Ketilept, 300 mg 60 pcs.

Cetilept has antipsychotic effects.

Pharmacodynamics

The mechanism of action. Quetiapine is an atypical antipsychotic drug that exhibits a higher affinity for serotonin receptors (5NT2) than for brain dopamine D1 and D2 receptors. Quetiapine also has a higher affinity for histamine and α1-adrenoceptors and a lower affinity for α2-adrenoceptors. Quetiapine has no detectable affinity for cholinergic muscarinic and benzodiazepine receptors. In standard tests, quetiapine exhibits antipsychotic activity.

Pharmacodynamic Effects

The results of studies of extrapyramidal symptoms (EPS) in animals revealed that quetiapine causes mild catalepsy at a dose that effectively blocks dopamine D2 receptors. Quetiapine causes a selective decrease in the activity of mesolimbic A10 dopaminergic neurons compared to A9 nigrostriatal neurons involved in motor function.

The clinical studies showed no differences between the use of quetiapine (at doses of 75-750 mg/day) and placebo in the incidence of extrapyramidal symptoms and the concomitant use of anticholinergic drugs. Quetiapine does not cause prolonged increases in plasma prolactin concentrations. Multiple fixed-dose studies have found no difference in prolactin levels when using quetiapine or placebo.

Quetiapine has been shown to be effective in treating both positive and negative symptoms of schizophrenia in clinical trials.

The effects of quetiapine on the 5NT2 and D2 receptors last up to 12 hours after taking the drug.

Pharmacokinetics

Quetiapine is well absorbed from the GI tract when taken orally and is actively metabolized in the liver. The major plasma metabolites have no marked pharmacological activity.

The bioavailability of quetiapine is not significantly affected by food intake. T1/2 is about 7 h. About 83% of quetiapine is bound to plasma proteins. The pharmacokinetics of vetiapine is linear; there are no differences in pharmacokinetics between 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 approximately 25% lower in patients with severe renal impairment (creatinine2 Cl) and in patients with liver damage (stabilized alcoholic cirrhosis), but individual clearance rates are within limits consistent with those of healthy individuals.

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

In a study of the pharmacokinetics of quetiapine in different dosages, it has been shown that when quetiapine is administered before ketoconazole or simultaneously with ketoconazole, the Cmax and AUC of quetiapine are increased by 235 and 522%, respectively, on average, and the clearance of quetiapine is decreased by 84%, on average. The T1/2 of quetiapine increased, but the mean Tmax was unchanged.

Quetiapine and some of its metabolites have weak inhibitory activity against cytochrome P450 enzymes 1A2, 2C9, 2C19, 2D6 and 3A4, but only at concentrations 10-50 times higher than those observed at the commonly used effective dose of 300-450 mg/day.

Based on in vitro results, concomitant administration of quetiapine with other drugs should not be expected to result in clinically significant inhibition of cytochrome P450-mediated metabolism of other drugs.

Indications

Active ingredient

Composition

1 tablet contains:

the active ingredient:

Quetiapine 300 mg (in the form of quetiapine fumarate);

auxiliary substances:

Microcrystalline cellulose,

Lactose monohydrate,

sodium carboxymethyl starch,

povidone,

magnesium stearate,

silicon dioxide,

triacetin,

macrogol,

How to take, the dosage

Ketilept is taken orally, regardless of meals, 2 times a day.

Adults. 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).

Since day 4, the usual effective daily dose of the drug Quetilept is 300 mg. Depending on clinical response and tolerability in each patient, the dose can be adjusted between 150 and 750 mg/day.

The safety of daily doses above 800 mg has not been evaluated in clinical trials.

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

Hepatic and renal insufficiency. It is recommended to start therapy with 25 mg/day, then increase the dose daily by 25-50 mg until an effective dose is achieved, depending on the patient’s clinical response and individual tolerance.

Interaction

Particular caution is required when prescribing Quetilepte in combination with other CNS-acting drugs.

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

The effect of other drugs on Quetilept:

Concomitant use of Quetilept with phenytoin leads to increased clearance of quetiapine in plasma, because phenytoin induces the 3A4 isoenzyme of cytochrome P450. The combination of quetiapine (250 mg 3 times/day) and phenytoin (100 mg 2 times/day) increased the mean clearance of quetiapine 5-fold after oral administration. Increased doses of Quetilept or other hepatic enzyme inducers (including carbamazepine, barbiturates, rifampicin, GCS) may be required to correct the symptoms of schizophrenia in patients receiving simultaneously quetiapine and phenytoin. In these cases, caution is required when withdrawing phenytoin and/or switching to valproate, which does not have enzyme-inducing properties.

The concomitant use of Quetilept with carbamazepine significantly increases the clearance of quetiapine, which leads to a decrease in the systemic exposure of quetiapine. Due to this interaction, higher doses of Quetilept may be required.

The concomitant use of Quetilept with ketoconazole (200 mg/day for 4 days), a strong inhibitor of the CYPCA isoenzyme, reduces clearance of quetiapine after oral administration by 84%, resulting in an average 235% increase in plasma concentration of quetiapine. Caution is required when combining Quetiapt with ketoconazole and other cytochrome P450 system isoenzyme inhibitors, azole antifungal drugs and macrolide antibiotics (including itraconazole, fluconazole, erythromycin); the dose of quetiaptic should be decreased accordingly.

Daily regular administration of cimetidine (400 mg 3 times/day for 4 days), which is a nonspecific enzyme inhibitor, resulted in a 20% reduction in average clearance of quetiapine (at 150 mg 3 times/day) from plasma after oral administration. There is no need to change the dose of the former when concomitant use of Quetilepte with cimetidine.

Tioridazine (200 mg 2 times/day) increased clearance of quetiapine (300 mg 2 times/day) from plasma after oral administration by 65%.

The concomitant use of quetiapine (300 mg 2 times daily) with the antipsychotic agent haloperidol (7.5 mg 2 times daily) or risperidone (3 mg 2 times daily) did not alter the equilibrium pharmacokinetics of quetiapine.

The concomitant use of quetiapine (300 mg 2 times/day) with the antidepressant and CYP3A4 and CYP2D6 inhibitor fluoxetine (60 mg once/day) or the known CYP2D6 inhibitor imipramine (75 mg 2 times/day) did not alter the equilibrium pharmacokinetics of quetiapine.

The effects of Quetileptus on other medications:
Repeated daily administration of quetiapine (up to 750 mg/day at 3 times daily administration) did not cause clinically significant changes in the clearance of antipyrine or its metabolites. This indicates that quetiapine has no significant inhibitory effect on hepatic enzymes involved in cytochrome P450-mediated metabolism of antipyrine.

The concomitant use of quetiapine (250 mg 3 times daily) with lithium did not affect any pharmacokinetic parameters of lithium in equilibrium.

The mean clearance of lorazepam after oral administration (a single dose of 2 mg) was reduced by 20% during quetiapine (250 mg 3 times/day).

Smoking had no effect on plasma clearance of vetiapine.

Because clinical studies have shown that quetiapine potentiates the cognitive and motor effects of alcohol in patients with psychosis, you should not take alcohol during treatment with Quetilept.

Special Instructions

Cardiovascular disease

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

Ketilept may cause orthostatic hypotension, especially during the initial period of dose refinement; this occurs more frequently in older than in younger patients.

The relationship between quetiapine administration and QTc interval prolongation has not been found. However, caution should be exercised when prescribing quetiapine concomitantly with drugs that prolong the QTc interval, especially in the elderly.

Convulsive seizures

There is no difference in the incidence of seizures in patients taking Quetilept or placebo. However, as with therapy with other antipsychotics, caution is advised when treating patients with a history of seizures.

Late dyskinesia

Quetilept, like other antipsychotics, may cause late dyskinesia with prolonged use. If signs and symptoms of tardive dyskinesia occur, consideration should be given to reducing the dose or withdrawing the drug.

Malignant neuroleptic syndrome

Malignant neuroleptic syndrome may be associated with ongoing antipsychotic treatment. Clinical manifestations of the syndrome include hyperthermia, altered mental status, muscle rigidity, autonomic nervous system instability, and increased CPK levels. In such cases, Cetilept should be discontinued and appropriate treatment should be given.

Sudden withdrawal reactions

Acute withdrawal symptoms (including nausea, vomiting, insomnia) have been described in very rare cases after abrupt cessation of high-dose antipsychotic drugs. Recurrence of psychosis symptoms and occurrence of disorders associated with involuntary movements (akathisia, dystonia, dyskinesia) are possible. Therefore, if it is necessary to discontinue the drug, gradual reduction of the dose is recommended.

Lactose intolerance

When formulating a diet for patients with lactose intolerance, note that film-coated tablets 100 mg, 200 mg and 300 mg contain 17.05 mg, 34.1 mg and 50.94 mg of lactose, respectively. This drug should not be administered to patients with rare hereditary galactose tolerance disorders, hereditary lactase lapp deficiency or glucose-galactose malabsorption syndrome. Taking into account that quetiapine mainly affects CNS, the drug should be used with caution in combination with other drugs with CNS depressant effect or alcohol.

In controlled clinical trials of quetiapine no cases of sustained severe neutropenia or agranulocytosis have been reported. During the follow-up period after drug registration, leukopenia and/or neutropenia subsided after discontinuation of quetiapine. Possible risk factors for leukopenia and/or neutropenia include pre-existing lower white blood cell counts and a history of drug-induced leukopenia and/or neutropenia.

As with other antipsychotics with alpha1-adrenoblocking activity, Cetilept may cause orthostatic hypotension with dizziness, tachycardia and (in some patients) syncope, especially during the initial period of dose adjustment.

In very rare cases, hyperglycemia and worsening of pre-existing diabetes have been noted while taking quetiapine.

Quetiapine administration has been found to be associated with decreases in thyroid hormone levels (T4 and free T4) caused by taking it at low doses. The maximum decrease occurred during the first two or four weeks of quetiapine administration, but no further decrease occurred with a prolonged course of treatment. Less significant decreases in Tc and reversible Tc were observed only when quetiapine was taken at higher doses. TTH and TSH (thyroxine-binding globulin) levels remained unchanged. In almost all cases, discontinuation of quetiapine resulted in restoration of T4 and free T4 levels regardless of the duration of treatment. No clinically significant hypothyroidism was detected.

Pediatric use

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

Influence on the ability to drive and operate vehicles

Due to the effect on the CNS, Quetiletipine may cause drowsiness. Therefore, in the first stages of treatment, for a period of time individually determined, the patient should be prohibited from driving motor vehicles or dangerous machinery. Thereafter, the degree of restriction is determined individually.

Contraindications

Hypersensitivity to any of the components of Ketilept;

childhood (efficacy and safety have not been studied).

With caution: in patients with cardiovascular and cerebrovascular disease or other conditions predisposing to arterial hypotension, advanced age, hepatic insufficiency, history of seizures.

Side effects

The most common side effects of quetiapine are somnolence, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension, and dyspepsia. According to summarized data from clinical trials, the number of patients discontinued due to adverse effects was approximately equal in the groups receiving placebo and quetiapine.
As with other antipsychotics, fainting, malignant neuroleptic syndrome, leukopenia, neutropenia, and peripheral edema have been reported while taking quetiapine.

The undesirable phenomena observed with quetiapine administration, classified by body system, are listed below in this order: Very common, >1/10; common, 1/100; infrequent, 1/1000; rare

The blood and lymphatic system: common, leukopenia; infrequent, eosinophilia; very rare, neutropenia.

Immune system disorders: infrequent – hypersensitivity.
Metabolism and nutrition: frequently – weight gain, increase of serum transaminases (ALT, ACT); very rarely – hyperglycemia, diabetes.

Nervous system disorders: very frequently – dizziness sleepiness; frequently – headache, anxiety, psychomotor agitation, tremor, fainting; rarely – epileptic seizures.

Chronic disorders: often – tachycardia

vascular disorders: often – orthostatic hypotension.

Respiratory disorders and functions of the chest cavity and mediastinum: often – rhinitis, pharyngitis.

Gastrointestinal disorders: often – dry mouth, constipation, diarrhea, dyspepsia, abdominal pain.

Disorders of the reproductive organs and mammary glands: rarely – priapism.

General disorders and tissue conditions at the site of administration: often – mild asthenia, peripheral edema; rarely – malignant neuroleptic syndrome.

Laboratory tests: infrequent – increase in gamma-glutamyltransferase (gamma-GT), increased triglyceride levels after meals, increased total cholesterol.

Others: low back pain, chest pain, subfebrile fever, myalgia, dry skin, decreased visual acuity.

Overdose

The data on quetiapine overdose are limited.

Symptoms: somnolence, over-sedation, tachycardia, decreased BP, extremely rare cases of severe overdose of quetiapine leading to death or coma have been reported.

Treatment: there are no specific antidotes to vetiapine. Symptomatic therapy and measures aimed at maintaining respiratory function, cardiovascular system, ensuring adequate oxygenation and ventilation are carried out.

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

Pregnancy use

Category C. The safety and efficacy of Quetiapine in pregnancy have not been established.

The use of Quetilpine in pregnancy is possible only when the expected benefit to the mother outweighs the potential risk to the fetus.

It is not known whether quetiapine is excreted with the breast milk. If it is necessary to use Quetilpin during lactation (breastfeeding), discontinuation of breastfeeding should be considered.

Similarities