Quetiapine, 25 mg 60 pcs

Pharmacodynamics:

Quetiapine is an atypical antipsychotic.

Quetiapine and its active metabolite N-dezalkylquetiapine (norquetiapine) interact with a wide range of brain neutrotransmitter receptors. Quetiapine and N-dezalkylquetiapine exhibit high affinity for 5HT2-serotonin receptors and brain D1 and D2 dopamine receptors. Antagonism to these receptors, combined with higher selectivity for 5NT2-serotonin receptors than for D2-dopamine receptors, accounts for the clinical antipsychotic properties with affinity for the 5NT1A-serotonin receptor, whereas N-dezalkylquetiapine exhibits high affinity for both. Inhibition of the noradrenaline transporter and partial agonism toward the 5NT1A-serotonin receptor by N-dezalkylquetiapine may account for the antidepressant effects. Quetiapine and N-desalkylquetiapine have high affinity to histamine and α1-adrenoreceptors and moderate affinity to α2-adrenoreceptors.

In addition, quetiapine has no or low affinity for muscarinic receptors, whereas N-dezalkylquetiapine exhibits moderate to high affinity for several muscarinic receptor subtypes with which anticholinergic (muscarinic-like) effects may be associated.

In standard tests, quetiapine exhibits antipsychotic activity. The specific contribution of the metabolite N-dezalkylquetiapine to the pharmacological activity of quetiapine has not been established. The results of a study of extrapyramidal symptoms (EPS) in animals revealed that quetiapine causes mild catalepsy at doses that effectively block D2 receptors. Quetiapine causes a selective decrease in the activity of mesolimbic A10-dopaminergic neurons compared to A9-nigrostriate neurons involved in motor function.

Efficacy

Quetiapine is effective for both positive and negative symptoms of schizophrenia. Quetiapine is effective as monotherapy for moderate to severe manic episodes.

There are no data on long-term use of quetiapine for the prevention of subsequent manic and depressive episodes.

The data on the use of quetiapine in combination with valproate seminatria or lithium preparations for moderate to severe manic episodes are limited, but this combination therapy was generally well tolerated.

In addition, quetiapine at doses of 300 mg and 600 mg is effective in patients with moderate to severe bipolar disorder types I and II. At the same time, the efficacy of quetiapine when taken at a dose of 300 mg and 600 mg per day is comparable.

Quetiapine is effective in patients with schizophrenia and mania when the drug is taken twice daily, despite the fact that the elimination half-life of quetiapine is about 7 hours. The effects of vetetiapine on 5NT2 and D2 receptors last up to 12 hours after taking the drug.

The incidence of EPS and concomitant use of m-cholinoblockers was comparable to that of placebo when quetiapine was administered with dose titration in schizophrenia. When quetiapine was administered in fixed doses of 75 to 750 mg/day to patients with schizophrenia, the incidence of EPS and the need for concomitant use of m-cholinoblockers did not increase.

When quetiapine was used in doses up to 800 mg/day to treat moderate to severe manic episodes, both as monotherapy and in combination with lithium or valproate semisodium, the incidence of EPS and concomitant use of m-cholinoblockers was comparable to that with placebo.

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Indications

– Treatment of acute and chronic psychosis, including schizophrenia.

Treatment of manic episodes in the structure of bipolar disorder. Treatment of depressive episodes of moderate to severe severity in the structure of bipolar disorder.

The drug is not indicated for the prevention of manic and depressive episodes.

Active ingredient

Composition

One film-coated tablet 25 mg contains:

The active ingredient: quetiapine fumarate – 28.780 mg converted to quetiapine – 25.000 mg.

Excipients (core): microcrystalline cellulose – 28.500 mg; lactose monohydrate – 19.000 mg; povidone type K-17 – 7.000 mg; sodium carboxymethyl starch (primogel) – 7.000 mg; calcium hydrophosphate dihydrate – 8.720 mg; magnesium stearate – 1.000 mg.

The film coating: VTVACOAT® RA-3P-261 finished film coating system – 2.500 mg [hypromellose (HPMC) 6 / E464 – 0.975 mg, titanium dioxide / E171 – 0.746 mg, polydexgroze / E 1200-0.375 mg, talc / E553b – 0.250 mg, macrogol 3350 – 0.150 mg, iron oxide red dye / E172 – 0.004 mg].

How to take, the dosage

Ingestion, regardless of meals.

The treatment of acute and chronic psychosis, including schizophrenia

Quetiapine is prescribed twice daily. The daily dose for the first 4 days of therapy is: Day 1 – 50 mg, Day 2 – 100 mg, Day 3 – 200 mg, Day 4 – 300 mg. Starting on day 4, the dose should be titrated to an effective dose, usually between 300 and 450 mg/day.

Depending on clinical effect and individual patient tolerance, the dose may vary from 150 to 750 mg/day.

The maximum recommended daily dose is 750 mg.

The treatment of manic episodes in the structure of bipolar disorder

Quetiapine is used as monotherapy or as adjuvant therapy to stabilize mood.

Quetiapine is prescribed twice daily. The daily dose for the first 4 days of therapy is: Day 1 – 100 mg, Day 2 – 200 mg, Day 3 – 300 mg, Day 4 – 400 mg.

Thereafter, by the 6th day of therapy, the daily dose of the drug can be increased to 800 mg. The increase in the daily dose should not exceed 200 mg per day. Depending on clinical effect and individual tolerability, the dose may vary between 200 and 800 mg/day. Typically, the effective dose is 400 to 800 mg/day.

The maximum recommended daily dose is 800 mg.

The treatment of depressive episodes in the structure of bipolar disorder

Quetiapine is prescribed once daily at bedtime. The daily dose for the first 4 days of therapy is: Day 1 – 50 mg, Day 2 – 100 mg, Day 3 – 200 mg, Day 4 – 300 mg. The recommended dose is 300 mg/day.

The maximum recommended daily dose is 600 mg. No clinical improvement has been noted with doses greater than 600 mg/day.

The lowest dose is reasonable to maintain remission.

Patients should be evaluated periodically to determine if maintenance therapy is needed.

If therapy is resumed less than 1 week after withdrawal, administration may be continued at a dose adequate for maintenance therapy.

In elderly patients, the starting dose of quetiapine is 25 mg/day. The dose should be increased daily by 25-50 mg until the effective dose is reached, which is likely to be lower than in younger patients.

In patients with hepatic impairment, it is recommended that therapy be started at 25 mg/day. It is recommended that the dose be increased daily by 25-50 mg until an effective dose is achieved.

Interaction

Caution should be exercised when combining quetiapine with other drugs affecting the central nervous system, as well as with alcohol.

Caution should be exercised when combining quetiapine with other drugs with anticholinergic (muscarinic-like) effects.

The cytochrome P450 (CYP) isoenzyme WA4 is the main isoenzyme responsible for the metabolism of quetiapine through the cytochrome P450 system. In healthy volunteers, co-administration of quetiapine (in dose 25 mg) with ketoconazole, an inhibitor of CYP3A4 isoenzyme, resulted in a 5-8 times increase in the area under the “concentration-time curve” (AUC) of quetiapine.

This is why co-administration of vetiapine and CYP3A4 isoenzyme inhibitors is contraindicated. It is also not recommended to use vetiapine together with grapefruit juice.

In a pharmacokinetic study with repeated administration of quetiapine prior to or concomitantly with carbamazepine resulted in a significant increase in quetiapine clearance and a corresponding decrease in AUC, on average, of 13%, compared with quetiapine administration without carbamazepine. In some patients, the decrease in AUC was even more pronounced. This interaction is accompanied by a decrease in plasma concentration of quetiapine and may reduce the effectiveness of quetiapine therapy.

The co-administration of quetiapine with phenytoin, another inducer of microsomal liver enzymes, was accompanied by an even more pronounced (approximately 450%) increase in clearance of quetiapine.

The use of quetiapine in patients receiving microsomal liver enzyme inducers is possible only if the expected benefit of quetiapine therapy exceeds the risk associated with withdrawal of the microsomal liver enzyme inducer drug. Changes in the dose of microsomal enzyme inducers should be gradual. If necessary, their substitution with drugs that do not induce microsomal liver enzymes (for example, valproic acid preparations) is possible.

The pharmacokinetics of quetiapine were not significantly changed by concomitant use of the antidepressant imipramine (CYP2D6 isoenzyme inhibitor) or fluoxetine (CYP3A4 and CYP2D6 isoenzyme inhibitor).

The pharmacokinetics of quetiapine are not significantly altered by concomitant use with the antipsychotic drugs risperidone or haloperidol. However, concomitant administration of quetiapine and thioridazine resulted in increased clearance of quetiapine by approximately 70%.

The pharmacokinetics of quetiapine are not significantly altered by concomitant use of cimetidine.

Lorazepam clearance is decreased by approximately 20% when 2 mg of lorazepam is taken once with quetiapine at a dose of 250 mg twice daily.

The pharmacokinetics of lithium preparations are not altered by concomitant use of quetiapine. No clinically significant changes in the pharmacokinetics of valproic acid and quetiapine have been observed when valproate seminatrium and quetiapine are used together.

Pharmacokinetic studies to study the interaction of quetiapine with drugs used for cardiovascular disease have not been conducted.

Caution should be exercised when combining quetiapine with drugs that may cause electrolyte imbalance and QTc interval prolongation.

Quetiapine did not induce induction of microsomal liver enzymes involved in the metabolism of phenazone.

False positive screening tests for methadone and tricyclic antidepressants by enzyme immunoassay have been reported in patients taking quetiapine. Chromatographic testing is recommended to confirm screening results.

Special Instructions

Children and adolescents (10 to 17 years of age)

In placebo-controlled studies in children and adolescents with schizophrenia and mania as part of bipolar disorder, the incidence of developing EPS was higher with quetiapine compared with placebo.

Suicidal ideation/suicidal thoughts or clinical deterioration

Depression in bipolar disorder is associated with an increased risk of suicidal ideation, self-harm, and suicide (suicide-related events). This risk persists until the onset of significant remission. Because it may be several weeks or more before a patient’s condition improves from the start of treatment, patients must be under close medical observation until improvement occurs.

Common clinical experience suggests that the risk of suicide may increase in the early stages of remission. Patients (especially those at high risk for suicide) and their caregivers should be warned to monitor for clinical deterioration, suicidal behavior or thoughts, unusual behavioral changes, and the need to see a physician immediately if they occur.

In clinical trials in depressed patients with bipolar disorder, the risk of suicidal events was 3.0% (7/233) for quetiapine and 0% (0/120) for placebo in patients aged 18-24 years; 1.8% (19/1616) for quetiapine and 1.8% (11/622) for placebo in patients over 25 years.

Other psychiatric disorders for which quetiapine is prescribed are also associated with an increased risk of suicide-related events. In addition, such conditions may be comorbid with a depressive episode. Thus, the precautions used in therapy for patients with a depressive episode should also be taken when treating patients with other psychiatric disorders.

The potential risk of suicidal events should be considered when abruptly discontinuing quetiapine therapy.

Patients with a history of suicidal events, as well as patients clearly expressing suicidal thoughts before initiating therapy, are at increased risk for suicidal intentions and suicide attempts and should be closely monitored during treatment.

A FDA (Food and Drug Administration, USA) meta-analysis of placebo-controlled trials of antidepressants, summarizing data from approximately 4,400 children and adolescents and 7,700 adult patients with psychiatric disorders, found an increased risk of suicidal behavior on antidepressants compared to placebo in children, adolescents and adult patients under 25 years of age. This meta-analysis does not include studies using quetiapine.

The rate of suicide-related events was 0.8% for both quetiapine (76/9327) and placebo (37/4845) in short-term placebo-controlled studies for all indications and in all age groups.

In these studies in patients with schizophrenia, the risk of suicide-related events was 1.4% (3/212) for quetiapine and 1.6% (1/62) for placebo in patients aged 18-24 years; 0.8% (13/1663) for quetiapine and 1.1% (5/463) for placebo in patients older than 25 years; 1.4% (2/147) for quetiapine and 1.3% (1/75) for placebo in patients under 18 years of age.

In patients with mania in bipolar disorder, the risk of suicidal events was 0% (0/60) for quetiapine and 0% (0/58) for placebo in patients aged 18-24 years; 1.2% (6/496) for quetiapine and 1.2% (6/503) for placebo in patients older than 25 years; 1.0% (2/192) for quetiapine and 0% (0/90) for placebo in patients under 18 years of age.

Sleepiness

Drowsiness and related symptoms, such as sedation, may occur during therapy with quetiapine. In clinical studies involving depressed patients with bipolar disorder, somnolence typically developed within the first three days of therapy. The severity of this side effect was mostly mild to moderate. If severe somnolence develops, patients with depression in the structure of bipolar disorder may require more frequent visits to the physician within 2 weeks from the onset of somnolence or until the severity of symptoms decreases. In some cases, discontinuation of quetiapine therapy may be necessary.

Patients with cardiovascular disease

Patients with cardiovascular and cerebrovascular disease, and other conditions predisposing to hypotension should be cautious when prescribing quetiapine.

Orthostatic hypotension may occur with quetiapine therapy, especially during dose titration at the beginning of therapy. Orthostatic hypotension and associated dizziness may increase the risk of accidental injury (falling), especially in elderly patients.

Patients should exercise caution until they have adjusted to these potential side effects. If orthostatic hypotension occurs, dose reduction or slower titration may be required.

Sleep apnea syndrome

Sleep apnea syndrome has been reported in patients taking quetiapine. Caution should be exercised when prescribing quetiapine in patients receiving medications that have a depressant effect on the central nervous system, as well as in patients with risk factors for sleep apnea (e.g., overweight/obesity, male gender) or with a history of sleep apnea.

Convulsive seizures

Extrapyramidal symptoms

An increased incidence of EPS has been noted in adult patients with bipolar depression when taking quetiapine for depressive episodes compared to placebo.

Akathisia, characterized by an uncomfortable sense of motor restlessness and a need to move, can occur while taking quetiapine and is manifested by the patient’s inability to sit or stand without moving. The dose of quetiapine should not be increased if these symptoms occur.

Late dyskinesia

If symptoms of tardive dyskinesia develop, it is recommended that the dose of the drug be reduced or gradually withdrawn. Symptoms of tardive dyskinesia may worsen or even occur after discontinuation of the drug.

Malignant neuroleptic syndrome

Severe neutropenia and agranulocytosis

Contraindications

– Hypersensitivity to any component of the drug.

– Co-use with cytochrome P450 inhibitors, such as antifungal drugs of azole group, erythromycin, clarithromycin and nefazodone, as well as HIV protease inhibitors.

– Children under 18 years of age (efficacy and safety not established).

– Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

In patients with cardiovascular and cerebrovascular disease or other conditions predisposing to arterial hypotension, advanced age, hepatic impairment, history of seizures, risk of stroke and aspiration pneumonia.

Side effects

The most common side effects of quetiapine (>10%) are drowsiness, dizziness, dry mouth, withdrawal syndrome, increased triglyceride concentration, increased total cholesterol concentration (mainly low-density lipoprotein cholesterol – LDL), decreased high-density lipoprotein cholesterol (HDL) concentration, increased body weight, decreased hemoglobin concentration, and extrapyramidal symptoms.

Very common (>1/10)

An effect on the central nervous system:

Dizziness1,4,17, drowsiness2,17, headache, extrapyramidal symptoms1,13

Gastrointestinal tract side:

Mouth dryness

General disorders:

Withdrawal syndrome1,10

Lab and instrumental changes:

Elevated triglyceride concentration1,11, total cholesterol (mainly LDL cholesterol)1,12, decreased HDL cholesterol concentration1,18, increased body weight9, decreased hemoglobin concentration23

Often (>1/100, < 1/10)

Hematopoietic system side:

Leukopenia1.25

From the central nervous system:

Dysarthria, unusual and nightmarish dreams, increased appetite

Cardiovascular system side:

Tachycardia1,4, palpitations19, orthostatic hypotension1,4,17

Visual side:

Blurred vision

Respiratory system side:

Dyspnea19

Gastrointestinal tract side:

Constipation, dyspepsia, vomiting21

General disorders:

Slightly pronounced asthenia, irritability, peripheral edema, fever

Overdose

A lethal outcome has been reported with 13.6 g of quetiapine in a patient participating in a clinical trial and a lethal outcome after ingestion of 6 g of quetiapine in a post-marketing study of the drug. At the same time, a case of quetiapine administered in a dose greater than 30 g without lethal outcome has been described. There have been reports of extremely rare cases of quetiapine overdose resulting in prolonged QTc interval, death or coma.

In patients with a history of severe cardiovascular disease, the risk of side effects may increase with overdose.

The symptoms noted in overdose were mostly the result of an increase in the known pharmacological effects of the drug, such as drowsiness and sedation, tachycardia, decreased blood pressure, and anticholinergic effects.

Pregnancy use

Pregnancy

The use of antipsychotic drugs, including quetiapine, in the third trimester of pregnancy poses a risk of adverse reactions of varying severity and duration in neonates, including EPS and/or withdrawal syndrome. Agitation, hypertension, hypotension, tremor, somnolence, respiratory distress syndrome, or feeding disturbances have been reported. Consequently, the condition of newborns should be closely monitored.

Breastfeeding period

The excretion of quetiapine with breast milk has been reported, but the extent of excretion has not been determined. Women should be advised to avoid breastfeeding while taking quetiapine.

Similarities