Quetiapine-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT QUETIAPINE-DARNITSA

Composition:

Active substance: quetiapine;

25 mg tablets: 1 film-coated tablet contains 28.78 mg of quetiapine fumarate equivalent to 25 mg of quetiapine;

100 mg tablets: 1 film-coated tablet contains 115.13 mg of quetiapine fumarate equivalent to 100 mg of quetiapine;

200 mg tablets: 1 film-coated tablet contains 230.27 mg of quetiapine fumarate equivalent to 200 mg of quetiapine;

Excipients:

hypromellose, calcium hydrogen phosphate dihydrate, lactose monohydrate, maize starch, sodium starch glycolate (type A), magnesium stearate, microcrystalline cellulose, talc, colloidal anhydrous silicon dioxide;

Film coating:

25 mg tablets: iron oxide red (E 172), iron oxide yellow (E 172), HPMC 2910/hypromellose 5cP (E 464), titanium dioxide (E 171), macrogol/PEG 400, yellow sunset FCF aluminium lake (E 110);

100 mg tablets: iron oxide yellow (E 172), HPMC 2910/hypromellose 5cP (E 464), titanium dioxide (E 171), macrogol/PEG 400;

200 mg tablets: hydroxypropylcellulose (E 463), HPMC 2910/hypromellose 6cP (E 464), titanium dioxide (E 171), talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

25 mg tablets: round, biconvex, film-coated tablets of peach color;

100 mg tablets: round, biconvex, film-coated tablets of yellow color, with a score on one side;

200 mg tablets: round, biconvex, film-coated tablets of white color, with a score on one side.

Pharmacotherapeutic group.

Agents acting on the nervous system. Antipsychotic agents. Quetiapine.

ATC code N05AH04.

Pharmacological Properties.

Pharmacodynamics.

Quetiapine is an atypical antipsychotic medicinal product. Quetiapine and its active metabolite norquetiapine interact with various types of neurotransmitter receptors. Quetiapine and norquetiapine have high selectivity for serotonin receptors (5HT2) and dopamine D1- and D2-receptors in the brain. This combination of receptor antagonism, with greater selectivity for 5HT2 receptors relative to D2 receptors, is considered to contribute to the clinical antipsychotic effects and low propensity for extrapyramidal side effects associated with quetiapine compared to typical antipsychotic agents. Quetiapine and norquetiapine also have high affinity for histaminergic and α1-adrenergic receptors, but lower affinity for α2-adrenergic receptors and serotonin 5HT1A receptors.

Quetiapine has no affinity for muscarinic cholinergic receptors or benzodiazepine receptors, whereas norquetiapine has moderate to high affinity for several subtypes of muscarinic receptors, which may explain the anticholinergic (muscarinic) effects.

Inhibition of the norepinephrine transporter (NET) by norquetiapine, as well as partial agonist activity at 5HT1A receptors, may contribute to the therapeutic efficacy of quetiapine as an antidepressant.

Quetiapine is active in tests of antipsychotic activity such as conditioned avoidance response. It also blocks the effects of dopamine agonists, measured either behaviorally or electrophysiologically, and increases concentrations of dopamine metabolites, a neurochemical index of D2 receptor blockade.

Pharmacokinetics.

Absorption.

Quetiapine-Darnytsia is well absorbed and rapidly metabolized after oral administration. Concomitant food intake does not have a significant effect on the bioavailability of the medicinal product. The peak molar concentration at steady state of the active metabolite norquetiapine is 35% of that of quetiapine.

The pharmacokinetics of quetiapine and norquetiapine are linear within the approved dose range.

Distribution.

Approximately 83% of quetiapine is bound to plasma proteins.

Metabolism.

Quetiapine is extensively metabolized in the liver. Studies using radiolabeled quetiapine have shown that less than 5% of quetiapine is excreted unchanged in urine or feces. In vitro studies have demonstrated that CYP3A4 is the primary cytochrome P450 enzyme responsible for quetiapine metabolism. The formation and elimination of norquetiapine occur predominantly via the CYP3A4 isoenzyme. Quetiapine and some of its metabolites (including norquetiapine) exhibit weak inhibitory effects in vitro on the cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4. Inhibition of CYP isoenzymes in vitro occurred only at concentrations 5–50 times higher than those achieved when using doses in the range of 300 to 800 mg per day in humans.

Based on these in vitro results, it is unlikely that co-administration of quetiapine with other active substances will lead to clinically significant inhibition of the metabolism of other active substances mediated by cytochrome P450.

Elimination.

The elimination half-lives of quetiapine and norquetiapine are approximately 7 and 12 hours, respectively. Approximately 73% of the radioactive label is excreted in urine and 21% in feces.

Less than 5% of the total radioactivity of the average molar fraction of the dose of free quetiapine and the active metabolite norquetiapine is excreted in urine.

Special Populations.

Gender.

The pharmacokinetics of quetiapine in women and men are not different.

Elderly Patients.

The mean clearance of quetiapine in elderly individuals is 30–50% lower than in individuals aged 18–65 years.

Patients with Renal Impairment.

In patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m²), the mean plasma clearance of quetiapine is reduced by approximately 25%, but individual clearance values remain within the range typical for healthy individuals.

Patients with Hepatic Impairment.

The mean plasma clearance of quetiapine is reduced by approximately 25% in patients with known hepatic impairment (stable alcoholic cirrhosis). Since quetiapine is extensively metabolized in the liver, increased plasma levels of quetiapine are expected in patients with hepatic impairment. Dose adjustment may be required for such patients.

Clinical characteristics.

Indications.

Treatment of schizophrenia.

Treatment of bipolar disorders, including:

− treatment of moderate to severe manic episodes in bipolar disorder;

− treatment of major depressive episodes in bipolar disorder.

For prevention of disease recurrence in patients with bipolar disorder whose manic or depressive episodes have responded to quetiapine treatment.

Contraindications.

Hypersensitivity to any component of the medicinal product.

Concomitant use of cytochrome P450 3A4 inhibitors, such as HIV protease inhibitors, azole antifungal agents, erythromycin, clarithromycin, and nefazodone, is contraindicated.

Interaction with other medicinal products and other forms of interaction.

Due to the primary effect of quetiapine on the central nervous system (CNS), quetiapine should be used with caution in combination with other centrally acting medicinal products and alcohol.

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

Caution should be exercised when treating patients who are taking other agents with anticholinergic (muscarinic) effects.

Cytochrome P450 (CYP) 3A4 is the primary enzyme responsible for CYP-mediated metabolism of quetiapine. In a study of interaction in healthy volunteers, concomitant administration of quetiapine (25 mg dose) with ketoconazole, a CYP3A4 inhibitor, resulted in a 5- to 8-fold increase in quetiapine AUC. Therefore, concomitant use of quetiapine with CYP3A4 inhibitors is contraindicated. Grapefruit juice should also not be consumed during quetiapine treatment.

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

Concomitant administration of quetiapine and phenytoin (a liver microsomal enzyme inducer) increases quetiapine clearance by up to 450%. For patients taking a liver enzyme inducer, initiation of quetiapine therapy should only be considered if the benefit outweighs the risks associated with discontinuation of the liver enzyme inducer. Any substitution of the inducer should be performed gradually and, if necessary, replaced with a non-inducer (e.g., sodium valproate) — see section "Special precautions".

The pharmacokinetics of quetiapine are not significantly altered by concomitant administration of antidepressants such as imipramine (a known CYP2D6 inhibitor) or fluoxetine (a known CYP3A4 and CYP2D6 inhibitor).

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

The pharmacokinetics of quetiapine were not altered after concomitant administration with cimetidine.

The pharmacokinetics of lithium were not altered by concomitant administration with quetiapine.

The pharmacokinetics of sodium valproate and quetiapine are not altered when administered concomitantly. However, in a retrospective study involving children and adolescents receiving sodium valproate, quetiapine, or a combination of these agents, a higher incidence of leukopenia and neutropenia was observed in the combination therapy group compared to the monotherapy groups.

No formal interaction studies with the most commonly used cardiovascular medicinal products have been conducted. Caution should be exercised when administering quetiapine concomitantly with medicinal products that alter electrolyte balance or prolong the QT interval.

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

Special precautions for use.

Since quetiapine is used for several indications, the safety profile of the medicinal product should be carefully considered with regard to the specific diagnosis established for the patient and the dose being administered.

Children.

Quetiapine is not recommended for use in children and adolescents under 18 years of age due to the 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, vomiting, rhinitis, syncope), or may have different consequences in children and adolescents (extrapyramidal symptoms and irritability). Additionally, increased blood pressure has been observed, which was not previously reported in trials involving adult patients. Furthermore, 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.

It is known that in placebo-controlled clinical trials involving pediatric patients, quetiapine therapy was associated with an increased incidence of extrapyramidal symptoms compared to placebo in patients treated for schizophrenia and bipolar mania (see section « Adverse reactions»).

Suicide/suicidal thoughts or clinical worsening.

Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicidal events and behaviours). This risk persists until significant/definite remission occurs. Since improvement may not occur during the first few weeks or longer of treatment, 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 recovery.

In addition, physicians should consider the potential risk of suicidal events and behaviours following abrupt discontinuation of quetiapine therapy due to the presence of 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 suicidal events and behaviours. Moreover, these conditions may coexist with severe depressive episodes. Therefore, the same precautionary measures should be taken when treating patients with other psychiatric disorders as when treating patients with severe depressive episodes.

It is known that patients with a history of suicidal events or behaviours, or those exhibiting significant levels of suicidal ideation prior to treatment initiation, are at higher risk of suicidal thoughts or suicide attempts and should be closely monitored during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressant use compared to placebo in patients under 25 years of age.

Pharmacological treatment, especially at the beginning of therapy and during subsequent dose adjustments, should be accompanied by close monitoring, particularly in high-risk individuals. Patients (and caregivers) should be advised to monitor for clinical worsening, suicidal behaviour or thoughts, and unusual changes in behaviour, and to seek immediate medical attention if these symptoms occur.

In short-term, placebo-controlled clinical trials involving patients with major depressive episodes in bipolar disorder, a higher risk of suicidal events and behaviours was observed in young patients (under 25 years of age) treated with quetiapine compared to those receiving placebo (3.0% vs. 0%, respectively).

In clinical trials among patients with major depressive disorder (MDD), the frequency of suicidal events and behaviours in young patients (under 25 years of age) was 2.1% (3/144) in the quetiapine group and 1.3% (1/75) in the placebo group. A population-based retrospective analysis of quetiapine use in treating MDD patients revealed an increased risk of self-harm and suicide in patients aged 24 to 64 years without prior self-harm history during quetiapine use in combination with other antidepressants.

Metabolic risk.

Given the observed risk of worsening metabolic profile, including changes in body weight, blood glucose, and lipid levels observed in clinical trials, metabolic parameters should be assessed at the beginning of treatment, and changes in these parameters should be monitored regularly throughout the treatment course. Worsening of these parameters should be managed considering clinical appropriateness.

Extrapyramidal symptoms.

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

Quetiapine use has been associated with the development of akathisia, characterized by subjective distress or stress-related restlessness and an urge to move, often accompanied by an inability to sit or stand still. These events are most likely to occur during the first few weeks of treatment. Dose escalation in these patients may be harmful.

Tardive dyskinesia.

If signs and symptoms of tardive dyskinesia appear, consideration should be given to reducing the dose or discontinuing quetiapine. Symptoms of tardive dyskinesia may worsen or even appear after discontinuation of treatment (see section «Adverse reactions»).

Somnolence and dizziness.

Treatment with quetiapine has been associated with somnolence and similar symptoms such as sedation. In clinical trials treating patients with bipolar depression and MDD, these symptoms typically occurred within the first three days of treatment and were mostly mild to moderate in intensity. Patients experiencing pronounced somnolence may require more frequent monitoring for at least 2 weeks after the onset of somnolence or until symptoms subside, or until consideration of treatment discontinuation.

Orthostatic hypotension.

Treatment with quetiapine has been associated with orthostatic hypotension and accompanying dizziness, which, like somnolence, usually occur during the initial dose titration period. These events may contribute to an increased frequency of accidental injuries (falls), especially in elderly patients. Patients should be advised to use the medicinal product with caution until they become aware of possible effects or the impact of the drug.

Quetiapine should be used with caution in patients with known cardiovascular diseases, cerebrovascular diseases, or other conditions that may lead to hypotension. Consideration should be given to reducing the dose or prolonging dose titration if orthostatic hypotension occurs, especially in patients with underlying cardiovascular disease.

Sleep apnea syndrome.

Cases of sleep apnea syndrome have been reported in patients taking quetiapine; therefore, quetiapine should be used with caution in patients who are concurrently receiving central nervous system depressants and have a history of sleep apnea or are at risk. This includes patients with excessive body weight/obesity or male patients.

Seizures.

No difference in seizure frequency was observed between patients taking quetiapine and those receiving placebo. There are no data on seizure occurrence in patients with epilepsy. As with other antipsychotic agents, caution is recommended when treating patients with a history of epileptic seizures (see section «Adverse reactions»).

Malignant neuroleptic syndrome.

Malignant neuroleptic syndrome has been associated with treatment with antipsychotic agents, including quetiapine. Clinical manifestations include hyperthermia, changes in mental status, muscle rigidity, autonomic instability, and elevated creatine phosphokinase levels. In such cases, quetiapine should be discontinued and appropriate pharmacological 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, careful monitoring of the patient is recommended, especially at the beginning of treatment and when increasing the dose. Symptoms of serotonin syndrome may include changes in mental status, autonomic instability, neuromuscular disturbances, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, 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) has been observed in clinical trials of quetiapine. Most cases of severe neutropenia occurred within two months after starting quetiapine treatment. A clear dose-dependent relationship has not been established. During the post-marketing period, some cases were fatal. Risk factors include prior history of low white blood cell count and a history of drug-induced neutropenia. However, some cases occurred in patients without prior risk factors. If the neutrophil count is < 1 × 10⁹/L, quetiapine treatment should be discontinued. Subsequently, patients should be monitored for signs of infection and neutrophil count should be determined (until the count exceeds 1.5 × 10⁹/L).

Neutropenia should be considered in patients with existing infection and fever, particularly in the absence of obvious disease factors, including fever of unknown origin, and appropriate clinical measures should be taken.

Patients should be advised to immediately report signs/symptoms indicating agranulocytosis or infection (such as fever, weakness, lethargy, or sore throat) at any time during quetiapine treatment. Such patients require timely determination of white blood cell count and absolute neutrophil count (ANC), especially in the absence of favourable factors.

Anticholinergic (muscarinic) syndrome.

Norquetiapine, the active metabolite of quetiapine, has moderate to high affinity for several subtypes of muscarinic receptors, which may explain the anticholinergic (muscarinic) syndrome. This contributes to the occurrence of adverse reactions reflecting anticholinergic effects when quetiapine is used concomitantly with other drugs having anticholinergic effects, particularly in overdose situations. Quetiapine should be used with caution in patients receiving drugs with anticholinergic (muscarinic) effects.

Quetiapine should be used with caution in patients with existing diagnosis or history of urinary retention, clinically significant prostatic hypertrophy, intestinal obstruction or related conditions, increased intraocular pressure, or angle-closure glaucoma.

Concomitant use of hepatic enzyme inducers.

See also section «Interactions 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 affect the efficacy of quetiapine therapy. In patients receiving a hepatic enzyme inducer, quetiapine treatment should only be initiated if, in the physician's opinion, the benefit of quetiapine outweighs the risks of discontinuing the hepatic enzyme inducer. It is important to gradually replace any inducer and, if necessary, substitute it with a medicinal product that does not have an enzyme-inducing effect on the liver (e.g., sodium valproate).

Weight gain.

Weight gain has been reported in patients treated with quetiapine, which should be monitored and managed considering clinical appropriateness according to recommendations for antipsychotic agents.

Hyperglycemia.

Rare cases of hyperglycemia and/or development or exacerbation of diabetes mellitus, sometimes accompanied by ketoacidosis or coma, including several fatal cases, have been reported. In some cases, these events occurred in patients with increased body weight, which may have been a predisposing factor. Appropriate clinical monitoring is recommended according to guidelines for antipsychotic agents. Patients treated with any antipsychotic agents, including quetiapine, should be monitored for possible signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). Patients with diabetes mellitus or risk factors for developing diabetes should be regularly tested for blood glucose levels. Body weight should be monitored regularly.

Lipids.

Elevations in triglycerides, LDL-cholesterol, and total cholesterol, as well as decreases in HDL-cholesterol levels, have been observed in clinical trials of quetiapine. Lipid level changes should be managed considering clinical appropriateness.

QT interval prolongation.

In clinical trials, quetiapine use according to instructions was not associated with sustained increases in the absolute QT interval. During the post-marketing period, QT interval prolongation has been observed with quetiapine use at therapeutic doses and in overdose. As with other antipsychotic agents, quetiapine should be used with caution in patients with cardiovascular diseases or a family history of QT interval prolongation. Caution should also be exercised when prescribing quetiapine with drugs that prolong the QT interval, particularly in elderly patients, patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalemia, or hypomagnesemia (see section «Interactions with other medicinal products and other forms of interaction»).

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.

Severe skin adverse reactions.

Very rare cases of severe cutaneous adverse reactions (SCAR) associated with quetiapine treatment have been reported, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), erythema multiforme, and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal.

SCAR typically present as a combination of symptoms: extensive skin rash or exfoliative dermatitis, fever, lymphadenopathy, and possible eosinophilia or neutrophilia. Most of these reactions occurred within 4 weeks after starting quetiapine therapy; some DRESS reactions occurred within 6 weeks after starting quetiapine. If signs and symptoms suggestive of such severe skin reactions occur, quetiapine should be immediately discontinued and alternative treatment considered.

Discontinuation of treatment.

Abrupt discontinuation of quetiapine may lead to a withdrawal syndrome characterized by insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability. Therefore, a gradual tapering of the drug over a period of at least one to two weeks is recommended (see section «Adverse reactions»).

Elderly patients with psychosis associated with dementia.

Quetiapine is not approved for the treatment of psychosis associated with dementia. When some atypical antipsychotic agents were used, an approximately threefold increased risk of cerebrovascular adverse events was observed. The mechanism of this increased risk remains unknown. An increased risk cannot be excluded when other antipsychotics are used or in other patient groups. Quetiapine should be used with caution in patients with risk factors for stroke.

Meta-analysis data on atypical antipsychotics show that elderly patients with psychosis associated with dementia are at increased risk of mortality compared to the placebo group. In two 10-week placebo-controlled trials of quetiapine in this patient group (n=710; mean age 83 years; range 56–99 years), mortality in patients treated with quetiapine was 5.5% versus 3.2% in the placebo group. Deaths during the trials were due to various causes expected in this patient population.

Elderly patients with Parkinson's disease.

A population-based retrospective study of quetiapine in the treatment of MDD patients showed an increased risk of mortality during quetiapine use in patients over 65 years of age. This association disappeared when patients with parkinsonism were excluded from the analysis. Caution should be exercised when prescribing quetiapine to this patient group.

Hepatic effects.

Quetiapine should be discontinued if jaundice occurs.

Dysphagia.

Cases of dysphagia have 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, including fatal outcomes, have been reported with quetiapine use, particularly in patients at higher risk of intestinal obstruction (including those receiving multiple drugs that reduce intestinal motility and patients unable to report symptoms of constipation).

Close monitoring of patients with impaired peristalsis or intestinal obstruction should be conducted, with the possibility of providing emergency medical assistance.

Venous thromboembolism.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic agents. Since patients receiving antipsychotic agents often have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during quetiapine treatment, and preventive measures taken.

Pancreatitis.

Cases of pancreatitis have been reported. Marketing reports indicated that many, although not all, patients had factors known to be associated with pancreatitis, such as elevated triglyceride levels, gallstones, or alcohol consumption.

Additional information.

Data on the use of quetiapine in combination with sodium divalproex or lithium in moderate to severe acute manic episodes are limited; however, such combination therapy was well tolerated. These data showed an additive effect by week 3 of treatment.

Irrational use and abuse.

Cases of irrational use and abuse of the medicinal product have been documented. Quetiapine should be prescribed with caution to patients with a history of alcohol or substance abuse.

Important information on excipients.

The medicinal product contains lactose; therefore, it should not be administered to patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

The medicinal product also contains the colouring agent sunset yellow FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Pregnancy.

First trimester.

Approximately 300 to 1000 published cases of pregnant women treated with quetiapine, including isolated reports of individual reactions, do not indicate an increased risk of developmental abnormalities following quetiapine use. However, based on all available data, a definitive conclusion cannot be made. Therefore, the medicinal product should be prescribed during pregnancy only if the expected benefit justifies the potential risk.

Third trimester.

Newborns whose mothers took antipsychotic agents (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. Reports include agitation, arterial hypertension, hypotension, tremor, somnolence, respiratory disorders, or feeding difficulties. Therefore, newborns should be closely monitored.

Breastfeeding period.

Limited data from published reports suggest that quetiapine passes into human breast milk, although this information is conflicting. Due to the lack of reliable data, the decision to discontinue breastfeeding or discontinue quetiapine therapy should be made considering the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility.

The effect of quetiapine on human fertility has not been evaluated. Effects related to increased prolactin levels have been observed in rats, but these are not directly relevant to humans.

Ability to affect reaction speed when driving or operating machinery.

Since quetiapine primarily acts on the CNS, the medicinal product may adversely affect activities requiring concentration. Therefore, patients should be advised to avoid driving or operating machinery until their individual sensitivity to this effect is determined.

Dosage and Administration.

The medicinal product can be administered regardless of food intake.

For the treatment of schizophrenia

The medicinal product Quetiapine-Darnytsia should be administered twice daily. The total daily dose during the first four days of treatment is 50 mg on day 1, 100 mg on day 2, 200 mg on day 3, and 300 mg on day 4. Starting from day 4, the dose should be adjusted within the range of effective doses – from 300 mg/day to 450 mg/day. Depending on the patient's clinical response and tolerability, the dose may be adjusted within the range of 150 mg/day to 750 mg/day.

For the treatment of moderate to severe manic episodes in bipolar disorder

The medicinal product Quetiapine-Darnytsia should be administered twice daily. The total daily dose during the first four days of treatment is 100 mg on day 1, 200 mg on day 2, 300 mg on day 3, and 400 mg on day 4. Dose adjustment up to 800 mg/day by day 6 should be performed in increments of no more than 200 mg/day.

The dose of the medicinal product may be adjusted within the range of 200 mg to 800 mg/day, depending on the individual patient's clinical response and tolerability. The effective dose range is from 400 mg to 800 mg/day.

For the treatment of major depressive episodes in bipolar disorder

The medicinal product Quetiapine-Darnytsia should be administered once daily at bedtime. The total daily dose during the first four days of treatment is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3), and 300 mg (day 4). The recommended daily dose is 300 mg. Clinical studies did not demonstrate additional benefit with the 600 mg dose compared to the 300 mg dose. The 600 mg dose may be effective in some individual patients. Doses above 300 mg should be prescribed only by a physician experienced in the treatment of bipolar disorder. According to clinical studies, in individual patients experiencing tolerability issues, dose reduction down to the minimum of 200 mg should be considered.

For prevention of relapse in patients with bipolar disorder whose manic or depressive episodes have been treated with quetiapine

To prevent subsequent manic, mixed, or depressive episodes in bipolar disorder, patients who responded to quetiapine during acute treatment should continue therapy with the same prescribed dose. The dose of Quetiapine-Darnytsia may be adjusted within the range of 300 mg to 800 mg/day, depending on the individual patient's clinical response and tolerability. It is important to use the lowest effective doses for maintenance therapy.

Elderly patients

As with other antipsychotic agents, the medicinal product Quetiapine-Darnytsia should be used with caution in elderly patients, especially during initial dose titration. Slower dose titration may be required, and the daily therapeutic dose may be lower than that used in younger patients, depending on the patient's clinical response and tolerability. The mean plasma clearance of quetiapine was 30–50% lower in elderly patients compared to younger patients.

The safety and efficacy of use in patients aged 65 years and older with depressive episodes in bipolar disorder have not been studied.

Patients with renal impairment

Dose adjustment is not required for patients with renal impairment.

Patients with hepatic impairment

Quetiapine is extensively metabolized by the liver. Therefore, the medicinal product should be used with caution in patients with known hepatic impairment, especially during initial dose titration. Treatment of patients with hepatic impairment should be initiated at 25 mg/day. The dose should be increased daily by increments of 25–50 mg/day until reaching an effective dose, depending on the individual patient's clinical response and tolerability.

Children

There is insufficient data on the safety and efficacy of quetiapine to support its use in children and adolescents under 18 years of age; therefore, quetiapine should not be used in pediatric practice.

Overdose.

Symptoms.

Reported signs and symptoms of overdose were consequences of the enhanced known pharmacological effects of the active substance, such as somnolence and sedation, tachycardia, hypotension, and anticholinergic effects. Overdose may lead to QT interval prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, disorientation, delirium and/or agitation, coma, and fatal outcome. Patients with pre-existing severe cardiovascular disease may be at increased risk of overdose effects (see section "Special precautions").

Treatment.

There is no specific antidote.

In cases of severe overdose symptoms, appropriate measures and intensive therapy should be considered, including restoration and maintenance of airway patency, ensuring adequate oxygenation and ventilation, and monitoring and supporting cardiovascular function.

Based on published literature, patients presenting with delirium and agitation along with clear signs of anticholinergic syndrome may be treated with physostigmine at a dose of 1–2 mg under continuous ECG monitoring. This is not a recommendation for standard treatment due to the potential negative effect of physostigmine on cardiac conduction. Physostigmine may be used only if there are no ECG abnormalities. Physostigmine should not be administered in cases of arrhythmias, any degree of heart block, or QRS complex widening.

In cases of persistent hypotension following quetiapine overdose, appropriate measures such as intravenous fluid administration and/or sympathomimetics should be used (adrenaline and dopamine should be avoided, as beta-adrenergic stimulation may worsen hypotension under conditions of alpha-adrenergic blockade caused by quetiapine).

Since prevention of absorption has not been studied in overdose, gastric lavage should be considered and, if possible, performed within 1 hour after drug intake (following intubation if the patient is unconscious), along with administration of activated charcoal combined with a laxative.

In cases of quetiapine overdose with persistent arterial hypotension, treatment should include appropriate measures such as intravenous fluid administration and/or sympathomimetics. Adrenaline and dopamine should be avoided, as beta-adrenergic stimulation may exacerbate hypotension in the presence of alpha-adrenergic blockade induced by quetiapine.

Gastric bezoar formation has been reported following overdose with prolonged-release quetiapine; appropriate diagnostic imaging is recommended to determine further management strategy.

In some cases, endoscopic removal of the pharmacobezoar has been successfully performed.

Close medical monitoring and observation should continue until full patient recovery.

Adverse Reactions

The most commonly observed adverse reactions during quetiapine administration include somnolence, dizziness, dry mouth, headache, withdrawal syndrome, elevated serum triglyceride levels, increased total serum cholesterol levels, weight gain, decreased hemoglobin levels, and extrapyramidal symptoms.

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

All adverse reactions are listed by system organ class and frequency of reporting: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Eye disorders:
Common – blurred vision.

Respiratory, thoracic and mediastinal disorders:
Common – dyspnoea^23;
Uncommon – rhinitis.

Gastrointestinal disorders:
Very common – dry mouth;
Common – constipation, dyspepsia, vomiting^25;
Uncommon – dysphagia^7;
Very rare – pancreatitis^1, intestinal obstruction, volvulus.

Hepatobiliary disorders:
Common – increased transaminase levels (alanine aminotransferase^3, gamma-glutamyl transferase^3);
Uncommon – increased aspartate aminotransferase levels^3;
Very rare – jaundice^5, hepatitis.

Renal and urinary disorders:
Uncommon – urinary retention.

Endocrine disorders:
Common – hyperprolactinaemia^15, decreased total T4^24, decreased free T4^24, decreased total T3^24, increased TSH^24;
Uncommon – decreased free T3^25, hypothyroidism, hypothyroidism^21;
Very rare – disturbance in antidiuretic hormone secretion.

Metabolism and nutrition disorders:
Very common – increased serum triglycerides^10,30, increased total cholesterol (particularly LDL-cholesterol)^11,30, decreased high-density lipoprotein levels^7,30, weight gain^8,30;
Common – increased appetite, increased glucose levels reaching values characteristic of hyperglycaemia^6,30;
Uncommon – hyponatraemia^19, diabetes mellitus^1,5, worsening of diabetes;
Very rare – metabolic syndrome^29.

Nervous system disorders:
Very common – dizziness^4,16, somnolence^2,16, headache, extrapyramidal symptoms^1,21;
Common – dysarthria;
Uncommon – seizures^1, restless legs syndrome, tardive dyskinesia^1,5, loss of consciousness^4,16.

Psychiatric disorders:
Common – unusual dreams, nightmares, suicidal thoughts and behaviour^20;
Very rare – sleepwalking and related phenomena such as talking during sleep and sleep-related eating disorders.

Cardiac disorders:
Common – tachycardia^4, palpitations^23, orthostatic hypotension^4,16;
Uncommon – QT interval prolongation^1,12,18, bradycardia^32;
Very rare – venous thromboembolism^1;
Frequency not known – stroke^33, cardiomyopathy, myocarditis.

Blood and lymphatic system disorders:
Very common – decreased hemoglobin^22;
Common – leukopenia^1,28, decreased neutrophil count, increased eosinophil levels^27;
Uncommon – neutropenia^1, thrombocytopenia, anaemia, decreased platelet count^13;
Very rare – agranulocytosis^26.

Immune system disorders:
Uncommon – hypersensitivity (including skin allergic reactions);
Very rare – anaphylactic reaction^5.

Skin and subcutaneous tissue disorders:
Very rare – angioedema^5, Stevens-Johnson syndrome^5;
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.

Reproductive system and breast disorders:
Uncommon – sexual dysfunction;
Very rare – priapism, galactorrhea, breast enlargement, menstrual disorder.

Pregnancy, puerperium and perinatal conditions:
Frequency not known – drug withdrawal syndrome in newborns^31.

General disorders and administration site conditions:
Very common – withdrawal symptoms^1,9;
Common – mild asthenia, peripheral edema, irritability, hyperthermia;
Very rare – neuroleptic malignant syndrome^1, hypothermia.

Investigations:
Very rare – increased creatine phosphokinase levels^7.

Notes:

1 – See section "Special precautions for use".

2 – Somnolence may occur during the first 2 weeks of treatment and usually resolves with continued quetiapine administration.

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

4 – As with other antipsychotic drugs that block α1-adrenergic receptors, quetiapine may frequently cause orthostatic hypotension, accompanied by dizziness, tachycardia, and in some patients by syncope, particularly during initial dose titration (see section "Special precautions for use").

5 – Frequency estimates for these adverse reactions were derived only from post-marketing data of quetiapine immediate-release formulation.

6 – Fasting blood glucose ≥ 126 mg/dL (≥ 7.0 mmol/L) or postprandial blood glucose ≥ 200 mg/dL (≥ 11.1 mmol/L) at least once.

7 – Increased incidence of dysphagia with quetiapine compared to placebo was observed only in clinical trials of bipolar depression.

8 – Based on > 7% increase in body weight compared to baseline. Occurs predominantly during the first weeks of therapy in adults.

9 – Withdrawal symptoms most commonly observed in short-term placebo-controlled monotherapy trials evaluating withdrawal symptoms: insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and irritability. The frequency of these reactions significantly decreased within one week after discontinuation of treatment.

10 – 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.

11 – 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).

12 – See text below.

13 – Platelets ≤ 100 × 10^9/L at least once.

14 – According to clinical trial reports of adverse reactions, increased blood creatine phosphokinase levels were not associated with neuroleptic malignant syndrome.

15 – 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.

16 – May lead to falls.

17 – HDL-cholesterol: < 40 mg/dL (1.025 mmol/L) in males; < 50 mg/dL (1.282 mmol/L) in females at any time.

18 – Number of patients with change in QTc interval from < 450 msec to ≥ 450 msec with increase ≥ 30 msec. In placebo-controlled trials of quetiapine, mean change and number of patients with shift to clinically significant levels were similar in quetiapine and placebo groups.

19 – Shift from > 132 mmol/L to ≤ 132 mmol/L at least once.

20 – Cases of suicidal thoughts and suicidal behaviour were reported during therapy with quetiapine or immediately after discontinuation of treatment (see sections "Special precautions for use" and "Pharmacological properties").

21 – See section "Pharmacological properties".

22 – Decrease in hemoglobin to ≤ 13 g/dL (8.07 mmol/L) in males, ≤ 12 g/dL (7.45 mmol/L) in females at least once occurred in 11% of patients treated with quetiapine across all studies, including open-label extension studies. For these patients, the mean maximum decrease in hemoglobin at any time was -1.50 g/dL.

23 – Reports of these reactions often occurred in the context of tachycardia, dizziness, orthostatic hypotension and/or concomitant cardiac/respiratory disorders.

24 – Based on deviation from normal baseline to potentially clinically significant values at any time after baseline in all studies. Deviation for total T4, free T4, total T3, and free T3 was < 0.8 × LLN (pmol/L), and for TSH > 5 mU/L at any time.

25 – Based on increased frequency of vomiting in elderly patients (≥ 65 years).

26 – Deviation of neutrophils from ≥ 1.5 × 10^9/L at baseline to < 0.5 × 10^9/L at any time during treatment.

27 – Based on deviation from normal baseline to potentially clinically significant values at any time after baseline in all studies. Deviation for eosinophils was > 1 × 10^9/L at any time.

28 – Based on deviation from normal baseline to potentially clinically significant values at any time after baseline in all studies. Deviation for leukocytes was ≤ 3 × 10^9/L at any time.

29 – Based on adverse reaction reports of metabolic syndrome from all clinical trials of quetiapine.

30 – During clinical trials, some patients experienced worsening of more than one metabolic parameter: body weight, blood glucose, and blood lipids.

31 – See section "Use in pregnancy or lactation".

32 – May occur during or shortly after initiation of therapy and may be associated with hypotension and/or syncope. Frequency is based on adverse reaction reports of bradycardia and related events observed in all clinical trials of quetiapine.

33 – Based on one retrospective non-randomized epidemiological study.

Cases of QT interval prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, and torsades de pointes have been reported with the use of neuroleptics, considered specific to this class of drugs.

Serious cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported in association with quetiapine treatment.

Paediatric population

The adverse reactions listed above observed in adults may also occur in children. Adverse reactions with higher frequency in this age group or not observed in adult patients include:

Endocrine disorders:
Very common – increased prolactin levels^1.

Metabolism and nutrition disorders:
Very common – increased appetite.

Nervous system disorders:
Very common – extrapyramidal symptoms^3;
Common – loss of consciousness.

Vascular disorders:
Very common – increased blood pressure^2.

Respiratory disorders:
Common – rhinitis.

Gastrointestinal disorders:
Very common – vomiting.

General disorders:
Common – irritability^3.

Notes:

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 levels > 100 µg/L.

2 – Based on deviation above clinically significant thresholds (according to National Institutes of Health criteria) or increase > 20 mmHg for systolic or > 10 mmHg for diastolic blood pressure at any time, derived from short-term (3–6 weeks) placebo-controlled trials in children and adolescents.

3 – Frequency corresponds to that observed in adults, but irritability may be associated with different clinical manifestations in children and adolescents compared to adults.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging. 10 tablets in a blister; 3 blisters in a carton.

Prescription status. Prescription only.

Manufacturer.

Jenapharm S.A.

Manufacturer's address and place of business.

18 Km Meresinou Avenue, Pallini, 153 51, Greece.

Marketing Authorization Holder.

JSC "Pharmaceutical Company "Darnitsa".

Address of Marketing Authorization Holder.

13 Boryspilska Street, Kyiv, 02093, Ukraine.