Quetilept, 100 mg 60 pcs.

Pharmacodynamics

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

Pharmacodynamic effects

Results from a study 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 found 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 h after taking the drug.

Pharmacokinetics

On oral administration, quetiapine is well absorbed from the GI tract and is actively metabolized in the liver. The major plasma metabolites have no marked pharmacological activity.

Eating does not significantly affect the bioavailability of quetiapine. T_1/2 is about 7 h. Approximately 83% of quetiapine is bound to plasma proteins. The pharmacokinetics of vetiapine are 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 the range consistent with those in 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 at different dosages, it has been shown that when quetiapine is administered before ketoconazole or simultaneously with ketoconazole, there is an average increase in C_max and AUC of quetiapine of 235% and 522% respectively, and a decrease in quetiapine clearance of 84%, on average. The T_1/2 of quetiapine increased, but the mean T_max did not change.

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 100 mg (in the form of quetiapine fumarate);

auxiliary substances:

Microcrystalline cellulose,

Lactose monohydrate,

sodium carboxymethyl starch,

povidone,

magnesium stearate,

silicon dioxide,

triacetin,

macrogol,

lactose monohydrate,

titanium dioxide,

hypromellose.

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 may 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.

The recommendation is 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. 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 isoenzymes (1A2, 2C9, 2C19, 2D6 and 3A4). CYP3A4 is the main enzyme responsible for P450-mediated metabolism of quetiapine. Effect of other drugs on Quetilept.

Phenytoin: Concomitant use of Quetilept with phenytoin leads to increased clearance of quetiapine in plasma because phenytoin induces cytochrome Р450 isoenzyme 3A4. The combination of quetiapine (250 mg 3) and phenytoin (100 mg 2) increased the mean clearance of quetiapine by a factor of 5 after oral administration. Increased doses of Quetiapt or other hepatic enzyme inducers (including carbamazepine, barbiturates, rifampicin, GCS) may be required to correct schizophrenia symptoms in patients receiving quetiapine and phenytoin simultaneously. In these cases, caution is required when withdrawing phenytoin and/or switching to valproate, which has no enzyme-inducing properties. Carbamazepine: concomitant use of Quetilept with carbamazepine significantly increases clearance of quetiapine, which leads to decreased systemic exposure of quetiapine.

Due to this interaction, higher doses of Quetilept may be required. CYP3A inhibitors: concomitant use of Quetilept with ketoconazole (200 mg/ for 4 days), a strong CYP3A isoenzyme inhibitor, 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 Quetilept with ketoconazole and other cytochrome P450 isoenzyme inhibitors, azole antifungal drugs and macrolide antibiotics (including itraconazole, fluconazole, erythromycin); the quetiapine dose should be decreased accordingly.

Cimetidine: Daily regular administration of cimetidine (400 mg 3 for 4 days), which is a non-specific enzyme inhibitor, resulted in a 20% reduction in average clearance of quetiapine (150 mg 3 each) from plasma after oral administration. There is no need to change the dose of the former when concomitant use of Quetilept with cimetidine. Thioridazine: Thioridazine (200 mg 2) increased clearance of quetiapine (300 mg 2) from plasma after oral administration by 65%.

Risperidone and haloperidol: Concomitant use of quetiapine (300 mg 2) with the antipsychotic haloperidol (7.5 mg 2) or risperidone (3 mg 2) did not alter the equilibrium pharmacokinetics of quetiapine. Fluoxetine and imipramine: concomitant use of quetiapine (300 mg 2) with the antidepressant and CYP3A4 and CYP2D6 inhibitor fluoxetine (60 mg once/) or the known CYP2D6 inhibitor imipramine (75 mg 2) did not alter the equilibrium pharmacokinetics of quetiapine.

The effect of Quetilepte on other drugs Antipyrine: Multiple daily administration of quetiapine (up to 750 mg/ when taken 3 times) 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. Lithium: Concomitant use of quetiapine (250 mg 3) with lithium did not affect any pharmacokinetic parameters of lithium in equilibrium.

Lorazepam: Mean clearance of lorazepam after oral administration (single dose of 2 mg) was reduced by 20% while taking quetiapine (250 mg 3). Smoking had no effect on plasma clearance of quetiapine. Because clinical studies have shown that quetiapine potentiates the cognitive and motor effects of alcohol in patients with psychosis, alcohol should not be taken during treatment with Quetiapine.

Special Instructions

Ketilept should be used with caution in patients with diagnosed cardiovascular disease, cerebral vascular disease or other conditions predisposing to arterial hypotension. Quetilept may cause orthostatic hypotension, especially during the initial period of dose refinement; this occurs more frequently in elderly than in younger patients. No relationship between quetiapine administration and QTc interval prolongation has been found. However, caution should be exercised when prescribing quetiapine concomitantly with drugs that prolong the QTc interval, especially in the elderly.

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

Cetilept, like other antipsychotics, may cause tardive 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 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, Quetilept 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, gradual reduction of the dose is recommended if discontinuation of the drug is necessary.

When formulating a diet for patients with lactose intolerance, note that film-coated tablets 25 mg, 100 mg, 150 mg, 200 mg and 300 mg contain 4.42 mg, 17.05 mg, 25.47 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 Sami lactose deficiency or glucose-galactose malabsorption syndrome.

Bearing in mind that quetiapine mainly affects the CNS, the drug should be used with caution in combination with other drugs with CNS depressant effects or alcohol. No cases of persistent severe neutropenia or agranulocytosis have been reported in controlled clinical trials of quetiapine. During the follow-up period after registration of the drug, leukopenia and/or neutropenia subsided after discontinuation of quetiapine administration.

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. Like other antipsychotics with alpha1-adrenoblocking activity, Cetilept may cause orthostatic hypotension with dizziness, tachycardia and (in some patients) fainting, 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.

The association of quetiapine administration with low-dose-induced reductions in thyroid hormone levels (T4 and free T4) has been established. The maximum decrease occurred during the first two or four weeks of quetiapine administration, but no further decrease occurred with a long course of treatment. Less significant decreases in Tz and reversible Tz were observed only at higher doses of quetiapine. 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.

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

Due to the effect on the CNS, Quetilept may cause somnolence. Therefore, during the first stages of treatment, for an individually determined period of time, the patient should be prohibited from driving motor vehicles or dangerous machinery. Thereafter, the degree of restriction is set on an individual basis.

Contraindications

Hypersensitivity to any of the components of Cetilept;

childhood (efficacy and safety not investigated).

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

Side effects

Overdose

Pregnancy use

Similarities