Ketilept - instructions for use, dose, side effects, contraindications

active substance: quetiapine 25 mg, 100 mg, 150 mg, 200 mg or 300 mg (in the form of 28.78 mg, 115.13 mg, 172.70 mg, 230.26 mg and 345.40 mg of quetiapine fumarate, respectively);

Excipients: microcrystalline cellulose, lactose monohydrate, sodium carboxymethyl starch (type A), povidone, magnesium stearate, silicon dioxide colloidal, anhydrous; shell: hypromellose, titanium dioxide, lactose monohydrate, macrogol 4000, triacetin (triacetylglycerol).

Sheath of tablets 150 mg and 200 mg also contains a ferric oxide iron oxide and a ferric oxide red dye.

Description:

Tablets 25 mg. White or almost white, round biconvex tablets coated with a film sheath, engraved with the letter E on one side and number 201 on the other side of the tablet, without or almost no odor.

Tablets of 100 mg. White or almost white, round biconvex tablets coated with a film sheath, engraved with the letter E and number 202 on one side of the tablet, with little or no odor. Tablets 150 mg.Pink, round, biconvex tablets coated with a film sheath, engraved with the letter E and number 203 on one side of the tablet, with little or no odor.

Tablets 200 mg. Dark pink, round, biconvex tablets coated with a film sheath, engraved with the letter E and number 204 on one side of the tablet, with little or no odor.

Tablets 300 mg. White or almost white, round biconvex tablets coated with a film sheath, engraved with the letter E and number 205 on one side of the tablet, without or almost no odor.

Pharmacotherapeutic group:Antipsychotic agent (antipsychotic)

ATX: & nbsp

N.05.A.H.04 Quetiapine

Pharmacodynamics:

Mechanism of action

Quetiapine is an atypical antipsychotic drug that exhibits a higher affinity for serotonin receptors (5HT₂) than to dopamine receptors D₁ and D₂ brain. Quetiapine also has a higher affinity for histamine and α₁-adrenoceptors and less in relation to α₂adrenoreceptors. There was no significant affinity for quetiapine for cholinergic muscarinic and benzodiazepine receptors. In standard tests quetiapine has antipsychotic activity.

Pharmacodynamic effects

The results of the study of extrapyramidal symptoms (EPS) in animals revealed that quetiapine causes a weak catalepsy in a dose effectively blocking dopamine D₂ 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.

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 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. In numerous studies with a fixed dose, there was no difference in the level of prolactin when using quetiapine or placebo.

In clinical trials quetiapine showed efficacy in treating both positive and negative symptoms of schizophrenia.

The effect of quetiapine on 5HT receptors₂ and D₂ lasts up to 12 hours after taking the drug.

Pharmacokinetics:

When administered orally quetiapine well absorbed from the gastrointestinal tract and actively metabolized in the liver. The main metabolites in the plasma do not have a pronounced pharmacological activity.

The intake of food does not significantly affect the bioavailability of quetiapine. Half-life is about 7 hours. Approximately 83% of quetiapine binds to plasma proteins. The pharmacokinetics of quetiapine is linear, there is no difference in pharmacokinetic parameters in men and women.

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

The mean plasma clearance of quetiapine is less than approximately 25% in patients with severe renal insufficiency (creatinine clearance less than 30 ml / min / 1.73 m²) and in patients with liver damage (stabilized alcoholic cirrhosis), but individual clearance rates are within the limits corresponding to healthy people.

Approximately 73% of quetiapine is excreted in urine and 21% with feces. Less than 5% of quetiapine is not metabolized and is excreted unchanged by the kidneys or with feces. It is established that CYP3A4 is the key enzyme of quetiapine metabolism, mediated by cytochrome P450.

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, an increase in the average maximum concentration (C_max) and the area under the curve "concentration-time" (AUC) quetiapine by 235% and 522%, respectively, and also led to a decrease in the clearance of quetiapine, on average, by 84%. Quetiapine half-life increased, but the mean time to reach maximum concentration (t_max) did not change.

Quetiapine and some of its metabolites have a weak inhibitory activity against cytochrome P450 1A2, 2C9, 2C19, 2D6 and 4, but only at concentrations 10-50 times higher than the concentrations observed at the usual effective dosage of 300-450 mg / day.

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

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.

Contraindications:

Hypersensitivity to any of the components of the drug, children's age (efficacy and safety are not investigated).

Carefully:

In patients with cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension, elderly age, hepatic insufficiency, convulsive fits in the anamnesis.

Pregnancy and lactation:

Category on the effect on pregnancy: C. Safety and efficacy of quetiapine during pregnancy are not established. Ketilpet® should not be used during pregnancy, except when the benefit to the mother exceeds the possible risk to the fetus.

The period of breastfeeding. It is not known whether quetiapine in human milk. Therefore, breastfeeding women are advised not to breast-feed while taking the drug Ketilept®.

Dosing and Administration:

Ketilept® should be taken orally, regardless of food intake.

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 (Day 2), 200 mg (Day 3), and 300 mg (Day 4).

Starting from the 4th day, the usual effective daily dose of the drug Ketilept® is from 300 to 450 mg / day.

Depending on the clinical effect and tolerability in each patient, the dose can be selected (vary) in the range from 150 mg to 750 mg per day.

The maximum recommended daily dose is 750 mg.

For the treatment of acute manic episodes in the structure of bipolar disorder

The drug is prescribed 2 times a 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 per day by the 6th day is possible with an increase of no more than 200 mg per 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 per day. The usual effective dose is in the range of 400 to 800 mg per day. The maximum recommended daily dose is 800 mg / day.

For the treatment of depressive episodes in the structure of bipolar disorder

Ketilept® appoint once a day at 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 / day.

Elderly patients

The recommended initial dose is 25 mg per day, and then the dose should be increased by 25-50 mg per day to an effective dose, which is likely to be 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.

Children and teenagers

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

Renal and hepatic impairment

It is recommended to begin therapy with 25 mg per 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.

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®, the drug can be continued in a dose adequate for maintenance therapy. With the resumption of therapy in patients who did not receive cetylipt® 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 of quetiapine are drowsiness, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension and dyspepsia. According to the summary of clinical studies, 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 treatment.

The undesirable phenomena observed with the introduction of quetiapine and classified according to the body systems are listed below in this order: very frequent (> 1/10); frequent (<1/10 and> 1/100); infrequent (<1/100 and> 1/1000); rare (<1/1000); very rare (<1/10 000).

System of blood and lymph

Frequent: leukopenia³. Infrequent: eosinophilia. Very rare: neutropenia³.

Violations immune systems

Infrequent: hypersensitivity.

Metabolism and nutrition

Frequent: weight gain⁴, increased serum transaminases (ALT, ACT)⁵. Very rare: hyperglycemia^1,7, diabetes^1,7.

Violations of the function of the nervous system

Very Frequent: dizziness^1,6, drowsiness². Frequent: headache, anxiety, psychomotor agitation, tremor, fainting^1,6. Infrequent: epileptic seizures¹.

Heart Dysfunction

Frequent: tachycardia^1,6.

Vascular disorders

Frequent: orthostatic hypotension^1,6.

Disturbances of respiration and functions of the thoracic and mediastinal organs

Frequent: rhinitis, pharyngitis.

Dysfunction of the gastrointestinal tract

Frequent: dry mouth, constipation, diarrhea, dyspepsia, abdominal pain.

Violations of the functions of the reproductive organs and mammary glands

Rare: priapism.

General disorders and condition of tissues at the site of administration

Frequent: mild asthenia, peripheral edema. Rare: malignant neuroleptic syndrome¹.

Laboratory research

Infrequent: increase in gamma-GT level⁵, increased triglyceride levels after meals, increased total cholesterol.

Other

Back pain, chest pain, subfebrile condition, myalgia, dry skin, decreased visual acuity.

(1) See section "Special instructions and precautions for use".

(2) Drowsiness is possible, especially during the first two weeks of the course of treatment, which usually takes place with the continued use of the drug Ketilept®.

(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 transaminases (ALT, ACT) or gamma-GT. These enhancements usually occurred with the continuation of the administration of quetiapine.

(6) Like other antipsychotics with alpha-1-adrenergic blocking activity, Ketilept® can cause orthostatic hypotension with dizziness, tachycardia and (in some patients) syncope, especially in the initial period of dose selection. See section 4.4 "Specific instructions and precautions for use".

(7) In very rare cases, when taking quetiapine, hyperglycemia and a worsening of the course of pre-existing diabetes were noted.

The relationship of quetiapine with the induced low doses of thyroid hormone levels (T₄ and free T₄). The maximum decrease occurred during the first two or four weeks of quetiapine, but with a prolonged course of treatment no further reduction occurred. In almost all cases, discontinuation of quetiapine led to the restoration of T levels₄ and free T₄regardless of the duration of the course of treatment.

Less significant decrease in T₃ and reversible T₃was observed only at higher doses of quetiapine. The levels of TSH and TSG (thyroxine-binding globulin) remained unchanged.

Clinically pronounced hypothyroidism was not detected.

Like other antipsychotics, quetiapine may cause lengthening of the interval QTc, but in clinical trials this effect was not constant.

The reactions to sudden withdrawal of the drug are described (see Special instructions).

Overdose:

Data on quetiapine overdose are limited.

Symptoms: these symptoms were mainly due to the increase in known pharmacological effects of the drug, such as drowsiness and excessive sedation, tachycardia and lowering blood pressure. Very rarely reported cases of severe overdose of quetiapine, leading to death or coma.

Treatment: there are no specific antidotes to quetiapine. In cases of serious intoxication, it is necessary to consider the possibility of symptomatic therapy and it is recommended to carry out activities aimed at maintaining the function of respiration, cardiovascular system, ensuring adequate oxygenation and ventilation.

Medical surveillance should be continued until the patient is fully recovered.

Interaction:

Special caution is required when prescribing the drug Ketilept® in combination with other drugs acting on the central nervous system.

Results of the study in vitro showed that quetiapine and 9 of its metabolites in vivo are weak inhibitors of metabolic processes mediated by cytochrome P450 (1A2, 2C9, 2C19, 2D6 and 4). CYP3A4 is the main enzyme mediating P-450 mediated quetiapine metabolism.

The effect of other drugs on Cetepype®

Phenytoin

Combination of the preparation Ketilept® with phenytoin leads to an increase in the clearance of quetiapine in plasma, tk. phenytoin induces isoenzyme 3A4 cytochrome P450. The combination of quetiapine (250 mg three times daily) and phenytoin (100 mg twice daily) increased the average clearance of quetiapine five times after oral administration.

To correct the symptoms of schizophrenia in patients receiving concomitantly quetiapine and phenytoin may require increased doses of the drug Ketilept® or other inducers of hepatic enzymes (eg, carbamazepine, barbiturates, rifampicin, or glucocorticoids). In these cases, caution is required when phyenoin is abolished and / or switched to valproate, which does not possess enzyme-inducing properties.

Carbamazepine

Co-administration with carbamazepine significantly increased the clearance of quetiapine,which reduced the systemic exposure of quetiapine. This interaction may require the use of higher doses of the preparation Ketilept®.

Inhibitors P450 3A

Co-administration with ketoconazole (200 mg per day for 4 days), a potent inhibitor of the cytochrome P450 OA enzyme, reduced quetiapine clearance after oral administration by 84%, resulting in an average increase in quetiapine concentration in blood by 235%. Therefore caution is required when combining Ketilept® with ketoconazole and other cytochrome P450 inhibitors, azole antifungals and macrolide antibiotics (eg, itraconazole, fluconazole and erythromycin); a corresponding reduction in the dose of quetiapine is necessary.

Cimetidine

Daily regular administration of cimetidine (400 mg three times daily for 4 days), which is a nonspecific enzyme inhibitor, resulted in a 20% decrease in the average clearance of quetiapine (150 mg three times daily) from plasma after oral administration. With the simultaneous use of the drug Ketilept® with cimetidine, there is no need to change the dose of the preparation Ketilept®.

Thioridazine

Thioridazine (200 mg twice daily) increased the clearance of quetiapine (300 mg twice daily) by 65% from the plasma after oral administration.

Risperidone and haloperidol

The combination of quetiapine (300 mg twice daily) with an antipsychotic haloperidol (7.5 mg twice daily) or risperidone (3 mg twice daily) did not alter the equilibrium pharmacokinetics of quetiapine.

Fluoxetine and imipramine

The combination of quetiapine (300 mg twice daily) with an antidepressant and an inhibitor CYP3A4 and CYP2D6 fluoxetine (60 mg once daily) or a known inhibitor CYP2D6 imipramine (75 mg twice daily) did not alter the equilibrium pharmacokinetics of quetiapine.

Influence of the drug Ketilept® for other medicinal products

Antipyrine

Multiple daily administration of quetiapine (up to 750 mg per day with a triple admission) did not cause clinically significant changes in the clearance of the antipyrine or its metabolites. This indicates that quetiapine does not have a significant inhibitory effect on hepatic enzymes involved in the metabolism of antipyrine mediated by cytochrome P450.

Lithium

The combination of quetiapine (250 mg three times daily) 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 3 times a day).

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

Clinical studies have shown that quetiapine potentiates cognitive and motor effects alcohol in patients with psychoses. Therefore, do not take alcohol during the course of treatment with the drug Ketilept®.

Special instructions:

Cardiovascular diseases

Ketilept ® should be used with caution in patients with diagnosed cardiovascular diseases, cerebral vascular diseases or other conditions predisposing to hypotension.

Ketilept® 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 taking quetiapine and increasing QTc-Interval. However, with the appointment of quetiapine simultaneously with drugs that extend the interval QTwith caution, especially in the elderly.

Convulsive seizures

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

Late dyskinesia

Ketilept®, like other antipsychotics, may cause tardive dyskinesia with prolonged use. In case of signs and symptoms of tardive dyskinesia, the question of dose reduction or the cancellation of Ketilept® 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, instability of the autonomic nervous system, increase in the level of creatine phosphokinase. In such cases Quetiapine should be canceled and the appropriate treatment performed.

Reactions of sudden cancellation

Symptoms of acute cancellation, including nausea, vomiting, and insomnia, are described in very rare cases after a sharp discontinuation of taking high doses of antipsychotics.Possible relapse of the symptoms of psychosis and the emergence of disorders associated with involuntary movements (akathisia, dystonia and 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 the film-coated tablets 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. This drug should not be given to patients with rare hereditary disorders of tolerance to galactose, a hereditary deficiency of lactose Sami or a syndrome of non-absorption of glucose-galactose. Taking into account that quetiapine, mainly affects the central nervous system, quetiapine should be used with caution in combination with other drugs that have an inhibitory effect on the central nervous system, or alcohol.

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

Due to the effect on the central nervous system, Ketilept® 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 machinery. In the future, the degree of restrictions should be set for each patient individually.

Form release / dosage:

Tablets, film-coated, 25, 100, 150, 200, 300 mg.

Packaging:

For 30 or 60 tablets in a bottle of brown glass with a polyethylene lid with a control of the first opening and with an accordion damper.

1 bottle with instructions for use in a cardboard box.

Or 10 tablets in a blister of PVC / PVDC / al.foil, 3 or 6 blisters in a cardboard box, along with instructions for use.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

5 years.

Do not use at the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-001052/08

Date of registration:26.02.2008 / 08.10.2014

Expiration Date:Unlimited

The owner of the registration certificate:EGIS ZAO Pharmaceutical Plant EGIS ZAO Pharmaceutical Plant Hungary

Manufacturer: & nbsp

EGIS PHARMACEUTICALS, Plc Hungary

Representation: & nbspEGIS ZAO Pharmaceutical Plant EGIS ZAO Pharmaceutical Plant Hungary

Information update date: & nbsp02.01.2018

Illustrated instructions

Instructions

Ketilept® (Ketilept®)