDL), and total cholesterol, as well as decreases in high-density lipoprotein (HDL) cholesterol, have been observed in clinical trials of quetiapine (see "Adverse reactions"). Appropriate treatment should be prescribed when changing lipid levels.

Metabolic risk.

Given the changes in body weight, blood glucose levels (see hyperglycemia), and lipid levels observed during clinical trials, it is necessary to evaluate the patient's metabolic parameters at the beginning of treatment, and changes in these parameters should be regularly monitored during the course of treatment. Deterioration of these parameters should be adjusted according to clinical judgment (see "Adverse reactions").

Prolongation of the QT interval.

During clinical trials and post-marketing use of quetiapine, quetiapine did not cause a persistent increase in absolute QT intervals. In the post-marketing period, prolongation of the QT interval has been observed with quetiapine at therapeutic doses (see "Adverse reactions") and with overdose (see "Overdose"). As with the use of other antipsychotics, caution should be exercised when prescribing quetiapine to patients with cardiovascular diseases or patients with a prolonged QT interval in their family history. Also, caution should be exercised when prescribing quetiapine with other drugs that are known to prolong the QT interval or with neuroleptics, especially in elderly patients, patients with congenital prolongation of the QT interval, congestive heart failure, hypertrophy of the heart, hypokalemia, or hypomagnesemia (see "Interaction with other medicinal products and other interactions").

Severe skin reactions.

It is known that during treatment with quetiapine, very rare cases of severe skin reactions (SCAR) have been reported, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), multifocal fixed drug eruption, and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal.

Severe skin reactions are accompanied by one or more symptoms: widespread skin rash, which may be accompanied by itching or pustules, exfoliative dermatitis, fever, lymphadenopathy, and possible eosinophilia or neutrophilia. Most of these reactions occurred within 4 weeks of starting treatment with quetiapine, and some DRESS reactions occurred within 6 weeks of starting quetiapine therapy. If signs and symptoms of these severe skin reactions appear, quetiapine should be discontinued immediately, and alternative treatment methods should be considered.

Discontinuation of the drug.

Acute withdrawal symptoms, such as insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability, have been described after the sudden discontinuation of quetiapine. Therefore, it is recommended to gradually discontinue the drug over a period of at least 1 to 2 weeks (see "Adverse reactions").

Elderly patients with psychosis associated with dementia.

Kventiax^®is not recommended for the treatment of psychosis associated with dementia.

In randomized, placebo-controlled trials in patients with dementia, the use of some atypical antipsychotics has been associated with an approximately 3-fold increased risk of cerebrovascular adverse events. The mechanism of such an increased risk is unknown. The increased risk cannot be excluded in the case of the use of other antipsychotics or for other categories of patients. Kventiax^®should be used with caution in patients with risk factors for stroke.

According to a meta-analysis of atypical antipsychotics, elderly patients who suffer from psychosis associated with dementia are at increased risk of mortality compared to placebo. In two 10-week, placebo-controlled trials in one group of patients (n = 710; mean age 83 years; range 56-99 years), mortality among patients treated with quetiapine was 5.5% compared to 3.2% in the placebo group. Mortality during the trials was due to various causes, which were expected for this group of patients.

Elderly patients with Parkinson's disease (PD)/parkinsonism.

A population-based retrospective study of quetiapine use in patients with major depressive disorder (MDD) showed an increased risk of mortality during the use of quetiapine in patients over 65 years of age. These data were not confirmed when the data of patients with Parkinson's disease were not taken into account in the analysis. Caution should be exercised when prescribing quetiapine to elderly patients with PD.

Dysphagia.

Dysphagia has been reported with the use of quetiapine. Caution should be exercised when using quetiapine in patients who are at risk of aspiration pneumonia.

Constipation and intestinal obstruction.

Constipation is a risk factor for the development of intestinal obstruction. With the use of quetiapine, cases of constipation and intestinal obstruction (see "Adverse reactions") have been registered, including fatal cases in patients who had a higher risk of developing intestinal obstruction, including those who were taking several medications that reduce intestinal peristalsis and/or medications that may not have been reported to cause constipation. Treatment of patients with intestinal obstruction/ileus should be carried out under close supervision and with emergency medical care.

Venous thromboembolism.

Cases of venous thromboembolism (VTE) have been reported with the use of neuroleptic drugs. Since patients who use neuroleptics often have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during quetiapine therapy, and preventive measures should be taken.

Pancreatitis.

There have been reports of pancreatitis during clinical trials and post-marketing use of quetiapine, but a causal relationship has not been established. In post-marketing reports, many patients had risk factors for pancreatitis, such as increased triglyceride levels (see "Special instructions. Lipids"), gallstones, and alcohol consumption.

Cardiomyopathy and myocarditis.

During clinical trials and the post-marketing period, cardiomyopathy and myocarditis have been reported, but a causal relationship with quetiapine has not been established. The feasibility of using quetiapine in patients with suspected cardiomyopathy or myocarditis should be reassessed.

Serotonin syndrome.

The simultaneous use of Kventiax^®and other serotonergic agents, such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, may lead to serotonin syndrome, a potentially life-threatening condition (see "Interaction with other medicinal products and other interactions").

If concomitant therapy with other serotonergic agents is clinically justified, careful monitoring of the patient is recommended, especially at the beginning of treatment and during dose increases. Symptoms of serotonin syndrome may include changes in mental status, vegetative instability, neuromuscular disorders, and/or gastrointestinal symptoms.

If there is a suspicion of serotonin syndrome, it is necessary to consider the possibility of reducing the dose or discontinuing therapy, depending on the severity of the symptoms.

Additional information.

Data on the use of quetiapine in combination with divalproex or lithium for manic episodes of moderate or severe degree are limited, but combination therapy has been well tolerated (see "Adverse reactions" and "Pharmacological properties"). An additive effect was observed on the third week of treatment.

Abuse and dependence.

There have been reports of abuse and dependence on the drug. Caution should be exercised when prescribing quetiapine to patients with a history of alcohol or drug abuse.

Lactose.

Kventiax^®tablets contain lactose. Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy.

First trimester.

A moderate amount of published data on pregnancy exposure (i.e., from 300 to 1000 pregnancy outcomes), including individual reports and some observational studies, does not indicate an increased risk of developmental anomalies due to treatment with quetiapine. However, based on all available data, a definitive conclusion cannot be drawn. Animal studies have shown reproductive toxicity. Therefore, quetiapine can be used during pregnancy only if the benefit justifies the potential risk.

Third trimester.

The use of antipsychotic drugs (including quetiapine) during the third trimester of pregnancy may lead to the occurrence of adverse reactions in newborns, including extrapyramidal disorders and/or withdrawal syndrome, which may vary in severity and duration after birth. There have been reports of agitation, hypertension, hypotension, tremor, somnolence, respiratory distress syndrome, and feeding disorders. Therefore, newborns whose mothers were treated with quetiapine during the third trimester of pregnancy should be under close supervision.

Breastfeeding.

Based on very limited data from published reports on the excretion of quetiapine in human breast milk, the excretion of quetiapine at therapeutic doses is undetermined. Given the lack of reliable data, it is necessary to make a decision to stop breastfeeding or discontinue quetiapine therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility.

The effect of quetiapine on human fertility has not been evaluated. It is known that in a study on rats, effects related to increased prolactin levels were observed, although they are not directly relevant to humans.

Ability to affect reaction speed when driving vehicles or operating other mechanisms.

Given that quetiapine primarily acts on the central nervous system, patients should not drive a car or operate other mechanisms until it is determined how they individually react to the influence of the drug.

Method of administration and dosage.

For each indication, different dosing regimens are prescribed. It should be ensured that the dose prescribed to the patient corresponds to their condition.

Treatment of schizophrenia.

Kventiax^®should be administered twice a day. The daily dose in the first four days is: 50 mg (first day), 100 mg (second day), 200 mg (third day), and 300 mg (fourth day). After 4 days of treatment, the dose should be titrated to the usual effective dose of 300-450 mg/day. Depending on the clinical response and tolerability, the dose can be adjusted within the range of 150 mg to 750 mg per day.

Treatment of manic episodes from moderate to severe degree in bipolar disorder.

Kventiax^®should be administered twice a day. The daily dose in the first four days of treatment is: day 1 - 100 mg, day 2 - 200 mg, day 3 - 300 mg, day 4 - 400 mg. The dose can be increased (but not more than 200 mg per day) to 800 mg/day by the 6th day of treatment.

Depending on the clinical efficacy and tolerability, the dose can be adjusted within the range of 200 mg to 800 mg per day. The usual effective dose is within the range of 400-800 mg/day.

Treatment of depressive episodes in bipolar disorder.

Kventiax^®should be administered once before bedtime. The total daily dose for the first four days of treatment is: 50 mg (first day), 100 mg (second day), 200 mg (third day), and 300 mg (fourth day). The recommended daily dose is 300 mg. In clinical trials, no additional benefit was observed in the group with a dose of 600 mg compared to the group with a dose of 300 mg (see "Pharmacological properties"). A dose of 600 mg may be effective for individual patients. Doses above 300 mg should be prescribed by a doctor with experience in treating bipolar disorder. Clinical trials have shown that for individual patients with poor tolerability of the drug, it is necessary to consider the feasibility of reducing the dose to the minimum - 200 mg.

Prevention of relapse in bipolar disorder.

For the prevention of subsequent manic, mixed, or depressive episodes in bipolar disorder, patients who responded to Kventiax^®SR in the acute treatment of bipolar disorder should continue treatment with Kventiax^®at the same dose prescribed before bedtime. The dose of Kventiax^®can be adjusted within the range of doses from 300 mg to 800 mg/day, depending on the clinical response and tolerability of each individual patient. It is important that the lowest effective doses be used for maintenance therapy.

Elderly patients.

As with other antipsychotics and antidepressants, Kventiax^®should be used with caution in elderly patients, especially at the beginning of treatment and during dose titration. A more gradual titration of the dose of Kventiax^®may be necessary, and the daily therapeutic dose may be lower than that used in younger patients. The average plasma clearance of quetiapine was decreased by 30-50% in elderly patients compared to younger patients.

The safety and efficacy of Kventiax^®in patients over 65 years of age with depressive episodes in bipolar disorder have not been studied.

Renal impairment.

There is no need to adjust the dose for patients with impaired renal function.

Hepatic impairment.

Quetiapine is actively metabolized in the liver. Therefore, Kventiax^®should be used with caution in patients with impaired liver function, especially during the initial period of dose titration. Treatment of patients with impaired liver function should be started with a dose of 25 mg/day. The dose can be increased in increments of 25-50 mg/day to achieve an effective dose, depending on the clinical response and tolerability of each individual patient.

Children.

The safety and efficacy of quetiapine for the treatment of children have not been studied; therefore, the drug should not be used in children and adolescents (under 18 years of age) (see "Special instructions").

Overdose.

Symptoms.

Manifestations and symptoms of overdose were a consequence of the enhancement of the known pharmacological effects of the drug, such as somnolence and sedation, tachycardia, hypotension, and anticholinergic effects.

Overdose may lead to prolongation of the QT interval, seizures, epileptic status, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium, and/or agitation, coma, and a fatal outcome.

Patients with existing severe cardiovascular disease may have an increased risk of overdose effects (see "Special instructions").

Treatment.

There is no specific antidote. In cases of significant poisoning, intensive symptomatic medical therapy should be performed, and the patency of the airways, adequate ventilation, and oxygenation should be restored and monitored.

According to available literature, patients with delirium, agitation, and obvious anticholinergic syndrome can be treated with physostigmine (1-2 mg) under continuous ECG monitoring. However, this treatment is not recommended as a standard due to the negative effects of physostigmine on cardiac conduction. Physostigmine can only be used when there are no aberrations on the ECG. It is not possible to use physostigmine in the presence of arrhythmia, blockage of the heart of any degree, or widening of the QRS complex.

Although the prevention of absorption in case of overdose has not been studied, in the event of a severe overdose, gastric lavage may be possible, but no later than 1 hour after taking the drug, and the use of activated charcoal.

In the event of an overdose of quetiapine and persistent hypotension, appropriate measures should be taken, such as intravenous fluid administration and/or sympathomimetics.

It is necessary to avoid the use of adrenaline and dopamine, as beta-stimulation may worsen the condition in the presence of hypotension due to alpha-blockade caused by quetiapine.

Close medical monitoring of the patient's condition should continue until full recovery.

Adverse reactions.

When taking quetiapine, the most common adverse reactions reported were somnolence, dizziness, dry mouth, headache, withdrawal symptoms (discontinuation of the drug), increased triglyceride levels in serum, increased total cholesterol (especially LDL cholesterol), decreased HDL cholesterol, weight gain, decreased hemoglobin level, and extrapyramidal symptoms.

As with the use of other antipsychotic drugs, the use of quetiapine was associated with weight gain, syncope, malignant neuroleptic syndrome, leukopenia, and peripheral edema.

The frequency of adverse reactions during treatment with quetiapine is presented below in the following classification: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), and unknown frequency (cannot be estimated based on available data).