Expiration date: 03/2025
Structure and Composition:
Tablets, film-coated. One tablet contains quetiapine 100, 200 or 300 mg
(In the form of quetiapine fumarate - 28.78 115.13 172.70 230.26 and 345.40 mg, respectively)
Excipients: lactose MCC monohydrate sodium carboxymethylstarch (type A) povidone magnesium stearate, silicon dioxide colloidal anhydrous
composition of the shell: titanium dioxide, hypromellose lactose monohydrate macrogol 4000, triacetin (triatsetilglitserol)
in addition to the shell tablets 150 mg and 200 mg: iron oxide yellow dye dye iron oxide red
Patients in dark glasses with a PE lid with control of the first opening and the damper bellows 30 or 60 pieces. or in blister 10 pcs. a stack of cardboard 3 or 6 blister.
Description pharmaceutical form:
Tablets, film-coated, 100 mg: white or almost white, round, biconvex, film-coated, engraved with the letters "E" and the numbers "202" - on one side of the tablet, without or almost odorless.
Tablets, film-coated, 200 mg: dark-pink, round biconvex, film-coated, engraved with the letters "E" and the numbers "204" - on one side of the tablet, without or almost odorless.
Tablets, film-coated, 300 mg: white or almost white, round biconvex, film-coated, engraved with the letters "E" and the numbers "205" - on one side of the tablet, without or almost odorless.
Pharmacokinetics:
When taken orally, quetiapine is well absorbed from the gastrointestinal tract and extensively metabolised in the liver. The major metabolites found in the plasma does not possess a pronounced pharmacological activity.
Food intake did not significantly affect the bioavailability of quetiapine. T1 / 2 is about 7 hours. Approximately 83% of quetiapine is bound to plasma proteins. The pharmacokinetics of quetiapine linear, differences in pharmacokinetic parameters 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 less than approximately 25% in patients with severe renal impairment (Cl creatinine <30 ml / min / 1,73m2) and in patients with liver disease (stable alcoholic cirrhosis), but the individual clearance figures are in the range corresponding to those in healthy humans.
Approximately 73% of quetiapine is excreted in urine and 21% - with the feces. Less than 5% of quetiapine is not metabolized and is excreted unchanged by the kidneys, or the faeces. It is found that CYP3A4 metabolism is a key enzyme quetiapine mediated by cytochrome P450.
The pharmacokinetics of quetiapine study in varying dosage is shown in appointing quetiapine before receiving ketoconazole or concurrently with ketoconazole, occurs Cmax increase and AUC quetiapine, on average 235 and 522%, respectively, as well as a decrease in clearance quetiapine, on average, 84% . T1 / 2 of quetiapine was increased, but the average Tmax was not changed.
Quetiapine and its metabolites have some weak inhibitory activity against the enzymes cytochrome R4501A2, 2C9, 2C19, 2D6 and 3A4, but only at concentrations exceeding 10-50 times the concentration observed with commonly used effective dosage of 300-450 mg / day.
Based on the results of in vitro, should not be expected that co-administration of quetiapine with other drugs will result in clinically significant ingibirovaniyumetabolizma other drugs mediated by cytochrome P450.
Description of the pharmacological actions:
Mechanism of action. Quetiapine is an atypical antipsychotic, which exhibits higher affinity for serotonin receptors (5HT2) receptors than for dopamine D1 and D2 brain. Quetiapine also has a high affinity for histamine and adrenoceptor & alpha1-and less towards adrenoceptor & alpha2-. There were no appreciable affinity for cholinergic muscarinic to quetiapine and benzodiazepine receptors. The standard tests shows quetiapine antipsychotic activity.
Pharmacodynamic effects
The results of the study of extrapyramidal symptoms (EPS) in animals revealed that quetiapine is weak catalepsy in a dose effective blocking dopamine D2-receptors. Quetiapine is a selective decrease in the activity of mesolimbic A10 dopaminergic neurones versus the A9 nigrostriatal neurones involved in motor function.
In clinical trials, there were no differences between the use of quetiapine (at a dose of 75-750 mg / day) and placebo in the incidence of cases of extrapyramidal symptoms and concomitant use of anticholinergics. Quetiapine does not cause long-term increase prolactin concentration in blood plasma. Numerous studies fixed dose there were no differences in the level of prolactin using quetiapine or placebo.
In clinical trials, quetiapine demonstrated efficacy in treating both positive and negative symptoms of schizophrenia.
Effects of quetiapine on 5HT2 and D2 receptors lasts up to 12 hours after ingestion.
Indications:
Treatment of conditions such as:
- acute and chronic psychoses, including schizophrenia
- manic episodes of bipolar disorder in the structure
- depressive episodes of moderate to severe degree of weight in the structure of bipolar disorder.
Contraindications:
- hypersensitivity to any component of the drug
- Children's age (efficacy and safety have not been studied).
Precautions: patients with cardiovascular and cerebrovascular disease, or other conditions predisposing to hypotension, advanced age, liver failure, seizures in history.
Application of pregnancy and breastfeeding:
Category on the effects on the fetus by FDA - C.
The safety and efficacy of quetiapine during pregnancy has not been established. Ketilept should not be used during pregnancy except in cases where the benefit to the mother outweighs the potential risk to the fetus.
The period of breast-feeding: It is unknown whether the quetiapine is released into breast milk in humans. Therefore, lactating women are advised not to breastfeed while receiving Ketilept drug.
Side effect:
The most common side effects of quetiapine are somnolence, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension and dyspepsia. In total According to clinical studies, the number of patients who stopped taking the drug because of side effects, is approximately the same in the groups receiving placebo and quetiapine.
As in the case of other antipsychotic drugs, while taking quetiapine marked syncope, neuroleptic malignant syndrome, leukopenia, neutropenia and peripheral edema.
Adverse events observed during administration of quetiapine and classified by body system, are listed below in the following order: very often -> 1/10 - <1/10 and> 1/100 infrequently - <1/100 and> 1/1000 rare - <1/1000 rarely - <1/10000.
Blood and lymphatic system: often - leukopenia, rarely - very rarely eosinophilia - neytropeniya3.
Immune system disorders: rarely - hypersensitivity.
Metabolism and nutrition: often - increase tela4 weight, increased serum transaminases (ALT, ACT) 5 very rarely - giperglikemiya1, diabetes diabet1,7.
Disorders of the nervous system: very often - golovokruzhenie1,6, sonlivost2 often - headache, anxiety, agitation, tremor, obmoroki1,6 rare - epileptic pripadki1.
Cardiac function: often - tahikardiya1,6.
Vascular disorders: often - orthostatic gipotenziya1,6.
Respiratory and functions of the organs of the chest cavity and mediastinum: often - rhinitis, pharyngitis.
Violations of the gastrointestinal tract function: often - dry mouth, constipation, diarrhea, dyspepsia, abdominal pain.
Violations of the functions of the reproductive organs and mammary glands: rarely - priapism.
General disorders and the condition of the tissue at the injection site: common - easy asthenia, peripheral edema, rarely - neuroleptic malignant sindrom1.
Laboratory tests: infrequently - raising glyutamiltranferazy gamma (gamma-GT) 5, improving postprandial triglycerides, increased total cholesterol.
Other: back pain, chest pain, low-grade fever, myalgias, skin dryness, decreased visual acuity.
1 See. "Special Instructions" section.
2 Can drowsiness, especially during the first two weeks of treatment, which usually passes with continued use of the drug Ketilept.
3 In controlled clinical trials quetiapine no cases of sustained severe neutropenia or agranulocytosis. The observation period after the registration of the drug leukopenia and / or neutropenia were after cessation of quetiapine. Possible risk factors for leucopenia and / or neutropenia include pre-existing reduction in the number of white blood cells and the presence of drug leukopenia and / or neutropenia in history.
4 The increase in body weight is observed mainly in the first weeks of treatment.
5 In some patients during administration of quetiapine observed asymptomatic increase in serum transaminases (ALT, ACT) or gamma-GT. This increase is usually held at the continuing administration of quetiapine.
6 As with other antipsychotics with alpha1-adrenoblokiruyuschey & activity Ketilept may cause orthostatic hypotension with dizziness, tachycardia, and (in some patients), syncope, especially in the initial period of dose adjustment (see. "Special Instructions" section).
7 In very rare cases during quetiapine marked hyperglycemia, and worsening of pre-existing diabetes.
The connection of quetiapine at low doses and reduce the levels of thyroid hormone (T4 and free T4). The maximum decrease occurred during the first two to four weeks of quetiapine, but long-term course of treatment further decline did not occur. In almost all cases, termination of quetiapine led to recovery of T4 and free T4 levels regardless of the duration of treatment.
Less than significant decrease in T3 and reverse T3 was only observed at the higher doses of quetiapine.
Levels of TSH and thyroxine-binding globulin (TBG) were unchanged. Symptomatic hypothyroidism is not detected.
As with other antipsychotics, quetiapine may cause lengthening of QTc interval in clinical trials, but this effect was not permanent. The reactions to the sudden cancellation of the drug (see. "Special Instructions").
Drug Interactions:
Extreme care is required when assigning Ketilept drug in combination with other drugs acting on the central nervous system.
The results of in vitro studies demonstrated that 9 quetiapine and its in vivo metabolites are weak inhibitors of metabolic processes mediated by the cytochrome P450 enzymes (1A2, 2C9, 2C19, 2D6 and 3A4). CYP3A4 is the main enzyme, carrying out P450 mediated metabolism of quetiapine.
The influence of other drugs on Ketilept.
Phenytoin: Ketilept combination drug phenytoin increases the clearance of quetiapine in the plasma, as Phenytoin induces the cytochrome P450 isoenzyme ZA4. Combining quetiapine (250 mg three times a day) and phenytoin (100 mg, 2 times daily) in 5 times the average clearance quetiapine increased after oral administration.
To correct the symptoms of schizophrenia in patients receiving both quetiapine and phenytoin may require higher doses Ketilept or other hepatic enzyme inducers (such as carbamazepine, barbiturates or corticosteroids rifampicin). In these cases, caution is required when canceling phenytoin and / or switch to valproate, which has no enzyme-inducing properties.
Carbamazepine: concomitant use with carbamazepine significantly increased the clearance of quetiapine, which reduced systemic quetiapine exposure. Due to this interaction may require higher doses of the drug Ketilept.
Inhibitors R4503A: combined use of ketoconazole (200 mg / day for 4 days), a potent inhibitor of the enzyme cytochrome R4503A, decreased clearance quetiapine after oral administration of 84%, resulting in a quetiapine plasma concentration is increased in the average by 235% . Therefore, caution is required in combination with the drug Ketilept ketoconazole and other inhibitors of cytochrome P450, azole antifungals and macrolide antibiotics (such as itraconazole, fluconazole and erythromycin) must be a corresponding reduction in the dose of quetiapine. Cimetidine: daily regular administration of cimetidine (400 mg three times a day for 4 days), which is a nonspecific inhibitor of enzymes, leading to a decrease of 20% of the mean clearance of quetiapine (150 mg three times a day) from the plasma after oral administration . With the simultaneous use of the drug cimetidine Ketilept with no need to change the dose of the drug Ketilept.
Thioridazine: a dose of (200 mg, 2 times a day) increased by 65% ??clearance of quetiapine (300 mg, 2 times a day) from the plasma after oral administration.
Risperidone and haloperidol: a combination of quetiapine (300 mg twice daily) haloperidol (7.5 mg, 2 times a day) or risperidone (3 mg 2 times a day) did not alter the pharmacokinetics of quetiapine equilibrium.
Fluoxetine and imipramine: Combining quetiapine (300 mg, 2 times a day) with the inhibitor, CYP3A4 and CYP2D6 fluoxetine (60 mg 1 time per day) or a known inhibitor of CYP2D6 imipramine (75 mg, 2 times a day) did not alter the equilibrium pharmacokinetics of quetiapine.
Effect of the drug on Ketilept other drugs
Antipyrine: repeated daily administration of quetiapine (up to 750 mg per day at 3-fold reception) did not cause clinically significant changes in the clearance of antipyrine or its metabolites. This indicates that quetiapine does not have a significant inhibitory effect on the liver enzymes involved in the metabolism of antipyrine mediated by cytochrome P450.
Lithium: a combination of quetiapine (250 mg three times a day) with lithium had no effect on any pharmacokinetic parameters of lithium in equilibrium.
Lorazepam: average clearance after oral administration of lorazepam (2 mg single dose) was reduced by 20% during quetiapine (250 mg three times a day).
Smoking did not affect clearance from the blood plasma of quetiapine.
Clinical studies have demonstrated that quetiapine potentiate the cognitive and motor effects of alcohol in patients with psychosis. Therefore, you should not drink alcohol during the course of treatment Ketilept.
Dosage and administration:
Inside, regardless of meals, 2 times a day.
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 (Day 1), 100 mg (in Day 2), 200 mg (Day 3) and 300 mg (Day 4).
Starting from the 4th day of the usual effective dose of the drug Ketilept is 300-450 mg / day. Depending on the clinical response and tolerability in each patient, the dose can be specified in the range of 150 to 750 mg / day. The maximum recommended dose - 750 mg / day.
Treatment of acute manic episodes of bipolar disorder in the structure: the drug is administered 2 times a day. The total daily dose for the first 4 days of treatment is 100 mg (Day 1), 200 mg (Day 2), 300 mg (Day 3) and 400 mg (Day 4). Further titration to 800 mg / day to day 6 with possible increase of not more than 200 mg / day. Depending on the clinical response and tolerability in each patient, the dose can be specified in the range of from 200 to 800 mg / day. The usual effective dose is in the range from 400 to 800 mg / day. Maksimalnaya recommended dose - 800 mg / day.
Treatment of depressive episodes of bipolar disorder in the structure: the drug is administered 1 time per day. The daily dose during the first 4 days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3), 300 mg (Day 4). The recommended dose is 300 mg / day. The maximum recommended daily dose - 600 mg / day.
Elderly patients: The recommended initial dose - 25 mg per day and then to increase the dose should be 25-50 mg per day to achieve an effective dose which is usually lower than in younger patients. Similarly, a more cautious titration and lower doses are recommended for debilitated patients or predisposed to hypotensive reactions.
Children and adolescents. Efficacy and safety of quetiapine in children and adolescents has not been established.
Renal and hepatic insufficiency. It is recommended to begin treatment with 25 mg / day, then increase the daily dose of 25-50 mg to achieve an effective dose, depending on the clinical response of the patient and individual tolerability.
Supportive therapy. For maintenance of remission advisable to use the lowest dose. Patients should be periodically examine in order to determine the need for maintenance treatment.
Resuming treatment in patients previously treated with quetiapine. With the resumption of therapy in less than 1 week after discontinuation of the drug Ketilept the drug can be continued at a dose used for maintenance therapy. With the resumption of therapy in patients who have not received Ketilept more than 1 week, you should follow the rules of the initial selection of the dose and to establish an effective dose of the patient's clinical response.
Overdose:
Data on overdose of quetiapine limited.
Symptoms: The symptoms reported were mainly the result of amplification of the known pharmacological effects of the drug such as drowsiness and excessive sedation, tachycardia and blood pressure reduction. Very rarely reported cases of severe overdose of quetiapine, resulting in death or coma.
Treatment: In cases of severe intoxication, symptomatic treatment should be carried out and measures aimed at the maintenance of respiratory function, cardiovascular system, ensuring adequate oxygenation and ventilation. Specific antidote to quetiapine no.
Medical monitoring should be continued until the patient's full recovery.
Special instructions:
Cardiovascular diseases. Ketilept should be used with caution in patients with diagnosed cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension.
Ketilept can cause orthostatic hypotension, particularly in the initial stage of dose refinement is often occurs in the elderly than in younger patients.
There was no relationship between quetiapine and increase the QTc-interval. However, the appointment of quetiapine in conjunction with drugs, prolongs the QTc interval, caution should be exercised, especially in the elderly.
Seizures. There were no differences in the incidence of seizures in patients treated with quetiapine or placebo. However, as well as in the treatment of other antipsychotics, it is recommended to use caution when treating patients with the presence of seizures in history.
Tardive Dyskinesia. Ketilept as other antipsychotic drugs, with long-term use may cause tardive dyskinesia. In case of signs and symptoms of tardive dyskinesia should consider lowering the dose or eliminate the drug Ketilept.
Neuroleptic malignant syndrome. It may be associated with antipsychotic treatment conducted. The clinical manifestations of the syndrome include hyperthermia, altered mental status, muscular rigidity, instability of the autonomic nervous system, increased creatine phosphokinase levels. In such cases, quetiapine should be discontinued and appropriate treatment.
Reactions sudden cancellation. Symptoms of acute cancellation, including nausea, vomiting, and insomnia have been described in very rare cases, after abrupt cessation of high doses of antipsychotic drugs. Possible recurrence of symptoms of psychosis and the emergence of disorders associated with involuntary movements (akathisia, dystonia and dyskinesia). Therefore, if necessary, discontinuation is recommended a gradual reduction in dose.
Lactose intolerance. In drawing up the diet for patients with lactose intolerance should be aware that the tablets covered with a film cover 25, 100, 150, 200 and 300 mg respectively contain 4.42 17.05 25.47 34.1 and 50.94 mg lactose. This drug should not be administered to patients with rare hereditary disorders galactose intolerance, hereditary deficiency syndrome or lactose Sami nevsasyvaniya glucose-galactose. Considering that quetiapine primarily affect the central nervous system, it should be used with caution in combination with other drugs having inhibitory action on the central nervous system, including alcohol.
Effects on ability to drive vehicles and mechanisms. Due to the effect on the central nervous system, Ketilept can cause drowsiness. Therefore, in the early stages of treatment, for individually defined period of time, the patient should not be allowed to drive motor vehicles or dangerous machinery. In the future, the degree of limitation should be established for each patient individually.
