Victoel (Tablets) Instructions for Use

Marketing Authorization Holder

Actavis Group PTC ehf. (Iceland)

Manufactured By

Actavis, Ltd. (Malta)

ATC Code

N05AH04 (Quetiapine)

Active Substance

Quetiapine (Rec.INN registered by WHO)

Dosage Forms

	Victoel	Film-coated tablets, 25 mg: 60 pcs.
		Film-coated tablets, 100 mg: 60 pcs.
		Film-coated tablets, 150 mg: 10, 30, 50, or 60 pcs.
		Film-coated tablets, 200 mg: 60 pcs.
		Film-coated tablets, 300 mg: 10, 30, 50 or 60 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow, round, biconvex, with an engraving “Q” on one side.

Excipients: povidone K29-32 – 10 mg, calcium hydrogen phosphate dihydrate – 10 mg, microcrystalline cellulose – 73.045 mg, sodium carboxymethyl starch (type A) – 18 mg, lactose monohydrate – 20.7 mg, magnesium stearate – 3.125 mg.

Film coating composition Opadry II yellow 33G32578 ~ 7.5 mg (hypromellose 6cP – 3 mg, titanium dioxide – 1.703 mg, lactose monohydrate – 1.575 mg, macrogol 3350 – 0.6 mg, triacetin – 0.45 mg, iron oxide yellow dye – 0.173 mg).

10 pcs. – blisters (6) – cardboard packs.

Film-coated tablets pale yellow, oval, biconvex, with an engraving “Q” on one side.

Excipients: povidone K29-32 – 15 mg, calcium hydrogen phosphate dihydrate – 15 mg, microcrystalline cellulose – 109.567 mg, sodium carboxymethyl starch (type A) – 27 mg, lactose monohydrate – 31.05 mg, magnesium stearate – 4.688 mg.

Film coating composition: Opadry II yellow 33G32605~ 11.25 mg (hypromellose 6cP – 4.5 mg, titanium dioxide – 2.786 mg, lactose monohydrate – 2.363 mg, macrogol 3350 – 0.9 mg, triacetin – 0.675 mg, iron oxide yellow dye – 0.027 mg).

5 pcs. – blisters (2) – cardboard packs.
5 pcs. – blisters (6) – cardboard packs.
5 pcs. – blisters (10) – cardboard packs.
5 pcs. – blisters (12) – cardboard packs.

Film-coated tablets white, oval, biconvex, with an engraving “Q” on one side.

Excipients: povidone K29-32 – 20 mg, calcium hydrogen phosphate dihydrate – 20 mg, microcrystalline cellulose – 146.09 mg, sodium carboxymethyl starch (type A) – 36 mg, lactose monohydrate – 41.4 mg, magnesium stearate – 6.25 mg.

Film coating composition Opadry II white 33G28435 ~ 15 mg (hypromellose 6cP – 6 mg, titanium dioxide – 3.75 mg, lactose monohydrate – 3.15 mg, macrogol 3350 – 1.2 mg, triacetin – 0.9 mg).

6 pcs. – blisters (10) – cardboard packs.

Film-coated tablets light orange, round, biconvex, with an engraving “Q” on one side.

Excipients: povidone K29-32 – 2.5 mg, calcium hydrogen phosphate dihydrate – 2.5 mg, microcrystalline cellulose – 18.261 mg, sodium carboxymethyl starch (type A) – 4.5 mg, lactose monohydrate – 5.175 mg, magnesium stearate – 0.781 mg.

Film coating composition Opadry II pink 33G34594 ~ 1.875 mg (hypromellose 6cP – 0.75 mg, titanium dioxide – 0.409 mg, lactose monohydrate – 0.394 mg, macrogol 3350 – 0.15 mg, triacetin – 0.113 mg, iron oxide red dye (E172) – 0.021 mg, iron oxide yellow dye (E172) – 0.039 mg).

10 pcs. – blisters (6) – cardboard packs.

Film-coated tablets white, oval, biconvex, with an engraving “Q” on one side and “300” on the other.

Excipients: povidone K29-32 – 30 mg, calcium hydrogen phosphate dihydrate – 30 mg, microcrystalline cellulose – 219.135 mg, sodium carboxymethyl starch (type A) – 54 mg, lactose monohydrate – 62.1 mg, magnesium stearate – 9.375 mg.

Film coating composition: Opadry II white 33G28435 ~ 22.5 mg (hypromellose 6cP – 9 mg, titanium dioxide – 5.625 mg, lactose monohydrate – 4.725 mg, macrogol 3350 – 1.8 mg, triacetin – 1.35 mg).

5 pcs. – blisters (2) – cardboard packs.
5 pcs. – blisters (6) – cardboard packs.
5 pcs. – blisters (10) – cardboard packs.
6 pcs. – blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Antipsychotic (neuroleptic) agent

Pharmacological Action

Quetiapine is an atypical antipsychotic drug that exhibits higher affinity for serotonin receptors (5HT₂) than for dopamine D₁ and D₂ receptors in the brain. Quetiapine also has a higher affinity for histamine and α₁-adrenergic receptors and a lower affinity for α₂-adrenergic receptors. No significant affinity of quetiapine for cholinergic, muscarinic, and benzodiazepine receptors has been detected. In standard tests, Quetiapine exhibits antipsychotic activity. Results from studies of extrapyramidal symptoms in animals revealed that Quetiapine causes weak catalepsy at a dose that effectively blocks dopamine D₂ receptors. Quetiapine causes a selective reduction in the activity of mesolimbic A₁₀ dopaminergic neurons compared to A₉ nigrostriatal neurons involved in motor function.

In clinical studies (with quetiapine at doses of 75-750 mg/day), no differences were found between quetiapine and placebo in the incidence of extrapyramidal symptoms and the concomitant use of anticholinergic drugs.

Quetiapine does not cause a prolonged increase in plasma prolactin concentration. In numerous fixed-dose studies, no differences in prolactin levels were found with quetiapine or placebo.

In clinical studies, Quetiapine has shown efficacy in treating positive and negative symptoms of schizophrenia.

The effect of quetiapine on 5HT₂ and D₂ receptors lasts up to 12 hours after drug administration.

Pharmacokinetics

When taken orally, Quetiapine is well absorbed from the gastrointestinal tract, reaching C_max in plasma after 1.5 hours. It is actively metabolized in the liver. The main metabolites found in plasma do not have significant pharmacological activity.

Food intake does not significantly affect the bioavailability of quetiapine. T_1/2 is about 7 hours. Approximately 83% of quetiapine is bound to plasma proteins. The pharmacokinetics of quetiapine are linear, and no differences in pharmacokinetic parameters are observed between men and women.

The CYP3A4 isoenzyme has been established as the key enzyme in the cytochrome P450-mediated metabolism of quetiapine.

The average clearance of quetiapine in elderly patients is 30% lower than in patients aged 18 to 65 years.

The average plasma clearance of quetiapine is reduced by approximately 25% in patients with severe renal failure (creatinine clearance less than 30 ml/min/1.73 m²), but individual clearance values are within the range corresponding to healthy individuals. In patients with impaired liver function (e.g., compensated alcoholic cirrhosis), the average plasma clearance of quetiapine is reduced by approximately 25%.

Approximately 73% of quetiapine is excreted by the kidneys and 21% through the intestines. Less than 5% of quetiapine is not metabolized and is excreted unchanged by the kidneys or through the intestines.

Quetiapine and some of its metabolites have weak inhibitory activity against cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6 and 3A4, but only at concentrations 10-50 times higher than those observed at the commonly used effective dosage of 300-450 mg/day.

Based on in vitro results, concomitant administration of quetiapine with other drugs is not expected to result in clinically significant inhibition of cytochrome P450-mediated metabolism of other drugs.

Indications

• For the treatment of acute and chronic psychoses, including schizophrenia;
• For the treatment of manic episodes in the structure of bipolar disorder;
• For the treatment of moderate to severe depressive episodes in the structure of bipolar disorder.

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

ICD codes

Dosage Regimen

Orally, regardless of meals.

Treatment of acute and chronic psychoses, including schizophrenia

Victoel is prescribed twice a 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 the 4th day, 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 may vary from 150 to 750 mg/day. The maximum recommended daily dose is 750 mg.

Treatment of manic episodes in the structure of bipolar disorder

Victoel is used as monotherapy or as adjunctive therapy for mood stabilization.

Victoel is prescribed twice a 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 the 6th day of therapy, the daily dose of the drug can be increased to 800 mg. The increase in daily dose should not exceed 200 mg per day.

Depending on the clinical effect and individual tolerance, the dose may vary from 200 to 800 mg/day. The usual effective dose is from 400 to 800 mg/day. The maximum recommended daily dose is 800 mg.

Treatment of depressive episodes in the structure of bipolar disorder

Victoel 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 of Victoel is 600 mg.

No clinical improvement was noted when the dose was increased above 600 mg.

Elderly

In elderly patients, the initial dose of Victoel 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 young patients.

Patients with renal impairment

Dose adjustment is not required.

Patients with hepatic impairment

In patients with hepatic impairment, it is recommended to start therapy with 25 mg/day. It is recommended to increase the dose daily by 25-50 mg until an effective dose is reached.

Adverse Reactions

The most common side effects when taking quetiapine are drowsiness, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension, and dyspepsia.

Taking quetiapine, like other antipsychotic drugs, may be accompanied by weight gain, fainting, development of neuroleptic malignant syndrome, leukopenia, neutropenia, and peripheral edema.

The frequency of adverse reactions is presented as follows: very common (≥ 1/10); common (≥ 1/100, <1/10); uncommon (≥ 1/1000, <1/100); rare (≥ 1/10000, <1/1000); very rare (<1/10000), including cases where the frequency is not known.

From the central and peripheral nervous system very common – drowsiness (drowsiness usually occurs within the first 2 weeks after starting therapy and usually resolves with continued use of quetiapine), dizziness (like other antipsychotic drugs, Quetiapine often causes orthostatic hypotension, which is accompanied by dizziness) headache; common – dysarthria, unusual and nightmare dreams, fainting (like other antipsychotic drugs, Quetiapine often causes orthostatic hypotension, which in some cases is accompanied by fainting, especially at the beginning of therapy), extrapyramidal symptoms; uncommon – convulsions, restless legs syndrome; very rare – tardive dyskinesia (the frequency of this side effect was assessed based on post-marketing surveillance results).

From the gastrointestinal tract very common – dry mouth; common – constipation, dyspepsia; uncommon – dysphagia; rare – jaundice (the frequency of this side effect was assessed based on post-marketing surveillance results); very rare – hepatitis (the frequency of this side effect was assessed based on post-marketing surveillance results).

From the cardiovascular system common – orthostatic hypotension (accompanied by dizziness, like other antipsychotic drugs, Quetiapine often causes orthostatic hypotension, which is accompanied by dizziness), tachycardia (like other antipsychotic drugs, Quetiapine often causes orthostatic hypotension, which is accompanied by tachycardia).

From the blood system common – leukopenia, eosinophilia; frequency not known – neutropenia.

From the immune system uncommon – hypersensitivity reactions; anaphylactic reactions (the frequency of this side effect was assessed based on post-marketing surveillance results);

From the skin very rare – angioedema (the frequency of this side effect was assessed based on post-marketing surveillance results), Stevens-Johnson syndrome (the frequency of this side effect was assessed based on post-marketing surveillance results);

Allergic reactions rare – eosinophilia, allergic reactions, including angioedema.

Changes in laboratory and instrumental parameters very common – increased concentration of triglycerides, total cholesterol (mainly low-density lipoprotein cholesterol); common – weight gain, increased activity of liver transaminases (AST and ALT) (asymptomatic increase in AST, ALT and GGT activity in blood serum is possible, usually reversible with continued use of quetiapine), decreased neutrophil count, hyperglycemia (increase in 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 – increased creatine phosphokinase activity not associated with neuroleptic malignant syndrome, thrombocytopenia;

From the respiratory system common – rhinitis.

Metabolic disorders very rare – diabetes mellitus (very rare cases of diabetes decompensation have been noted. The frequency of this side effect was assessed based on post-marketing surveillance results).

Other very common – withdrawal syndrome; common – asthenia, peripheral edema, blurred vision; rare – priapism, neuroleptic malignant syndrome.

When taking antipsychotic agents, QT interval prolongation, ventricular arrhythmia, sudden death, cardiac arrest, and torsades de pointes tachycardia have been reported.

Quetiapine therapy is associated with a small dose-dependent decrease in the concentration of thyroid hormones, in particular, total thyroxine (T₄) and free T₄. The maximum decrease in total and free T₄ was recorded at the 2nd and 4th week of quetiapine therapy without a further decrease in hormone concentrations during long-term treatment. Subsequently, there were no signs of clinically significant changes in the concentration of thyroid-stimulating hormone. In almost all cases, the concentration of total and free T₄ returned to baseline after discontinuation of quetiapine therapy, regardless of the duration of treatment. A slight decrease in total triiodothyronine (T₃) and reverse T₃ was noted only when using high doses. The level of thyroxine-binding globulin (TBG) remained unchanged, and no increase in thyroid-stimulating hormone (TSH) level was noted.

Contraindications

Hypersensitivity to any of the components of the drug, children under 18 years of age, concomitant use with cytochrome P450 inhibitors (azole antifungal drugs, erythromycin, clarithromycin, nefazodone, protease inhibitors); lactation period; patients with rare hereditary diseases, such as lactose intolerance, lactase deficiency or glucose-galactose malabsorption (due to the presence of lactose monohydrate in the composition).

Use with caution. In patients with cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension; elderly age, hepatic insufficiency, history of convulsive seizures, pregnancy.

Use in Pregnancy and Lactation

Category C. The safety and efficacy of quetiapine during pregnancy have not been established.

The use of the drug during pregnancy is possible only if the intended benefit to the mother outweighs the potential risk to the fetus. It is not known whether Quetiapine is excreted in breast milk. If it is necessary to use quetiapine during lactation (breastfeeding), the issue of discontinuing breastfeeding should be decided.

Use in Hepatic Impairment

Use with caution: hepatic insufficiency.

Use in Renal Impairment

Dosage adjustment is not required for patients with renal insufficiency.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Special attention should be paid to elderly patients. The risk-benefit ratio should be individually assessed in each case.

Special Precautions

Patients with cardiovascular diseases

Caution should be exercised when prescribing Victoel to patients with cardiovascular and cerebrovascular diseases and other conditions predisposing to hypotension. Orthostatic hypotension may occur during therapy with Victoel, especially during the initial dose titration period (observed more frequently in elderly patients than in young patients). If orthostatic hypotension occurs, a dose reduction or slower dose titration may be required.

Patients with hepatic insufficiency

Quetiapine is extensively metabolized in the liver. Therefore, caution should be exercised when using Victoel in patients with hepatic insufficiency, especially at the start of therapy.

QT interval prolongation

No relationship has been identified between quetiapine use and QT interval prolongation. However, QT interval prolongation has been noted in cases of its overdose. Caution should be exercised when prescribing Victoel to patients with cardiovascular diseases and a history of QT interval prolongation, as well as when used concomitantly with drugs that prolong the QT interval, other antipsychotics, especially in the elderly, patients with congenital long QT syndrome, chronic heart failure, myocardial hypertrophy, hypokalemia, or hypomagnesemia.

Tardive dyskinesia

With long-term use of Victoel, there is a potential for the development of tardive dyskinesia. If symptoms of tardive dyskinesia appear, it is necessary to reduce the dose or discontinue further treatment with quetiapine.

Severe neutropenia

In clinical studies of quetiapine, cases of severe neutropenia (neutrophil count < 0.5*10⁹/L) were infrequently reported. Most 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 treatment. A possible risk factor for the occurrence of neutropenia is a prior low white blood cell count and a history of drug-induced neutropenia. In patients with a neutrophil count < 1.0*10⁹/L, Victoel should be discontinued. The patient should be monitored for possible signs of infection and neutrophil levels should be controlled (until the level exceeds 1.5*10⁹/L).

Hyperglycemia

During treatment with Victoel, hyperglycemia may develop or diabetes may worsen in patients with a history of diabetes. Clinical monitoring of patients with diabetes and patients with risk factors for developing diabetes is recommended.

Lipid levels

During treatment with Victoel, an increase in the concentration of triglycerides and cholesterol is possible.

Elderly patients with dementia

Some atypical antipsychotics in randomized placebo-controlled studies increased the risk of cerebrovascular adverse events in patients with dementia. The mechanism of this increased risk is not understood. A similar risk of increased frequency of cerebrovascular adverse events cannot be excluded for other antipsychotic drugs or other patient populations. Victoel 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 group compared to the placebo group. No causal relationship has been established between quetiapine treatment and the risk of increased mortality in elderly patients with dementia.

Seizures

No differences were found in the frequency of seizures in patients taking Quetiapine or placebo. However, as with therapy with other antipsychotic drugs, caution is recommended when treating patients with a history of seizures.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome may be associated with antipsychotic treatment. Clinical manifestations of the syndrome include hyperthermia, altered mental status, muscle rigidity, autonomic nervous system instability, and increased creatine phosphokinase concentration. In such cases, Victoel should be discontinued and appropriate treatment instituted.

Acute reactions associated with drug withdrawal

With abrupt withdrawal of high doses of antipsychotic drugs, the following acute reactions (withdrawal syndrome) may be observed – nausea, vomiting, rarely – insomnia. Cases of exacerbation of psychotic symptoms and the appearance of involuntary movement disorders (akathisia, dystonia, dyskinesia) have been reported. Therefore, it is recommended to discontinue the drug gradually over a period of at least one to two weeks.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide in children, adolescents, and young adults (under 24 years of age). This risk persists until significant remission occurs. Since improvement in the patient’s condition may take several weeks or longer 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.

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. Thus, the precautions used in the treatment of patients with a depressive episode should also be taken when treating patients with other mental disorders. Patients with a history of suicidal events, as well as patients who explicitly express suicidal thoughts before starting therapy, are at increased risk of suicidal intentions and suicide attempts and should be closely monitored during treatment.

Taking into account the effect of quetiapine on the central nervous system, Victoel should be used with caution in combination with other drugs that have a depressant effect on the central nervous system, or with alcohol.

Effect on ability to drive and operate machinery

Victoel may cause drowsiness, therefore, during treatment, patients are not recommended to work with hazardous machinery, including driving vehicles.

Overdose

Cases of quetiapine intake in doses exceeding 30 g without fatal outcome have been described. Cases of quetiapine overdose leading to QT interval prolongation, death, or coma have been reported very rarely.

In patients with a history of severe cardiovascular disease, the risk of adverse effects from overdose may be increased.

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

Treatment There are no specific antidotes for quetiapine. In cases of serious intoxication, the possibility of symptomatic therapy should be considered and measures aimed at maintaining respiratory function, cardiovascular function, and ensuring adequate oxygenation and ventilation are recommended. The patient should be under medical supervision until complete recovery.

Drug Interactions

When co-administered with drugs that have a strong inhibitory effect on the CYP3A4 isoenzyme (such as azole antifungals and macrolide antibiotics), the plasma concentration of quetiapine may increase.

In a pharmacokinetic study of quetiapine at various doses, when quetiapine was administered before or simultaneously with ketoconazole, it led to an average increase in C_max and AUC of quetiapine by 235% and 522%, respectively, and also led to a decrease in the clearance of quetiapine by an average of 84%. The T_1/2 of quetiapine increased, but the mean time to reach C_max did not change. In such cases, lower doses of quetiapine should be used. Special attention should be paid to elderly and debilitated patients. The risk-benefit ratio should be individually assessed for each patient. Concomitant administration of quetiapine with drugs that induce liver enzyme systems, such as carbamazepine, may reduce the plasma concentration of the drug, which may require an increase in the dose of quetiapine, depending on the clinical effect. In a pharmacokinetic study of quetiapine at various doses, when administered before or simultaneously with carbamazepine (a liver enzyme inducer), such concomitant administration led to a significant increase in the clearance of quetiapine. This increase in quetiapine clearance reduced the AUC by an average of 13% compared to the use of quetiapine without carbamazepine.

Concomitant administration of quetiapine with another inducer of liver microsomal enzymes – phenytoin, also led to an increase in the clearance of quetiapine. When quetiapine and phenytoin (or other liver enzyme inducers such as barbiturates, rifampicin) are used concomitantly, an increase in the dose of quetiapine may be required. A decrease in the dose of quetiapine may also be required upon discontinuation of phenytoin or carbamazepine or another liver enzyme system inducer or when switching to a drug that does not induce liver microsomal enzymes (for example, valproic acid).

The pharmacokinetics of lithium preparations are not altered when co-administered with quetiapine.

No clinically significant changes in the pharmacokinetics of valproic acid and quetiapine were noted with the combined administration of valproate semisodium and quetiapine. Quetiapine did not cause induction of liver enzyme systems involved in the metabolism of phenazone.

The pharmacokinetics of quetiapine are not significantly altered when co-administered with antipsychotic drugs: risperidone or haloperidol. However, concomitant use of quetiapine and thioridazine led to an increase in the clearance of quetiapine.

The CYP3A4 isoenzyme is a key enzyme involved in the cytochrome P450-mediated metabolism of quetiapine. The pharmacokinetics of quetiapine are not significantly altered with the concomitant use of cimetidine, which is a cytochrome P450 inhibitor.

The pharmacokinetics of quetiapine were not significantly altered when co-administered with the antidepressant imipramine (an inhibitor of the CYP2D6 isoenzyme) or fluoxetine (an inhibitor of the CYP3A4 and CYP2D6 isoenzymes).

Drugs that depress the central nervous system and ethanol increase the risk of adverse effects.

It is not recommended to take Quetiapine together with grapefruit juice.

Storage Conditions

Store the drug at a temperature not exceeding 25°C (77°F). Keep out of reach of children!

Shelf Life

The shelf life is 2 years. Do not use after the expiration date stated 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.