Quetiapin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETIPINE (QUETIAPINE)

Composition:

Active substance: quetiapine;

1 tablet contains 25 mg or 100 mg or 200 mg or 300 mg of quetiapine (as quetiapine fumarate);

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone, dibasic calcium phosphate dihydrate, magnesium stearate;

coating of 25 mg tablets: polyethylene glycol, titanium dioxide (E 171), hypromellose, iron oxide red (E 172), iron oxide yellow (E 172);

coating of 100 mg tablets: polyethylene glycol, titanium dioxide (E 171), hypromellose, iron oxide yellow (E 172);

coating of 200 mg and 300 mg tablets: polyethylene glycol, hypromellose, titanium dioxide (E 171), talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

25 mg tablets – round, biconvex, film-coated tablets, peach-colored, with the imprint «Р» or smooth on one side and the imprint «25» on the other side;

100 mg tablets – round, biconvex, film-coated tablets, yellow-colored, with the imprint «Р» or smooth on one side and the imprint «100» on the other side;

200 mg tablets – round, biconvex, film-coated tablets, white-colored, with the imprint «Р» or smooth on one side and the imprint «200» on the other side;

300 mg tablets – elongated, biconvex, film-coated tablets, white-colored, with the imprint «Р» or smooth on one side and the imprint «300» on the other side.

Pharmacotherapeutic group. Antipsychotic agents. Quetiapine. ATC code N05AH04.

Pharmacological Properties.

Pharmacodynamics.

Quetiapine is a dibenzothiazepine derivative exerting antipsychotic effects. Quetiapine and its active metabolite, N-desalkyl quetiapine, interact with a broad range of neurotransmitter receptors. The contribution of the N-desalkyl metabolite to the overall pharmacological effect of the drug remains unclear.

Quetiapine has affinity for brain serotonin receptors 5-HT2 and 5-HT1A (in vitro Ki values are 288 and 557 nM, respectively) and dopamine receptors D1 and D2 (in vitro Ki values are 558 and 531 nM, respectively). This combination of receptor antagonism, with relatively greater selectivity for 5-HT2 receptors compared to D2 receptors, is believed to underlie the drug's clinical antipsychotic properties as well as its relatively low incidence of extrapyramidal symptoms. Quetiapine also exhibits high affinity for histamine H1 receptors (in vitro Ki = 10 nM) and alpha1-adrenergic receptors (in vitro Ki = 13 nM), with lower affinity for alpha2-adrenergic receptors (in vitro Ki = 782 nM). Quetiapine does not bind to muscarinic cholinergic or benzodiazepine receptors.

N-desalkyl quetiapine, similar to quetiapine, shows affinity for brain serotonin 5-HT2 receptors and dopamine D1 and D2 receptors.

In addition, like quetiapine, N-desalkyl quetiapine exhibits high affinity for serotonin 5-HT1 receptors, as well as for histaminergic and alpha1-adrenergic receptors, with lower affinity for alpha2-adrenergic receptors.

Pharmacokinetics.

Within the clinically relevant dose range, the pharmacokinetics of quetiapine and N-desalkyl quetiapine are linear. Quetiapine kinetics do not differ between men and women, or between smokers and non-smokers.

Absorption. Quetiapine is well absorbed from the gastrointestinal tract following oral administration. A radiolabeled drug study showed that approximately 73% is excreted in urine and 21% in feces within one week. The bioavailability of quetiapine is practically unchanged when the drug is taken with food, although Cmax and AUC increase by 25% and 15%, respectively. Peak plasma concentrations are reached within 2 hours after oral administration. At steady state, the molar concentration of the active metabolite N-desalkyl quetiapine is approximately 35% of that of quetiapine.

Distribution. The volume of distribution of quetiapine is 10±4 L/kg, and plasma protein binding is 83%.

Elimination and Metabolism. The elimination half-life of quetiapine is approximately 6–7 hours following repeated administration at clinically recommended doses. For N-desalkyl quetiapine, the half-life is approximately 12 hours. On average, less than 5% of the molar amount of unchanged quetiapine and its active metabolite is excreted in urine.

Quetiapine is extensively metabolized in the liver, with less than 5% of the administered dose recovered as unchanged compound in urine and feces one week after administration of radiolabeled quetiapine. Due to extensive hepatic metabolism, higher plasma concentrations of quetiapine are expected in patients with impaired liver function, and dose adjustment may therefore be necessary.

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

The primary cytochrome P450 enzyme responsible for quetiapine metabolism is CYP3A4. The formation of the N-desalkyl metabolite and elimination of quetiapine occur primarily via this enzyme.

In vitro studies have shown that quetiapine and some of its metabolites (including N-desalkyl quetiapine) are weak inhibitors of the cytochrome P450 enzymes 1A2, 2C9, 2C19, 2D6, and 3A4. However, this inhibition in vitro is observed only at concentrations 5 to 50 times higher than those achieved in humans receiving doses of 300–800 mg/day.

Clinical characteristics.

Indications.

Treatment of schizophrenia.

Treatment of manic episodes associated with bipolar disorders.

Contraindications.

Hypersensitivity to any component of the drug.

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

Interaction with other medicinal products and other forms of interaction.

Since quetiapine affects the central nervous system, it should be used with caution in combination with other agents acting on the central nervous system.

Quetiapine should be used with caution together with serotonergic medicinal products, such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, as the risk of developing serotonin syndrome—a potentially life-threatening condition—is increased (see section "Special precautions for use").

Quetiapine potentiates the effects of alcohol; therefore, alcohol consumption should be avoided during quetiapine therapy.

Cytochrome P450 (CYP) 3A4 is the primary enzyme responsible for quetiapine metabolism. In interaction studies in healthy volunteers, concomitant administration of quetiapine (25 mg) with ketoconazole (a CYP 3A4 inhibitor) resulted in a 5- to 8-fold increase in quetiapine AUC. Therefore, concomitant use of quetiapine with CYP 3A4 inhibitors is contraindicated. Grapefruit juice should also be avoided during quetiapine therapy.

In a multiple-dose study assessing the pharmacokinetics of quetiapine administered before and during treatment with carbamazepine (a hepatic enzyme inducer), concomitant use of carbamazepine significantly increased quetiapine clearance. This increase in clearance reduced systemic exposure to quetiapine (measured as AUC) to approximately 13% of exposure when quetiapine was administered alone, although a greater effect was observed in some patients. Due to this interaction, lower plasma concentrations may occur, potentially affecting the efficacy of quetiapine therapy.

Concomitant administration of quetiapine and phenytoin (another microsomal enzyme inducer) resulted in an increase in quetiapine clearance by approximately 450%. Initiation of quetiapine therapy in patients receiving a hepatic enzyme inducer should only be considered if the physician determines that the benefit of quetiapine outweighs the risks associated with discontinuation of the enzyme inducer. Importantly, any changes in the use of the inducer should be made gradually. If necessary, it should be replaced with a non-inducer (e.g., sodium valproate) (see section "Special precautions for use").

The pharmacokinetics of quetiapine are not significantly altered by concomitant administration of antidepressants such as imipramine (a known CYP 2D6 inhibitor) or fluoxetine (a known CYP 3A4 and CYP 2D6 inhibitor).

Concomitant use of antipsychotics such as risperidone or haloperidol did not cause significant changes in quetiapine pharmacokinetics. Concurrent administration of quetiapine and thioridazine resulted in an increase in quetiapine clearance by approximately 70%.

The pharmacokinetics of quetiapine were unchanged when administered concomitantly with cimetidine.

The pharmacokinetics of lithium were not altered when administered concomitantly with quetiapine.

In a study comparing lithium plus quetiapine versus placebo plus quetiapine in adult patients with acute mania, increased incidence of extrapyramidal symptoms (particularly tremor), somnolence, and weight gain were observed in the group receiving lithium compared to the placebo group.

No clinically significant changes in the pharmacokinetics of sodium valproate and quetiapine were observed when administered concomitantly. In a retrospective study involving children and adolescents receiving sodium valproate, quetiapine, or a combination of both, an increased incidence of leukopenia and neutropenia was observed in the group receiving both agents compared to groups receiving either agent alone.

Interaction studies with cardiovascular drugs have not been conducted.

Caution should be exercised when administering quetiapine concomitantly with medicinal products that alter electrolyte balance or prolong the QT interval.

False positive results in enzyme immunoassays for methadone and tricyclic antidepressants have been reported in patients taking quetiapine. Suspicious screening immunoassay results should be confirmed using an appropriate chromatographic method.

Quetiapine may act as an antagonist to levodopa and dopamine agonists.

Quetiapine does not induce hepatic enzyme systems involved in antipyrine metabolism.

Co-administration of quetiapine (150 mg twice daily) and divalproex (500 mg twice daily) increases the maximum plasma concentration (Cmax) of total valproic acid by 11%. These changes are not clinically significant.

Quetiapine may be taken independently of food intake or with food.

Interactions with herbal preparations have not been established.

Special precautions for use.

Children

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

It should also be noted that the long-term impact of quetiapine treatment on growth and sexual maturation has not been studied beyond 26 weeks. The long-term effects on cognitive and behavioral development are unknown.

During clinical trials involving pediatric and adolescent patients, quetiapine treatment was associated with a higher incidence of extrapyramidal symptoms compared to placebo in patients treated for schizophrenia and bipolar mania.

Suicide/suicidal thoughts or clinical worsening

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

In addition, the potential risk of suicide-related events after abrupt discontinuation of quetiapine therapy should be considered due to known risk factors associated with the condition being treated.

Other psychiatric disorders for which quetiapine is prescribed may also be associated with an increased risk of suicide-related events. Moreover, these disorders may coexist with depressive episodes.

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

Patients with a history of suicide-related events or those exhibiting significant levels of suicidal thinking prior to starting therapy are at higher risk of developing suicidal thoughts or attempting suicide and should be closely monitored during treatment. A meta-analysis of antidepressant clinical trials in adult patients with psychiatric disorders showed an increased risk of suicidal behavior in patients under 25 years of age.

Close monitoring of patients, especially those at high risk, should accompany pharmacological therapy, particularly at the beginning of treatment and during subsequent dose adjustments. Patients (and caregivers) should be warned to monitor for clinical worsening, suicidal behavior or thoughts, and unusual changes in behavior, and to seek immediate medical attention if symptoms occur.

Metabolic risk

Due to changes observed during clinical trials in body weight, blood glucose (see hyperglycemia), and lipid parameters, there is a potential for worsening of the metabolic risk profile in individual patients, which may require appropriate management.

Extrapyramidal symptoms

In clinical trials, quetiapine was associated with an increased frequency of extrapyramidal symptoms compared to placebo in patients treated for major depressive episodes associated with bipolar disorder and major depressive disorder.

Quetiapine use has been associated with the development of akathisia, characterized by subjective distress or unpleasant restlessness and a compelling need to move, often accompanied by an inability to sit or stand still. These events are more likely to occur during the first few weeks of treatment. Increasing the dose in patients who develop such symptoms may be harmful.

Tardive dyskinesia

If signs or symptoms of tardive dyskinesia appear, consideration should be given to reducing the dose or discontinuing quetiapine. Symptoms of tardive dyskinesia may worsen or even emerge after discontinuation of therapy.

Somnolence

Quetiapine treatment is associated with somnolence and related symptoms such as sedation. In clinical trials, these symptoms in patients with bipolar depression typically occurred within the first 3 days of treatment and were mostly mild to moderate in intensity. For patients with bipolar depression or depressive episodes who experience somnolence, monitoring may be required for 2 weeks after the onset of somnolence or until symptoms resolve, or consideration may be needed to discontinue treatment.

Orthostatic hypotension

Quetiapine treatment has been associated with orthostatic hypotension and related dizziness, which, similar to somnolence, usually occur during the dose titration period. These effects may increase the frequency of accidental injuries (falls), especially in elderly patients. Therefore, patients should be advised to exercise caution until they become accustomed to the potential effects of the medication.

Quetiapine should be used with caution in patients with known cardiovascular or cerebrovascular diseases or other conditions that may lead to arterial hypotension. Quetiapine may cause orthostatic hypotension, particularly at the beginning of dose titration; therefore, dose reduction or a longer titration period may be necessary in such cases.

Sleep apnea syndrome

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

Seizures

During clinical trials, there was no difference in seizure frequency between patients taking quetiapine and those in the placebo group. As with other antipsychotic medications, quetiapine should be used cautiously 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, altered mental status, muscle rigidity, autonomic instability, and elevated creatine phosphokinase levels. In such cases, quetiapine should be discontinued and appropriate treatment initiated.

Serotonin syndrome

Concomitant use of quetiapine with other serotonergic medicinal products, such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, may lead to serotonin syndrome—a potentially life-threatening condition (see section "Interaction with other medicinal products and other forms of interaction").

If concomitant treatment with other serotonergic medicinal products is clinically justified, close monitoring of the patient is recommended, especially at the beginning of treatment and during dose increases. Symptoms of serotonin syndrome may include changes in mental status, autonomic instability, neuromuscular disturbances, and/or gastrointestinal symptoms.

In case of suspected serotonin syndrome, consideration should be given to reducing the dose or discontinuing therapy depending on the severity of symptoms.

Severe neutropenia and agranulocytosis

Severe neutropenia (neutrophil count <0.5×10⁹/L) was infrequently observed in clinical trials of quetiapine. Agranulocytosis (severe neutropenia with infection) has been reported rarely in patients receiving quetiapine during clinical trials and in the post-marketing period (including fatal cases). Most cases of severe neutropenia occurred within two months of starting quetiapine therapy. No clear dose relationship has been established. During the post-marketing period, normalization of leukopenia and/or neutropenia occurred after discontinuation of quetiapine. Possible risk factors for neutropenia include pre-existing low leukocyte or neutrophil counts and drug-induced neutropenia in the patient's history. Cases of agranulocytosis have occurred in patients without pre-existing risk factors. Neutropenia should be considered in patients with infection, especially in the absence of obvious predisposing factors, and in patients with unexplained fever, and appropriate clinical measures should be taken.

Quetiapine treatment should be discontinued if the neutrophil count in blood is <1.0×10⁹/L. Patients should be monitored for signs and symptoms of infection and neutrophil levels (until levels exceed <1.5×10⁹/L) (see section "Pharmacodynamic properties").

Anticholinergic (muscarinic) effects

Norquetiapine, the active metabolite of quetiapine, has moderate to high affinity for several muscarinic receptor subtypes. Quetiapine should be used with caution in patients receiving other medicinal products with anticholinergic effects.

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

Interactions

See also section "Interaction with other medicinal products and other forms of interaction."

Concomitant use of quetiapine with a strong hepatic enzyme inducer, such as carbamazepine or phenytoin, significantly reduces quetiapine plasma concentrations, which may compromise the effectiveness of quetiapine therapy. Treatment with quetiapine in patients receiving a hepatic enzyme inducer should only be initiated if the physician considers the benefit of quetiapine use to outweigh the risks of discontinuing the enzyme inducer. It is important that any changes in the use of the inducer occur gradually. If necessary, the inducer should be replaced with a non-inducer (e.g., sodium valproate).

Effect on body weight

Weight gain has been reported during quetiapine treatment and should be monitored and clinically managed as with other antipsychotic medications.

Hyperglycemia

Hyperglycemia and/or development or exacerbation of diabetes mellitus have occasionally been associated with ketoacidosis or coma, rarely reported, including several cases with fatal outcomes. There have been reports of several cases with prior weight gain, which may be a contributing factor. Appropriate clinical monitoring should be performed according to existing guidelines for antipsychotic agents. Patients treated with any antipsychotic medicinal product, including quetiapine, should be monitored for signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes mellitus or risk factors for diabetes should be regularly checked for worsening glucose control. Body weight should be continuously monitored.

Lipids

Elevated triglycerides, LDL cholesterol, and total cholesterol, and decreased HDL cholesterol levels have been observed in clinical trials of quetiapine. Appropriate treatment should be initiated if lipid levels change.

QT interval prolongation

In clinical trials and during use according to medical instructions, quetiapine did not cause sustained increases 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 family history of prolonged QT interval. Caution should also be exercised when prescribing quetiapine with other medicinal products known to prolong the QT interval or when used concomitantly with neuroleptics, especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalemia, or hypomagnesemia.

Cardiomyopathy and myocarditis

Cases of cardiomyopathy and myocarditis have been reported during clinical trials and in the post-marketing period (see section "Adverse reactions"). In patients suspected of having cardiomyopathy or myocarditis, consideration should be given to discontinuing quetiapine treatment.

Discontinuation of the medication

Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability have been described after abrupt discontinuation of quetiapine. Therefore, a gradual discontinuation of the medication over a period of at least one to two weeks is recommended.

Elderly patients with psychosis associated with dementia

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

In trials of dementia patients, use of some atypical antipsychotics was associated with approximately a threefold increased risk of cardiovascular adverse events. The mechanism of this increased risk is unknown. An increased risk cannot be excluded for other antipsychotics or other patient groups. Quetiapine should be used with caution in patients with risk factors for stroke.

Meta-analyses of atypical antipsychotics indicate that elderly patients with psychosis associated with dementia are at increased risk of mortality compared to placebo. However, data from quetiapine trials in elderly patients with dementia have not established a causal relationship between quetiapine treatment and mortality.

Dysphagia

Dysphagia has been reported with quetiapine use. Quetiapine should be used with caution in patients at risk of aspiration pneumonia.

Constipation and intestinal obstruction

Constipation is a risk factor for intestinal obstruction. Cases of constipation and intestinal obstruction have been reported with quetiapine use. These reports include fatal cases in patients at higher risk of intestinal obstruction, including those receiving multiple medications that reduce gastrointestinal motility and/or medications not previously reported to cause constipation symptoms.

Venous thromboembolism

Cases of venous thromboembolism have been reported with the use of neuroleptic agents. Since patients receiving neuroleptics often have acquired risk factors for venous thromboembolism, all possible risk factors should be identified before and during quetiapine therapy, and preventive measures should be taken.

Pancreatitis

Cases of pancreatitis have been reported in clinical trials and during 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: elevated triglycerides, gallstones, and alcohol consumption.

Additional information

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

Lactose

The tablets contain lactose. This medicinal product should not be administered to patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Misuse and abuse

Cases of misuse and abuse have been reported. Caution is required when prescribing quetiapine to patients with a history of alcohol or drug abuse.

Use in elderly patients

In elderly patients, plasma clearance of quetiapine is on average 30–50% lower compared to patients aged 18–65 years. In addition, this patient group usually has a higher incidence of impaired liver, central nervous system, and cardiovascular function. All of this necessitates caution when using the drug in elderly patients.

Renal impairment

No dose adjustment is necessary for patients with renal impairment.

Hepatic impairment

Use of quetiapine in patients with existing liver disease requires caution. Precautions should also be taken when using concomitant medications with potential hepatotoxicity. Before initiating quetiapine therapy in patients with known or suspected liver dysfunction, measurement of transaminase levels is recommended. Such tests should also be performed periodically during treatment.

Quetiapine treatment should be discontinued if jaundice develops.

Use during pregnancy or breastfeeding

Patients should inform their physician if they are pregnant or planning pregnancy while being treated with quetiapine. The safety and efficacy of quetiapine during pregnancy have not been studied. Therefore, when prescribing quetiapine to pregnant women, the potential benefit of such therapy should be weighed against the potential risk to the fetus.

Based on information from several pregnancies during which quetiapine was used, symptoms of neonatal withdrawal have been reported in newborns. Newborns whose mothers took quetiapine during pregnancy have exhibited withdrawal symptoms.

Newborns whose mothers took antipsychotic medications (including quetiapine) during the third trimester are at risk of adverse reactions, including extrapyramidal symptoms and/or withdrawal symptoms, which may vary in severity and duration after birth. Observed adverse reactions include agitation, arterial hypertension, hypotension, tremor, somnolence, respiratory disorders, or feeding difficulties. Therefore, newborns should be closely monitored.

It is unknown how much quetiapine is excreted in breast milk. Due to the potential for adverse reactions, quetiapine is contraindicated during breastfeeding.

Ability to affect reaction speed when driving or operating machinery

Patients should refrain from driving vehicles or operating machinery requiring heightened attention or physical coordination while taking this medication.

Dosage and Administration.

For adults, take twice daily, 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 Day 4 onwards, the dose should be titrated to the usual effective dose range of 300–450 mg per day. Depending on clinical efficacy and individual tolerability, the dose may be adjusted within the range of 150–750 mg per day.

Switching from one dose to another should occur over 2 days, as steady-state levels of quetiapine in the body are not yet achieved within 1–2 days. If dose adjustment is necessary, it is recommended to change the dose by 25–50 mg at a time (when administered twice daily).

Bipolar Manic Disorders

For monotherapy or as adjunctive therapy with mood stabilizers, the total daily dose during the first 4 days of treatment is 100 mg (Day 1), 200 mg (Day 2), 300 mg (Day 3), and 400 mg (Day 4). Further dose escalation up to 800 mg per day by Day 6 should be done gradually, increasing the daily dose by no more than 200 mg per day.

Dose selection should be based on clinical response and individual drug tolerability.

Dosing in Specific Patient Populations

Elderly Patients.

As with other antipsychotic agents, caution should be exercised when using this medication in elderly patients, especially at the beginning of treatment. Therapy should be initiated at a dose of 25 mg/day. The dose should be increased by 25–50 mg/day until an effective dose is reached, which is likely to be lower than that required in younger patients.

Patients with Hepatic Impairment.

This medication should be used with caution in these patient groups. The initial dose of quetiapine is 25 mg/day. This dose may be increased by 25–50 mg/day until the effective dose is achieved.

Missed Dose

If a dose is missed, the medication should be taken as soon as possible. However, if the next scheduled dose is approaching, the patient should resume the regular dosing schedule without compensating for the missed dose. Under no circumstances should a double dose be taken.

Children.

The safety and efficacy of quetiapine in pediatric patients have not been established; therefore, the drug should not be used in pediatric practice.

Overdose.

Patients with concomitant cardiovascular diseases are most susceptible to adverse consequences of overdose.

Data on quetiapine overdose are limited. Cases of ingestion exceeding 20 g have been reported; no fatalities were recorded, and patients recovered without sequelae. Since widespread clinical use, there have been very rare reports of quetiapine overdose resulting in fatal outcome, coma, or QT prolongation.

Symptoms. Typically, these are symptoms representing more pronounced manifestations of the drug's usual pharmacological effects (e.g., somnolence, sedation, tachycardia, hypotension). The following events have been reported in cases of quetiapine monotherapy overdose: QT prolongation, seizures, epileptic status, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium, and/or agitation.

Patients with pre-existing severe cardiovascular disease are at increased risk of overdose effects.

Treatment. There is no specific antidote for quetiapine. In cases of severe poisoning, it should also be considered that the overdose may involve multiple drugs. In severe cases, intensive supportive therapy is required, including maintaining airway patency, ensuring adequate oxygenation and ventilation, and measures to support cardiovascular function. Published reports describe resolution of severe CNS reactions, including coma and delirium, following intravenous administration of physostigmine (1–2 mg) under continuous ECG monitoring.

In cases of persistent arterial hypotension due to quetiapine overdose, appropriate measures should be taken, such as intravenous fluid administration and/or sympathomimetic agents (adrenaline and dopamine should be avoided, as stimulation of beta-adrenergic receptors may worsen hypotension in the presence of alpha-adrenergic blockade induced by quetiapine).

Since prevention of absorption in overdose has not been studied, consideration should be given to gastric lavage (after intubation if the patient is unconscious) and administration of activated charcoal with a laxative.

Careful medical supervision is required until the patient's condition is fully normalized.

Adverse Reactions

Frequency of adverse reactions: very common (≥ 10%), common (≥ 1%, < 10%), uncommon (≥ 0.1%, < 1%), rare (≥ 0.01%, < 0.1%), very rare (< 0.01%), and frequency not known (cannot be estimated from available data).

The most commonly reported adverse reactions with quetiapine are: somnolence, dizziness, dry mouth, headache, withdrawal symptoms (upon discontinuation of the drug), increased serum triglyceride levels, increased total cholesterol levels (especially LDL-cholesterol), decreased HDL-cholesterol levels, weight gain, decreased hemoglobin levels, and extrapyramidal symptoms.

As with other antipsychotics, quetiapine use has been associated with weight gain, syncope, neuroleptic malignant syndrome, leukopenia, and peripheral edema.

Blood and lymphatic system disorders

Very common: decreased hemoglobin levels (decrease in hemoglobin levels to ≤13 g/dL (8.07 mmol/L) in men, ≤12 g/dL (7.45 mmol/L) in women, observed at least once in 11% of patients treated with quetiapine across all studies, including open-label trials. The mean maximum decrease in hemoglobin levels at any time in these patients was -1.50 g/dL).

Common: leukopenia (defined as deviation from normal baseline to potentially clinically significant values at any time after baseline in all studies. Leukocyte deviation was ≤3×10⁹ cells/L at any time); neutrophil count decrease; eosinophilia (defined as deviation from normal baseline to potentially clinically significant values at any time after baseline in all studies. Eosinophil deviation was >1×10⁹ cells/L at any time).

Uncommon: thrombocytopenia (platelets ≤100×10⁹/L at least once), anemia, decreased platelet count.

Rare: agranulocytosis (neutrophil deviation from ≥1.5×10⁹/L at baseline to <0.5×10⁹/L at any time during treatment).

Frequency not known: neutropenia.

Immune system disorders

Uncommon: hypersensitivity (including skin allergic reactions).

Very rare: anaphylactic reaction.

Endocrine system disorders

Common: hyperprolactinemia (prolactin levels (patients >18 years): >20 µg/L (>869.56 pmol/L) in males; >30 µg/L (>1304.34 pmol/L) in females – at any time); decreased total T4, decreased free T4, decreased total T3, increased TSH (based on deviation from normal baseline to potentially clinically significant values at any time after baseline in all studies. Deviation in total T4, free T4, total T3, and free T3 was <0.8×ULN (pmol/L) and TSH deviation was >5 mIU/L at any time).

Uncommon: decreased free T3, hypothyroidism.

Very rare: inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders

Very common: increased serum triglyceride levels (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 once); 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 once. Increase in LDL-cholesterol ≥30 mg/dL (≥0.769 mmol/L) occurred very commonly. The mean value among patients with such increase was 41.7 mg/dL (1.07 mmol/L)); decreased HDL-cholesterol (HDL-cholesterol: <40 mg/dL (1.025 mmol/L) in males; <50 mg/dL (1.282 mmol/L) in females at any time); weight gain (defined as >7% increase in body weight from baseline. Occurs predominantly during the first weeks of therapy in adults).

Common: increased appetite, elevated blood glucose levels to hyperglycemia levels (fasting blood glucose ≥126 mg/dL (≥7.0 mmol/L) or postprandial blood glucose ≥200 mg/dL (≥11.1 mmol/L) at least once).

Uncommon: hyponatremia (shift from >132 mmol/L to ≤132 mmol/L at least once); diabetes mellitus, worsening of pre-existing diabetes.

Rare: metabolic syndrome.

Psychiatric disorders

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

Rare: sleepwalking and related phenomena such as sleep talking and sleep-related eating disorders.

Nervous system disorders

Very common: dizziness, somnolence, headache, extrapyramidal symptoms. Somnolence usually occurs during the first 2 weeks of treatment and typically resolves with continued quetiapine use.

Common: dysarthria.

Uncommon: seizures, restless legs syndrome, tardive dyskinesia, loss of consciousness.

Cardiac disorders

Common: tachycardia, palpitations, postural hypotension.

Uncommon: QT interval prolongation, bradycardia.

Number of patients with change in QTc interval duration from <450 msec to ≥450 msec with an increase of ≥30 msec. In placebo-controlled trials of quetiapine, the mean change and number of patients with shifts to clinically significant levels were similar in quetiapine and placebo groups. Bradycardia may occur during or shortly after initiation of therapy and may be associated with hypotension and/or loss of consciousness. Frequency is based on reports of adverse reactions of bradycardia and related events observed in all clinical trials of quetiapine.

Frequency not known: cardiomyopathy, myocarditis.

Eye disorders

Common: blurred vision.

Uncommon: eye pain.

Vascular disorders

Common: orthostatic hypotension.

Rare: venous thromboembolism.

Renal and urinary disorders

Uncommon: urinary retention.

Respiratory, thoracic and mediastinal disorders

Common: dyspnea.

Uncommon: rhinitis.

Gastrointestinal disorders

Very common: dry mouth.

Common: constipation, dyspepsia, vomiting (with increased frequency in elderly patients (≥65 years)).

Uncommon: dysphagia.

Rare: pancreatitis, intestinal obstruction/ileus.

Hepatobiliary disorders

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

Uncommon: increased aspartate aminotransferase (AST) levels in serum.

Rare: jaundice, hepatitis.

Asymptomatic elevations (shift from normal to >3×ULN at any time) in transaminase levels (ALT, AST) or gamma-GT (gamma-glutamyl transferase) have been observed in some patients receiving quetiapine. These elevations were usually reversible with continued quetiapine treatment.

Skin and subcutaneous tissue disorders

Common: rash.

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

Frequency not known: toxic epidermal necrolysis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms (DRESS), cutaneous vasculitis.

Musculoskeletal and connective tissue disorders

Very rare: rhabdomyolysis.

Pregnancy, postpartum and perinatal conditions

Frequency not known: withdrawal syndrome in newborns, neonatal abstinence.

Reproductive system and breast disorders

Uncommon: sexual dysfunction.

Rare: priapism, galactorrhea, breast enlargement, menstrual cycle disturbances.

General disorders and administration site conditions

Very common: withdrawal symptoms (upon discontinuation). The most frequently observed withdrawal symptoms in short-term placebo-controlled monotherapy trials evaluating withdrawal symptoms were insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability. The frequency of these reactions significantly decreased within one week after stopping treatment.

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

Rare: neuroleptic malignant syndrome, hypothermia.

Laboratory test abnormalities

Rare: increased blood creatine phosphokinase levels. According to reports from clinical trials on adverse reactions, increased blood creatine phosphokinase levels were not associated with neuroleptic malignant syndrome.

Cases of prolonged QT interval, ventricular arrhythmia, sudden unexplained death, cardiac arrest, and torsade de pointes-type arrhythmias have been reported with the use of neuroleptic drugs and are considered class-specific.

Children

The adverse reactions listed above observed in adults also occur in children. The table below summarizes adverse reactions with higher incidence in this age group or not observed in adult patients.

1. Prolactin levels (patients <18 years): >20 µg/L (>869.56 pmol/L) in males; >26 µg/L (>1130.428 pmol/L) in females at any time. Less than 1% of patients had prolactin elevations >100 µg/L.
2. Based on deviations above clinically significant thresholds (adapted criteria from the National Institute for Health and Care Excellence) or increases of >20 mm Hg in systolic or >10 mm Hg in diastolic blood pressure at any time, derived from short-term (3–6 weeks) placebo-controlled trials in children and adolescents.
3. Note: The frequency corresponds to that observed in adults; however, irritability may present with different clinical manifestations in children and adolescents compared to adults.

Shelf life.

5 years.

Storage conditions.

Store out of reach of children at a temperature not exceeding 30 °C.

Packaging.

25 mg, 100 mg, or 200 mg: 10 tablets per blister, 3 blisters per cardboard box; 300 mg: 100 tablets in bottles.

Prescription status.

Prescription only.

Manufacturer. Pharmascience Inc.

Manufacturer's address and place of business.

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