Servitel, 25 mg 60 pcs

Quetiapine

Indications

For the treatment of schizophrenia.

For the treatment of manic episodes in bipolar disorder.

The drug is not indicated for the prevention of manic episodes in bipolar disorder.

Pharmacological effect

Pharmacotherapeutic group

antipsychotic (neuroleptic)

ATX code

N05AH04

Pharmacodynamics:
Quetiapine is an atypical antipsychotic drug. Quetiapine and its active metabolite N-desalkyl quetiapine interact with neurotransmitter receptors in the brain. Quetiapine and N-desalkyl quetiapine exhibit high affinity for serotonin receptors type 5HT1 and dopamine receptors types D1 and D2 of the brain. Higher selectivity for serotonin receptors of the 5HT2 type than for dopamine receptors of the D2 type determines the main clinical antipsychotic properties of quetiapine and the low incidence of extrapyramidal side effects. In addition, N-desalkyl quetiapine exhibits high affinity for the norepinephrine transporter. Quetiapine and N-desalkyl quetiapine have high affinity for histamine and α1-adrenergic receptors and less affinity for α2-adrenergic receptors and serotonin receptors of the 5HT1 type. Quetiapine does not show noticeable affinity for cholinergic muscarinic and benzodiazepine receptors. In standard tests, quetiapine exhibits antipsychotic activity. The specific contribution of the N-desalkyl metabolite of quetiapine to the pharmacological activity of quetiapine has not been established.

Results from studies of extrapyramidal symptoms (EPS) in animals revealed that quetiapine causes mild catalepsy at doses that effectively block 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.

Clinical studies (using quetiapine at a dose of 75-750 mg/day) showed no differences between quetiapine and placebo in the incidence of extrapyramidal symptoms and the concomitant use of anticholinergic drugs. Quetiapine does not cause a prolonged increase in plasma prolactin concentrations.

Quetiapine is effective in treating both positive and negative symptoms of schizophrenia. Long-term support of clinical improvement in those patients in whom a positive effect developed at the very beginning of treatment.

The duration of action of quetiapine on 5HT2 and D2 receptors is less than 12 hours after taking the drug.

Pharmacokinetics:

When administered orally, quetiapine is well absorbed from the gastrointestinal tract and is actively metabolized in the liver. Food intake does not significantly affect the bioavailability of quetiapine. Approximately 83% of quetiapine is bound to plasma proteins.

The equilibrium molar concentration of the active metabolite N-desalkyl quetiapine is 35% of the equilibrium molar concentration of quetiapine. The half-life of quetiapine and N-desalkyl quetiapine is approximately 7 and 12 hours, respectively. The pharmacokinetics of quetiapine and N-desalkyl quetiapine are linear; there are no differences in pharmacokinetic parameters between men and women. It has been established that CYP3A4 is a key isoenzyme in the metabolism of quetiapine, mediated by cytochrome P450. N-dealkyl quetiapine is formed with the participation of the CYP3 A4 isoenzyme.

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 reduced by approximately 25% in patients with severe renal impairment (creatinine clearance less than 30 ml/min/1.73 m2), but individual clearance values ​​are within the range of values ​​corresponding to healthy volunteers. In patients with impaired liver function (eg, compensated alcoholic cirrhosis), the average plasma clearance of quetiapine is reduced by approximately 25%. Since quetiapine is extensively metabolized in the liver, in patients with liver failure, increased plasma concentrations of quetiapine may occur, which requires dose adjustment.

On average, less than 5% of the molar dose of the free quetiapine and N-dealkyl quetiapine plasma fraction is excreted in the urine. Approximately 73% of quetiapine is excreted by the kidneys and 21% through the intestines. Less than 5% of quetiapine is not metabolized and is excreted unchanged by the kidneys or intestines.

In a study of the pharmacokinetics of quetiapine at various doses, the use of quetiapine before taking ketoconazole or simultaneously with ketoconazole led to an increase, on average, in the maximum concentration (Cmax) and area under the concentration-time curve (AUC) of quetiapine by 235% and 522%, respectively, and also to a decrease in quetiapine clearance, on average, by 84%. The half-life of quetiapine increased, but the mean time to reach maximum concentration (tmax) did not change.

Quetiapine and some of its metabolites, including N-desalkyl quetiapine, have weak inhibitory activity against cytochrome P450 isoenzymes 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 use of quetiapine with other drugs should not be expected to result in clinically significant inhibition of cytochrome P450-mediated metabolism of other drugs.

Active ingredient

Quetiapine

Composition

1 film-coated tablet contains:

Dosage 25 mg:

active substance: quetiapine hemifumarate 28.78 mg, equivalent to 25 mg quetiapine;

excipients: hypromellose – 1.40 mg, calcium hydrogen phosphate dihydrate – 3.50 mg, lactose monohydrate – 7.00 mg, corn starch – 13.82 mg, sodium carboxymethyl starch – 3.50 mg, magnesium stearate – 0.89 mg, microcrystalline cellulose – 7.94 mg, talc – 1.75 mg, colloidal silicon dioxide – 1.42 mg;

tablet shell: opadry pink 02B34304 – 2.00 mg (iron dye red oxide (E172) – 0.031 mg, iron dye yellow oxide (E172) – 0.028 mg, hypromellose-2910 (E464) – 1.25 mg, titanium dioxide (E171) – 0.56 mg, macrogol 400 – 0.125 mg, sunset yellow dye (E110) – 0.003 mg).

Contraindications

Hypersensitivity to any of the components of the drug. Combined use with cytochrome P450 inhibitors (antifungals of the azole group, erythromycin, clarithromycin, nefazodone, protease inhibitors); lactase deficiency, glucose-galactose malabsorption, lactose intolerance; psychoses in elderly patients with dementia; children under 18 years of age; lactation period; pregnancy.

With caution:

In patients with cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension; old age; liver failure; history of seizures.

Side Effects

The most common side effects when taking quetiapine: drowsiness, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension and dyspepsia.

Taking quetiapine, like other antipsychotic drugs, may be accompanied by weight gain, fainting, the development of neuroleptic malignant syndrome, leukopenia, neutropenia and peripheral edema.

The frequency of adverse reactions is given in the following gradation: very often (≥ 1/10); often (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000), including cases whose frequency is unknown.

From the central nervous system: very often – drowsiness2, dizziness4, headache; often – dysarthria, unusual and nightmares, fainting4, extrapyramidal symptoms; infrequently – convulsions1, restless legs syndrome; very rarely – tardive dyskinesia6.

From the cardiovascular system: often – orthostatic hypotension, tachycardia4.

From the gastrointestinal tract: very often – dry mouth; often – constipation, dyspepsia; infrequently – dysphagia; rarely – jaundice6; very rarely – hepatitis6.

From the respiratory system: often – rhinitis.

From the blood system: often – leukopenia1; uncommon – eosinophilia; frequency unknown – neutropenia1.

From the immune system: rarely – hypersensitivity reaction; very rarely – anaphylactic reactions6.

From the skin: very rarely – angioedema6, Stevens-Johnson syndrome6.

Metabolic disorders: very rarely – diabetes mellitus1,5,6.

Changes in laboratory and instrumental parameters: very often – increased concentration of triglycerides, total cholesterol (mainly low-density lipoprotein cholesterol); often – weight gain, increased activity of liver transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT))3, decreased number of neutrophils, hyperglycemia7; uncommon – increased creatine phosphokinase activity not associated with neuroleptic malignant syndrome, thrombocytopenia.

Other: very often – withdrawal syndrome; often – asthenia, peripheral edema, blurred vision; rarely – priapism, neuroleptic malignant syndrome.

1. See the “Special Instructions” section.

2. Somnolence usually occurs within the first 2 weeks after initiation of therapy and usually resolves with continued use of quetiapine.

3. An asymptomatic increase in the activity of AST, ALT and γ-glutamyl transpeptidase (GGT) in the blood serum is possible, usually reversible with continued use of quetiapine.

4. Like other antipsychotic drugs, quetiapine often causes orthostatic hypotension, which is accompanied by dizziness, tachycardia and, in some cases, fainting, especially at the beginning of therapy.

5. Very rare cases of decompensation of diabetes mellitus have been reported.

6. The frequency of this side effect was assessed based on the results of post-marketing surveillance.

7. Increased fasting blood glucose > 126 mg/dL (> 7.0 mmol/L) or postprandial blood glucose > 200 mg/dL (> 11.1 mmol/L) at least once.

QT prolongation, ventricular arrhythmia, sudden death, cardiac arrest, and torsade de pointes (TdP) are considered adverse effects of antipsychotic drugs.

Quetiapine therapy is associated with a small dose-dependent decrease in the concentration of thyroid hormones, in particular total thyroxine (T4) and free T4. The maximum decrease in total and free T4 was recorded in the 2nd and 4th weeks of quetiapine therapy, without a further decrease in hormone concentrations during long-term treatment. There were no further signs of clinically significant changes in thyroid-stimulating hormone concentrations. In almost all cases, the concentration of total and free T4 returned to baseline after cessation of quetiapine therapy, regardless of the duration of treatment. A slight decrease in total triiodothyronine (T3) and reverse T3 was observed only when using high doses. The level of thyroxine-binding globulin (TBG) remained unchanged, and no increase in the level of thyroid-stimulating hormone (TSH) was observed.

Interaction

With the simultaneous administration of drugs that have a strong inhibitory effect on the CYP3A4 isoenzyme (such as azole antifungals and macrolide antibiotics), the concentration of quetiapine in plasma may increase.

In a study of the pharmacokinetics of quetiapine at various dosages, administration of quetiapine before or simultaneously with ketoconazole led to an increase in the maximum concentration (Cmax) and area under the concentration-time curve (AUC) of quetiapine by 5-8 times, as well as a decrease in the clearance of quetiapine. The half-life of quetiapine increased, but the mean time to reach maximum concentration (tmax) did not change. In such cases, lower doses of quetiapine should be used.

Particular attention should be paid to elderly and debilitated patients. It is necessary to assess the risk-benefit ratio individually for each patient. Therefore, co-administration of quetiapine and cytochrome CYP3A4 inhibitors is contraindicated. It is also not recommended to take quetiapine with grapefruit juice. Co-administration of quetiapine with drugs that induce the liver enzyme system, such as carbamazepine, may reduce the plasma concentration of the drug, which may require an increase in the dose of quetiapine, depending on the clinical effect.

In a study of the pharmacokinetics of quetiapine at various dosages, when administered before or simultaneously with carbamazepine (an inducer of liver enzymes), it led to a significant increase in the clearance of quetiapine. This increase in quetiapine clearance decreased AUC by an average of 13% compared with quetiapine without carbamazepine.

The simultaneous administration of quetiapine with another inducer of microsomal liver enzymes, phenytoin, also led to an increase in the clearance of quetiapine. When quetiapine is co-administered with phenytoin (or other hepatic enzyme inducers such as barbiturates, rifampicin), an increase in the dose of quetiapine may be required. It may also be necessary to reduce the dose of quetiapine when phenytoin or carbamazepine or another liver enzyme inducer is discontinued or replaced with a drug that does not induce liver microsomal enzymes (for example, valproic acid).

The pharmacokinetics of lithium preparations does not change with simultaneous administration of quetiapine.

There were no clinically significant changes in the pharmacokinetics of valproic acid and quetiapine when co-administered with semisodium valproate and quetiapine.

Quetiapine did not cause induction of hepatic enzyme systems involved in the metabolism of phenazone.

The pharmacokinetics of quetiapine does not change significantly when administered concomitantly with antipsychotic drugs – risperidone or haloperidol. However, simultaneous administration of quetiapine and thioridazine resulted in increased clearance of quetiapine.

The pharmacokinetics of quetiapine does not change significantly with simultaneous use of cimetidine, which is an inhibitor of cytochrome P450.

The pharmacokinetics of quetiapine did not change significantly with simultaneous administration of the antidepressant imipramine (inhibitor of the CYP2D6 isoenzyme) or fluoxetine (inhibitor of the CYP3A4 and CYP2D6 isoenzymes).

Pharmacokinetic studies examining the interaction of quetiapine with drugs used for cardiovascular diseases have not been conducted. Caution should be exercised when using quetiapine in combination with drugs that can cause electrolyte imbalance and prolongation of the QTc interval.

Caution should be exercised when combining quetiapine with other drugs that affect the central nervous system, as well as with alcohol, as this may increase the risk of developing quetiapine side effects.

Storage conditions

At a temperature not higher than 25°C. Keep out of the reach of children.

Shelf life

3 years.

Manufacturer

Jenefarm S.A., Greece