KETÏLEPT

Active material: Quetiapine
When ATH: N05AH04
CCF: Antipsychotic drug (anxiolytic)
ICD-10 codes (testimony): F20, F21, F22, F23, F25, F29, F30, F31
When CSF: 02.01.02.04
Manufacturer: EGG PHARMACEUTICALS Plc (Hungary)

Pharmaceutical form, composition and packaging

Pills, Film-coated white or nearly white, round, lenticular, engraved letters “IS” and the number of “202” on one side, with little or no odor.

Excipients: microcrystalline cellulose, lactose monohydrate, sodium karboksikrahmal (Type A), povidone, magnesium stearate, Colloidal anhydrous silica.

The composition of the shell: gipromelloza, Titanium dioxide, lactose monohydrate, macrogol 4000, triacetine (triacetilglicerol).

10 PC. – blisters (3) – packs cardboard.
10 PC. – blisters (6) – packs cardboard.
30 PC. – vials of dark glass (1) – packs cardboard.
60 PC. – vials of dark glass (1) – packs cardboard.

Pills, Film-coated dark pink, round, lenticular, engraved letters “IS” and the number of “204” on one side, with little or no odor.

Excipients: microcrystalline cellulose, lactose monohydrate, sodium karboksikrahmal (Type A), povidone, magnesium stearate, colloidal silicon dioxide (anhydrous).

The composition of the shell: gipromelloza, Titanium dioxide, lactose monohydrate, macrogol 4000, triacetine (triacetilglicerol), dye iron oxide yellow, iron oxide red dye.

10 PC. – blisters (3) – packs cardboard.
10 PC. – blisters (6) – packs cardboard.
30 PC. – vials of dark glass (1) – packs cardboard.
60 PC. – vials of dark glass (1) – packs cardboard.

Pills, Film-coated white or nearly white, round, lenticular, engraved letters “IS” and the number of “205” on one side, with little or no odor.

Excipients: microcrystalline cellulose, lactose monohydrate, sodium karboksikrahmal (Type A), povidone, magnesium stearate, Colloidal anhydrous silica.

The composition of the shell: gipromelloza, Titanium dioxide, lactose monohydrate, macrogol 4000, triacetine (triacetilglicerol).

10 PC. – blisters (3) – packs cardboard.
10 PC. – blisters (6) – packs cardboard.
30 PC. – vials of dark glass (1) – packs cardboard.
60 PC. – vials of dark glass (1) – packs cardboard.

Pharmacological action

Antipsychotic drug (anxiolytic). It exhibits a high affinity for the serotonin 5-HT₂-Receptor, than for the dopamine D₁– and D₂-brain receptors. It also has a greater affinity for histamine and α₁-adrenoceptors and smaller towards α₂-adrenoceptor. There were no appreciable affinity of quetiapine for m-choline- and benzodiazepine receptors.

The standard tests quetiapine shows antipsychotic activity.

Results of the study of extrapyramidal symptoms (EPS) animals showed, that quetiapine causes weak catalepsy in a dose, effectively blocking the dopamine D₂-receptors.

Quetiapine causes selective reduction of activity A10 mesolimbic dopaminergic neurons compared to the A9 nigrostriatal neurons, involved in motor function.

In clinical trials (dose 75-750 mg / day) there were no differences between the quetiapine and placebo in the incidence of cases of CSE and the concomitant use of anticholinergic drugs.

Quetiapine does not cause long-term increase of the concentration of prolactin in the blood plasma. Numerous studies fixed dose there was no difference in the level of prolactin using quetiapine or placebo.

In clinical studies, quetiapine shown efficacy in the treatment of positive and, and negative symptoms of schizophrenia.

Effects of quetiapine by 5-HT₂– and D₂-It continues until buds 12 h after dosing.

Pharmacokinetics

Absorption

When using inside quetiapine is well absorbed from the gastrointestinal tract. Food intake did not significantly affect the bioavailability of quetiapine.

Distribution

Plasma protein binding – about 83%.

Metabolism

Quetiapine actively metaboliziruetsya in baked. Established, that CYP3A4 is the key enzyme CYP-mediated metabolism of quetiapine.

The main metabolites, located in a plasma, do not possess a pronounced pharmacological activity. Quetiapine and some of its metabolites have poor inhibitory activity against isozymes CYP1A2, CYP2С9, CYP2C19, CYP2D6 и CYP3А4, but only at concentrations of, in 10-50 times the concentration, observed with normal effective dose 300-450 mg / day.

Deduction

T_1/2 is about 7 no. About 73% quetiapine is excreted in the urine and 21% with feces. Less 5% Quetiapine is not metabolized and excreted unchanged by the kidneys or faeces.

Pharmacokinetics in special clinical situations

The average plasma clearance of quetiapine is less about 25% in patients with severe renal insufficiency (CC<30 ml / min / 1.73 m²) and in patients with liver disease (stable alcoholic cirrhosis), but the individual clearance figures are within, relevant to healthy people.

The study pharmacokinetics of quetiapine in varying doses to the appointment quetiapine receiving ketoconazole or concurrently with ketoconazole, It resulted in an increase, average, C_max and AUC quetiapine of 235% and 522%, respectively, and also led to a decrease in clearance of quetiapine, average, on 84%. T_1/2 quetiapine increased, but the average time to reach C_max It did not change.

Based on in vitro, not be expected to, that co-administration of quetiapine with other drugs will result in clinically significant inhibition of CYP-mediated metabolism of other drugs.

The average clearance of quetiapine in elderly patients 30-50% less, than in patients between the ages of 18 to 65 years.

The pharmacokinetics of quetiapine linear, differences in pharmacokinetic parameters in men and women is not observed.

Testimony

- Acute and chronic psychosis, including schizophrenia;

- The treatment of manic episodes in bipolar disorder.

Dosage regimen

Ketïlept^® It should be taken into 2 times / day, regardless of the meal.

In Adult total daily dose is in the first 4 days of therapy is 50 mg (1-Day), 100 mg (2-Day), 200 mg (3-Day) and 300 mg (4-Day). Starting from 4th day, usual effective daily dose is 300 mg.

Depending on the clinical response and tolerability in each patient, dose can be specified in the range of 150 mg 750 mg / day. Safety of daily doses above 800 mg in clinical studies has not been evaluated.

At acute manic episodes in bipolar disorder total daily dose is in the first 4 days of therapy is 100 mg (1-Day), 200 mg (2-Day), 300 mg (3-Day) and 400 mg (4-Day). Subsequent 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, dose can be specified in the range of 200 mg 800 mg / day.

Typically, an effective dosage is in the range of 400 to 800 mg / day.

For maintenance of remission is advisable to apply the lowest dose. Patients should be periodically investigate to determine the need for maintenance therapy.

With the resumption of therapy less than 1 a week after the cancellation Ketilepta^®, the drug can be continued at a dose, used for maintenance therapy. When resuming therapy in patients, who did not receive Ketilept^® better 1 of the week, must comply with the rules of the initial dose adjustment and to establish an effective dose for the patient's clinical response.

The recommended starting dose in elderly patients is 25 mg / day, then the dose should be increased by 25-50 mg / day to achieve effective dose, which is usually below, than in younger patients. Careful selection and lower dose is also recommended for debilitated patients or predisposed to hypotensive reactions.

Patients with kidney and hepatic insufficiency It recommended to start therapy 25 mg / day, then increase the daily dose of 25-50 mg to achieve effective dose, depending on the patient's clinical response and tolerability of the individual.

Side effect

The most common side effects are drowsiness, quetiapine, dizziness, dry mouth, umerennaya asthenia, constipation, tachycardia, ortostaticheskaya gipotenziya and dyspepsia. By total number of clinical trials of patients, stop taking the drug because of side effects, approximately the same Group, placebo and quetiapine. As in the case of use of other antipsychotics, while taking quetiapine marked fainting, neuroleptic malignant syndrome, leukopenia, neutropenia and peripheral edema.

Adverse events, observed with quetiapine and classified by body system, are listed in the following order: Often >1/10); often (<1/10 and > 1/100); sometimes (<1/100 and >1/1000); rarely (<1/1000); rarely (<1/10.000).

From the hematopoietic system: often – leukopenia; sometimes – eozinofilija; rarely – neutropenia.

Metabolism: often – weight gain (mainly in the first week of treatment), increase in serum transaminases (GOLD, ACT); sometimes – increase the level of GGT, total cholesterol, postprandial triglyceride (asymptomatic increase usually took place while continuing the introduction of quetiapine); rarely – giperglikemiâ, diabetes.

From the central and peripheral nervous system: Often – dizziness, drowsiness (especially during the first two weeks of treatment, usually passes with continued use of the drug); often – headache, alarm, psychomotor agitation, tremor, swoon; sometimes – seizures.

Cardio-vascular system: often – tachycardia, orthostatic hypotension.

The respiratory system: often – rhinitis, pharyngitis.

From the digestive system: often – dry mouth, constipation, diarrhea, dyspepsia, abdominal pain.

Reproductive system: rarely – priapism.

Allergic reactions: sometimes – hypersensitivity.

Other: often – legkaya asthenia, peripheral edema; lower back pain, chest pain, subfebrilitet, myalgia, xerosis, reduced visual acuity; rarely – neuroleptic malignant syndrome.

Contraindications

- Pregnancy;

- Lactation (breast-feeding);

- Children's age (efficacy and safety have not been established);

- Hypersensitivity to the drug.

FROM caution use the drug in patients with hepatic insufficiency, seizures in history, cardiovascular and cerebrovascular diseases, or other conditions, predisposing to hypotension; in elderly patients.

Pregnancy and lactation

Category C. The safety and efficacy of quetiapine during pregnancy has not been established.

Application Ketilepta^® Pregnancy may only, when the intended benefits to the mother outweighs the potential risk to the fetus.

Unknown, whether it is allocated quetiapine in breast milk. If necessary, use Ketilepta^® lactation (breast-feeding) should decide the issue of termination of breastfeeding.

Cautions

Cardiovascular diseases

Ketïlept^® should be used with caution in patients with diagnosed cardiovascular disease, cerebrovascular diseases or other conditions, predisposing to hypotension.

Ketïlept^® can cause orthostatic hypotension, especially in the initial period of dose specification; This often occurs in the elderly, than in younger patients.

There was no relationship between quetiapine and an increase in the QT interval_c. But, the appointment of quetiapine together with drugs, prolong the QT interval_from, Care must be taken, especially in the elderly.

Seizures

There were no differences in the incidence of seizures in patients, taking Ketilept^® or placebo. But, as well as in the treatment of other antipsychotic drugs, It recommended caution in patients with the presence of a history of seizures.

Pozdnyaya dyskinesia

Ketïlept^®, Like other antipsychotics, prolonged use can cause tardive dyskinesia. In case of signs and symptoms of tardive dyskinesia should consider dose reduction or drug discontinuation.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome may be associated with the ongoing antipsychotic treatment. The clinical manifestations of the syndrome include hyperthermia, altered mental status, muscle rigidity, volatility of the autonomic nervous system, an increase CPK urovnja. In such cases Ketilept^® It should be repealed and treated appropriately.

Reactions sudden cancellation

Symptoms of acute cancel (incl. nausea, vomiting, insomnia) described in very rare cases after abrupt cessation of antipsychotic drugs in high doses. Possible recurrence of psychotic symptoms and the appearance of disorders, associated with involuntary movements (akathisia, dystonia, dyskinesia). Therefore, if necessary, discontinuation is recommended a gradual reduction of the dose.

Lactose intolerance

In drawing up the diet for patients with lactose intolerance should be considered, tablets, Film-coated 100 mg, 200 mg 300 mg contain lactose, respectively 17.05 mg, 34.1 mg 50.94 mg. This drug should not be administered to patients with rare hereditary disorders of tolerance to galactose, Sami hereditary lactase deficiency or malabsorption syndrome glucose-galactose. Taking into account, Chto quetiapine, mainly, It affects the CNS, the drug should be used with caution in combination with other drugs, having a depressing effect on the central nervous system, or alcohol.

In controlled clinical trials, no cases of quetiapine 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 history.

As with other antipsychotics with alpha₁-adrenoblokiruyuschey activity, Ketïlept^® may cause orthostatic hypotension with dizziness, tachycardia and (some patients) swoon, especially in the initial period titration.

In very rare cases during quetiapine marked hyperglycemia, and worsening of pre-existing diabetes.

The connection to the reception kvetiamina induced by low doses of decreased levels of thyroid hormone (T₄ and a free T₄). The maximum decrease occurred during the first two to four weeks of quetiapine, but the duration of treatment further decline did not occur. Less than significant decrease in T_from and reverse T_from It was only observed at the higher doses of Quetiapine. Levels of TSH and TBG (thyroxine-binding globulin) remained unchanged. In nearly all cases, cessation of quetiapine led to recovery of T levels₄ and free T₄ regardless of the duration of treatment. Symptomatic hypothyroidism is not detected.

Use in Pediatrics

The efficacy and safety of quetiapine in children and adolescents has not been established.

Effects on ability to drive and use machines

Due to the effect on the central nervous system Ketilept^® May 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 is set individually.

Overdose

Data on overdose of quetiapine limited.

Symptoms: drowsiness, chrezmernaya sedation, tachycardia, decrease in blood pressure. Very rarely reported cases of severe overdose of quetiapine, resulting in death or coma.

Treatment: specific antidotes for quetiapine no. Symptomatic therapy and activities, aimed at maintaining respiratory function, Cardiovascular, ensuring adequate oxygenation and ventilation.

Medical supervision should continue until complete recovery of the patient.

Drug Interactions

Special care is required when assigning Ketilepta^® in combination with other drugs, acting on the central nervous system.

The results of in vitro studies have shown, Chto quetiapine and 9 its metabolites in vivo are weak inhibitors of metabolic processes, mediated by cytochrome P450 isoenzymes (1A2, 2C9, 2C19, 2D6 and 3A4). CYP3A4 is the major enzyme, performing P450 mediated metabolism of quetiapine.

The influence of other drugs on Ketilept^®

Phenytoin: simultaneous use Ketilepta^® phenytoin increases the clearance of quetiapine in the plasma, tk. Phenytoin induces the cytochrome P450 isoenzyme 3A4. The combination of quetiapine (by 250 mg 3 times / day) and phenytoin (by 100 mg 2 times / day) in 5 times the average clearance of quetiapine increased after ingestion.

To correct the symptoms of schizophrenia patients, poluchayushtih odnovremenno quetiapine and phenytoin, may require higher doses Ketilepta^® or other hepatic enzyme inducers (incl. karʙamazepina, ʙarʙituratov, rifampicin, GCS). In these cases, caution is required when canceling phenytoin and / or switch to valproate, which lacks the enzyme-inducing properties.

Carbamazepine: simultaneous use Ketilepta^® carbamazepine significantly increases the clearance of quetiapine, It is leading to reduced systemic quetiapine exposure. Because of this interaction may require higher doses Ketilepta^®.

Inhibitors CYRZA: simultaneous use Ketilepta^® ketoconazole (by 200 mg / day for 4 days), a potent inhibitor of the isoenzyme CYRZA, reduces the clearance of quetiapine after ingestion on 84%, whereby the concentration of quetiapine in the blood plasma increased, average, on 235%. Care should be taken in combination Ketilepta^® ketoconazole and other inhibitors of cytochrome P450 isozymes, azole antifungals and macrolide antibiotics (incl. itraconazole, fluconazole, Erythromycin); must accordingly reduce the dose of quetiapine.

Cimetidine: regular daily administration of cimetidine (by 400 mg 3 times / day for 4 days), which is a nonspecific enzyme inhibitors, It resulted in a 20% reduction in average clearance quetiapine (by 150 mg 3 times / day) from plasma following ingestion. In an application Ketilepta^® with cimetidine is not necessary to change the dose of the first.

Tioridazin: tioridazin (by 200 mg 2 times / day) on 65% increased clearance of quetiapine (by 300 mg 2 times / day) from plasma following ingestion.

Risperidone and galoperidol: the simultaneous use of quetiapine (by 300 mg 2 times / day) with antipsychotic haloperidol (by 7.5 mg 2 times / day) or risperidone (by 3 mg 2 times / day) It did not alter the pharmacokinetics of quetiapine at steady state.

Fluoxetine and imipramine: the simultaneous use of quetiapine (by 300 mg 2 times / day) with an antidepressant and an inhibitor of CYP3A4 and CYP2D6 fluoxetine (by 60 mg 1 time / day) or a known inhibitor of CYP2D6 imipramine (by 75 mg 2 times / day) not alter the pharmacokinetics of quetiapine equilibrium.

Influence Ketilepta^® other drugs

Antipirin: multiple daily administration of quetiapine (to 750 mg / day at 3-fold reception) It did not cause clinically significant changes in clearance of antipyrine or its metabolites. This indicates that, that quetiapine has no significant inhibitory effect on liver enzymes, involved in the metabolism of antipyrine, mediated by cytochrome P450.

Lithium: the simultaneous use of quetiapine (by 250 mg 3 times / day) lithium had no effect on any pharmacokinetic parameters of lithium in equilibrium.

Lorazepam: the average clearance of lorazepam after ingestion (single dose 2 mg) was down 20% while taking quetiapine (by 250 mg 3 times / day).

Smoking did not affect clearance from the blood plasma quetiapine.

As clinical studies have shown, that quetiapine potentiate the cognitive and motor effects of alcohol in patients with psychosis, should not drink alcohol during the course of treatment Ketilept^®.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children at or above 25 ° C.

Do not use after the date printed on the package.