Composition, form of production and packaging
The tablets covered with a film shell of white or almost white color, round, biconcave, with engraving of the letter "E" on one side and number "201" - on the other, without or almost without a smell.
1 tab.
quetiapine fumarate 28.78 mg,
which corresponds to the content of quetiapine 25 mg
Excipients: microcrystalline cellulose, lactose monohydrate, sodium carboxymethyl starch (type A), povidone, magnesium stearate, silicon dioxide colloidal anhydrous.
Composition of the membrane: hypromellose, titanium dioxide, lactose monohydrate, macrogol 4000, triacetin (triacetylglycerol).
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
30 pcs. - bottles of dark glass (1) - packs of cardboard.
60 pcs. - bottles of dark glass (1) - packs of cardboard.
The tablets covered with a film shell of white or almost white color, round, biconcave, with an engraving of the letter "E" and number "202" on one side, without or almost without a smell.
1 tab.
quetiapine fumarate 115.13 mg,
which corresponds to the content of quetiapine 100 mg
Excipients: microcrystalline cellulose, lactose monohydrate, sodium carboxymethyl starch (type A), povidone, magnesium stearate, silicon dioxide colloidal anhydrous.
Composition of the membrane: hypromellose, titanium dioxide, lactose monohydrate, macrogol 4000, triacetin (triacetylglycerol).
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
30 pcs. - bottles of dark glass (1) - packs of cardboard.
60 pcs. - bottles of dark glass (1) - packs of cardboard.
The tablets covered with a film cover of pink color, round, biconcave, with an engraving of the letter "E" and number "203" on one side, without or almost without a smell.
1 tab.
quetiapine fumarate 172.7 mg,
which corresponds to the content of quetiapine 150 mg
Excipients: microcrystalline cellulose, lactose monohydrate, sodium carboxymethyl starch (type A), povidone, magnesium stearate, silicon dioxide colloidal anhydrous.
Sheath composition: hypromellose, titanium dioxide, lactose monohydrate, macrogol 4000, triacetin (triacetylglycerol), iron dye oxide yellow, iron oxide dye red.
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
30 pcs. - bottles of dark glass (1) - packs of cardboard.
60 pcs. - bottles of dark glass (1) - packs of cardboard.
The tablets covered with a film cover of dark pink color, round, biconcave, with engraving of the letter "E" and number "204" on one side, without or almost no smell.
1 tab.
quetiapine fumarate 230.26 mg,
which corresponds to the content of quetiapine 200 mg
Excipients: microcrystalline cellulose, lactose monohydrate, sodium carboxymethyl starch (type A), povidone, magnesium stearate, silicon dioxide colloidal anhydrous.
Sheath composition: hypromellose, titanium dioxide, lactose monohydrate, macrogol 4000, triacetin (triacetylglycerol), iron dye oxide yellow, iron oxide dye red.
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
30 pcs. - bottles of dark glass (1) - packs of cardboard.
60 pcs. - bottles of dark glass (1) - packs of cardboard.
The tablets coated with a white or almost white film cover are round, biconcave, with the engraving of the letter "E" and the number "205" on one side, without or almost no odor.
1 tab.
quetiapine fumarate 345.4 mg,
which corresponds to the content of quetiapine 300 mg
Excipients: microcrystalline cellulose, lactose monohydrate, sodium carboxymethyl starch (type A), povidone, magnesium stearate, silicon dioxide colloidal anhydrous.
Composition of the membrane: hypromellose, titanium dioxide, lactose monohydrate, macrogol 4000, triacetin (triacetylglycerol).
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
30 pcs. - bottles of dark glass (1) - packs of cardboard.
60 pcs. - bottles of dark glass (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2016.
PHARMACHOLOGIC EFFECT
Antipsychotic drug (antipsychotic). Has a higher affinity for serotonin 5-HT 2 -receptors than for dopamine D 1 - and D 2 -receptors of the brain. Also has a higher affinity for histamine and? 1- adrenoreceptors and less in relation to? 2- adrenoreceptors. There was no significant affinity for quetiapine for m-cholino- and benzodiazepine receptors.
In standard tests, quetiapine displays antipsychotic activity.
The results of the study of extrapyramidal symptoms (EPS) in animals revealed that quetiapine causes a weak catalepsy in a dose effectively blocking dopamine D 2receptors.
Quetiapine causes a selective decrease in the activity of mesolimbic A10 dopaminergic neurons in comparison with A9 nigrostriural neurons involved in motor function.
In clinical trials (at a dose of 75-750 mg / day), there was no difference between the use of quetiapine and placebo in the incidence of EPS and the concomitant use of anticholinergic drugs.
Quetiapine does not cause a prolonged increase in the concentration of prolactin in the blood plasma. In numerous studies with a fixed dose, there was no difference in the concentration of prolactin with quetiapine or placebo.
In clinical studies, quetiapine has shown efficacy in treating both positive and negative symptoms of schizophrenia.
The effect of quetiapine on 5-HT 2 - and D 2 -receptors lasts up to 12 hours after taking the drug.
PHARMACOKINETICS
Suction
When used internally, quetiapine is well absorbed from the digestive tract. The intake of food does not significantly affect the bioavailability of quetiapine.
Distribution
Binding to plasma proteins is approximately 83%.
Metabolism
Quetiapine is actively metabolized in the liver. It was found that CYP3A4 is the key enzyme of CYP-mediated quetiapine metabolism.
The main metabolites in the plasma do not have a pronounced pharmacological activity. Quetiapine and some of its metabolites have a weak inhibitory activity against the isoenzymes CYP1A2, CYP2C9, CYP2S19, CYP2D6 and CYP3A4, but only at concentrations 10-50 times higher than the concentrations observed at the usual effective dose of 300-450 mg / day.
Excretion
T 1/2 is about 7 hours. Approximately 73% of quetiapine is excreted in the urine and 21% with feces. Less than 5% of quetiapine is not metabolized and is excreted unchanged by kidneys or feces.
Pharmacokinetics in special clinical cases
The average plasma clearance of quetiapine is less than approximately 25% in patients with severe renal insufficiency (CK <30 mL / min / 1.73 m 2 ) and in patients with liver damage (stabilized alcoholic cirrhosis), but individual clearance rates are within the limits corresponding to healthy people.
In a study of the pharmacokinetics of quetiapine in varying dosages with the administration of quetiapine prior to the administration of ketoconazole or concomitantly with ketoconazole, the mean C max and AUC of quetiapine increased by 235% and 522% , respectively, and also led to a decrease in quetiapine clearance, on 84%. T1/2 of quetiapine increased, but the mean time to reach C max did not change.
Based on the results in vitro, it should not be expected that simultaneous administration of quetiapine with other drugs will lead to a clinically pronounced inhibition of CYP-mediated metabolism of other drugs.
The average clearance of quetiapine in elderly patients is 30-50% less than in patients aged 18 to 65 years.
The pharmacokinetics of quetiapine is linear, there is no difference in pharmacokinetic parameters in men and women.
INDICATIONS
- Acute and chronic psychoses, including schizophrenia;
- treatment of manic episodes in the structure of bipolar disorder;
- treatment of depressive episodes from medium to severe severity in the structure of bipolar disorder.
DOSING MODE
Ketilept В® should be taken orally, regardless of food intake.
Adults with acute and chronic psychoses, including schizophrenia, the drug is prescribed 2 times / day. The total daily dose for the first 4 days of therapy is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3), and 300 mg (day 4). Starting from the 4th day, the usual effective daily dose of the preparation Ketilept В® ranges from 300 mg to 450 mg.
Depending on the clinical effect and tolerance in each patient, the dose can be selected (vary) in the range from 150 mg to 750 mg / day. The maximum recommended daily dose is 750 mg.
To treat acute manic episodes in the structure of bipolar disorder, the drug is prescribed 2 times / day. The total daily dose for the first 4 days of therapy is 100 mg (day 1), 200 mg (day 2), 300 mg (day 3), and 400 mg (day 4). Further selection of a dose up to 800 mg / day by the 6th day is possible with an increase of no more than 200 mg / day. Depending on the clinical response and tolerability in each patient, the dose can be selected in the range from 200 mg to 800 mg / day.
The usual effective dose is in the range from 400 to 800 mg / day.
The maximum recommended daily dose is 800 mg.
To treat depressive episodes in the structure of bipolar disorder, the drug is prescribed 1 time / day for the night. The daily dose for the first 4 days of therapy is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3), and 300 mg (day 4). The recommended dose is 300 mg / day. The maximum recommended daily dose is 600 mg.
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 the withdrawal of the drug Ketilept В® , the drug can be continued at a dose adequate for maintenance therapy. At the resumption of therapy in patients who did not receive Cetilept В® for more than 1 week, the rules of initial dose selection should be followed and an effective dose should be established based on the patient's clinical response.
The recommended initial dose in elderly patients is 25 mg / day, then the dose should be increased by 25-50 mg / day until an effective dose is obtained, which is usually lower than in young patients. Likewise, a more cautious dose selection and reduced doses are recommended for impaired patients or those prone to hypotensive reactions.
Patients with renal and hepatic insufficiency are recommended to begin therapy with 25 mg / day, then daily to increase the dose of 25-50 mg to achieve an effective dose, depending on the patient's clinical response and individual tolerability.
The efficacy and safety of quetiapine in children and adolescents has not been established.
SIDE EFFECT
The most frequent side effects of quetiapine are drowsiness, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension and dyspepsia.According to the summary of clinical trials, the number of patients who discontinued the drug due to side effects is approximately the same in the groups receiving placebo and quetiapine. As with other antipsychotics, fainting, malignant neuroleptic syndrome, leukopenia, neutropenia and peripheral edema were noted during quetiapine.
The undesirable phenomena observed when taking quetiapine and classified according to the body systems are listed in the following order: very often (> 1/10); often (<1/10 and> 1/100); infrequently (<1/100 and> 1/1000); rarely (<1/1000); very rarely (<1/10 000).
On the part of the hematopoiesis system: often - leukopenia 3 ; infrequently - eosinophilia; very rarely - neutropenia 3 .
From the side of metabolism: often - an increase in body weight 4 , an increase in serum transaminases (ALT, ACT) 5 ; infrequently - increased levels of GGT 5 , total cholesterol, triglycerides after meals; very rarely - hyperglycemia 1.7 , diabetes mellitus 1.7 .
From the nervous system: very often - dizziness 1.6 , drowsiness 2 ; often - headache, anxiety, psychomotor agitation, tremor, fainting 1.6 ; infrequently epileptic seizures 1 .
From the side of the cardiovascular system: often - tachycardia 1.6 , orthostatic hypotension 1.6 .
From the respiratory system: often - rhinitis, pharyngitis.
From the digestive system: often - dry mouth, constipation, diarrhea, dyspepsia, abdominal pain.
From the side of the reproductive system: rarely - priapism.
Allergic reactions: sometimes - hypersensitivity.
Other: often - mild asthenia, peripheral edema; back pain, chest pain, subfebrile, myalgia, dry skin, decreased visual acuity; rarely - malignant neuroleptic syndrome 1 .
1 See "Special instructions".
2 Drowsiness is possible, especially during the first 2 weeks of treatment, which usually occurs when the use of the preparation Ketilept В® continues.
3 In controlled clinical trials of quetiapine, no cases of persistent severe neutropenia or agranulocytosis have been reported. During follow-up after drug registration, leukopenia and / or neutropenia occurred after quetiapine was discontinued. Possible risk factors for leukopenia and / or neutropenia include a previous decrease in the number of white blood cells and the presence of drug-induced leukopenia and / or neutropenia in a history.
4 The increase in body weight is mainly observed in the first weeks of treatment.
5 In some patients, asymptomatic increases in serum transaminase (ALT, ACT) or GGT, which usually occurs with the continuation of quetiapine therapy, have been observed during the use of quetiapine.
6 Like other antipsychotics with alpha 1- adrenergic blocking activity, Ketilept В® can cause orthostatic hypotension with dizziness, tachycardia and (in some patients) syncope, especially in the initial period of dose selection.
7 In very rare cases, during the administration of quetiapine, hyperglycemia and worsening of the course of pre-existing diabetes mellitus were noted.
CONTRAINDICATIONS
- Pregnancy;
- lactation period (breastfeeding);
- Children's age (effectiveness and safety not established);
- Hypersensitivity to the components of the drug.
With caution apply the drug in patients with hepatic insufficiency, convulsive seizures in the history, cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension; in elderly patients.
PREGNANCY AND LACTATION
Category C. The safety and efficacy of quetiapine in pregnancy has not been established.
The use of the drug Ketilept В® during pregnancy is possible only if the intended benefit to the mother exceeds the potential risk to the fetus.
It is not known whether quetiapine is excreted in breast milk. If you need to use the drug Ketilept В® during lactation (breastfeeding), you should decide whether to stop breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER
Patients with renal insufficiency are recommended to begin therapy with 25 mg / day, then daily to increase the dose of 25-50 mg to achieve an effective dose, depending on the patient's clinical response and individual tolerability.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution apply the drug in patients with hepatic insufficiency.
Patients with hepatic insufficiency are recommended to begin therapy with 25 mg / day, then daily to increase the dose of 25-50 mg to achieve an effective dose, depending on the clinical response of the patient and individual tolerability.
APPLICATION FOR CHILDREN
Contraindication: child age (efficacy and safety not established).
APPLICATION IN ELDERLY PATIENTS
With caution apply the drug in elderly patients.
SPECIAL INSTRUCTIONS
Cardiovascular diseases
Ketilept В® should be used with caution in patients with diagnosed cardiovascular diseases, cerebral vascular diseases or other conditions predisposing to hypotension.
Cetepype В® can cause orthostatic hypotension, especially in the initial period of dose adjustment; this is more common in the elderly than in younger patients.
There was no correlation between the use of quetiapine and the increase in the QT interval c . However, when prescribing quetiapine concomitantly with drugs that extend the interval of QT c , care must be taken, especially in elderly patients.
Convulsive seizures
There were no differences in the incidence of seizures in patients taking ceftilept В® or placebo. However, as with other antipsychotics, caution should be exercised in the treatment of patients with a history of seizures.
Late dyskinesia
Ketilept В® , like other antipsychotics, with prolonged use can cause tardive dyskinesia. 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, muscular rigidity, instability of the autonomic nervous system, an increase in the level of CK. In such cases, cetyleptВ® should be discontinued and treated accordingly.
Reactions of sudden cancellation
Symptoms of acute withdrawal (including nausea, vomiting, insomnia) are described in very rare cases after a sharp discontinuation of antipsychotic drugs in high doses. Possible relapse of the symptoms of psychosis and the emergence of disorders associated with involuntary movements (akathisia, dystonia, dyskinesia).Therefore, if it is necessary to stop taking the drug, a gradual dose reduction is recommended.
Lactose intolerance
When preparing a diet for patients with lactose intolerance, it should be taken into account that tablets coated with a film coat of 25 mg, 100 mg, 150 mg, 200 mg and 300 mg contain lactose, respectively, 4.42 mg, 17.05 mg, 25.47 mg, 34.1 mg and 50.94 mg. The drug should not be given to patients with rare hereditary disorders of tolerance to galactose, hereditary lactase deficiency lapp or glucose-galactose absorption disorder.
Given that quetiapine mainly affects the central nervous system, the drug should be used with caution in combination with other drugs that have a CNS depressant effect or alcohol.
A relationship has been established between the use of quetiapine in low doses and the decrease in thyroid hormone levels (T 4 and free T 4 ). The maximum decrease occurred during the first 2 or 4 weeks of taking quetiapine, but with a prolonged course of treatment no further reduction occurred. In almost all cases, discontinuation of quetiapine treatment resulted in the restoration of T 4 and free T 4 levels, regardless of the duration of the course of treatment. A less significant decrease in T 3 and reversible T 3 was observed only with the use of quetiapine in higher doses. The levels of TSH and TSG (thyroxine-binding globulin) remained unchanged. Clinically pronounced hypothyroidism was not detected.
Like other antipsychotics, quetiapine may induce prolongation of the QT c interval, but in clinical trials this effect was not permanent.
Impact on the ability to manage vehicles and mechanisms
Due to the effect on the CNS, it may cause drowsiness. Therefore, during the first stages of treatment, during an individually defined period of time, the patient should be prohibited from driving motor vehicles or dangerous mechanisms. In the future, the degree of restrictions is set individually.
OVERDOSE
Data on quetiapine overdose are limited.
Symptoms: drowsiness, excessive sedation, tachycardia, decreased blood pressure. Very rarely reported cases of severe overdose of quetiapine, resulting in death or coma.
Treatment: specific antidotes quetiapine no. Symptomatic therapy and activities aimed at maintaining respiratory function, cardiovascular system, ensuring adequate oxygenation and ventilation.
Medical supervision should continue until the patient's full recovery.
DRUG INTERACTION
Special care is required when assigning Ketilept В® in combination with other drugs acting on the central nervous system.
The results of in vitro studies have shown that quetiapine 9 and its in vivo metabolites are weak inhibitors of metabolic processes mediated by the cytochrome P450 isozymes system (1A2, 2C9, 2C19, 2D6 and 3A4). CYP3A4 is the major enzyme performing P450 mediated metabolism of quetiapine.
The effect of other drugs on Ketilept В®
Phenytoin: simultaneous application Ketilept preparation В®with phenytoin leads to increased clearance of quetiapine in the plasma, as phenytoin induces cytochrome P450 isoenzyme 3A4. Combining quetiapine (250 mg 3 times / day) and phenytoin (100 mg, 2 times / day) 5 times increased the average clearance quetiapine after ingestion.
For correction the symptoms of schizophrenia in patients receiving both quetiapine and phenytoin, may require higher doses Ketilept В® or other hepatic enzyme inducers (including carbamazepine, barbiturates, rifampicin, SSC). In these cases, care is required when canceling phenytoin and / or transition to valproate, which has no enzyme-inducing properties.
Carbamazepine: simultaneous application Ketilept preparation В®carbamazepine quetiapine significantly increases the clearance, leading to reduction of quetiapine systemic exposure. Due to this interaction may require higher doses of the drug Ketilept В® .
Inhibitors CYR3A: simultaneous application Ketilept preparation В® with ketoconazole (200 mg / day for 4 days), a potent inhibitor of isozyme CYR3A reduces quetiapine clearance after ingestion by 84%, resulting in a quetiapine plasma concentration is increased, on average, to 235%. Care should be taken when combined preparation Ketilept В®ketoconazole and other inhibitors of cytochrome P450 isoenzymes, antifungals from the group consisting of azoles and macrolide antibiotics (including itraconazole, fluconazole, erythromycin); should correspondingly reduce the dose of quetiapine.
Cimetidine: daily regular administration 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 plasma after oral administration . With the simultaneous application of the drug Ketilept В® with cimetidine is not necessary 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 plasma after oral administration.
Risperidone and haloperidol: simultaneous application of quetiapine (300 mg, 2 times / day) with antipsychotic haloperidol (7.5 mg of 2 times / day) or risperidone (3 mg, 2 times / day) did not alter the pharmacokinetics of quetiapine in the equilibrium state.
Fluoxetine and imipramine: simultaneous application 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 / day) did not alter the equilibrium pharmacokinetics of quetiapine.
Effect of drug Ketilept В® other drugs
Antipyrin:repeated daily administration of Quetiapine (up to 750 mg / day, with 3-fold reception) did not cause clinically significant changes in the clearance of antipyrine or its metabolites. This indicates that quetiapine has no significant inhibitory action on the hepatic enzymes involved in the metabolism of antipyrine mediated by cytochrome P450.
Lithium: simultaneous application of quetiapine (250 mg 3 times / day) with lithium had no effect on any pharmacokinetic parameters of lithium in equilibrium.
Lorazepam: average clearance of lorazepam after intake (single dose of 2 mg) was reduced by 20% during quetiapine (250 mg 3 times / day).
Smoking did not affect the clearance of quetiapine in the blood plasma.
As clinical studies have demonstrated that quetiapine potentiate the cognitive and motor effects of ethanol in patients with psychosis, one should not drink alcohol during the course of treatment Ketilept В® .
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 25 В° C. Shelf life - 5 years.
