Quetiapine-SZ (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

N05AH04 (Quetiapine)

Active Substance

Quetiapine (Rec.INN registered by WHO)

Dosage Forms

	Quetiapine-SZ	Film-coated tablets, 25 mg: 30, 60 or 90 pcs.
		Film-coated tablets, 100 mg: 30, 60 or 90 pcs.
		Film-coated tablets, 200 mg: 30, 60 or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from beige-yellow to beige in color, round, biconvex; the tablets are white or almost white on the cross-section.

Excipients: microcrystalline cellulose 102, lactose monohydrate (milk sugar) – 44 mg, povidone K30 (medium molecular weight polyvinylpyrrolidone), croscarmellose sodium (primellose), magnesium stearate.

Shell composition: hypromellose, polysorbate-80 (tween-80), talc, titanium dioxide (E171), yellow iron oxide dye (E172).

10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.
30 pcs. – blister packs (1) – cardboard packs.
30 pcs. – blister packs (2) – cardboard packs.
30 pcs. – blister packs (3) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
60 pcs. – polymer jars (1) – cardboard packs.
90 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.
60 pcs. – polymer bottles (1) – cardboard packs.
90 pcs. – polymer bottles (1) – cardboard packs.

Film-coated tablets yellow in color, round, biconvex; the tablets are white or almost white on the cross-section.

Excipients: microcrystalline cellulose 102, lactose monohydrate (milk sugar) – 32 mg, povidone K30 (medium molecular weight polyvinylpyrrolidone), croscarmellose sodium (primellose), magnesium stearate.

Shell composition: hypromellose, polysorbate-80 (tween-80), talc, titanium dioxide (E171), aluminum lake based on quinoline yellow dye (E104).

10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.
30 pcs. – blister packs (1) – cardboard packs.
30 pcs. – blister packs (2) – cardboard packs.
30 pcs. – blister packs (3) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
60 pcs. – polymer jars (1) – cardboard packs.
90 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.
60 pcs. – polymer bottles (1) – cardboard packs.
90 pcs. – polymer bottles (1) – cardboard packs.

Film-coated tablets pink in color, round, biconvex; the tablets are white or almost white on the cross-section.

Excipients: microcrystalline cellulose 102, lactose monohydrate (milk sugar) – 44.5 mg, povidone K30 (medium molecular weight polyvinylpyrrolidone), croscarmellose sodium (primellose), magnesium stearate.

Shell composition: hypromellose, polysorbate-80 (tween-80), talc, titanium dioxide (E171), aluminum lake based on azorubine (carmoisine) dye (E122) – 0.08 mg.

10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.
30 pcs. – blister packs (1) – cardboard packs.
30 pcs. – blister packs (2) – cardboard packs.
30 pcs. – blister packs (3) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
60 pcs. – polymer jars (1) – cardboard packs.
90 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.
60 pcs. – polymer bottles (1) – cardboard packs.
90 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Psycholeptics; antipsychotics; diazepines, oxazepines, thiazepines and oxepines

Pharmacological Action

Mechanism of action

Quetiapine is an atypical antipsychotic drug. Quetiapine and its active metabolite N-desalkyl Quetiapine interact with neurotransmitter receptors in the brain. Quetiapine and N-desalkyl Quetiapine exhibit high affinity for serotonin type 5-HT₂ receptors and dopamine type D₁ and D₂ receptors in the brain. Higher selectivity for serotonin 5-HT₂ receptors than for dopamine D₂ receptors determines the main clinical antipsychotic properties of quetiapine and the low incidence of extrapyramidal side effects. In addition, N-desalkyl Quetiapine exhibits high affinity for the norepinephrine transporter. Quetiapine and N-desalkyl Quetiapine have high affinity for histamine and α₁-adrenergic receptors and lower affinity for α₂-adrenergic receptors and serotonin 5-HT₁ receptors. Quetiapine does not show significant affinity for cholinergic muscarinic and benzodiazepine receptors.

In standard tests, Quetiapine exhibits antipsychotic activity. The specific contribution of the N-desalkyl quetiapine metabolite to the pharmacological activity of quetiapine has not been established.

Results from studies of extrapyramidal symptoms (EPS) in animals revealed that Quetiapine causes weak catalepsy at doses that effectively block dopamine D₂ receptors. Quetiapine causes a selective decrease in the activity of mesolimbic A10-dopaminergic neurons compared to A9-nigrostriatal neurons involved in motor function.

Pharmacodynamic effects

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

Quetiapine is effective as monotherapy for manic episodes of moderate to severe intensity. There are no data on the long-term use of quetiapine for the prevention of subsequent manic and depressive episodes. Data on the use of quetiapine in combination with valproate semitarium or lithium preparations for manic episodes of moderate to severe intensity are limited, but this combination therapy was generally well tolerated. In addition, Quetiapine at doses of 300 mg and 600 mg is effective in patients with bipolar disorder type I and II of moderate to severe intensity. The efficacy of quetiapine at a dose of 300 mg/day and 600 mg/day is comparable.

Quetiapine is effective in patients with schizophrenia and mania when taken twice a day, despite the fact that the T_1/2 of quetiapine is about 7 hours. The effect of quetiapine on 5-HT₂ and D₂ receptors lasts up to 12 hours after administration.

Quetiapine does not cause a prolonged increase in plasma prolactin concentration. In studies with various fixed doses of the drug, no differences in prolactin levels were found when using quetiapine or placebo. The prolactin level when using various fixed doses of quetiapine did not differ from the prolactin level when taking placebo.

When taking quetiapine with dose titration for schizophrenia, the frequency of EPS and concomitant use of anticholinergic drugs was comparable to that when taking placebo. When prescribing quetiapine in fixed doses from 75 to 750 mg/day to patients with schizophrenia, the incidence of EPS and the need for concomitant use of anticholinergic drugs did not increase.

When using quetiapine in doses up to 800 mg/day for the treatment of manic episodes of moderate to severe intensity, both as monotherapy and in combination with lithium preparations or valproate semitarium, the frequency of EPS and concomitant use of anticholinergic drugs was comparable to that when taking placebo.

Pharmacokinetics

Absorption

When taken orally, Quetiapine is well absorbed from the gastrointestinal tract and actively metabolized in the liver.
Food intake does not significantly affect the bioavailability of quetiapine.

Distribution

Approximately 83% of quetiapine is bound to plasma proteins. The equilibrium molar concentration of the active metabolite N-desalkyl quetiapine is 35% of that of quetiapine.

Linearity (non-linearity)

The pharmacokinetics of quetiapine and N-desalkyl quetiapine are linear.

Metabolism

CYP3A4 has been identified as the key isoenzyme for cytochrome P450-mediated metabolism of quetiapine. N-desalkyl Quetiapine is formed with the participation of the CYP3A4 isoenzyme. Quetiapine and some of its metabolites (including N-desalkyl Quetiapine) have weak inhibitory activity against CYP1A2, 2C9, 2C19, 2D6 and 3A4 isoenzymes, but only at concentrations 5-50 times higher than those observed at the commonly used effective dose of 300-800 mg/day. Based on in vitro results, concomitant administration of quetiapine with other drugs is not expected to lead to clinically significant inhibition of cytochrome P450-mediated biotransformation of other drugs.

Elimination

The T_1/2 of quetiapine and N-desalkyl quetiapine is about 7 and 12 hours, respectively.

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

Pharmacokinetics in special patient groups

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

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

Patients with hepatic impairment. In patients with hepatic impairment (compensated alcoholic cirrhosis), the average plasma clearance of quetiapine is reduced by approximately 25%. Since Quetiapine is intensively metabolized in the liver, an increase in plasma concentration of quetiapine is possible in patients with hepatic impairment, which requires dose adjustment.

Gender. No differences in pharmacokinetic parameters between men and women are observed.

Indications

Adults aged 18 years and over

• Treatment of schizophrenia;
• Treatment of manic episodes in the structure of bipolar disorder;
• Treatment of depressive episodes of moderate to severe intensity in the structure of bipolar disorder.

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

ICD codes

Dosage Regimen

Take orally, regardless of meals.

Adults

Treatment of schizophrenia

Quetiapine-SZ is prescribed 2 times/day. The daily dose for the first 4 days of therapy is: day 1 – 50 mg, day 2 – 100 mg, day 3 – 200 mg, day 4 – 300 mg.

Starting from day 4, the dose should be titrated to an effective dose, usually in the range of 300 to 450 mg/day. Depending on the clinical effect and individual patient tolerance, the dose can 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-SZ is used as monotherapy or in combination with normothymic drugs.

Quetiapine-SZ is prescribed 2 times/day. The daily dose for the first 4 days of therapy is: day 1 – 100 mg, day 2 – 200 mg, day 3 – 300 mg, day 4 – 400 mg. Further, by day 6 of therapy, the daily dose of the drug can be increased to 800 mg. The increase in daily dose should not exceed 200 mg/day.

Depending on the clinical effect and individual tolerance, the dose can vary from 200 to 800 mg/day. The effective dose is usually from 400 to 800 mg/day.

The maximum recommended daily dose is 800 mg.

Treatment of depressive episodes in the structure of bipolar disorder

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

The maximum recommended daily dose is 600 mg.

The antidepressant effect of Quetiapine-SZ was confirmed when used at doses of 300 and 600 mg/day. In short-term therapy, the efficacy of quetiapine at doses of 300 and 600 mg/day was comparable (see section “Pharmacological Action”).

Special patient groups

Elderly patients

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

Patients with impaired renal function

Dose adjustment is not required.

Patients with impaired liver function

Quetiapine is intensively metabolized in the liver. Therefore, caution should be exercised when using Quetiapine-SZ in patients with hepatic impairment, especially at the beginning of therapy. It is recommended to start therapy with Quetiapine-SZ at a dose of 25 mg/day and increase the dose daily by 25-50 mg until an effective dose is reached.

Adverse Reactions

Summary of safety profile

Most frequently (≥10%) – drowsiness, dizziness, dry mouth, withdrawal syndrome, increased triglyceride concentration, increased total cholesterol concentration (mainly LDL), decreased HDL cholesterol concentration, weight gain, decreased hemoglobin concentration and EPS.

Tabulated summary of adverse reactions

Adverse reactions are distributed by system-organ classes in descending order of their severity, indicating the frequency of their occurrence according to the World Health Organization (WHO) classification: very common (≥1/10); common (≥1/100, but <1/10); uncommon (≥1/1000, but <1/100); rare (≥1/10000, but <1/1000); very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

1. See section “Special Precautions”.

2. Drowsiness usually occurs within the first 2 weeks after initiation of therapy and generally resolves with continued quetiapine administration.

3. Asymptomatic increases (≥3 times ULN at any time) in serum AST, ALT, and GGT activity may occur, generally reversible during continued Quetiapine-SZ treatment.

4. Like other antipsychotics and alpha₁-adrenergic blockers, Quetiapine frequently causes orthostatic hypotension, accompanied by dizziness, tachycardia, and in some cases, syncope, especially at the start of therapy (see section “Special Precautions”).

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

6. The frequency of this adverse effect was assessed based on post-marketing surveillance data.

7. Increase in fasting blood glucose ≥126 mg/dL (≥7.0 mmol/L) or postprandial blood glucose ≥200 mg/dL (≥11.1 mmol/L) on at least one occasion.

8. A higher frequency of dysphagia with Quetiapine-SZ compared to placebo was noted only in patients with depression within bipolar disorder.

9. Increase from baseline body weight of at least 7%. Occurs mainly at the start of therapy in adults.

10. In short-term, placebo-controlled monotherapy studies of Quetiapine-SZ withdrawal, the following symptoms were observed: insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability. The frequency of withdrawal syndrome decreased significantly 1 week after discontinuation.

11. Increase in triglycerides ≥200 mg/dL (≥2.258 mmol/L) in patients ≥18 years or ≥150 mg/dL (≥1.694 mmol/L) in patients <18 years, on at least one occasion.

12. Increase in total cholesterol ≥240 mg/dL (≥6.2064 mmol/L) in patients ≥18 years or ≥200 mg/dL (≥5.172 mmol/L) in patients <18 years, on at least one occasion.

13. See further in the text.

14. Decrease in platelet count ≤100×10⁹/L, on at least one occasion.

15. Not associated with neuroleptic malignant syndrome. Based on clinical study data.

16. Increase in prolactin in patients ≥18 years: >20 µg/dL (≥869.56 pmol/L) in men; > 30 µg/dL (≥1304.34 pmol/L) in women.

17. May lead to falls.

18. Decrease in HDL cholesterol <40 mg/dL (<1.03 mmol/L) in men and <50 mg/dL (<1.29 mmol/L) in women.

19. These phenomena were often noted in the context of tachycardia, dizziness, orthostatic hypotension, and/or concomitant cardiovascular or respiratory pathology.

20. Based on potentially clinically significant deviations from the normal baseline level, noted in all clinical studies. Changes in total T4, free T4, total T3, free T3 to values <80% of the lower limit of normal (pmol/L) at any time. Change in TSH >5 mIU/L at any time.

21. Based on increased frequency of vomiting in elderly patients (age ≥65 years).

22. In short-term quetiapine monotherapy studies in patients with pre-treatment neutrophil count ≥1.5×10⁹/L, cases of neutropenia (neutrophil count <1.5×10⁹/L) were noted in 1.9% of patients in the quetiapine group vs. 1.5% in the placebo group. Decrease in neutrophil count ≥0.5 but <1.0×10⁹/L occurred with a frequency of 0.2% in both the quetiapine and placebo groups. Decrease in neutrophil count <0.5×10⁹/L on at least one occasion was noted in 0.21% of patients in the quetiapine group vs. 0% in the placebo group.

23. Decrease in hemoglobin ≤13 g/dL in men and ≤12 g/dL in women, on at least one occasion, was noted in 11% of patients taking quetiapine in all clinical studies, including long-term therapy. In short-term placebo-controlled studies, a decrease in hemoglobin ≤13 g/dL in men and ≤12 g/dL in women, on at least one occasion, was noted in 8.3% of patients in the quetiapine group compared to 6.2% in the placebo group.

24. Based on potentially clinically significant deviations from the initially normal level, noted in all clinical studies. Increase in eosinophil count ≥1×10⁹/L at any time.

25. Based on potentially clinically significant deviations from the initially normal level, noted in all clinical studies. Decrease in white blood cell count ≤3×10⁹/L at any time.

26. May develop at the time of or shortly after initiation of therapy and be accompanied by hypotension and/or syncope. Frequency established based on reports of bradycardia and related adverse events in all quetiapine clinical studies.

27. Based on frequency assessment in patients who participated in all quetiapine clinical studies and had severe neutropenia (<0.5×10⁹/L) in combination with infections.

28. See section “Pregnancy and Lactation”.

Description of selected adverse reactions

QT interval prolongation, ventricular arrhythmia, sudden death, cardiac arrest, and bidirectional ventricular tachycardia are considered adverse effects inherent to antipsychotics.

The frequency of EPS in short-term clinical studies in adult patients with schizophrenia and mania within bipolar disorder was comparable in the quetiapine and placebo groups (patients with schizophrenia: 7.8% for quetiapine and 8% for placebo; mania within bipolar disorder: 11.2% for quetiapine and 11.4% for placebo).

The frequency of EPS in short-term clinical studies in adult patients with depression within bipolar disorder was 8.9% in the quetiapine group and 3.8% in the placebo group. The frequency of individual EPS symptoms (such as akathisia, extrapyramidal disorders, tremor, dyskinesia, dystonia, restlessness, involuntary muscle contractions, psychomotor agitation, and muscle rigidity) was generally low and did not exceed 4% in each treatment group. In long-term quetiapine clinical studies for schizophrenia and bipolar disorder, the frequency of EPS was comparable in the quetiapine and placebo groups.

Dose-dependent decreases in thyroid hormone levels may occur during quetiapine therapy. The frequency of potentially clinically significant changes in thyroid hormone levels in short-term clinical studies for total T4 was 3.4% in the quetiapine group and 0.6% in the placebo group; for free T4 – 0.7% in the quetiapine group vs. 0.1% in the placebo group; for total T3 – 0.54% in the quetiapine group vs. 0.0% in the placebo group; for free T3 – 0.2% in the quetiapine group vs. 0.0% in the placebo group. A change in TSH was noted with a frequency of 3.2% in the quetiapine group and 2.7% in the placebo group. In short-term monotherapy clinical studies, the frequency of potentially clinically significant changes in T3 and TSH was 0.0% in both the quetiapine and placebo groups; for T4 and TSH it was 0.1% in the quetiapine group vs. 0.0% in the placebo group. These changes are generally not associated with clinically apparent hypothyroidism. The maximum decrease in total and free T4 was recorded at week 6 of quetiapine therapy, with no further decrease in hormone levels during long-term treatment. In almost all cases, total and free T4 levels returned to baseline after discontinuation of quetiapine therapy, regardless of treatment duration. Thyroxine-binding globulin (TBG) levels, measured in 8 patients, remained unchanged.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the drug’s benefit-risk balance. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the Eurasian Economic Union member states.

Contraindications

• Hypersensitivity to quetiapine or to any of the excipients of the drug;
• Concomitant use with cytochrome P450 inhibitors, such as azole antifungals, erythromycin, clarithromycin and nefazodone, as well as HIV protease inhibitors (see section “Drug Interactions”);
• Children under 18 years of age (efficacy and safety have not been established in this population);
• Pregnancy (see section “Pregnancy and Lactation”);
• Breastfeeding period (see section “Pregnancy and Lactation”).

With caution

In patients with cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension, elderly age, hepatic impairment, history of seizures.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of quetiapine in pregnant women are lacking. The use of Quetiapine-SZ during pregnancy is only possible if the expected benefit to the woman justifies the potential risk to the fetus.

When antipsychotic drugs, including quetiapine, are used in the third trimester of pregnancy, newborns are at risk of developing adverse reactions of varying severity and duration, including EPS and/or withdrawal syndrome. Agitation, hypertonia, hypotonia, tremor, drowsiness, respiratory distress syndrome, or feeding disorders have been reported. Therefore, newborns should be carefully monitored.

Breastfeeding period

Information on the penetration of quetiapine or its metabolites into human breast milk is lacking. Quetiapine-SZ should not be used during breastfeeding.

Fertility

Data on the effect of quetiapine on human fertility are lacking.

Use in Hepatic Impairment

Caution should be exercised when using Quetiapine-SZ in patients with hepatic impairment, especially at the start of therapy. It is recommended to initiate therapy with Quetiapine-SZ at a dose of 25 mg/day and increase the dose daily by 25-50 mg until an effective dose is reached.

Use in Renal Impairment

No dose adjustment is required for patients with renal impairment.

Pediatric Use

The use of quetiapine in patients under 18 years of age is contraindicated (efficacy and safety have not been established in this population).

Geriatric Use

The drug should be prescribed with caution to elderly patients.

Special Precautions

Suicide/suicidal thoughts or clinical worsening

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 occurs. Since it may take several weeks or longer for improvement to occur from the start of treatment, patients should be closely monitored until improvement occurs. According to common clinical experience, the risk of suicide may increase in the early stages of remission. Patients (especially those at high risk of suicide) and their caregivers should be warned to monitor for clinical worsening, suicidal behavior or thoughts, unusual changes in behavior, and the need to seek immediate medical attention if they occur.

According to clinical studies in patients with depression in bipolar disorder, the risk of suicide-related events was 3.0% (7/233) for quetiapine and 0% (0/120) for placebo in patients aged 18-24 years; 1.8% (19/1616) for quetiapine and 1.8% (11/622) for placebo for patients over 25 years.

Other mental disorders for which Quetiapine is prescribed are also associated with an increased risk of suicide-related events. Furthermore, such conditions may be comorbid with a depressive episode. Therefore, the precautions used in the treatment of patients with a depressive episode should also be applied when treating patients with other mental disorders.

The potential risk of suicide-related events should be considered upon abrupt discontinuation of quetiapine therapy.

Patients with a history of suicidal events, as well as patients who explicitly express suicidal thoughts prior to initiation of therapy, are at increased risk of suicidal ideation and suicide attempts and should be closely monitored during treatment. An FDA meta-analysis of placebo-controlled antidepressant trials, pooling data from approximately 4400 children and adolescents and 7700 adult patients with mental disorders, found an increased risk of suicidal behavior with antidepressants compared to placebo in children, adolescents, and young adults under 25 years of age. This meta-analysis did not include studies where Quetiapine was used (see section “Pharmacological Action”).

According to short-term placebo-controlled studies across all indications and all age groups, the frequency of suicide-related events was 0.8% for both quetiapine (76/9327) and placebo (37/4845).

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

In patients with mania in bipolar disorder, the risk of suicide-related events was 0% (0/60) for quetiapine and 0% (1/58) for placebo in patients aged 18-24 years; 1.2% (6/496) for quetiapine and 1.2% (6/503) for placebo in patients over 25 years; 1.0% (2/193) for quetiapine and 0% (0/90) for placebo in patients under 18 years.

Drowsiness

Drowsiness and related symptoms, such as sedation, may occur during quetiapine therapy (see section “Adverse Reactions”). In clinical studies involving patients with depression within bipolar disorder, drowsiness generally developed within the first three days of therapy. The severity of this adverse reaction was mostly mild or moderate. If severe drowsiness develops, patients with depression within bipolar disorder may require more frequent physician visits for 2 weeks from the onset of drowsiness or until symptom severity decreases. In some cases, discontinuation of quetiapine therapy may be necessary.

Patients with cardiovascular diseases

Caution should be exercised when prescribing quetiapine to patients with cardiovascular and cerebrovascular diseases, and other conditions predisposing to hypotension. Orthostatic hypotension may occur during quetiapine therapy, especially during dose titration at the start of therapy. Orthostatic hypotension and associated dizziness may increase the risk of accidental injury (falls), especially in elderly patients. Patients should exercise caution until they adapt to these potential adverse reactions. If orthostatic hypotension occurs, a dose reduction or slower titration may be required.

Sleep apnea syndrome

Sleep apnea syndrome has been reported in patients taking Quetiapine. Caution should be exercised when prescribing quetiapine to patients taking drugs that depress the CNS, as well as to patients with risk factors for sleep apnea (e.g., overweight/obesity, male gender) or with a history of sleep apnea.

Seizures

No difference in the frequency of seizures was found between patients taking Quetiapine or placebo. However, as with other antipsychotic drugs, caution is recommended when treating patients with a history of seizures (see section “Adverse Reactions”).

Extrapyramidal symptoms

An increased frequency of EPS has been observed in adult patients with depression within bipolar disorder taking quetiapine for depressive episodes compared to placebo (see section “Adverse Reactions”).

Akathisia may occur during quetiapine treatment, characterized by an unpleasant feeling of motor restlessness and a need to move, and manifested by the patient’s inability to sit or stand still. If such symptoms occur, the dose of quetiapine should not be increased.

Tardive dyskinesia

If symptoms of tardive dyskinesia appear, it is recommended to reduce the dose or discontinue the drug gradually (see section “Adverse Reactions”). Symptoms of tardive dyskinesia may worsen or even appear after discontinuation of the drug.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome may develop during treatment with antipsychotic drugs, including quetiapine (see section “Adverse Reactions”). Clinical manifestations of the syndrome include hyperthermia, altered mental status, muscle rigidity, autonomic nervous system lability, and increased CPK activity. In such cases, Quetiapine should be discontinued and appropriate treatment instituted.

Severe Neutropenia and Agranulocytosis

In short-term placebo-controlled clinical trials of quetiapine monotherapy, cases of severe neutropenia (neutrophil count <0.5×10⁹/L) without infection were reported infrequently. Agranulocytosis (severe neutropenia associated with infections) has been reported in patients receiving Quetiapine during clinical trials (rarely) and during post-marketing use (including fatal outcomes). Most of these cases of severe neutropenia occurred several months after the start of quetiapine therapy. No dose-dependent effect was identified. Leukopenia and/or neutropenia resolved after discontinuation of quetiapine therapy. A possible risk factor for the occurrence of neutropenia is a prior low white blood cell count and a history of drug-induced neutropenia.

Agranulocytosis has also been observed in patients without risk factors. The possibility of developing neutropenia should be considered in patients with an infection, especially in the absence of obvious predisposing factors, or in patients with unexplained fever; such cases should be managed according to clinical guidelines.

In patients with a neutrophil count <1.0×10⁹/L, quetiapine should be discontinued. The patient should be monitored for possible symptoms of infection and neutrophil levels should be monitored (until the level exceeds 1.5×10⁹/L).

Drug Interactions

The use of quetiapine in combination with potent inducers of hepatic microsomal enzymes, such as carbamazepine and phenytoin, leads to a decrease in plasma quetiapine concentration and may reduce the effectiveness of therapy with Quetiapine-SZ.

Prescription of Quetiapine-SZ to patients receiving inducers of hepatic microsomal enzymes is possible only if the expected benefit of quetiapine therapy outweighs the risk associated with discontinuation of the hepatic microsomal enzyme inducer. The dose adjustment of hepatic microsomal enzyme inducers should be gradual. If necessary, they can be replaced with drugs that do not induce hepatic microsomal enzymes (for example, valproic acid preparations).

Hyperglycemia

During quetiapine administration, hyperglycemia or exacerbation of diabetes mellitus may develop (in some cases with the development of ketoacidosis or coma, including fatal outcomes), in patients with a history of diabetes mellitus. Patients receiving Quetiapine and other antipsychotics should be monitored for possible symptoms of hyperglycemia, such as polyuria (increased urine output), polydipsia (pathologically increased thirst), polyphagia (increased appetite), and weakness. Patients with diabetes mellitus and patients with risk factors for developing diabetes mellitus should also be monitored for possible worsening of glycemic control (see the “Adverse Reactions” section). Body weight should be monitored regularly.

Lipid Levels

During quetiapine administration, an increase in the concentration of triglycerides, cholesterol, and LDL, as well as a decrease in the concentration of HDL, may occur (see the “Adverse Reactions” section).

Metabolic Disorders

Increased body weight, elevated blood glucose and lipid levels in some patients may lead to a worsening of the metabolic profile, which requires appropriate monitoring.

QT Interval Prolongation

No relationship has been identified between quetiapine administration and a persistent increase in the absolute QT interval value. However, QT interval prolongation has been observed with drug overdose (see the “Overdose” section). Caution should be exercised when prescribing quetiapine, as with other antipsychotic drugs, to patients with cardiovascular diseases and a history of QT interval prolongation. Caution is also necessary when prescribing quetiapine concomitantly with drugs that prolong the QTc interval, other antipsychotics, especially in the elderly, patients with congenital long QT syndrome, chronic heart failure, myocardial hypertrophy, hypokalemia, or hypomagnesemia (see the “Drug Interactions” section).

Cardiomyopathy and Myocarditis

Cases of cardiomyopathy and myocarditis have been observed during clinical trials and post-marketing use, but a causal relationship with the drug has not been established. The appropriateness of quetiapine therapy should be evaluated in patients with suspected cardiomyopathy or myocarditis.

Severe Cutaneous Adverse Reactions

The development of severe cutaneous adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, erythema multiforme, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome), which are potentially life-threatening adverse drug reactions, has been reported with the use of quetiapine. Severe cutaneous adverse reactions usually manifest with one or more of the following symptoms: extensive skin rash, which may be itchy or accompanied by pustules, exfoliative dermatitis, fever, lymphadenopathy, and potential eosinophilia or neutrophilia. If severe cutaneous adverse reactions occur, quetiapine should be discontinued.

Acute Withdrawal Reactions

Upon abrupt discontinuation of quetiapine, the following acute reactions (withdrawal syndrome) may be observed – nausea, vomiting, insomnia, headache, dizziness, and irritability. Therefore, it is recommended to discontinue the drug gradually over at least 1 or 2 weeks.

Misuse and Abuse

Cases of misuse and abuse of the drug have been reported. Caution should be exercised when prescribing quetiapine to patients with a history of alcohol or drug abuse.

Elderly Patients with Dementia

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

Some atypical antipsychotics in randomized placebo-controlled trials approximately tripled the risk of cerebrovascular complications in patients with dementia. The mechanism of this increased risk is not understood. A similar risk of increased frequency of cerebrovascular complications cannot be excluded for other antipsychotic drugs or other patient populations. Quetiapine-SZ should be used with caution in patients at risk of stroke.

An analysis of the use of atypical antipsychotics for the treatment of psychosis associated with dementia in elderly patients revealed an increased mortality rate in the group of patients receiving drugs of this class compared to the placebo group. Furthermore, two 10-week placebo-controlled trials of quetiapine in a similar patient group (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 death noted in these patients were consistent with those expected in this population. No causal relationship has been established between quetiapine treatment and the risk of increased mortality in elderly patients with dementia.

Anticholinergic (Muscarinic-like) Effects

Norsertindole, an active metabolite of quetiapine, has affinity (from moderate to high) for several muscarinic receptor subtypes. This is associated with adverse drug reactions due to the anticholinergic action of quetiapine when used at recommended doses or in combination with other drugs that have anticholinergic effects, as well as in overdose. Caution should be exercised when using quetiapine concomitantly with drugs that have anticholinergic (muscarinic-like) effects. Caution should be exercised when prescribing quetiapine to patients with urinary retention or a history of urinary retention, clinically significant prostatic hyperplasia, intestinal obstruction or related conditions, increased intraocular pressure, or narrow-angle glaucoma (see sections “Drug Interactions”, “Adverse Reactions”, “Overdose”).

Hepatic Disorders

If jaundice develops, Quetiapine-SZ should be discontinued.

Dysphagia

Dysphagia (see the “Adverse Reactions” section) and aspiration have been observed during quetiapine therapy. A causal relationship between aspiration pneumonia and quetiapine use has not been established. However, caution should be exercised when prescribing the drug to patients at risk of aspiration pneumonia.

Venous Thromboembolism

Cases of venous thromboembolism have been observed during treatment with antipsychotics. Since patients taking antipsychotics often have risk factors for venous thromboembolism, risk factors should be assessed and preventive measures taken before starting and during therapy with antipsychotic drugs, including quetiapine.

Constipation and Intestinal Obstruction

Constipation is a risk factor for intestinal obstruction. The development of constipation and intestinal obstruction (see the “Adverse Reactions” section) has been observed during quetiapine use, including fatal cases in patients at high risk of intestinal obstruction, including those receiving multiple concomitant drugs that reduce intestinal motility, even in the absence of complaints of constipation.

Pancreatitis

Cases of pancreatitis have been observed during clinical trials and post-marketing use, but a causal relationship with the drug has not been established. Post-marketing reports indicate that many patients had risk factors for pancreatitis, such as elevated triglyceride levels, cholelithiasis, and alcohol consumption.

Additional Information

Data on the concomitant use of quetiapine with divalproate or lithium in acute manic episodes of mild or moderate severity are limited. Good tolerability of this combination therapy and an additive effect at the 3rd week of therapy have been noted.

Excipients

The drug Quetiapine-SZ contains lactose monohydrate (milk sugar). Patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Quetiapine-SZ in the 200 mg dose contains aluminum lacquer based on the dye azorubine (carmoisine) E 122, which may cause allergic reactions.

Children

Quetiapine-SZ is not indicated for use in children and adolescents under 18 years of age due to insufficient data on use in this age group. According to the results of clinical trials of quetiapine, some adverse reactions (increased appetite, increased serum prolactin concentration, vomiting, runny nose, and fainting) were observed in children and adolescents with greater frequency than in adult patients. Some adverse reactions (EPS) in children and adolescents may have different consequences compared to adult patients. An increase in blood pressure, not observed in adult patients, was also noted. Changes in thyroid function were also observed in children and adolescents.

The effect on growth, puberty, mental development, and behavioral reactions with long-term use (more than 26 weeks) of quetiapine has not been studied.

In placebo-controlled trials in children and adolescents with schizophrenia and mania in bipolar disorder, the incidence of EPS was higher with quetiapine use compared to placebo.

Effect on Ability to Drive and Use Machines

Due to its effect on the central nervous system, Quetiapine-SZ may affect the speed of psychomotor reactions and cause drowsiness; therefore, during treatment, patients are not recommended to work with machinery requiring increased concentration, including driving vehicles, until individual tolerance to therapy is established.

Overdose

A fatal outcome was reported after ingestion of 13.6 g of quetiapine in a patient participating in a clinical trial, as well as a fatal outcome after ingestion of 6 g of quetiapine in a post-marketing study of the drug. At the same time, a case of ingestion of quetiapine in a dose exceeding 30 g without a fatal outcome has been described.

There are reports of extremely rare cases of quetiapine overdose leading to QTc interval prolongation, death, or coma.

In patients with a history of severe cardiovascular disease, the risk of adverse effects from overdose may be increased (see the “Special Precautions” section).

Symptoms noted in overdose were mainly a consequence of an enhancement of the known pharmacological effects of the drug, such as drowsiness and sedation, tachycardia, and decreased blood pressure.

Treatment There is no specific antidote for quetiapine. In cases of serious intoxication, the possibility of multiple drug overdose should be considered. Measures aimed at maintaining respiratory and cardiovascular function, ensuring adequate oxygenation and ventilation are recommended. Gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal and laxatives may help remove unabsorbed quetiapine, but the effectiveness of these measures has not been studied.

Close medical supervision should continue until the patient’s condition improves.

Drug Interactions

Caution should be exercised when Quetiapine-SZ is used concomitantly with other drugs that affect the central nervous system, as well as with alcohol.

The cytochrome P450 isoenzyme (CYP3A4) is the primary isoenzyme responsible for the metabolism of quetiapine, which occurs with the participation of cytochrome P450 system isoenzymes. In studies on healthy volunteers, the concomitant use of quetiapine (at a dose of 25 mg) with ketoconazole, a CYP3A4 inhibitor, led to a 5-8 fold increase in the AUC of quetiapine.

Therefore, concomitant administration of quetiapine and inhibitors of the CYP3A4 isoenzyme is contraindicated. It is also not recommended to take Quetiapine together with grapefruit juice.

In a pharmacokinetic study, administration of quetiapine in various doses before or simultaneously with carbamazepine intake led to a significant increase in the 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. Such interaction is accompanied by a decrease in plasma quetiapine concentration and may reduce the effectiveness of quetiapine therapy. Concomitant administration of quetiapine with phenytoin, another inducer of the hepatic microsomal system, was accompanied by an even more pronounced (approximately 450%) increase in quetiapine clearance. Prescription of Quetiapine-SZ to patients receiving inducers of the hepatic enzyme system is possible only if the expected benefit of quetiapine therapy outweighs the risk associated with discontinuation of the hepatic enzyme inducer. The dose adjustment of hepatic microsomal enzyme inducers should be gradual. If necessary, they can be replaced with drugs that do not induce microsomal enzymes (for example, valproic acid preparations).

The pharmacokinetics of quetiapine were not significantly altered with the concomitant administration of the antidepressant imipramine (a CYP2D6 inhibitor) or fluoxetine (a CYP3A4 and CYP2D6 inhibitor).

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

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

With a single dose of 2 mg of lorazepam during administration of quetiapine at a dose of 250 mg twice daily, the clearance of lorazepam decreases by approximately 20%.

The pharmacokinetics of lithium preparations are not altered with the concomitant administration of quetiapine. No clinically significant changes in the pharmacokinetics of valproic acid and quetiapine were noted with the concomitant administration of semisodium valproate and quetiapine.

Pharmacokinetic studies on the interaction of quetiapine with drugs used for cardiovascular diseases have not been conducted.

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

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

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.