Quetiapine-Vial - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate 30.22 mg, microcrystalline cellulose 30.00 mg, sodium carboxymethyl starch 5.00 mg, povidone-K30 - 3.50 mg, magnesium stearate - 1.00 mg.

Shell composition: talc - 0.60 mg, titanium dioxide - 0.60 mg, povidone-K30 0.46 mg, macrogol-6000 0.42 mg, polysorbate 80-0.54 mg, triacetin 0.36 mg, iron oxide yellow - 0.30 mg, iron oxide red - 0.32 mg.

Composition per one tablet 100 mg:

Active substance: quetiapine fumarate - 115.13 mg, in terms of quetiapine - 100.0 mg.

Excipients: lactose monohydrate - 120.87 mg, microcrystalline cellulose - 60.00 mg, sodium carboxymethyl starch - 20.00 mg, povidone-K30 - 10.00 mg, magnesium stearate - 4.00 mg.

Shell composition: talc - 1,65 mg, titanium dioxide - 1,65 mg, povidone-K30 - 1,32 mg, macrogol-6000 - 1,15 mg, polysorbate-80 - 1,52 mg, triacetin - 1,00 mg, iron oxide yellow - 1.71 mg.

Composition per one tablet 200 mg:

Active substance: quetiapine fumarate - 230.26 mg, in terms of quetiapine - 200.0 mg.

Excipients: lactose monohydrate - 241.74 mg, microcrystalline cellulose - 120.00 mg, sodium carboxymethyl starch - 40,0, povidone-K30 - 22.00 mg, magnesium stearate - 10.00 mg.

Shell composition: talc - 2.97 mg, titanium dioxide - 2.97 mg, povidone-K30 - 2.38 mg, macrogol-6000 - 2.07 mg, polysorbate-80 - 2.74 mg, triacetin - 1.80 mg, iron oxide yellow - 3.07 mg.

Description:

Dosage of 25 mg: round, biconvex tablets, covered with a film shell of red-brown color, with a risk on one side; On the cross section, a shell of red-brown color and a nucleus of white or almost white color is visible.

Dosage of 100 mg: round, biconvex tablets, covered with a film coating of light yellow color, with a risk on one side; On the cross-section, a light-yellow shell and a white or almost white core are visible.

Dosage of 200 mg: oblong, biconvex tablets covered with a film coating of light yellow color, with a risk on one side; On the cross-section, a light-yellow shell and a white or almost white core are visible.

Pharmacotherapeutic group:Antipsychotic agent (antipsychotic)

ATX: & nbsp

N.05.A.H.04 Quetiapine

Pharmacodynamics:

Mechanism of action

Quetiapine is an atypical antipsychotic. Quetiapine and its active metabolite N-desalkylkvetiapine (norquetiapine) interacts with a wide spectrum of neutron-trans-receptor receptors of the brain. Quetiapine and N- dealkalkvetiapine show a high affinity for 5HT₂-serotonin receptors and D₁- and D₂dopamine receptors of the brain. Higher selectivity to 5HT₂serotonin receptors, than to D₂dopamine receptors, causes the main clinical antipsychotic properties of the drug and a low incidence of extrapyramidal side effects. Quetiapine has no affinity for the carrier of norepinephrine and has a low affinity for SHT_1Aserotonin receptors, while N-dealkylketiapine shows a high affinity for both. Inhibition of naradrenaline and partial agonism with 5HT_1A-serotonin receptors, manifested by the metabolite, can cause antidepressant effects of the drug. Quetiapine and N-dealkalketiapine have a high level of histamine and α₁-adrenoceptors and moderate affinity for α₂adrenoreceptors. Quetiapine does not show a significant affinity for muscarinic receptors, while its metabolite N-dealkylketiapine exhibits moderate or high affinity for several subtypes of muscarinic receptors.

In standard tests in animals quetiapine has antipsychotic activity. The specific contribution of the metabolite N-dealkylkvetiapine in the pharmacological activity of quetiapine is not established.

The results of the study of extrapyramidal symptoms (EPS) in animals revealed that quetiapine causes a weak catalepsy in doses effectively blocking D₂- dopamine receptors. Quetiapine causes a selective decrease in the activity of mesolimbic A10-dopaminergic neurons in comparison with A9-nigrostri- neal neurons involved in motor function. When quetiapine was administered with a dose titration in schizophrenia, the frequency of EPS and the concomitant use of m-holinoblockers was comparable to that of placebo.

The drug is well tolerated when taken at recommended doses, including by elderly patients. In placebo-controlled trials in elderly patients with dementia with quetiapine, the incidence of cerebrovascular complications did not exceedthose in the placebo group.

The drug is effective against both positive and negative symptoms of schizophrenia. Quetiapine is effective as a monotherapy in manic episodes from moderate to severe severity. Data on the prolonged use of the drug for the prevention of subsequent manic and depressive episodes are absent. Data on the use of quetiapine in combination with valproate or lithium preparations for moderate to severe manic episodes are limited, but the combination was generally well tolerated, the incidence of EPS and concomitant use of m-cholinoblockers was comparable to that of placebo. Quetiapine is effective in doses of 300 mg and 600 mg in patients with type I and II bipolar disorder from moderate to severe severity. The effectiveness of the drug at a dose of 300 mg and 600 mg 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 is approximately 7 hours.

The effect of quetiapine on 5HT₂- and D₂-receptors lasts up to 12 hours after taking the drug.

In a clinical study in patients with depressive episodes in the structure of bipolar I and II disorders, the use of quetiapine in dose of 300 mg in day with greater efficacy compared with placebo reduced the overall score on the scale of depression MADRS (Montgomery-Asberg Depression Rating Scale, The Montgomery-Asberg Depression Rating Scale). In 4 additional quetiapine clinical trials of 8 weeks in patients with moderate and severe depressive episodes in the structure of bipolar disorder, quetiapine in doses of 300 mg and 600 mg showed greater efficacy compared with placebo: an average improvement in scores of the scale MADRS and improvement in the overall score MADRS (not less than 50%) in comparison with the initial values.

In a short-term (9-week) study in patients without dementia aged 66 to 89 years with major depressive disorder quetiapine in doses ranging from 50 mg to 300 mg (the dose was selected with a clinical response, the average daily dose was 160 mg) reduced the symptoms of depression compared with placebo.

The frequency of EPS and the increase in body weight in stable patients with schizophrenia does not increase with prolonged therapy with the drug.

In studies of major depressive disorder by criteria DSM-IV (Diagnostic and Statistical Manual of Mental Disorders (4^th ed.)) did not observe an increase in the risk of suicidal behavior and suicidal thinking when taking the drug compared with placebo.

With the use of quetiapine in a dose of 75-750 mg per day compared with placebo, there were no differences in the incidence of cases of extrapyramidal symptoms and the concomitant use of anticholinergic drugs. Quetiapine does not cause a prolonged increase in the concentration of prolactin in the blood plasma. There was no difference in prolactin concentration with quetiapine or placebo at a fixed dose. With the use of quetiapine in doses up to 800 mg / day for the treatment of manic episodes from moderate to severe severity both in monotherapy and in combination with a lithium preparation or semiphosphate valproate, the incidence of EPS and concomitant use of m-cholinergic blockers was comparable to that of placebo.

In two short-term (6-week) studies of combination therapy of a depressive episode with quetiapine at a dose of 150 mg / day and 300 mg / day with amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine,paroxetine, sertraline or venlafaxine in patients with a suboptimal response to antidepressant monotherapy, an improvement in depressive symptoms on a scale MADRS (Montgomery-Asberg Depression Rating Scale, The Montgomery-Asberg Depression Rating Scale) (mean 2-3.3 scores) compared with antidepressant monotherapy.

Pharmacokinetics:

Quetiapine is well absorbed from the gastrointestinal tract. The intake of food does not significantly affect the bioavailability of quetiapine. The maximum concentration of quetiapine and N-dealkylkvetiapine in blood plasma is achieved approximately 6 hours after taking the drug. The equilibrium molar concentration of the active metabolite N-dealkylkvetiapine is 35% of that of quetiapine. The pharmacokinetics of quetiapine and N-dealkylkvetiapine is linear and is dose-dependent when taken in a dose of up to 800 mg once a day.

When taking the drug once a day at a dose equivalent to the daily dose of the drug taken in two doses, similar areas were observed under the curves of the "concentration versus time" (AUC), but the maximum concentration in the plasma (C_mOh) was 13% less. Value AUC metabolite N-dealkylkvetiapine was 18% less. Studies on the effect of food intake on the bioavailability of quetiapine have shown that eating high-fat foods results in a statistically significant increase in C_mOh and AUC for the drug - approximately 50% and 20%, respectively. Low-fat diet did not have a significant effect on C_mOh and AUC quetiapine. Approximately 83% of quetiapine binds to plasma proteins.

Metabolised in the liver. Determined that CYP3A4 is the key enzyme of quetiapine metabolism, mediated by cytochrome P450. N-zecalkylketiapine is formed with the participation of isoenzyme CYP3A4.

Quetiapine and some of its metabolites (including N-desalkylketiapine) have a weak inhibitory activity against cytochrome P isoenzymes450 1A2, 2C9, 2C19, 2D6 and 3A4, but only in concentrations 5-50 times higher than the concentrations observed at the usual effective dose of 300-800 mg per day. Based on the results in vitro, it should not be expected that simultaneous use of quetiapine with other drugs will lead to a clinically pronounced inhibition of the metabolism of other drugs mediated by cytochrome P450.

According interaction studies in healthy volunteers quetiapine 25 mg and ketoconazole induced 5-8-fold increase in the AUC quetiapine. Based on these data, simultaneous use of quetiapine with inhibitors CYP3A4 is contraindicated.

The half-life of quetiapine and N-dealkylkvetiapine is about 7 and 12 hours respectively. On average, at least 5% molar fraction of the dose and quetiapine free N-dezalkilkvetiapina not metabolized and eliminated from the plasma in unchanged form by the kidneys or the intestine. Approximately 73% of quetiapine is excreted by the kidneys and 21% by the intestine. Quetiapine actively metabolized in the liver, less than 5% of quetiapine is not metabolized and excreted unchanged via the kidneys or the intestine.

Differences in pharmacokinetic parameters in men and women are not observed.

The average creatinine clearance (CC) in elderly patients is 30-50% less than in patients aged 18 to 65 years.

The average quetiapine plasma clearance of less than about 25% in patients with severe renal impairment (creatinine clearance <30 mL / min / 1.73 m²), but individual clearance rates are within the values found in healthy volunteers.

In patients with hepatic insufficiency (compressed alcohol cirrhosis), the mean plasma clearance of quetiapine is reduced by approximately 25%. Because the quetiapine intensively metabolized in the liver, patients with liver failure may increase the plasma concentration of quetiapine, which requires dose adjustment.

Indications:

- Schizophrenia;

- Manic episodes in the structure of bipolar disorder;

- Depressive episodes from medium to severe severity in the structure of bipolar disorder.

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

Contraindications:

- Hypersensitivity to any component of the drug;

- Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption;

- Simultaneous use with inhibitors of cytochrome P450 isoenzymes, including antifungal agents, azole derivatives, erythromycin, clarithromycin, nefadozone, HIV protease inhibitors (see section "Interaction with other medicinal products").

- Psychoses in elderly patients with dementia.

Despite the fact that the effectiveness and safety of the drug in children and adolescents aged 10-17 years was studied in clinical studies, the use of the drug in patients under the age of 18 years is not shown.

Carefully:

Patients with hepatic insufficiency, epilepsy and epileptic seizures (in the anamnesis), cardiovascular and cerebrovascular diseases or other conditions predisposing to hypotension, patients with risk factors for stroke or aspiration pneumonia, elderly age, simultaneous use with drugs that increase interval QT (including those with neuroleptics), patients with congenital syndrome of interval lengthening QT, with congestive heart failure, myocardial hypertrophy, hypokalemia or hypomagnesemia, combination with drugs that have an inhibitory effect on the central nervous system (CNS) or alcohol.

Pregnancy and lactation:

The safety and efficacy of quetiapine in pregnant women have not been established. Based on the available data, it is impossible to make an unambiguous conclusion about the toxicity of quetiapine in the first trimester of pregnancy, studies in animals have shown the presence of quetiapine in reproductive toxicity.As a consequence, during pregnancy, the drug can be used only if the expected benefit for a woman justifies the potential risk to the fetus. When using antipsychotics, including quetiapine, in the third trimester of pregnancy, neonates have a risk of developing adverse reactions of varying severity and duration, including EPS and / or withdrawal syndrome. There was reported on excitation, hypertension, hypotension, tremor, drowsiness, respiratory distress syndrome, or feeding disorders. In this regard, careful monitoring of the condition of newborns whose mothers are used quetiapine during pregnancy.

Quetiapine excretion with breast milk has been reported, but the degree of excretion of quetiapine with human milk is not known. It is necessary to stop breastfeeding while taking the drug.

In experimental animal studies, no mutagenic and clastogenic effects of quetiapine were identified. For quetiapine in doses less than 1/4 of the maximum recommended dose for a person (800 mg), embryo and fetotoxic effects are not established.There are data on the embryotoxicity of quetiapine, which was manifested when administered in rats and rabbits at doses equivalent to one to two times the maximum recommended doses for humans, indicating the toxic effect of quetiapine on the body of pregnant animals, which manifested itself as a decrease in the body weight of females and / or an increase in mortality among them. When quetiapine was administered to pregnant female rats at doses equivalent to three maximum recommended doses for humans, there was an increase in mortality in offspring in pre- and postnatal periods. The negative effect of quetiapine on the fertility of rats (decreased male fertility, pseudopregnancy, an increase in the period between two estrus, an increase in the precoital interval, and a decrease in the frequency of pregnancy) were revealed. However, the obtained data can not be fully transferred to humans in connection with the existing specific differences in the hormonal control of reproduction.

Dosing and Administration:

Inside, 2-3 times a day, regardless of food intake.

There are different schemes of drug use, the doctor should give clear instructions to the patient on the dosing regimen.

Adults

Acute and chronic psychoses, including schizophrenia

The drug is prescribed 2 times a day. The total daily dose for the first 4 days of therapy is 50 mg (1 day), 100 mg (day 2), 200 mg (day 3), 300 mg (day 4). Starting from the 4th day, the dose should be adjusted to an effective dosage, usually in the range of 300 to 450 mg / day. In the future, in case of need for dose adjustment, an increase in the daily dose by 50-100 mg with intervals of 2 days is recommended. Depending on the clinical effect and individual patient tolerance, the dose may vary from 150 to 750 mg / day. The maximum daily dose of quetiapine is 750 mg.

Treatment of manic episodes in the structure of bipolar disorder

Quetiapine is used as a monotherapy or in combination with drugs that have a normotimic effect. The drug is prescribed 2 times a day. The daily dose for the first 4 days of therapy is: 100 mg (1 day), 200 mg (2 day), 300 mg (3 day), 400 mg (4 day). In the future, by the 6th day of therapy, the daily dose of the drug can be increased to 800 mg. The increase in the daily dose should not occur faster than 200 mg per day. The daily dose is divided into 2 divided doses. Depending on the clinical effect and individual patient tolerance, the dose may vary from 200 to 800 mg / day. Usually the effective dose is from 400 to 800 mg / day.The maximum daily dose of quetiapine is 800 mg.

Treatment of depressive episodes from moderate to severe in the structure of bipolar disorder

Quetiapine is prescribed 1 time per day at night. The daily dose for the first 4 days of therapy is: Day 1 - 50 mg, Day 2 - 100 mg, Day 3 - 200 mg, Day 4 300 mg. The recommended dose is 300 mg / day. The maximum daily dose is 600 mg. The antidepressant effect of quetiapine was confirmed when used at a dose of 300 and 600 mg per day. With short-term therapy, the effectiveness of quetiapine in doses of 300 and 600 mg was comparable.

Elderly patients

In elderly patients, the initial dose of the drug is 25 mg / day. The dose should be increased daily by 25-50 mg until an effective dose is obtained, which is likely to be less than in young patients. In elderly patients quetiapine (as well as other neuroleptics) should be used with caution, especially at the beginning of therapy. The selection of an effective dose of the drug in such patients may be slower, and the daily therapeutic dose is lower than in young patients. The average plasma clearance of quetiapine in elderly patients is 30-50% lower than in young patients.In addition, patients of this group are more likely to have liver, kidney, nervous and cardiovascular diseases, and concomitant medication is most often prescribed.

Patients with renal insufficiency

Correction of the dose is not required.

Patients with hepatic insufficiency

Quetiapine is extensively metabolized in the liver. Therefore, care should be taken when using the drug in patients with hepatic insufficiency, especially at the beginning of therapy. It is recommended to begin therapy with quetiapine at a dose of 25 mg / day and increase the dose daily by 25-50 mg until a therapeutic effect is achieved.

Supportive therapy

To maintain remission, it is advisable to use the lowest dose. Patients should be periodically examined to determine the need for maintenance therapy.

Renewal of interrupted treatment in patients previously treated with quetiapine

With the resumption of therapy less than 1 week after quetiapine withdrawal, the drug can be continued at a dose adequate for maintenance therapy. With the resumption of therapy in patients who did not receive quetiapine more than 1 week, you should follow the rules of initial dose selection and establish an effective dose for the clinical response of the patient.

Side effects:

The most frequent side effects (≥10%) of quetiapine are drowsiness, dizziness, headache, dry mouth syndrome "cancel", increasing the concentration of triglycerides, total cholesterol (mainly cholesterol and low-density lipoprotein) lowering the concentration of high density lipoproteins, increasing body weight, decreased hemoglobin concentration and extrapyramidal symptoms.

As in the case of use of other antipsychotics, during quetiapine marked syncope, neuroleptic malignant syndrome, leukopenia, neutropenia, increased body weight and peripheral edema.

The undesirable phenomena observed when taking quetiapine and classified according to the body systems are listed in the following order: Often (≥1/10); often (<1/10 and ≥ 1/100); infrequently (<1/100 and ≥1 / 1000); rarely (<1/1000 and ≥1 / 1000); rarely (<1/10 000), frequency, unspecified (it is not possible to set the frequency according to available data).

On the part of the hematopoiesis system: Often - decrease in concentration hemoglobin; often - leukopenia, a decrease in the number of neutrophils, eosinophilia; infrequently - thrombocytopenia, decrease in the number of platelets, anemia; rarely - agranulocytosis; very rarely - neutropenia.

From the endocrine system: often - an increase in the concentration of prolactin in the serum, a decrease in the concentration of total and free T₄in the blood, a decrease in the total T₃ in the blood, increased concentration of TSH in the blood; infrequent - a decrease in the concentration of free T₃ in blood; very rarely - the syndrome of inadequate secretion of antidiuretic hormone.

From the side of metabolism: very often - an increase in the concentration of triglycerides in the blood serum, total cholesterol (mainly due to low-density lipoproteins), a decrease in the concentration of high-density lipoproteins, an increase in body weight (mainly in the first weeks of treatment); often - hyperglycemia or decompensation of diabetes mellitus, increased appetite; infrequently - diabetes, hyponatremia.

From the side of the central nervous system and the psyche: very often - dizziness, drowsiness, headache, extrapyramidal symptoms; often - dysarthria, syncopal conditions,unusual and nightmarish dreams, suicidal thoughts and behavior, increased appetite: infrequent - fainting, convulsions, depression, tardive dyskinesia, restless legs syndrome; rarely - malignant neuroleptic syndrome (hyperthermia, muscle rigidity, - altered mental status, lability in the autonomic nervous system, increased activity of creatine phosphokinase), somnambulism, and other disorders related to sleep.

From the cardiovascular system: often - tachycardia, orthostatic hypotension, palpitation, increased blood pressure; infrequent bradycardia, prolongation of the QT interval on the ECG; rarely - venous thromboembolism.

From the respiratory system: often - dyspnea; infrequently - Rhinitis, pharyngitis.

From the digestive system: very often - dry mouth; often - vomiting, constipation, indigestion; infrequently - dysphagia; rarely - intestinal obstruction / ileus, pancreatitis, jaundice, hepatitis.

On the part of the reproductive system: infrequently - sexual dysfunction; rarely - priapism (painful erection), galactorrhea, menstrual irregularities.

Allergic reactions: infrequently - skin rash, hypersensitivity reactions; very rarely - angioedema, Stevens-Johnson syndrome.

From the side of the organ of vision: often blurred vision.

From the side of the kidneys and urinary system: infrequently - retention of urine.

From the immune system: infrequently - hypersensitivity reactions; very rarely - angioedema, Stevens-Johnson syndrome.

Laboratory indicators: very often hypercholesterolemia, hypertriglyceridemia; often - increased activity of "liver" transaminases (predominantly ALT), increased activity of ƴ-glutamyltransferase, hyperglycemia; infrequent - a decrease in the concentration of total and free thyroxine (in the first 4 weeks), as well as the concentration of total and reversible triiodothyronine (only when taking high doses of quetiapine); rarely - increased activity of creatine phosphokinase.

Other: often - withdrawal syndrome; often - asthenia, peripheral edema, fever, increased sweating; rarely - malignant neuroleptic syndrome, back pain, chest pain, subfebrile condition, myalgia, dry skin, decreased vision; very rarely - rhabdomyolysis; frequency unknown - withdrawal syndrome in newborns.

Interval lengthening QT, ventricular arrhythmia, sudden death, cardiac arrest and bidirectional ventricular tachycardia are considered side effects of neuroleptics. Frequency of extrapyramidal symptoms (EPS) in short-term clinical studies in adult patients with schizophrenia and mania in bipolar disorder structure comparable to placebo group and quetiapine (patients with schizophrenia: 7.8% quetiapine group and 8.0% in the placebo group; mania structure of bipolar disorder: 11.2% in the quetiapine group and 11.4% in the placebo group). The incidence of EPS in short-term clinical trials in adult patients with depression in the structure of bipolar disorder in the quetiapine group was 8.9%, in the placebo group 3.8%. The frequency of individual symptoms of EPS (such as akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, anxiety, involuntary muscle contractions, agitation and muscle rigidity) was generally low and did not exceed 4% in each of the groups. In long-term studies of quetiapine in schizophrenia and bipolar disorder in adults, the incidence of EPS was comparable in quetiapine and placebo groups.

Against the background of quetiapine therapy, a dose-dependent decrease in the concentration of thyroid hormones can be noted. The frequency of potentially significant clinical changes in the concentration of thyroid hormones in short-term clinical trials for general T₄was 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 free T₃ - 0.2% in the quetiapine group versus 0.0% in the placebo group. The change in TSH was noted with a frequency of 3.2% in the quetiapine group and 2.7% in the placebo group. In short-term clinical trials of monotherapy, the frequency of potentially clinically significant changes in T₃ and TTG was 0.0% in the quetiapine group and placebo, and for T₄ and TTG was 0.1% compared to the placebo group - 0.0%. These changes, as a rule, are not associated with clinically pronounced hypothyroidism. Maximum reduction in total and free T₄ registered at the 6th week of quetiapine therapy, without further reduction in the concentration of hormones during long-term treatment. In practically all cases, the concentration of the total and free T₄ returned to baseline after quetiapine therapy was discontinued, regardless of the duration of treatment.The concentration of tyrosine-binding globulin at measurement in 8 patients remained unchanged.

Overdose:

It reported lethal outcome when receiving 13.6 mg of quetiapine in a patient who participated in a clinical study, as well as the lethal outcome after receiving 6g quetiapine in post-marketing surveillance of the application of the drug.

At the same time, a case of taking quetiapine in a dose exceeding 30 g is described, without a lethal outcome.

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

In patients with severe cardiovascular disease history, the risk of side effects may increase in overdose see. Section "Special instructions").

Symptoms noted in overdose were mainly due to increased dose-related side effects of the drug, such as drowsiness and sedation, tachycardia and lowering blood pressure.

Treatment: There is no specific antidote to quetiapine. In cases of severe intoxication, one should remember about the possibility of an overdose with several medications.It is recommended to carry out activities aimed at maintaining the function of breathing and cardiovascular system, ensuring adequate ventilation and oxygenation. Reports have been published on the resolution of severe adverse effects from the central nervous system, including coma and delirium, after intravenous injection of physostigmine (1-2 mg) under constant ECG monitoring.

In the case of refractory hypotension with an overdose of quetiapine treatment is carried out by intravenous fluid and / or sympathomimetic drugs (do not prescribe epshnephrine and dopamine, since stimulation of β-adrenoreceptors can cause an increase in hypotension against the blockade of α-adrenergic receptors with quetiapine).

Gastric lavage (after intubation, if the patient is unconscious) and the use of activated charcoal and laxatives can promote the removal of unabsorbed quetiapine, but the effectiveness of these measures has not been studied. Careful medical supervision is necessary until the patient's condition improves.

Interaction:

Special caution is required in the appointment of quetiapine in combination with other drugs acting on the central nervous system,as well as with alcohol.

Results of the study in vitro showed that quetiapine and 9 of its metabolites in vivo are weak inhibitors of metabolic processes mediated by isoenzymes of the cytochrome P system450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). CYP3A4 is the main enzyme that mediates P450 metabolism of quetiapine.

The effect of other drugs on quetiapine

Phenytoin: simultaneous use of quetiapine with phenytoin leads to an increase in the clearance of quetiapine in plasma, phenytoin induces isoenzyme CYP3A4 cytochrome P450. The combination of quetiapine (250 mg 3 times / day) and phenytoin (100 mg twice a day) increased the average clearance of quetiapine after oral administration five times.

To correct the symptoms of schizophrenia in patients receiving concomitantly quetiapine and phenytoin, higher doses of quetiapine or other inducers of microsomal liver enzymes (including carbamazepine, barbiturates, rifampicin, glucocorticosteroids) may be required. In these cases care should be taken when phenytoin is withdrawn and / or switched to valproic acid, which does not possess enzyme-inducing properties.

Carbamazepine: simultaneous use of quetiapine with carbamazepine significantly increases the clearance of quetiapine, which leads to a decrease in the systemic exposure of quetiapine. Because of this interaction, higher doses of quetiapine may be required. In a pharmacokinetic study with repeated administration of quetiapine before or simultaneously with carbamazepine, a significant increase in the clearance of quetiapine and a corresponding decrease AUC on average by 13%, compared with the use of quetiapine without carbamazepine. In some patients, a decrease AUC was even more pronounced.

Inhibitors CYP3A4: concurrent use of quetiapine with ketoconazole (200 mg / day for 4 days), potent inhibitor of isoenzyme CYP3A4, reduces the clearance of quetiapine after oral administration by 84%, as a result of which the concentration of quetiapine in the blood plasma increases. With the simultaneous use of quetiapine with ketoconazole, other inhibitors of cytochrome P isoenzymes450 (including antifungal agents, azole derivatives (including itraconazole, fluconazole), macrolide antibiotics (including erythromycin), the dose of quetiapine should be corrected.

Cimetidine: regular daily use of cimetidine (400 mg 3 times / day.) for 4 days), which is a nonspecific inhibitor of enzymes, leading to 20% reduction in average clearance of quetiapine (150 mg 3 times / day.) from the blood plasma after reception inside. With the simultaneous use of quetiapine with cimetidine, there is no need to change the dose of the first.

Thioridazine: thioridazine (200 mg, 2 times / day.) 65% increased quetiapine clearance (300 mg, 2 times / day.) From the blood plasma after ingestion.

Risperidone and haloperidol: simultaneous use of quetiapine (300 mg, 2 times / day.) haloperidol (7.5 mg 2x / d.), or risperidone (3 mg, 2 times / day.) did not alter the pharmacokinetics of quetiapine in the equilibrium state.

Fluoxetine and imipramine: simultaneous use of quetiapine (300 mg, 2 times / day.) with an antidepressant, and an inhibitor of CYP3A4 and CYP2D6 fluoxetine (60 mg 1 time / day.), or a known inhibitor of CYP2D6 imipramine (75 mg, 2 times / cut.) alter the equilibrium pharmacokinetics of quetiapine .

Effect of quetiapine on other drugs

Phenazone: repeated daily administration of Quetiapine (up to 750 mg / day., with 3-fold reception) did not cause clinically significant changes in clearance phenazone or its metabolites.This indicates that quetiapine does not have a significant inhibitory effect on hepatic enzymes involved in the metabolism of phenazone, mediated by cytochrome P450.

Lithium: simultaneous use of quetiapine (250 mg 3 times / day) with lithium did not affect any pharmacokinetic parameters of lithium in the equilibrium state.

Lorazepam: the average clearance of lorazepam after oral administration (a single dose of 2 mg) was reduced by 20% during the administration of quetiapine (250 mg 2 times / day).

Smoking did not affect the clearance of quetiapine from the blood plasma.

Since clinical studies have shown that quetiapine potentiates the cognitive and motor effects of alcohol in patients with psychoses, should not take alcohol during the course of treatment with the drug quetiapine.

In the groups of patients concurrently taking quetiapine and valproic acid preparations, cases of more severe leukopenia and neutropenia were recorded in comparison with the monotherapy groups.

The pharmacokinetic interaction between quetiapine and drugs used in cardiovascular diseases has not been studied.

Caution should be exercised in the combined use of quetiapine and drugs that extend the interval QTc, including: antiarrhythmic drugs of class 1A (for example, quinidine, procainamide), or class 3 (amiodarone, sotalol), antibiotics (for example, gatifloxacin, moxifloxacin), or other drugs that extend the interval QTc (e.g., pentamidine, methadone). When quetiapine was used, cases of lengthening of the interval QTc in patients with concomitant diseases, in patients taking medications that cause electrolyte imbalance or an increase QTc, as well as with an overdose of quetiapine.

Special instructions:

Drowsiness

During treatment with quetiapine, drowsiness and related symptoms may occur, for example, sedation (see section "Side effect"). In clinical studies involving patients with depression in the structure of bipolar disorder, sleepiness tended to develop during the first three days of therapy.

The severity of this side effect was mainly insignificant or moderate. With the development of severe drowsiness or a decrease in the severity of symptoms, patients may require more frequent physical examinations within 2 weeks of the onset of drowsiness.In some cases, discontinuation of therapy with the drug may be required.

Dizziness

Quetiapine can cause orthostatic hypotension, and dizziness, especially in the initial period of dose selection, is more likely to occur in the elderly than in younger patients. Dizziness may increase the risk of accidental injuries (falls), especially in elderly patients, and therefore, care should be taken.

Patients with cardiovascular diseases

Quetiapine should be used with caution in patients with diagnosed cardiovascular diseases, cerebrovascular diseases of the brain or other conditions predisposing to hypotension. On the background of therapy, orthostatic hypotension may occur, especially during dose selection at the beginning of therapy. When orthostatic hypotension occurs, a dose reduction or a slower increase in dose may be required.

Venous thromboembolism

Against the background of taking neuroleptics, cases of venous thromboembolism were noted. Before the start of therapy and during therapy with antipsychotic drugs, including quetiapine,should assess the risk factors and take preventive measures.

QT interval extension

There was no correlation between the use of quetiapine and prolonged interval elongation QT. However, the lengthening of the interval QT was noted with an overdose of the drug. Patients with cardiovascular disease and the previously noted lengthening of the interval QT Caution should be exercised when applying quetiapine. Also, care should be taken when applying quetiapine simultaneously with drugs that extend the interval QT, other neuroleptics, especially in the elderly, in patients with the syndrome of congenital lengthening of the interval QT, chronic heart failure, myocardial hypertrophy, hypokalemia, or hypomagnesemia.

Children and teens

Quetiapine is not indicated for use in children and adolescents under 18 years due to inadequate data on efficacy and safety in this population. According to the results of clinical studies, some side effects (increased appetite, increased concentration of prolactin in the blood plasma and extrapyramidal symptoms) in children and adolescents were observed with a greater frequency than in adults.There was also an increase in blood pressure, as well as a change in thyroid function, which was not observed in adults. Influence on growth, puberty, mental development, 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 extrapyramidal disorders was higher with quetiapine than with placebo.

Convulsions

There were no differences in the incidence of seizures in patients taking quetiapine or placebo. However, as with other antipsychotics, caution should be exercised in the treatment of patients with a history of seizures.

Extrapyramidal symptoms (EPS)

An increase in the incidence of EPS in adult patients with depression in the structure of bipolar disorder with quetiapine was observed compared with placebo.

Late dyskinesia

There is a possibility of an increased risk of developing tardive dyskinesia with an increase in the duration of treatment and the total cumulative dose of quetiapine.Nevertheless, the syndrome can develop after relatively short courses at low doses. Despite the fact that the prevalence of tardive dyskinesia is higher among elderly patients, especially older women, it is impossible to assume the likelihood of its development in different patients. Treatment with antipsychotic drugs can suppress (partially suppress) the symptoms and thereby hide the underlying process. In case of signs and symptoms of tardive dyskinesia, the question of dose reduction or drug cancellation should be considered.

Malignant neuroleptic syndrome

Malignant neuroleptic syndrome can be associated with ongoing antipsychotic treatment. Clinical manifestations of the syndrome include hyperthermia, altered mental status, muscle rigidity, lability in the autonomic nervous system, an increase in the level of activity of creatine phosphokinase. In such cases, it is necessary to cancel the drug and conduct appropriate treatment.

Severe neutropenia

In clinical studies of monotherapy with quetiapine, cases of severe neutropenia (neutrophil count <0.5x10⁹/ l) without infection.Agranulocytosis (severe neutropenia associated with infections) was reported in patients who received quetiapine in the framework of clinical studies (rarely), as well as post-registration (including fatal). Most cases of severe neutropenia occurred several months after initiation of therapy with the drug. There was no dose-response effect. Leukopenia and / or neutropenia were resolved after quetiapine therapy was discontinued. A possible risk factor for neutropenia is a previous reduced number of leukocytes in the blood and cases of drug-induced neutropenia in the anamnesis. The development of agranulocytosis was noted in patients and without risk factors. It is necessary to consider the possibility of developing neutropenia in patients with infection, especially in the absence of obvious predisposing factors, or in patients with unexplained fever; these cases should be observed in accordance with clinical recommendations.

In patients with a neutrophil count <1x10⁹/ l, quetiapine should be discontinued.The patient should be observed to identify possible symptoms of infection and monitor the neutrophil count (up to a level of 1.5x10⁹/ l).

Hyperglycaemia

Against the background of quetiapine, hyperglycemia may develop: an increase in fasting blood glucose ≥ 126 mg / dl (≥7.0 mmol / L) or postprandial blood glucose ≥ 200 mg / dL (≥11.1 mmol / L) a single definition or exacerbation of diabetes mellitus, sometimes accompanied by ketoacidosis or coma, in patients with diabetes mellitus in history. Clinical observation of patients with diabetes mellitus and patients with risk factors for developing diabetes is recommended. Regular body weight control and symptoms of hyperglycemia such as polydipsia, polyuria, polyphagia, and weakness are required in patients taking antipsychotics, including quetiapine.

Concentration of lipids in plasma

Against the background of taking quetiapine, an increase in the concentration of triglycerides and cholesterol in the plasma, as well as a decrease in high-density lipoproteins.

Metabolic disorders

An increase in body weight, an increase in the concentration of glucose and lipids in the blood in some patients can lead to a deterioration in the metabolic profile, which requires observation.Perhaps an asymptomatic increase (≥3 times the upper limit of the norm) ACT, ALT and GGT in blood plasma, as a rule, reversible against the background of the continued use of quetiapine.

Body mass

A 6-week, placebo-controlled clinical trial of quetiapine resulted in a more than 7% increase in the body weight of patients with schizophrenia with quetiapine (23% quetiapine versus 6% placebo), monotherapy (21% quetiapine group compared with 7% of the placebo group), and in the combination therapy, 13% of the quetiapine group, compared with 4% in the placebo group. In the treatment of depression in bipolar disorder, weight gain was noted in 8% of patients who received quetiapine, compared with the placebo group of 2%. In this regard, careful monitoring of body weight of patients is necessary.

Reactions of sudden cancellation

With the sharp cancellation of quetiapine, the following acute reactions (withdrawal syndrome) can occur: nausea, vomiting, insomnia, headache, dizziness and irritability. Therefore, it is recommended to cancel the drug gradually for at least one or two weeks.

Elderly patients with dementia

Quetiapine is not indicated for the treatment of psychoses associated with dementia.

In randomized trials, it was shown that some atypical antipsychotics approximately 3-fold increased the risk of developing cerebrovascular complications in patients with dementia. The mechanism of this increase in risk has not been studied. A similar risk of increasing the incidence of cerebrovascular complications can not be ruled out for other antipsychotic drugs or other groups of patients.

Quetiapine should be used with caution in patients at risk of stroke. Analysis of the use of atypical antipsychotics for the treatment of psychoses associated with dementia in elderly patients revealed an increase in the death rate in the group of patients receiving these drugs, compared with placebo. In two 10-week, placebo-controlled trials of quetiapine in a similar group of patients (n= 710; mean age 83 years, age range 56-99 years) showed that the mortality rate in the group of patients taking quetiapine, was 5.5% and 3.2% in the placebo group. The causes of deaths corresponded to those expected for this population. There was no cause-effect relationship between quetiapine treatment and risk of increased mortality in elderly patients with dementia.

Disorders from the side of the liver

If jaundice develops, stop taking the drug.

Dysphagia

Dysphagia and aspiration were observed with quetiapine therapy. The causal relationship between taking the drug and developing aspiration pneumonia has not been established. However, care should be taken when prescribing the drug to patients with a high risk of developing aspiration pneumonia.

Constipation and obstruction of the intestine

Constipation is a risk factor for intestinal obstruction. Against the background of the use of quetiapine, the development of constipation and intestinal obstruction was noted, including fatal cases in patients at high risk of intestinal obstruction, including those receiving concomitant medications that reduce bowel motility, even in the absence of complaints.

Pancreatitis

During clinical trials, post-registration use, cases of pancreatitis development have been noted, but a cause-and-effect relationship has not been established. Post-marketing reports indicated data, including those that are risk factors for pancreatitis, such as increased triglyceride concentrations,cholelithiasis, and alcohol use.

Suicide / suicidal thoughts or clinical worsening

In children, adolescents and young people (under 24 years) with depression, other mental disorders, antidepressants, increase the risk of suicidal thoughts and suicidal behavior. Conducted FDA a meta-analysis of placebo-controlled trials of antidepressants, summarizing data from approximately 4,400 children and adolescents and 7,700 adults with psychotic disorders, revealed an increased risk of suicidal behavior compared with placebo in children, adolescents and adults under 25 years of age (this meta-analysis did not include research where used quetiapine). Therefore, in the appointment of quetiapine and any other antidepressants in young people (aged 18-24 years), the risk of suicide and the benefits of their use should be correlated. Any depressive disorder in itself increases the risk of suicide. This risk remains until the onset of severe remission. According to clinical experience, the risk of suicide may increase in the early stages of the onset of remission. Other psychotic disorders in which it is prescribed quetiapine. are also associated with an increased risk of suicidal events. In addition, such conditions can be comorbid with a depressive episode. Therefore, during treatment, all patients should be monitored for early detection of abnormalities or behavioral changes, as well as suicidal tendencies. With a sharp cessation of quetiapine therapy, the risk of suicide should be taken into account. Patients with a history of suicidal events, as well as patients who express suicidal thoughts before starting therapy, are at increased risk and should be carefully monitored during treatment. According to clinical studies in patients, suicide occurred in 3.0% of cases of quetiapine versus 0% in the placebo group in persons under 25 years of age.

Interaction with other drugs

The use of quetiapine in combination with strong inducers of microsomal liver enzymes, such as carbamazepine and phenytoin helps to reduce the concentration of quetiapine in the blood plasma and can reduce the effectiveness of quetiapine therapy. The administration of quetiapine to patients receiving inducers of microsomal liver enzymes is possible only if,if the expected benefit from quetiapine therapy exceeds the risk associated with the cancellation of the inductor preparation of microsomal liver enzymes. The change in the dose of inductor preparations of microsomal liver enzymes should be gradual. If necessary, they can be replaced with drugs that do not induce microsomal enzymes (for example, preparations of valproic acid).

Effect on the ability to drive transp. cf. and fur:

Quetiapine may cause drowsiness and other disorders from the CNS. Therefore, during the first stages of treatment, during an individually defined period of time, the patient should be prohibited from driving or working with dangerous mechanisms. In the future, the degree of restrictions is set individually.

Form release / dosage:

Film-coated tablets, 25 mg, 100 mg and 200 mg.

Packaging:

Tablets 25 mg: 50 tablets per container of high density polyethylene with a screw cap made of high-density polyethylene with control of the first opening. 1 container, along with instructions for use in a pack of cardboard.

For 24 tablets in a blister of PVC and aluminum foil, 2 blisters together with instructions for use in a pack of cardboard.

Tablets 100 mg: For 30 or 60 tablets in a container of high-density polyethylene with a screw cap made of high-density polyethylene with control of the first opening; 1 container, together with instructions for use in a pack of cardboard.

For 10 tablets in a blister of PVC and aluminum foil, 3 blisters together with instructions for use in a pack of cardboard.

Tablets 200 mg: 20 tablets per container of high-density polyethylene with a screw cap made of high-density polyethylene with control of the first opening; 1 container, together with instructions for use in a pack of cardboard.

For 10 tablets in a blister of PVC and aluminum foil, 2 blisters together with instructions for use in a pack of cardboard.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003995

Date of registration:05.12.2016

Expiration Date:05.12.2021

The owner of the registration certificate:VIAL, LLC VIAL, LLC Russia

Manufacturer: & nbsp

SUZHOU DAWNRAYS PHARMACEUTICALS, Co.Ltd. China

Representation: & nbspVIAL, LLCVIAL, LLC

Information update date: & nbsp27.12.2017

Illustrated instructions

Instructions

Quetiapine Vial (Quetiapine-vial)