SEVELAMER SASE - VISTA

INSTRUCTIONS for medical use of the drug QUETIAPINE (QUETIAPINE)

Composition

active substance: quetiapine; 1 tablet contains 25 mg or 100 mg, or 200 mg, or 300 mg of quetiapine (in the form of quetiapine fumarate); excipients: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose (type A), povidone, calcium phosphate dihydrate dibasic, magnesium stearate; shell of 25 mg tablets: polyethylene glycol, titanium dioxide (E 171), hydroxypropylmethylcellulose, iron oxide red (E 172), iron oxide yellow (E 172); shell of 100 mg tablets: polyethylene glycol, titanium dioxide (E 171), hydroxypropylmethylcellulose, iron oxide yellow (E 172); shell of 200 mg and 300 mg tablets: polyethylene glycol, hydroxypropylmethylcellulose, titanium dioxide (E 171), talc.

Pharmaceutical form

Tablets, film-coated.

Main physical and chemical properties

25 mg tablets - round, biconvex, film-coated tablets, peach-colored, with an imprint "P" or smooth on one side and with an imprint "25" on the other side; 100 mg tablets - round, biconvex, film-coated tablets, yellow, with an imprint "P" or smooth on one side and with an imprint "100" on the other side; 200 mg tablets - round, biconvex, film-coated tablets, white, with an imprint "P" or smooth on one side and with an imprint "200" on the other side; 300 mg tablets - elongated, biconvex, film-coated tablets, white, with an imprint "P" or smooth on one side and with an imprint "300" on the other side.

Pharmacotherapeutic group

Antipsychotic drugs. Quetiapine. ATC code N05A H04.

Pharmacological properties

Pharmacodynamics

Quetiapine is a derivative of dibenzothiazepine, which has a neuroleptic effect. Quetiapine and its active metabolite N-desalkylquetiapine interact with a number of neurotransmitter receptors. It remains unclear what contribution to the pharmacological effect of the drug is made by the N-desalkylated metabolite.

Quetiapine is affine to serotonin receptors of the brain 5HT2 and 5HT1A (in vitro Ki is 288 and 557 nM, respectively) and to dopamine receptors D1 and D2 (in vitro Ki is 558 and 531 nM, respectively). It is believed that this combination of receptor antagonism with relative selectivity of interaction with 5HT2 receptors, compared to D2, underlies the clinical antipsychotic properties of the drug, as well as the relatively low frequency of development of extrapyramidal symptoms. Quetiapine also exhibits high affinity for histamine receptors H1 (in vitro Ki is 10 nM) and adrenergic receptors alpha1 (in vitro Ki is 13 nM) with lower affinity for adrenergic receptors alpha2 (in vitro Ki is 782 nM). Quetiapine does not bind to cholinergic muscarinic and benzodiazepine receptors.

N-desalkylquetiapine, like quetiapine, exhibits affinity for serotonin receptors of the brain 5HT2 and dopamine receptors D1 and D2.

In addition, similar to quetiapine, N-desalkylquetiapine exhibits high affinity for serotonin receptors 5HT1 and histaminergic and adrenergic receptors alpha1 with lower affinity for adrenergic receptors alpha2.

Pharmacokinetics

In a clinically significant dose range, the pharmacokinetics of quetiapine and N-desalkylquetiapine are linear. The kinetics of quetiapine in men and women, in smokers and non-smokers, do not differ.

Absorption. Quetiapine is well absorbed in the gastrointestinal tract when taken orally. In a study with a drug labeled with radioactive isotopes, it was shown that approximately 73% is excreted in the urine and 21% in the feces within one week. The bioavailability of quetiapine is practically unchanged when taken with food, while the values of Cmax and AUC increase by 25% and 15%, respectively. The maximum content of the drug in plasma is reached within 2 hours after oral administration. The molar concentration of the active metabolite N-desalkylquetiapine in a steady state is 35% of that of quetiapine.

Distribution. The volume of distribution of quetiapine is 10 ± 4 l / kg, and the binding to plasma proteins is 83%.

Elimination and metabolism. The half-life of quetiapine is approximately 6-7 hours when taken repeatedly in clinically recommended doses. This indicator for N-desalkylquetiapine is approximately 12 hours. On average, the molar fraction of free quetiapine and its active metabolite excreted in the urine is less than 5%.

Quetiapine is intensively metabolized in the liver, and the initial compound accounts for less than 5% of the dose that entered the body within a week after administration. Given the intensive metabolism of quetiapine in the liver, it should be expected that in patients with impaired liver function, the content of the drug in the plasma will be higher, so dose adjustment may be necessary.

The main metabolic reactions of quetiapine involve the oxidation of the side alkyl chain, hydroxylation of the dibenzothiazepine ring, sulfoxidation, and conjugation (phase 2). The main metabolites of quetiapine in human plasma are oxidation and sulfoxidation products, none of which have pharmacological activity.

The main enzyme of the cytochrome P450 system responsible for the metabolism of quetiapine is P450 3A4. The formation of the N-desalkyl derivative and the elimination of quetiapine are carried out mainly under the action of this enzyme.

In vitro studies have shown that quetiapine and some of its metabolites (including N-desalkylquetiapine) are weak inhibitors of the P450 1A2, 2C9, 2C19, 2D6, and 3A4 enzymes. However, such inhibition in vitro is observed only at concentrations that are 5-50 times higher than the concentrations in the human body when taking the drug in doses of 300-800 mg / day.

Clinical characteristics

Indications

Treatment of schizophrenia.

Treatment of manic episodes associated with bipolar disorders.

Contraindications

Increased sensitivity to any of the components that make up the drug.

Concomitant use of cytochrome P450 inhibitors, such as HIV protease inhibitors, azole antifungal drugs, erythromycin, clarithromycin, and nefazodone.

Interaction with other drugs and other types of interactions

Given that quetiapine affects the central nervous system, it should be used with caution in combination with other drugs that affect the central nervous system.

Quetiapine should be used with caution in combination with serotonergic drugs, such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, as the risk of developing serotonin syndrome, a potentially life-threatening condition, increases (see "Special instructions").

Quetiapine potentiates the effects of alcohol, so when treating with quetiapine, you should avoid consuming alcohol.

Cytochrome P450 (CYP) 3A4 is the enzyme that is primarily responsible for the metabolism of quetiapine. In a study of the interaction in healthy volunteers, the concomitant use of quetiapine (25 mg) with ketoconazole (a CYP 3A4 inhibitor) caused an increase in the AUC of quetiapine by 5-8 times. Therefore, the concomitant use of quetiapine with CYP 3A4 inhibitors is contraindicated. It is also not recommended to consume grapefruit juice during the treatment with quetiapine.

During a study of repeated use of doses in order to evaluate the pharmacokinetics of quetiapine, which was prescribed before and during treatment with carbamazepine (an inducer of liver enzymes), the concomitant use of carbamazepine significantly increased the clearance of quetiapine. This increase in clearance reduced the systemic exposure of quetiapine (measured by the area under the AUC curve) to a level that was, on average, 13% of the exposure when quetiapine was used alone, although in some patients a greater effect was observed. As a result of this interaction, lower concentrations may be created in the plasma, which may affect the effectiveness of quetiapine therapy.

The concomitant use of quetiapine and phenytoin (another inducer of microsomal enzymes) caused an increase in the clearance of quetiapine by approximately 450%. Starting therapy with quetiapine in patients who are taking an inducer of liver enzymes can only be done if the doctor believes that the benefits of using quetiapine outweigh the risks associated with discontinuing the inducer of liver enzymes. It is important that any changes in the intake of the inducer occur gradually. If necessary, it should be replaced with a non-inducer (e.g., sodium valproate) (see "Special instructions").

The pharmacokinetics of quetiapine is not significantly affected by the concomitant use of such antidepressants as imipramine (a known inhibitor of CYP 2D6) or fluoxetine (a known inhibitor of CYP 3A4 and CYP 2D6).

The concomitant use of antipsychotics such as risperidone or haloperidol did not cause significant changes in the pharmacokinetics of quetiapine. Concomitant use of quetiapine and thioridazine caused an increase in the clearance of quetiapine by approximately 70%.

When used concomitantly with cimetidine, the pharmacokinetics of quetiapine did not change.

The pharmacokinetics of lithium did not change when used concomitantly with quetiapine.

In a study comparing the combination of lithium with quetiapine and placebo with quetiapine in adult patients with acute mania, an increase in the frequency of cases of extrapyramidal phenomena (especially tremors), drowsiness, and weight gain was observed in the group with the addition of lithium compared to the group with the addition of placebo.

In the pharmacokinetics of sodium valproate and quetiapine, no clinically significant changes were observed when used concomitantly. In a retrospective study involving children and adolescents who received sodium valproate, quetiapine, or a combination of these drugs, an increase in the number of cases of leukopenia and neutropenia was observed in the group that took both drugs compared to the groups that received these medications separately.

Studies of the interaction with cardiovascular drugs have not been conducted.

Cautious use of quetiapine is recommended when used concomitantly with drugs that disrupt electrolyte balance or prolong the QT interval.

In patients who used quetiapine, there were cases of false-positive results of enzyme immunoassay for the presence of methadone and tricyclic antidepressants. It is recommended to verify suspicious results of screening immunoassay using a suitable chromatographic method.

Quetiapine may act as a levodopa antagonist and a dopamine agonist.

Quetiapine does not induce liver enzyme systems involved in the metabolism of antipyrine.

The combined use of quetiapine (150 mg twice a day) and divalproex (500 mg twice a day) increases the maximum concentration (Cmax) of total valproic acid in plasma by 11%. These changes are not clinically significant.

Quetiapine can be taken regardless of food intake or with food.

Interactions with phytopreparations have not been established.

Special instructions

Children

Quetiapine is not recommended for use in children due to the lack of data indicating its effectiveness in this age group. Clinical studies of quetiapine have shown that, in addition to the known safety profile established for adults, the frequency of some adverse events is higher in children than in adults (increased appetite, increased prolactin levels in serum, and extrapyramidal symptoms), as well as one event that was not previously observed in studies involving adult patients (increased blood pressure). In addition, changes in thyroid function tests were observed in children and adolescents.

It should also be noted that the delayed effect of quetiapine treatment on growth and sexual maturation has not been studied for a period of more than 26 weeks. The long-term effect on cognitive and behavioral development is unknown.

During clinical studies involving pediatric and adolescent patients, treatment with quetiapine was associated with an increased frequency of extrapyramidal symptoms in patients being treated for schizophrenia and bipolar mania.

Suicide/suicidal thoughts or clinical deterioration

Depression in bipolar disorder is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicide-related events). This risk persists until significant remission is established. Since improvement may not be observed during the first weeks of treatment or later, patients should be closely monitored until such improvement is seen. According to general clinical experience, the risk of suicide may increase during the early stages of improvement.

In addition, it is necessary to take into account the potential risk of suicidal-related events after abrupt discontinuation of quetiapine treatment due to known risk factors for the disease being treated.

Other mental disorders for which quetiapine is prescribed may also be associated with an increased risk of suicidal-related events. In addition, these disorders may occur simultaneously with depressive episodes.

When treating patients with other mental disorders, the same precautions should be taken as when treating patients with severe depressive episodes.

Patients who have a history of suicidal-related events or who demonstrate a significant level of suicidal thinking before starting therapy have a higher risk of suicidal thoughts or attempts and should be under close supervision during treatment. The goal of medication therapy, especially at the beginning of treatment and with further dose changes, should be accompanied by careful monitoring of patients, particularly those at high risk. Patients (and caregivers) need to be warned about the need to monitor for clinical deterioration, suicidal behavior, or unusual changes in behavior and to seek medical help immediately if symptoms appear.

Metabolic risk

Given the changes observed during clinical studies regarding body weight, blood glucose (see hyperglycemia), and lipids, there is a likelihood of worsening the metabolic risk profile in individual patients, for which appropriate treatment should be prescribed.

Extrapyramidal symptoms

Quetiapine has been associated with an increased frequency of extrapyramidal symptoms compared to placebo in patients receiving treatment for episodes of major depression associated with bipolar disorder and major depressive disorder.

Tardive dyskinesia

If signs and symptoms of tardive dyskinesia appear, the question of reducing the dose or discontinuing quetiapine should be considered. Symptoms of tardive dyskinesia may worsen, and even appear, after discontinuation of therapy.

Somnolence

Treatment with quetiapine is associated with somnolence and similar symptoms, such as sedation. In clinical studies, such symptoms occurred, as a rule, within the first 3 days of treatment and were predominantly mild to moderate in intensity. Regarding patients with bipolar depression and patients with depressive episodes, in whom somnolence occurs, monitoring may be required for 2 weeks after the appearance of somnolence or until the symptoms disappear, or it may be necessary to consider discontinuing treatment.

Orthostatic hypotension

Treatment with quetiapine was accompanied by orthostatic hypotension and associated dizziness, which, similar to somnolence, usually occur during the dose titration period. These phenomena may contribute to an increased frequency of accidental injuries (falls), especially among elderly patients. Therefore, patients should be advised to be careful until they get used to the possible effects of the drug.

Quetiapine should be used with caution in patients with known cardiovascular and cerebrovascular diseases or other conditions that may lead to arterial hypotension. Quetiapine may cause orthostatic hypotension, especially at the beginning of dose titration, so in such cases, a decrease in dose or a more prolonged titration may be necessary.

Sleep apnea syndrome

Sleep apnea syndrome has been registered in patients taking quetiapine. In patients who are taking concomitant central nervous system depressants and who have a history of or are at risk of sleep apnea, such as those who are overweight/obese or male, quetiapine should be used with caution.

Seizures

During clinical studies, there was no difference in the frequency of seizures in patients taking quetiapine and patients in the placebo group. As with the treatment of other antipsychotic drugs, it is recommended to use the drug with caution in patients with a history of seizures.

Malignant neuroleptic syndrome

Malignant neuroleptic syndrome may be associated with antipsychotic treatment, including quetiapine. Clinical manifestations include hyperthermia, changes in mental status, muscle rigidity, vegetative instability, and increased creatine phosphokinase levels. In such a case, the use of quetiapine should be discontinued, and appropriate treatment should be started.

Serotonin syndrome

Concomitant use of quetiapine and other serotonergic drugs, such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, may lead to serotonin syndrome - a potentially life-threatening condition (see "Interaction with other drugs and other types of interactions").

If concomitant treatment with other serotonergic drugs is clinically justified, careful monitoring of the patient is recommended, especially at the beginning of treatment and when increasing the dose. Symptoms of serotonin syndrome may include changes in mental status, instability of the vegetative nervous system, neuromuscular disorders, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, the question of reducing the dose or discontinuing therapy should be considered, depending on the severity of the symptoms.

Severe neutropenia and agranulocytosis

Severe neutropenia (neutrophil count <0.5 × 10^9 / L) has rarely been observed in clinical studies of quetiapine. Agranulocytosis (severe neutropenia with infection) has been reported rarely in patients taking quetiapine during clinical trials and in the post-marketing period (including cases with a fatal outcome). Most cases of severe neutropenia occurred within 2 months of starting quetiapine therapy. No clear relationship with dose has been established. During the post-marketing period, normalization of leukopenia and/or neutropenia occurred after discontinuation of quetiapine therapy. Possible risk factors for neutropenia include pre-existing decreased leukocyte and neutropenia caused by drugs in the history. There have been cases of agranulocytosis in patients without pre-existing risk factors. It is necessary to consider the possibility of developing neutropenia in patients with infection, especially in the absence of obvious contributing factors, as well as in patients with unexplained fever, and to take appropriate clinical measures.

It is recommended to discontinue quetiapine treatment if the neutrophil count in the blood is <1.0 × 10^9 / L. Patients are recommended to be monitored for signs and symptoms of infection and neutrophil count (until they exceed 1.5 × 10^9 / L).

Anticholinergic (muscarinic) effects

Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several subtypes of muscarinic receptors. Quetiapine should be used with caution in patients receiving drugs that also have anticholinergic effects.

Quetiapine should be used with caution in patients with urinary retention (also in history), clinically significant prostatic hyperplasia, intestinal obstruction, or a related condition, with increased intraocular pressure, or with narrow-angle glaucoma.

Interactions

See also "Interaction with other drugs and other types of interactions".

The concomitant use of quetiapine with a potent inducer of liver enzymes, such as carbamazepine or phenytoin, significantly reduces the concentration of quetiapine in the plasma, which may impair the effectiveness of quetiapine therapy. Treatment with quetiapine in patients who are taking an inducer of liver enzymes can only be started if the doctor believes that the benefits of using quetiapine outweigh the risks associated with discontinuing the inducer of liver enzymes. It is important that any changes in the intake of the inducer occur gradually. If necessary, it should be replaced with a non-inducer (e.g., sodium valproate).

Influence on body weight

Weight gain has been reported during treatment with quetiapine, which, as with the use of antipsychotic drugs, should be monitored and clinically corrected.

Hyperglycemia

Hyperglycemia and/or the development or exacerbation of diabetes mellitus have sometimes been associated with quetiapine, rarely reported, including several cases with fatal outcomes. There were reports of several cases with prior weight gain, which may be a contributing factor. Appropriate clinical monitoring is recommended in accordance with existing guidelines for the use of antipsychotic drugs. Patients treated with any antipsychotic drugs, including quetiapine, should be monitored for signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes or risk factors for diabetes should be regularly checked for impaired glucose control. Weight should be constantly monitored.

Lipids

Increased levels of triglycerides, LDL, and total cholesterol, as well as decreased levels of HDL cholesterol, have been observed in clinical studies of quetiapine. When changing lipid levels, appropriate treatment should be prescribed.

QT interval prolongation

In clinical studies, quetiapine did not cause a persistent increase in absolute QT intervals. However, QT interval prolongation has been observed in cases of overdose. As with other antipsychotics, caution should be exercised when prescribing quetiapine to patients with cardiovascular diseases or patients with a prolonged QT interval in their family history. Also, caution should be exercised when prescribing quetiapine with other drugs that are known to prolong the QT interval or when used concomitantly with neuroleptics, especially in elderly patients, patients with congenital prolonged QT interval, congestive heart failure, hypertrophy of the heart, hypokalemia, or hypomagnesemia.

Cardiomyopathy and myocarditis

During clinical studies and in the post-marketing period, cardiomyopathy and myocarditis have been reported (see "Adverse reactions"). In patients with suspected cardiomyopathy or myocarditis, the question of discontinuing quetiapine treatment should be considered.

Discontinuation of the drug

Acute withdrawal symptoms, such as insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability, have been described after sudden discontinuation of quetiapine. Therefore, it is recommended to gradually discontinue the drug over a period of at least 1 to 2 weeks.

Elderly patients with psychosis associated with dementia

Quetiapine is not recommended for the treatment of psychosis associated with dementia.

In studies in patients with dementia, the use of some atypical antipsychotics has been associated with an increased risk of approximately 3 times the risk of cerebrovascular adverse events. The mechanism of such an increased risk is unknown. The increased risk cannot be excluded for other antipsychotics or for other categories of patients. Quetiapine should be used with caution in patients with risk factors for stroke.

According to a meta-analysis of atypical antipsychotics, it is known that elderly patients with psychosis associated with dementia are at increased risk of fatal outcomes compared to placebo. However, according to studies of quetiapine in elderly patients with dementia, a causal relationship between quetiapine treatment and fatal outcomes has not been established.

Dysphagia

Dysphagia has been observed with quetiapine. Caution should be exercised when using quetiapine in patients who are at risk of aspiration pneumonia.

Constipation and intestinal obstruction

Constipation is a risk factor for the development of intestinal obstruction. With the use of quetiapine, cases of constipation and intestinal obstruction have been registered. These reports include reports of fatal cases in patients who have a higher risk of developing intestinal obstruction, including those patients who are taking several medications that reduce intestinal peristalsis and/or medications for which there may not have been reports of causing symptoms of constipation.

Venous thromboembolism

Venous thromboembolism has been observed with the use of neuroleptic drugs. Since patients who use neuroleptics often have acquired risk factors for venous thromboembolism, all possible risk factors for its occurrence should be identified before and during quetiapine therapy, and preventive measures should be taken.

Pancreatitis

There have been reports of pancreatitis in clinical trials and post-marketing use, but a causal relationship has not been established. In post-marketing reports, many patients had factors known to be associated with pancreatitis: increased triglycerides, gallstones, alcohol consumption.

Additional information

Data on the use of quetiapine in combination with divalproex or lithium for manic episodes of moderate or severe degree are limited; however, combination therapy was well tolerated. These data showed an additive effect on the third week of treatment.

Lactose

Tablets contain lactose. Patients with rare hereditary galactose intolerance, total lactase deficiency, or malabsorption of glucose-galactose should not use this drug.

Incorrect use and abuse

There have been reports of incorrect use and abuse. It is necessary to be careful when prescribing quetiapine to patients with a history of alcohol or drug abuse.

Use in elderly patients

In elderly patients, the clearance of quetiapine in plasma is reduced by an average of 30-50% compared to that in patients aged 18-65 years. In addition, this category of patients more often has impaired liver, central nervous system, and cardiovascular function. All this requires caution when using the drug in elderly patients.

Impaired renal function

There is no need to adjust the dose for patients with impaired renal function.

Impaired liver function

The use of quetiapine in patients with existing liver diseases requires caution. It is necessary to take precautions and when using concomitant drugs with potential hepatotoxicity. Before starting quetiapine therapy, it is recommended to determine the content of transaminases in patients with known or suspected liver function impairment. Such studies should also be performed periodically during treatment with the drug.

Quetiapine treatment should be discontinued in case of jaundice development.

Use during pregnancy or breastfeeding

When treating with quetiapine, patients should inform their doctor about the presence of pregnancy or plans to become pregnant. The safety and efficacy of quetiapine during pregnancy have not been studied. Therefore, when prescribing quetiapine to pregnant women, the potential benefits of such therapy should be weighed against the potential risk to the fetus.

According to information on several pregnancies during which quetiapine was used, there were reports of the development of symptoms of neonatal abstinence in newborns. In newborns whose mothers took quetiapine during pregnancy, withdrawal symptoms from the drug were observed.

Newborns whose mothers took antipsychotic drugs (including quetiapine) in the third trimester are at risk of adverse reactions, including extrapyramidal symptoms and/or withdrawal symptoms, which can vary in severity and duration after birth. The following adverse reactions have been observed: agitation, arterial hypertension, hypotension, tremor, somnolence, respiratory disorders, and feeding disorders. Therefore, newborns should be under close supervision.

It is not known how much quetiapine passes into breast milk. Given the potential side effects, the use of quetiapine during breastfeeding is contraindicated.

Ability to affect reaction speed when driving vehicles or operating other mechanisms

When using the drug, it is recommended to refrain from driving vehicles and performing work that requires increased attention or physical coordination.

Method of application and dosage

Administered to adults 2 times a day, regardless of food intake.

Schizophrenia

The total daily dose during the first 4 days of therapy is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3), and 300 mg (day 4).

Starting from the 4th day and onwards, the dose should be titrated to the usual effective dose of 300-450 mg per day. Depending on clinical efficacy and individual tolerability, the dose can be adjusted within the range of 150-750 mg per day.

The transition from one dose to another occurs within 2 days, since within 1-2 days, a steady state for quetiapine in the body is not yet achieved. If it is necessary to increase or decrease the dose of the drug, it is recommended to change the dose each time by 25-50 mg (when taken 2 times a day).

Bipolar manic disorders

For monotherapy or as an adjunct to mood stabilizers, the total daily dose during the first 4 days of therapy is 100 mg (day 1), 200 mg (day 2), 300 mg (day 3), and 400 mg (day 4). Further dose increase to 800 mg per day on day 6 should be done gradually with a dose increase of no more than 200 mg per day.

Dose selection is based on clinical response and individual tolerability of the drug.

Dosing regimen for individual patient categories

Elderly patients

As with other antipsychotic drugs, the drug should be used with caution in elderly patients, especially at the beginning of treatment. Treatment should be started with a dose of 25 mg/day. The dose should be increased daily by 25-50 mg/day to achieve an effective dose, which is likely to be lower than in younger patients.

Patients with impaired liver function

These categories of patients should be given the drug with caution. The initial dose of quetiapine is 25 mg/day. This dose can be increased by 25-50 mg/day to achieve an effective dose.

Missed dose

In case of a missed dose, the drug should be taken as soon as possible. However, if it is almost time for the next dose, it is necessary to proceed to the regular intake schedule without compensating for the missed dose. Under no circumstances should a double dose of the drug be taken.

Children

The safety and efficacy of quetiapine for the treatment of children have not been studied, so the drug should not be used in pediatric practice.

Overdose

Patients with concomitant cardiovascular diseases are most likely to be susceptible to the negative consequences of an overdose.

Data on quetiapine overdose are limited. There have been reports of quetiapine use in doses exceeding 20 grams; no fatal cases have been reported, and patients have recovered without consequences. After the widespread introduction of quetiapine into medical practice, there have been very rare reports of overdose, resulting in a fatal outcome or coma, or QT prolongation.

Symptoms. These are usually symptoms that are more pronounced manifestations of the usual pharmacological effects of the drug (e.g., somnolence, sedative effect, tachycardia, arterial hypotension). The following events have been registered in the conditions of monotherapy overdose of quetiapine: QT prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, confusion, and/or agitation.

In patients with existing severe cardiovascular disease, there is an increased risk of overdose effects.

Treatment. There is no specific antidote for quetiapine. In cases of severe poisoning, intensive therapy is necessary, including support of airway patency, ensuring adequate oxygenation and ventilation, and measures to support cardiovascular function. Regarding this situation, published reports describe cases of elimination of serious reactions from the central nervous system, including coma and delirium, with intravenous administration of physostigmine (1-2 mg) under continuous ECG monitoring.

In cases of persistent arterial hypotension with quetiapine overdose, appropriate measures should be taken, such as intravenous administration of fluids and/or sympathomimetics (it is recommended to avoid the use of adrenaline and dopamine, since the stimulation of beta-adrenergic receptors can deepen hypotension in the presence of alpha-adrenergic receptor blockade caused by quetiapine).

Since the prevention of absorption has not been studied in cases of overdose, it is necessary to consider the need for gastric lavage (after intubation, if the patient is unconscious) and the use of activated charcoal with a laxative.

Until the patient's condition returns to normal, close medical supervision is necessary.

Adverse reactions

The frequency of adverse reactions: very common (≥ 10%), common (≥ 1% to <10%), uncommon (≥ 0.1% to <1%), rare (≥ 0.01% to <0.1%), and very rare (<0.01%) and unknown frequency (cannot be estimated based on available data).

When taking quetiapine, the most common adverse reactions reported were: somnolence, dizziness, dry mouth, headache, withdrawal symptoms (discontinuation of the drug), increased levels of triglycerides in serum, increased total cholesterol (especially LDL cholesterol), decreased HDL cholesterol, weight gain, decreased hemoglobin, and extrapyramidal symptoms.

As with other antipsychotic drugs, the use of quetiapine was associated with weight gain, syncope, malignant neuroleptic syndrome, leukopenia, and peripheral edema.

From the blood and lymphatic system

Very common: decreased hemoglobin level (decrease in hemoglobin level to ≤13 g/dl (8.07 mmol/l) in men, ≤12 g/dl (7.45 mmol/l) in women, at least in one examination, observed in 11% of patients treated with quetiapine, in all studies, including open ones. The average maximum decrease in hemoglobin level at any time was -1.50 g/dl).

Common: leukopenia (based on deviation from normal initial to potentially clinically significant values at any time after initial in all studies. Deviation of leukocytes was ≤3 × 10^9 cells/l at any time); decreased neutrophil count; increased eosinophil count (based on deviation from normal initial to potentially clinically significant values at any time after initial in all studies. Deviation of eosinophils was >1 × 10^9 cells/l at any time).

Uncommon: thrombocytopenia (platelets ≤100 × 10^9/l as a minimum in one case), anemia, decreased platelet count.

Rare: agranulocytosis (deviation of neutrophils from ≥1.5 × 10^9/l from baseline to <0.5 × 10^9/l at any time during treatment).

Unknown: neutropenia.

From the immune system

Uncommon: hypersensitivity (including allergic skin reactions).

Very rare: anaphylactic reaction.

From the endocrine system

Common: hyperprolactinemia (prolactin level (patients >18 years): >20 μg/l (>869.56 pmol/l) in men; >30 μg/l (>1304.34 pmol/l) in women at any time); decreased total T4, decreased free T4, decreased total T3, increased TSH (based on deviation from normal initial to potentially clinically significant values at any time after initial in all studies. Deviation of total T4, free T4, total T3, and free T3 was <0.8 × LLN (pmol/l) and deviation of TSH was >5 mmol/l at any time).

Uncommon: decreased free T3, hypothyroidism.

Very rare: inadequate secretion of antidiuretic hormone.

From metabolism and nutrition

Very common: increased levels of triglycerides in serum (triglyceride level ≥200 mg/dl (≥2.258 mmol/l) (patients ≥18 years) or ≥150 mg/dl (≥1.694 mmol/l) (patients <18 years) at least in one case); increased total cholesterol (especially LDL cholesterol) (cholesterol level ≥240 mg/dl (≥6.2064 mmol/l) (patients ≥18 years) or ≥200 mg/dl (≥5.172 mmol/l) (patients <18 years) at least in one case. Increase in LDL cholesterol level ≥30 mg/dl (≥0.769 mmol/l) was very common. The average value among patients with such an increase was 41.7 mg/dl (1.07 mmol/l)); decreased HDL cholesterol; weight gain (based on >7% increase in body weight compared to initial. Occurs mainly during the first weeks of therapy in adults).

Common: increased appetite, increased blood glucose levels to hyperglycemic levels (blood glucose level ≥126 mg/dl (≥7.0 mmol/l) or postprandial glucose level ≥200 mg/dl (≥11.1 mmol/l) at least in one case).

Uncommon: hyponatremia (shift from >132 mmol/l to ≤132 mmol/l at least in one examination); diabetes mellitus, exacerbation of previously existing diabetes.

Rare: metabolic syndrome.

Mental disorders

Common: unusual dreams and nightmares, suicidal thoughts and suicidal behavior. Cases of suicidal thoughts and suicidal behavior were reported during treatment with quetiapine or immediately after discontinuation of the drug.

Rare: somnambulism and related phenomena, such as talking in sleep and sleep-related eating disorders.

From the nervous system

Very common: dizziness, somnolence, headache, extrapyramidal symptoms. Somnolence usually occurs within the first 2 weeks of treatment and usually disappears with prolonged use of quetiapine.

Common: dysarthria.

Uncommon: seizures, restless legs syndrome, tardive dyskinesia, syncope.

From the heart

Common: tachycardia, palpitations, postural hypotension.

Uncommon: QT interval prolongation, bradycardia.

The number of patients in whom the QTc interval changed from <450 ms to ≥450 ms with an increase of ≥30 ms. In placebo-controlled studies of quetiapine, the average change and the number of patients who had a shift to a clinically significant level were similar in the quetiapine and placebo groups. Bradycardia may occur during or near the start of therapy and may be associated with hypotension and/or syncope. The frequency of occurrence is based on reports of adverse reactions of bradycardia and related phenomena observed in all clinical studies of quetiapine.

Unknown: cardiomyopathy, myocarditis.

From the eyes

Common: blurred vision.

Uncommon: eye pain.

From the vascular system

Common: orthostatic hypotension.

Rare: venous thromboembolism.

From the kidneys and urinary tract

Uncommon: urinary retention.

Respiratory, thoracic, and mediastinal disorders

Common: dyspnea.

Uncommon: rhinitis.

From the gastrointestinal tract

Very common: dry mouth.

Common: constipation, dyspepsia, vomiting (according to the increased frequency of vomiting in elderly patients (≥65 years)).

Uncommon: dysphagia.

Rare: pancreatitis, intestinal obstruction/ileus.

From the hepatobiliary system

Common: increased alanine aminotransferase (ALT) in serum, increased gamma-glutamyltransferase (GGT) levels.

Uncommon: increased aspartate aminotransferase (AST) in serum.

Rare: jaundice, hepatitis.

A asymptomatic increase (shift from normal to >3 × ULN at any time) in ALT, AST, or GGT levels was observed in some patients when using quetiapine. Such increases were usually reversible with continued quetiapine treatment.

From the skin and subcutaneous tissue

Common: rash.

Very rare: in individual cases, allergic reactions are possible, including angioedema, Stevens-Johnson syndrome.

Unknown frequency: toxic epidermal necrolysis, multiforme erythema, drug reaction with eosinophilia and systemic symptoms (DRESS), skin vasculitis.

From the musculoskeletal system and connective tissue

Very rare: rhabdomyolysis.

Pregnancy, postpartum, and perinatal conditions

Unknown frequency: withdrawal syndrome in newborns, neonatal abstinence.

From the reproductive system and breast

Uncommon: sexual dysfunction.

Rare: priapism, galactorrhea, breast swelling, menstrual disorder.

General disorders and administration site conditions

Very common: withdrawal symptoms (discontinuation of the drug). Withdrawal symptoms that were most commonly observed during short-term placebo-controlled clinical studies of monotherapy, in which withdrawal symptoms were evaluated: insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability. The frequency of these reactions decreased significantly within a week after discontinuation of treatment.

Common: mild asthenia, peripheral edema, irritability, pyrexia, abdominal pain, back pain, and anorexia.

Rare: malignant neuroleptic syndrome, hypothermia.

Changes in laboratory parameters

Rare: increased creatine phosphokinase level in blood. According to reports of clinical studies on adverse reactions, an increase in creatine phosphokinase level in blood is not associated with malignant neuroleptic syndrome.

Children

The above-mentioned adverse reactions that were observed in adults also occur in children. The table below summarizes adverse reactions with a higher frequency of occurrence in this age group of patients or those that were not observed in adult patients.

1. Prolactin levels (patients <18 years): >20 μg/l (>869.56 pmol/l) in men; >26 μg/l (>1130.428 pmol/l) in women at any time. Less than 1% of patients had an increase in prolactin level >100 μg/l.

2. Based on deviation above clinically significant limits (adapted National Institute of Health Care criteria) or increase >20 mmHg for systolic or >10 mmHg for diastolic blood pressure at any time, obtained from short-term (3-6 weeks) placebo-controlled studies in children and adolescents.

3. Note: The frequency corresponds to that observed in adults, but irritability may be associated with different clinical manifestations in children and adolescents compared to adults.

Shelf life

5 years.

Storage conditions

Store in a place inaccessible to children at a temperature not exceeding 30°C.

Packaging

25 mg or 100 mg, or 200 mg, 10 tablets in a blister pack, 3 blister packs in a cardboard box, 300 mg, 100 tablets in bottles.

Release category

By prescription only.

Manufacturer

Pharmascience Inc.

Manufacturer's location and address

6111 Royalmount Avenue, 100, Montreal, Quebec H4P 2T4, Canada.