Quetiapine pills 200mg №60

Trade name:

Quetiapine

International Nonproprietary Name (INN):

quetiapine

Dosage form

film coated tablets

Composition

One tablet, film coated, contains:

Dosage 25 mg

active substance: Quetiapine fumarate (quetiapine hemifumarate) in terms of quetiapine - 25,000 mg;

Excipients: microcrystalline cellulose - 8.718 mg, lactose monohydrate - 4.500 mg, sodium carboxymethyl starch (sodium starch glycolate, type A) - 3.500 mg, povidone K-30 - 2,000 mg, talc - 1.250 mg, silicon dioxide, colloidal - 0.750 mg, Magnesium stearate - 0.500 mg;

film cover: [hypromellose - 0.900 mg, talc - 0.300 mg, titanium dioxide - 0.165 mg, macrogol 4000 (polyethylene glycol 4000) - 0.135 mg] or [dry mixture for film coating containing hypromellose (60%), talc (20%), titanium dioxide (11%), macrogol 4000 (polyethylene glycol 4000) (9%)] - 1,500 mg.

Dosage 100 mg

active substance: quetiapine fumarate (quetiapine hemifumarate) in terms of quetiapine - 100,000 mg;

Excipients: microcrystalline cellulose - 34.870 mg, lactose monohydrate - 18,000 mg, sodium carboxymethyl starch (sodium starch glycolate, type A) - 14,000 mg, povidone K-30 - 8,000 mg, talc - 5,000 mg, silicon dioxide, colloidal - 3,000 mg, magnesium stearate - 2,000 mg;

film cover: [hypromellose - 3,600 mg, talc - 1,200 mg, titanium dioxide - 0.660 mg,macrogol 4000 (polyethylene glycol 4000) - 0.540 mg] or [dry mixture for film coating containing hypromellose (60%), talc (20%), titanium dioxide (11%), macrogol 4000 (polyethylene glycol 4000) (9%)] - 6,000 mg.

Dosage 200 mg

active substance: quetiapine fumarate (quetiapine hemifumarate) in terms of quetiapine - 200,000 mg;

Excipients: microcrystalline cellulose - 69.740 mg, lactose monohydrate - 36,000 mg, sodium carboxymethyl starch (sodium starch glycolate, type A) - 28,000 mg, povidone K-30 - 16,000 mg, talc - 10,000 mg, silicon dioxide, colloidal - 6,000 mg, magnesium stearate - 4,000 mg;

film cover: [hypromellose - 7,200 mg, talc - 2,400 mg, titanium dioxide - 1,320 mg, macrogol 4000 (polyethylene glycol 4000) - 1,080 mg] or [dry mixture for film coating containing hypromellose (60%), talc (20%), titanium dioxide (11%), macrogol 4000 (polyethylene glycol 4000) (9%)] - 12,000 mg.

Dosage 300 mg

active substance: quetiapine fumarate (quetiapine hemifumarate) in terms of quetiapine - 300,000 mg;

Excipients: microcrystalline cellulose - 104.610 mg, lactose monohydrate - 54,000 mg, sodium carboxymethyl starch (sodium starch glycolate, type A) - 42,000 mg, povidone K-30 - 24,000 mg, talc - 15,000 mg, silicon dioxide, colloidal - 9,000 mg, magnesium stearate - 6,000 mg;

film cover: [hypromellose - 10,800 mg, talc - 3,600 mg, titanium dioxide - 1.980 mg, macrogol 4000 (polyethylene glycol 4000) - 1,620 mg] or [dry mix for film coating containing hypromellose (60%), talc (20%), titanium dioxide (11%), macrogol 4000 (polyethylene glycol 4000) (9%)] - 18,000 mg.

Description

Round biconvex tablets, film-coated white or almost white.In cross section, the core is white or almost white.

Pharmacotherapeutic group

Antipsychotic (neuroleptic)

Pharmacological properties

Pharmacodynamics

Mechanism of action

Quetiapine is an atypical antipsychotic drug. Quetiapine and its active metabolite N-dezalkilkvetiapin (norkvetiapin) interact with a wide range of brain neutrotransmitter receptors. Quetiapine and N-desalkylcvetiapine exhibit high affinity for 5HT₂serotonin, D₁- and D₂- dopamine receptors in the brain. Antagonism of these receptors in combination with higher selectivity for 5HT₂serotonin receptors than k D₂- dopamine receptors, causes clinical antipsychotic properties of quetiapine and a low incidence of extrapyramidal side effects. Quetiapine has no affinity for the norepinephrine transporter and has a low affinity for 5HT_1A-serotonin receptors, while N-dezalkilkvetiapin exhibits high affinity for both. Inhibition of the vector of norepinephrine and partial agonism against 5HT_1A-serotonin receptors, manifested by N-dezalklkvetiapinom, can cause the antidepressant effect of the drug. Quetiapine and N-desalkylcvetiapine have a high affinity for histamine and a₁-adrenoreceptors and moderate affinity for a₂-adrenorenoretseptoryam. In addition, quetiapine does not have or has low affinity for muscarinic receptors, while N-dezalkilkvetiapin shows moderate or high affinity for several subtypes of muscarinic receptors.

In standard tests, quetiapine exhibits antipsychotic activity.

The specific contribution of the metabolite N-dezalkilkvetiapina in the pharmacological activity of quetiapine is not installed.

The results of the study of extrapyramidal symptoms (EPS) in animals revealed that quetiapine causes weak catalepsy in doses that effectively block D₂dopamine receptors. Quetiapine causes a selective decrease in the activity of mesolimbic A10 dopaminergic neurons in comparison with A9 nigrostriatal neurons involved in motor function.

Efficiency

Quetiapine is effective against both positive and negative symptoms of schizophrenia.

Quetiapine is effective as monotherapy in manic episodes of moderate to severe severity. Data on the long-term use of quetiapine for the prevention of subsequent manic and depressive episodes are not available. Data on the use of quetiapine in combination with valproate seminatrii or lithium preparations for manic episodes of moderate to severe severity are limited, but this combination therapy was generally well tolerated. In addition, quetiapine at a dose of 300 mg and 600 mg is effective in patients with bipolar I and II disorders from moderate to severe severity. At the same time, the effectiveness of quetiapine at a dose of 300 mg and 600 mg per day is comparable.

Quetiapine is effective in patients with schizophrenia and mania when taking the drug 2 times a day, despite the fact that the half-life of quetiapine is about 7 hours. Effect of Quetiapine on 5HT₂- and D₂-receptors last up to 12 hours after taking the drug.

When quetiapine was administered with dose titration in schizophrenia, the frequency of EPS and the concomitant use of m-anticholinergic blockers were comparable to those taken with placebo. When prescribing quetiapine in fixed doses from 75 to 750 mg / day for patients with schizophrenia, the incidence of EPS and the need for concomitant use
m-holinoblokatorov not increased.

When quetiapine was used in doses up to 800 mg / day to treat manic episodes of moderate to severe severity, both in monotherapy and in combination with lithium or valproate, the frequency of EPS and the concomitant use of m-anticholinergic blockers were comparable to placebo

Pharmacokinetics

When administered orally, quetiapine is well absorbed from the gastrointestinal tract and is actively metabolized in the liver.

Eating does not significantly affect the bioavailability of quetiapine. Approximately 83% of quetiapine is bound to plasma proteins.

The equilibrium molar concentration of the active metabolite of N-dezalkilkvetiapina is 35% of that of quetiapine. The half-life of quetiapine and N-dezalkilkvetiapina is about 7 and 12 hours, respectively. Pharmacokinetics of quetiapine and
N-dezalkilkvetiapina linear, pharmacokinetic differences in men and women is not observed.

The average clearance of quetiapine in elderly patients is 30-50% less than in patients aged 18 to 65 years.

The average plasma clearance of quetiapine is reduced by approximately 25% in patients with severe renal insufficiency (creatinine clearance less than 30 ml / min / 1.73 m²). In patients with hepatic insufficiency (compensated alcoholic cirrhosis), the average plasma clearance of quetiapine is reduced by approximately 25%. Since quetiapine is extensively metabolized in the liver, elevated plasma concentrations of quetiapine are possible in patients with hepatic insufficiency, which requires a dose adjustment.

On average, less than 5% of the molar dose of the fraction of free quetiapine and plasma N-dezalkilkvetiapina excreted by the kidneys. Approximately 73% of quetiapine is excreted by the kidneys and 21% through the intestines. Less than 5% of quetiapine is not metabolized and is excreted unchanged by the kidneys or through the intestines.

It has been established that CYP3A4 is a key isoenzyme of quetiapine metabolism mediated by cytochrome P450. N-dezalkilkvetiapin is formed with participation of an isoenzyme CYP3A4.

Quetiapine and some of its metabolites (including N-dezalkilkvetiapin) have a weak inhibitory activity against cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6 and 3A4, but only at a concentration 5-50 times higher than the concentration observed at the commonly used effective dosage 300-800 mg / day

Based on in vitro results, it should not be expected that the simultaneous administration of quetiapine with other drugs will result in clinically pronounced inhibition of the metabolism of other drugs mediated by cytochrome P450.

Indications for use

For treatment:

- schizophrenia;

- manic episodes in the structure of bipolar disorder;

- depressive episodes of moderate to severe severity in the structure of bipolar disorder.

The drug is not indicated for the prevention of manic and depressive episodes.

Contraindications

- hypersensitivity to any of the components of the drug, including lactase deficiency, glucose-galactose malabsorption and intolerance to galactose;

- combined use with cytochrome P450 inhibitors, such as antifungals of the azoles group, Erythromycin , Clarithromycin and nefazodone, as well as HIV protease inhibitors (see the section "Interaction with other drugs");

- age up to 18 years.

Carefully

- in patients with cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension;

- elderly age;

- liver failure;

- convulsive seizures in history;

- The risk of stroke;

- risk of developing aspiration pneumonia.

Use during pregnancy and during breastfeeding

The safety and effectiveness of quetiapine in pregnant women have not been established. Therefore, during pregnancy, quetiapine can be used only if the expected benefit to the woman justifies the potential risk to the fetus.

When using antipsychotic drugs, including quetiapine, in the third trimester of pregnancy, newborns are at risk of developing adverse reactions of varying severity and duration, including EPS and / or "withdrawal" syndrome.Arousal, hypertension, hypotension, tremor, drowsiness, respiratory distress syndrome, or feeding disorders have been reported. In this regard, it is necessary to carefully monitor the condition of newborns.

Reports of the excretion of quetiapine with breast milk have been published, but the degree of excretion has not been established. Women should be advised to avoid breastfeeding while taking quetiapine.

Dosage and administration

Quetiapine can be used regardless of the meal.

Adults

Schizophrenia treatment

Quetiapine is administered 2 times a day. The daily dose for the first 4 days of therapy is:
The 1st day - 50 mg, 2nd day - 100 mg, the 3rd day - 200 mg, the 4th day - 300 mg. Starting from the 4th day, the dose should be selected to be effective, usually in the range from 300 to 450 mg / day. Depending on the clinical effect and individual tolerance by the patient, the dose may vary from 150 to 750 mg / day. The maximum recommended daily dose is 750 mg.

Treatment of manic episodes in the structure of bipolar disorder

Quetiapine is used as monotherapy or in combination with drugs that have a normal-chemical effect.

Quetiapine is administered 2 times a day. The daily dose for the first 4 days of therapy is:
The 1st day - 100 mg, the 2nd day - 200 mg, the 3rd day - 300 mg, the 4th day - 400 mg. Further, by the 6th day of therapy, the daily dose of the drug can be increased to 800 mg. Increasing the daily dose should not exceed 200 mg per day.

Depending on the clinical effect and individual tolerance, the dose can vary from 200 to 800 mg / day.Usually the effective dose is from 400 to 800 mg / day. The maximum recommended daily dose is 800 mg.

Treatment of depressive episodes in the structure of bipolar disorder

Quetiapine is administered once a day at night. The daily dose for the first 4 days of therapy is: 1st day - 50 mg, 2nd day - 100 mg, 3rd day - 200 mg, 4th day - 300 mg. The recommended dose is 300 mg / day. The maximum recommended daily dose of Quetiapine is 600 mg.

The antidepressant effect of quetiapine was confirmed by using it at a dose of 300 and 600 mg / day. With short-term therapy, the efficacy of quetiapine in doses of 300 and 600 mg / day was comparable (see the Pharmacodynamics section).

Elderly

In elderly patients, the initial dose of quetiapine is 25 mg / day. The dose should be increased daily by 25-50 mg to achieve an effective dose, which is likely to be less than in younger patients.

Patients with renal failure

Dose adjustment is not required.

Patients with liver failure

Quetiapine is extensively metabolized in the liver. Therefore, care should be taken when applying it to patients with hepatic insufficiency, especially at the beginning of therapy. It is recommended to start therapy with quetiapine with a dose of 25 mg / day and increase the dose daily by 25-50 mg until the effective dose is reached.

Side effect

Classification of the incidence of side effects (WHO):

very frequent> 1/10;

frequent from> 1/100 to <1/10;

infrequent from> 1/1000 to <1/100;

rare from> 1/10000 to <1/1000;

very rare <1/10000, including individual messages;

frequency unknown: according to the available data, it is not possible to establish the frequency of occurrence.

From the side of the central nervous system:

very often - dizziness, drowsiness, headache, extrapyramidal symptoms;

often - dysarthria, unusual and nightmare dreams, increased appetite;

infrequently - convulsions, restless legs syndrome, tardive dyskinesia, syncope;

rarely somnambulism and similar phenomena.

From the gastrointestinal tract:

very often - dry mouth;

often - constipation, dyspepsia , vomiting;

infrequently - dysphagia;

rarely, intestinal obstruction / ileus;

From the hemopoietic system:

often - leukopenia;

frequency is unknown - neutropenia.

Since the cardiovascular system:

often - tachycardia, orthostatic hypotension, palpitations;

infrequently - bradycardia;

On the part of the respiratory system:

often - shortness of breath;

infrequently - rhinitis.

From the kidneys and urinary tract:

infrequently - urinary retention.

Liver and biliary tract:

rarely jaundice;

very rarely - hepatitis.

On the part of the immune system:

infrequently - hypersensitivity reactions;

very rarely - Anaphylactic reactions.

From the reproductive system:

rarely - priapism, galactorrhea.

Skin and Subcutaneous Tissues:

very rarely - angioedema, Stevens-Johnson syndrome.

On the part of the organ of vision:

often - blurred vision.

Metabolic disorders:

very rarely - diabetes.

Changes in laboratory and instrumental indicators:

very often - an increase in the concentration of triglycerides, an increase in the concentration of total cholesterol (mainly cholesterol of low-density lipoprotein - LDL), a decrease in the concentration of cholesterol of high-density lipoprotein (HDL), an increase in body weight, a decrease in hemoglobin concentration;

often - an increase in the activity of alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), a decrease in the number of neutrophils, an increase in the number of eosinophils, hyperglycemia, an increase in the concentration of prolactin in plasma, a decrease in the concentration of total and free T₄decreasing the concentration of total T₃, increasing the concentration of thyroid stimulating hormone (TSH);

infrequently - increased activity of aspartate aminotransferase (AST), thrombocytopenia, prolongation of the QT interval, decrease in the concentration of free T₃;

rarely - increased activity of creatine phosphokinase, agranulocytosis.

Common disorders:

very often - "cancel" syndrome;

often - slightly pronounced asthenia, irritability, peripheral edema, fever;

rarely - neuroleptic malignant syndrome, hypothermia;

frequency is unknown - "cancellation" syndrome in newborns.

Lengthening of the QT interval, ventricular arrhythmia, sudden death, cardiac arrest and bidirectional ventricular tachycardia are considered to be side effects of neuroleptics.

The frequency of EPS in short-term clinical studies in adult patients with schizophrenia and mania in the structure of bipolar disorder was comparable in the quetiapine and placebo groups (patients with schizophrenia: 7.8% in the quetiapine group and 8.0% in the placebo group; mania in the structure of bipolar disorder : 11.2% in the quetiapine group and 11.4% in the placebo group).

The frequency of EPS in short-term clinical studies in adult patients with depression in the structure of bipolar disorder in the quetiapine group was 8.9%, in the placebo group - 3.8%. At the same time, the frequency of individual symptoms of EPS (such as akathisia, extrapyramidal disorders, tremor, dyskinesia, dystonia, anxiety, involuntary muscle contraction, psychomotor agitation and muscle rigidity) was generally low and did not exceed 4% in each of the therapeutic groups. In long-term clinical studies of quetiapine in schizophrenia and bipolar disorder in adult patients, the incidence of EPS was comparable in the quetiapine and placebo groups.

With quetiapine therapy, a dose-dependent decrease in thyroid hormone concentrations may be observed. The frequency of potentially clinically significant changes in the concentration of thyroid hormones in short-term clinical studies for general T₄ was 3.4% in the quetiapine group and 0.6% in the placebo group; for free T₄ - 0.7% in the quetiapine group versus 0.1% in the placebo group; for general T₃ - 0.54% in the quetiapine group versus 0.0% in the placebo group; for free T₃ - 0.2% in the quetiapine group versus 0.0% in the placebo group. The change in the concentration of TSH was observed with a frequency of 3.2% in the quetiapine group and 2.7% in the placebo group. In short-term clinical studies of monotherapy, the frequency of potentially clinically significant changes in T₃ and TSH was 0.0% in the quetiapine and placebo groups; for T₄ and TSH was 0.1% in the quetiapine group versus 0.0% in the placebo group. These changes, as a rule, are not associated with clinically pronounced hypothyroidism. Maximum reduction in total and free T₄ registered on the 6th week of quetiapine therapy, without further reducing the concentration of hormones during long-term treatment. In almost all cases, the concentration of total and free T₄ returned to baseline after stopping quetiapine therapy, regardless of the duration of treatment. The concentration of thyroxin-binding globulin (TSH) when measured in 8 patients remained unchanged.

Overdose

A fatal outcome was reported with 13.6 g of quetiapine in a patient participating in a clinical trial, as well as a fatal outcome after taking 6 g of quetiapine in a post-marketing study. At the same time, a case of taking quetiapine ina dose exceeding 30 g, without lethal outcome.

There are reports of extremely rare cases of quetiapine overdose, leading to an increase in QTc interval, death or coma.

In patients with a history of severe cardiovascular diseases, the risk of side effects in overdose may increase (see the section "Special Instructions").

The symptoms noted during overdose were mainly the result of an increase in the known pharmacological effects of the drug, such as drowsiness and sedation, tachycardia and a decrease in blood pressure.

There are no specific antidotes for Quetiapine. In cases of severe intoxication should be aware of the possibility of overdose with several drugs. It is recommended to carry out activities aimed at maintaining the function of respiration and the cardiovascular system, ensuring adequate oxygenation and ventilation. Published reports on the resolution of severe undesirable effects on the part of the central nervous system, including coma and delirium, after intravenous administration of physostigmine (at a dose of 1-2 mg) under constant ECG monitoring.

In the event of refractory hypotension with an overdose of quetiapine, treatment should be carried out by intravenous administration of a liquid and / or spasmimetic drugs (epinephrine and dopamine should not be prescribed, since stimulation
β-adrenergic receptors may cause an increase in hypotension against a blockade of α-adrenergic receptors quetiapine).

Gastric lavage (after intubation, if the patient is unconscious), the administration of Activated carbon and laxatives may contribute to the elimination of unabsorbed Quetiapine, but the effectiveness of these measures has not been studied.

Close medical surveillance should continue until the patient's condition improves.

Interaction with other drugs

Caution should be exercised in the combined use of quetiapine with other drugs affecting the central nervous system, as well as with alcohol.

The cytochrome P450 (CYP) 3A4 isoenzyme is the main isoenzyme responsible for the metabolism of quetiapine through the cytochrome P450 system. In healthy volunteers, the combined use of quetiapine (at a dose of 25 mg) with Ketoconazole , an inhibitor of the CYP3A4 isoenzyme, led to an increase in the area under the concentration-time curve (AUC) of quetiapine 5-8 times.

Therefore, the combined use of quetiapine and CYP3A4 isoenzyme inhibitors is contraindicated. It is also not recommended to take Quetiapine along with grapefruit juice.

In a pharmacokinetic study with repeated use of quetiapine before or simultaneously with taking Carbamazepine , a significant increase in clearance of quetiapine and, accordingly, a decrease in AUC, by an average of 13%, compared with taking quetiapine without carbamazepine. In some patients, the decrease in AUC was even more pronounced. This interaction is accompanied by a decrease in the concentration of quetiapine in the blood plasma and may reduce the effectiveness of quetiapine therapy. The joint appointment of quetiapine with phenytoin, another inducer of the microsomal system of the liver, was accompanied by an even more pronounced (approximately 450%) increase in the clearance of quetiapine. Quetiapine use by patientsreceiving inducers of liver microsomal enzymes, is possible only if the expected benefit of quetiapine therapy exceeds the risk associated with the abolition of the drug-inducer of liver microsomal enzymes. Changing the dose of inductors of liver microsomal enzymes should be gradual. If necessary, they may be replaced with drugs that do not induce microsomal liver enzymes (for example, with valproic acid).

The pharmacokinetics of quetiapine did not change significantly with the simultaneous use of imipramine antidepressant (CYP2D6 inhibitor) or Fluoxetine (CYP3A4 and CYP2D6 inhibitor).

The pharmacokinetics of quetiapine does not change significantly when used simultaneously with the antipsychotic drugs Risperidone or Haloperidol. However, simultaneous administration of quetiapine and thioridazine resulted in an increase in clearance of quetiapine by about 70%.

The pharmacokinetics of quetiapine does not change significantly with simultaneous use of cimetidine.

With a single dose of 2 mg of lorazepam while receiving quetiapine at a dose of 250 mg 2 times a day, the clearance of lorazepam is reduced by about 20%.

The pharmacokinetics of lithium preparations do not change with simultaneous use of quetiapine. No clinically significant changes in the pharmacokinetics of valproic acid and quetiapine were observed with the combined use of valproate seminatrium and quetiapine.

Pharmacokinetic studies on the interaction of quetiapine with drugs used in cardiovascular diseases have not been conducted.

Caution should be exercised when combined with quetiapine and drugs that can cause electrolyte imbalance and prolonged QTs.

Quetiapine did not induce the induction of liver microsomal enzymes involved in phenazone metabolism.

False-positive screening tests for the detection of methadone and tricyclic antidepressants were observed in patients taking quetiapine using enzyme immunoassay. A chromatographic examination is recommended to confirm screening results.

special instructions

Children and teenagers (aged 10 to 17 years)

The drug quetiapine is not indicated for use in children and adolescents under 18 years of age due to insufficient data on the use in this age group. According to the results of clinical studies, some side effects (increased appetite, increased concentration of prolactin in the blood plasma and EPS) in children and adolescents were observed with greater frequency than in adult patients. An increase in blood pressure was also observed, which was not observed in adult patients. In children and adolescents, a change in thyroid function was also observed.

The effect on growth, puberty, mental development and behavioral reactions with prolonged use (more than 26 weeks) of quetiapine has not been studied.

In placebo-controlled studies in children and adolescents with schizophrenia and mania in the structure of bipolar disorder, the incidence of EPS was higher with quetiapine compared with placebo.

Suicide / suicidal thoughts or clinical deterioration

Depression in bipolar disorder is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicidal events). This risk persists until the onset of severe remission. Due to the fact that it may take several weeks or more to improve the condition of a patient from the start of treatment, patients must be under close medical supervision until improvement occurs. According to generally accepted clinical experience, the risk of suicide may increase in the early stages of the onset of remission.

According to clinical studies in patients with depression in bipolar disorder, the risk of development of events associated with suicide was 3.0% (7/233) for quetiapine and 0% (0/120) for placebo in patients aged 18-24 years; 1.8% (19/1616) for quetiapine and 1.8% (11/622) for placebo for patients over 25 years of age.

Other mental disorders for which quetiapine is prescribed are also associated with an increased risk of suicide-related events. In addition, such conditions can be comorbid with a depressive episode. Thus, the precautions used in the treatment of patients with a depressive episode should be taken in the treatment of patients with other mental disorders.

When abruptly discontinuing quetiapine therapy, the potential risk of suicide related events should be taken into account.

Patients with a history of suicidal events, as well as patients who clearly express suicidal thoughts before starting therapy, belong to the group of