Quetiapine

Brand Canonpharma

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Available since: 2019-09-19

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Clinical Pharmacology

Pharmacotherapeutic group

Antipsychotic (neuroleptic).

ATC code: N05AH04.

Pharmacological properties

Pharmacodynamics

Quetiapine belongs to the group of atypical antipsychotics. (neuroleptic). Quetiapine and its active metabolite N-dezalkilkvetiapin (norkvetiapin) interact with a wide range of brain neutrotransmitter receptors. Quetiapine
and norkvetiapin exhibit higher affinity for serotonin receptors (5HT2) than dopamine D1- and D2 receptors in the brain. This combination of receptor antagonism with greater selectivity for 5HT2 compared with D2 receptors is believed to cause clinical antipsychotic properties and low ability of quetiapine to cause extrapyramidal side effects (EPE) compared with typical antipsychotics. In addition, quetiapine does not have an affinity for the noradrenaline transporter and has a low affinity for the 5HT2-serotonin receptor, while norkvetiapin exhibits a high affinity for both. Quetiapine and norkvetiapin also have high affinity for histaminergic and adrenergic
α1 receptors as well as low affinity for adrenergic
α2 receptors and serotonin receptors 5HT1A. No selective affinity for the m-choline and benzodiazepine receptors was detected. Reduces the activity of mesolimbic A10-dopaminergic neurons, in comparison with A9-nigrostrial neurons involved in motor functions. The duration of association with 5HT2-serotonin and D2-dopamine receptors is less than 12 hours. Quetiapine does not have or has a low affinity for muscarinic receptors, while norkvetiapin exhibits moderate or high affinity for several muscarinic receptor subtypes.

In standard tests, quetiapine exhibits antipsychotic activity.

The specific contribution of the metabolite N-dezalkilkvetiapina in the pharmacological activity of quetiapine is not installed.

The results of the study of extrapyramidal symptoms (EPS) in animals revealed that quetiapine causes weak catalepsy in doses that effectively block D2 receptors.

Quetiapine is effective against both positive and negative symptoms of schizophrenia.

Quetiapine is effective as a monotherapy for manic episodes of moderate to severe severity. Data on the long-term use of quetiapine for the prevention of subsequent manic and depressive episodes are not available. Data on the use of quetiapine in combination with valproate seminatriya or lithium preparations for manic episodes of moderate to severe severity is limited, but this combination therapy, in general, was well tolerated. In addition, quetiapine at a dose of 300 mg and 600 mg is effective in patients with bipolar I and II disorders from moderate to severe severity. At the same time, the effectiveness of quetiapine at a dose of 300 mg and 600 mg per day is comparable.

Quetiapine is effective in patients with schizophrenia and mania when taking the drug 2 times a day, despite the fact that the half-life of quetiapine is about 7 hours.

The effects of quetiapine on the 5HT2 and D2 receptors continue up to 12 hours after taking the drug.

When quetiapine was administered with dose titration in schizophrenia, the frequency of EPS and the concomitant use of m-anticholinergic blockers were comparable to those taken with placebo. When prescribing quetiapine in fixed doses from 75 to 750 mg / day in patients with schizophrenia, the incidence of EPS and the need for concomitant use of m-cholinoblockers did not increase.

When quetiapine is used in doses up to 800 mg / day for the treatment of manic episodes of moderate to severe severity, both as monotherapy and in combination with lithium preparations or valproate seminatrii, the frequency of EPS and concomitant use
m-holinoblokatorov was comparable to that when receiving a placebo.

Quetiapine does not cause a prolonged increase in the concentration of prolactin in the blood plasma. There were no differences in the concentration of prolactin when using quetiapine or placebo in a fixed dose.

Pharmacokinetics

Suction

When used internally, quetiapine is well absorbed from the gastrointestinal tract (GIT). Eating does not significantly affect the bioavailability.

Distribution

Communication with plasma proteins - 83%. The pharmacokinetics of quetiapine is linear, the difference between men and women is not observed.

Equilibrium molar concentration of active metabolite
N-dezalkilkvetiapina is 35% of that of quetiapine.

Metabolism

Extensively metabolized in the liver with the formation of pharmacologically inactive metabolites under the action of CYP3A4 isoenzyme mediated by cytochrome P450. Quetiapine and some of its metabolites have a weak inhibitory effect on cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, but only in concentrations 10-50 times higher than those that occur with the commonly used effective dose of 300-450 mg / day.

According to a study of interactions in healthy volunteers, it was shown that the concomitant use of quetiapine (at a dose of 25 mg) and ketoconazole (a CYP3A4 inhibitor) caused a 5-8-fold increase in the AUC of quetiapine. Based on these data, the simultaneous use of quetiapine with CYP3A4 inhibitors is contraindicated.

The major metabolites in the blood plasma do not have pronounced pharmacological activity.

Removal

Excreted by the kidneys 73%, through the intestines - 21%. Less than 5% of quetiapine is not metabolized and is excreted unchanged by the kidneys or with feces.

The elimination half-life (T1 / 2) is 7 h.

Pharmacokinetics in different groups of patients

Floor

There are no differences in pharmacokinetic parameters in men and women.

Elderly patients

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

Renal dysfunction

The average plasma clearance of quetiapine is reduced by approximately 25% in patients with severe renal insufficiency (creatinine clearance less than 30 ml / min / 1.73m2), but the individual clearance values are within the values found in healthy volunteers.

Liver dysfunction

In patients with hepatic insufficiency (compensated alcoholic cirrhosis), the average plasma clearance of quetiapine is reduced by approximately 25%. Since quetiapine is extensively metabolized in the liver, elevated plasma concentrations of quetiapine are possible in patients with hepatic insufficiency, which requires a dose adjustment.

Based on the in vitro results, one should not expect that the simultaneous administration of quetiapine with other drugs will lead to clinically pronounced inhibition of the metabolism of other drugs mediated by cytochrome P450.

Indications

schizophrenia treatment;
treatment of bipolar disorder;
moderate and severe manic episodes in the structure of bipolar disorder;
severe episodes of depression in the structure of bipolar disorder.

Composition

Dosage 400 mg

1 tablet, film coated, contains:

Active ingredients: Quetiapine 400 mg.

Excipients: Hyprolosis (hydroxypropylcellulose Klutsel LF), calcium hydrogen phosphate dihydrate, calcium stearate, starch, pregelatinized corn starch, magnesium stearate, sodium carboxymethyl starch, microcrystalline cellulose.

Film coating composition: Aquapolish® D blue, incl. [Hypromellose (hydroxypropylmethylcellulose), glycerol (glycerin), microcrystalline cellulose, talc, Kandurin dye, silver gloss, indigo carmine dye.

Quetiapine is marketed under different brands and generic names, and comes in different dosage forms:

Brand name	Manufacturer	Country	Dosage form
Quetiapine	Canonpharma	Russia	pills
Quetiapine	Vertex	Russia	pills
Quetiapine	North Star	Russia	pills
Seroquel	AstraZeneca	UK	pills
Quentiax	Krka dd Novo mesto AO	Slovenia	pills
Ketilept	Egis	Hungary	pills

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Dosage and Administration

Quetiapine can be used regardless of the meal.

Adults

Treatment of schizophrenia:

Quetiapine is administered 2 times a day. The daily dose for the first 4 days of therapy is: 1st day - 50 mg, 2nd day - 100 mg, 3rd day - 200 mg, 4th day - 300 mg. Starting from the 4th day, the dose should be selected to be effective, usually ranging from 300 to 450 mg / day. Depending on the clinical effect and individual tolerance by the patient, the dose may vary from 150 to 750 mg / day. The maximum recommended daily dose is 750 mg.

Treatment of manic episodes in the structure of bipolar disorder

Quetiapine is used as monotherapy or in combination with drugs that have a normochemical effect. Quetiapine is administered 2 times a day. The daily dose for the first 4 days of therapy is: 1st day - 100 mg, 2nd day - 200 mg, 3rd day - 300 mg, 4th day - 400 mg. In the future, by the 6th day of therapy, the daily dose of the drug can be increased to 800 mg. Increasing the daily dose should not exceed 200 mg per day. Depending on the clinical effect and individual tolerance, the dose can vary from 200 to 800 mg / day. Usually, the effective dose is 400 to 800 mg / day. The maximum recommended daily dose is 800 mg.

Treatment of depressive episodes in the structure of bipolar disorder

Quetiapine is administered once a day at night. The daily dose for the first 4 days of therapy is: 1st day - 50 mg, 2nd day - 100 mg, 3rd day - 200 mg, 4th day - 300 mg. The recommended dose is 300 mg / day. The maximum recommended daily dose of Quetiapine is 600 mg. The antidepressant effect of Quetiapine was confirmed when it was used at a dose of 300 and 600 mg / day. With short-term therapy, the effectiveness of Quetiapine in doses of 300 and 600 mg / day. was comparable (see Pharmacodynamics section).

Elderly:

In elderly patients, the initial dose of Quetiapine is 25 mg / day. The dose should be increased daily by 25-50 mg to achieve an effective dose, which is likely to be less than in younger patients.

Patients with renal failure:

Dose adjustment is not required.

Patients with liver failure:

Quetiapine is extensively metabolized in the liver. Therefore, care should be taken when applying quetiapine in patients with hepatic insufficiency, especially at the beginning of therapy. It is recommended to start Quetiapine therapy with a dose of 25 mg / day and increase the dose daily by 25-50 mg until the effective dose is reached.

Adverse reactions

From the side of the central nervous system: headache, drowsiness, dizziness, anxiety; rarely - ZNS.

Since the cardiovascular system: orthostatic hypotension, tachycardia, arterial hypertension.

On the part of the digestive system: constipation, dry mouth, dyspepsia, diarrhea, transient increase in liver enzymes (ALT, AST, GGT), abdominal pain.

From the side of blood-forming organs: asymptomatic leukopenia and / or neutropenia; rarely eosinophilia.

From the musculoskeletal system: myalgia.

On the part of the respiratory system: rhinitis.

Dermatological reactions: skin rash, dry skin.

On the part of the organ of hearing: pain in the ear.

On the part of the urogenital system: urinary tract infections.

On the part of metabolism: a slight increase in cholesterol and triglycerides in the blood.

On the part of the endocrine system: a small dose-dependent reversible decrease in the level of thyroid hormones (in particular, total and free T4).

Other: asthenia, back pain, weight gain, fever, chest pain.

Contraindications

Hypersensitivity to any of the components of the drug, including lactase deficiency, glucose-galactose malabsorption and intolerance to galactose. Combined use with cytochrome P450 inhibitors, such as antifungal drugs of the azoles group, erythromycin, clarithromycin and nefazodone, as well as protease inhibitors (see the section "Interaction with other drugs"). Although the efficacy and safety of Quetiapine in children and adolescents aged 10-17 years have been studied in clinical studies, the use of Quetiapine in patients under the age of 18 years is not shown.

Carefully

In patients with cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension, old age, liver failure, convulsive seizures in the anamnesis.

Drug interactions

Caution should be exercised in the combined use of quetiapine with other drugs affecting the central nervous system, as well as with alcohol. The cytochrome P450 (CYP) 3A4 isoenzyme is the main isoenzyme responsible for the metabolism of quetiapine through the cytochrome P450 system. When studying healthy volunteers, co-administration of quetiapine (at a dose of 25 mg) with ketoconazole, a CYP3A4 inhibitor, led to an increase in the area under the concentration-time curve (AUC) of quetiapine 5-8 times. Therefore, co-administration of quetiapine and cytochrome CYPZA4 inhibitors is contraindicated. It is also not recommended to take Quetiapine along with grapefruit juice. In a pharmacokinetic study, the administration of quetiapine in various dosages before or simultaneously with carbamazepine resulted in a significant increase in clearance of quetiapine and, accordingly, a decrease in AUC, on average, by 13%, compared with taking quetiapine without carbamazepine. In some patients, the decrease in AUC was even more pronounced. This interaction is accompanied by a decrease in the concentration of quetiapine in the plasma and may reduce the effectiveness of quetiapine therapy. The joint appointment of Quetiapine with phenytoin, another inducer of the microsomal system of the liver, was accompanied by an even more pronounced (approximately 450%) increase in the clearance of Quetiapine. Appointment of quetiapine to patients receiving inducers of the liver enzyme system is possible only if the expected benefit of quetiapine therapy exceeds the risk associated with the abolition of hepatic enzyme inducer drug. Changes in the dose of microsomal enzyme inducer drugs should be gradual. If necessary, they may be replaced by drugs that do not induce microsomal enzymes (for example, valproic acid drugs). The pharmacokinetics of quetiapine did not change significantly with the simultaneous administration of imipramine antidepressant (CYP2D6 inhibitor) or fluoxetine (CYPA4 and CYP2D6 inhibitor). The pharmacokinetics of quetiapine does not significantly change when administered concurrently with the antipsychotic drugs risperidone or haloperidol. However, simultaneous administration of quetiapine and thioridazine led to an increase in clearance of quetiapine by approximately 70%. The pharmacokinetics of quetiapine does not change significantly with simultaneous use of cimetidine. With a single dose of 2 mg of lorazepam while receiving quetiapine at a dose of 250 mg 2 times a day, the clearance of lorazepam is reduced by about 20%. The pharmacokinetics of lithium do not change with the appointment of quetiapine. There were no clinically significant changes in the pharmacokinetics of valproic acid and quetiapine with co-administration of valproate seminatri and Quetiapine. Pharmacokinetic studies on the interaction of Quetiapine with drugs used in cardiovascular diseases have not been conducted. Caution must be exercised in the combined use of Quetiapine and drugs that can cause electrolyte imbalance and prolonged QTc interval. Quetiapine did not induce hepatic enzyme systems involved in the metabolism of phenazone.

Pregnancy and Lactation

Safety and efficacy of Quetiapine in pregnant women have not been established. Therefore, during pregnancy Quetiapine can only be used if the expected benefit to the woman justifies the potential risk to the fetus. The degree of excretion of quetiapine with human milk is not known. Women should be advised to avoid breastfeeding while taking Quetiapine.

Special instructions

Drowsiness

During quetiapine therapy, drowsiness and associated symptoms, such as sedation, may occur (see the “Side Effects” section). In clinical studies involving patients with depression in the structure of bipolar disorder, drowsiness typically developed during the first three days of therapy. The severity of this side effect was mostly mild or moderate. With the development of severe drowsiness in patients with depression in the structure of bipolar disorder, more frequent visits to the doctor may be required within 2 weeks from the onset of drowsiness or until symptoms decrease. In some cases, it may be necessary to discontinue Quetiapine therapy.

Patients with cardiovascular diseases

Care should be taken when prescribing quetiapine in patients with cardiovascular and cerebrovascular diseases and other conditions predisposing to hypotension. During quetiapine therapy, orthostatic hypotension may occur, especially during dose titration at the beginning of therapy. If orthostatic hypotension occurs, it may be necessary to reduce the dose or to titrate it more slowly.

Convulsive seizures

There were no differences in the incidence of seizures in patients taking quetiapine or placebo. However, as with the treatment of other antipsychotic drugs, caution is advised when treating patients with a history of convulsive seizures (see the “Side Effects” section).

Extrapyramidal symptoms

There was an increase in the incidence of EPS in adult patients with depression in the structure of bipolar disorder while taking Quetiapine for depressive episodes compared with placebo (see the “Side Effects” section).

Tardive dyskinesia

If symptoms of tardive dyskinesia develop, it is recommended to reduce the dose of the drug or gradually cancel it (see the “Side Effects” section). Malignant Neuroleptic Syndrome

While taking antipsychotic drugs, including Quetiapine, a malignant neuroleptic syndrome may develop (see the “Side Effects” section). Clinical manifestations of the syndrome include hyperthermia, altered mental status, muscular rigidity, lability of the autonomic nervous system, and an increase in the activity of creatine phosphokinase. In such cases, quetiapine should be discontinued and appropriate treatment carried out.

Severe neutropenia

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Interaction with other drugs

See also the section "Interaction with other drugs". The use of Quetiapine in combination with strong inducers of the liver enzyme system, such as carbamazepine and phenytoin, reduces the plasma Quetiapine concentration and may decrease the effectiveness of Quetiapine therapy. Appointment of quetiapine to patients receiving inducers of the liver enzyme system is possible only if the expected benefit of quetiapine therapy exceeds the risk associated with the abolition of hepatic enzyme inducer drug.Changes in the dose of microsomal enzyme inducer drugs should be gradual. If necessary, they may be replaced by drugs that do not induce microsomal enzymes (for example, valproic acid preparations).

Hyperglycemia

Hyperglycemia or exacerbation of diabetes mellitus is possible in patients with diabetes mellitus in the history of taking quetiapine. Clinical observation of patients with diabetes mellitus and patients with risk factors for the development of diabetes mellitus is recommended (see the “Side Effects” section). Lipid level

While taking quetiapine, triglycerides and cholesterol concentrations may be elevated (see the “Side Effects” section).

QT lengthening

No relationship was found between taking quetiapine and a persistent increase in the absolute value of the QT interval. However, the prolongation of the QT interval was noted with an overdose of the drug (see the “Overdose” section). Caution should be exercised when prescribing quetiapine, as well as other antipsychotic drugs, in patients with cardiovascular diseases and previously noted lengthening of the QT interval. Care must also be taken when prescribing quetiapine at the same time as drugs that prolong the QTc interval and other neuroleptics, especially in the elderly, patients with congenital lengthening of the QT interval, chronic heart failure, myocardial hypertrophy, hypocalmia, or hypomagneemia (see “Interaction with others”). drugs ”).

Acute reactions associated with drug withdrawal

With abrupt cancellation of quetiapine, the following acute reactions (“withdrawal” syndrome) can occur - nausea, vomiting, insomnia, headache, dizziness and irritability. Therefore, it is recommended to discontinue the drug gradually over a period of at least one or two weeks.

Elderly patients with dementia

Quetiapine is not indicated for the treatment of psychoses associated with dementia. Some atypical antipsychotics in randomized, placebo-controlled studies increased the risk of cerebrovascular complications in patients with dementia by about 3 times. The mechanism of this increase in risk has not been studied. A similar risk of increasing the frequency of cerebrovascular complications cannot be excluded for other antipsychotic drugs or other groups of patients. Quetiapine should be used with caution in patients at risk for stroke. An analysis of the use of atypical antipsychotics for the treatment of psychoses associated with dementia in elderly patients revealed an increase in the mortality rate in the group of patients who received drugs in this group, compared with the placebo group. In addition, two 10-week placebo-controlled Quetiapine studies in a similar group of patients (n = 710; mean age: 83 years; age range: 56-99 years) showed that the mortality rate in the group of patients taking Quetiapine was 5, 5%, and 3.2% in the placebo group. The causes of the deaths noted in these patients corresponded to those expected for this population. There is no causal relationship between Quetiapine treatment and the risk of increased mortality in elderly patients with dementia.

Suicide / suicidal thoughts or clinical deterioration

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicidal events). This risk persists until the onset of severe remission. Due to the fact that it may take several weeks or more to improve the condition of the patient from the start of treatment, patients must be under close medical supervision until the onset of improvement. According to generally accepted clinical experience, the risk of suicide may increase in the early stages of the onset of remission. Other mental disorders for which quetiapine is prescribed are also associated with an increased risk of suicide-related events.In addition, such conditions can be comorbid with a depressive episode. Thus, the precautions used in the treatment of patients with a depressive episode should be taken in the treatment of patients with other mental disorders. Patients with a history of suicidal events, as well as patients who clearly express suicidal thoughts before starting therapy, are at increased risk of suicidal intent and suicidal attempts and should be carefully monitored during treatment. A FDA (Food and Drug Administration, USA) meta-analysis of placebo-controlled antidepressant studies summarizing the data on approximately 4,400 children and adolescents and 7,700 adult patients with mental disorders revealed an increased risk of suicidal behavior compared with antidepressants compared to placebo children, adolescents and adult patients under the age of 25 years. This meta-analysis does not include studies where quetiapine was used (see the Pharmacodynamics section). According to short-term placebo-controlled studies for all indications and in all age groups, the incidence of suicide-related events was 0.9% for both quetiapine (61/6270) and placebo (27/3047). In these studies, in patients with schizophrenia, the risk of development of events associated with suicide 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 for patients over 25 years of age; 1.4% (2/147) for quetiapine and 1.3% (1/75) for placebo in patients under the age of 18 years. In patients with mania with bipolar disorder, the risk of suicidal events was 0% (0/67) for quetiapine and 0% (1/57) for placebo in patients aged 18-24; 1.2% (6/496) for quetiapine and 1.2% (6/503) for placebo in patients over 25 years of age; 1.0% (2/193) for quetiapine and 0% (0/90) for placebo in patients under the age of 18 years (see section "Special Instructions"). In patients with depression in bipolar disorder, the risk of development of events associated with suicide 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 for patients over 25 years of age. Studies involving patients with depression in bipolar disorder under the age of 18 years have not been conducted.

Influence on ability to drive motor transport and control mechanisms

Quetiapine may cause drowsiness, therefore, during treatment, patients are not recommended to work with mechanisms that are dangerous, including driving is not recommended.

Overdosage

A fatal outcome was reported when 13.6 g of quetiapine was administered to a patient participating in a clinical trial, as well as a lethal outcome after taking 6 g of quetiapine in a post-marketing study of the drug. At the same time, described the case of taking quetiapine in a dose exceeding 30 g, without death. There are reports of extremely rare cases of quetiapine overdose, leading to an increase in QTc interval, death or coma. In patients with a history of severe cardiovascular diseases, the risk of side effects during overdose may increase (see the section "Special Instructions"). The symptoms noted during overdose were mainly the result of an increase in the known pharmacological effects of the drug, such as drowsiness and sedation, tachycardia and a decrease in blood pressure. There are no specific antidotes for Quetiapine. In cases of severe intoxication should be aware of the possibility of an overdose of several drugs. It is recommended to carry out activities aimed at maintaining the function of respiration and the cardiovascular system, ensuring adequate oxygenation and ventilation.Gastric lavage (after intubation, if the patient is unconscious) and the appointment of activated carbon and laxatives may contribute to the removal of unabsorbed Quetiapine, but the effectiveness of these measures has not been studied. Close medical supervision should continue until the patient's condition improves.