Quetiapine-Darnitsa

APPROVED
Order of the Ministry of Health of Ukraine No. 278 dated February 10, 2022
Marketing Authorization No. UA/19202/01/01, No. UA/19202/01/02, No. UA/19202/01/03

INSTRUCTION
for medical use of 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 of quetiapine fumarate, equivalent to 100 mg of quetiapine;

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

excipients:

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

film coating:

25 mg tablets: red ferric oxide (Е 172), yellow ferric oxide (Е 172), HPMC 2910/hypromellose 5сР (Е 464), titanium dioxide (Е 171), macrogol/PEG 400, sunset yellow FCF aluminum lake (Е 110);

100 mg tablets: yellow ferric oxide (Е 172), HPMC 2910/hypromellose 5сР (Е 464), titanium dioxide (Е 171), macrogol/PEG 400;

200 mg tablets: hydroxypropyl cellulose (Е 463), HPMC 2910/hypromellose 6сР (Е 464), titanium dioxide (Е 171), talc.

Pharmaceutical form. Film-coated tablets.

Main physical and chemical properties:

25 mg tablets: peach, round, biconvex film coated tablets;

100 mg tablets: yellow, round, biconvex film coated tablets, scored on one side;

200 mg tablets: white round, biconvex film coated tablets, scored on one side.

Pharmacotherapeutic group.

Psycholeptics. Antipsychotics. Quetiapine.

ATC code: N05A H04.

 

Pharmacological properties.

Pharmacodynamics.

Quetiapine is an atypical antipsychotic agent. Quetiapine and its active metabolite, norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and norquetiapine exhibit a high selectivity for brain serotonin (5HT₂) and dopamine D₁- and D₂-receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT₂ relative to D₂-receptors which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal side effect liability of quetiapine compared to the typical antipsychotics. Quetiapine and norquetiapine also have high affinity for the histaminergic and adrenergic α₁-receptors, with a lower affinity for the adrenergic α₂- and serotonin 5HT₁A-receptors.

Quetiapine has no appreciable affinity for the cholinergic muscarinic or benzodiazepine receptors, while norquetiapine has moderate to high affinity for several muscarinic receptor subtypes, which may explain anti-cholinergic (muscarinic) effects.

Inhibition of norepinephrine transporter (NET) and partial agonist action at 5HT₁A sites by norquetiapine may contribute to quetiapine therapeutic efficacy as an antidepressant.

Quetiapine is active in the tests for antipsychotic activity, such as conditioned avoidance. It also blocks the action of dopamine agonists, measured either behaviorally or electrophysiologically, and elevates the dopamine metabolite concentrations, a neurochemical index of D₂-receptor blockade.

Pharmacokinetics.

Absorption.

Quetiapine-Darnitsa is well absorbed and extensively metabolized following oral administration. The bioavailability of quetiapine is not significantly affected by the administration with food. Steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of that observed for quetiapine.

The pharmacokinetics of quetiapine and norquetiapine are linear across the approved concentrations.

Distribution.

Quetiapine is approximately 83% bound to plasma proteins.

Metabolism.

Quetiapine is extensively metabolized by the liver. Administration of radio-labeled quetiapine have demonstrated that less than 5% of quetiapine is not metabolized and is eliminated as unchanged drug-related material in the urine or feces. In vitro investigations established that CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. Norquetiapine is primarily formed and eliminated via CYP3A4. Quetiapine and several of its metabolites (including norquetiapine) were found to be weak inhibitors of cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities in vitro. In vitro CYP inhibition is observed only at concentrations approximately 5- to 50-fold higher than those observed at a dose range of 300 to 800 mg/day in humans.

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

Elimination.

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

The average molar dose fraction of free quetiapine and the active human plasma metabolite norquetiapine is < 5% excreted in the urine.

 

Special populations.

Gender.

The pharmacokinetics of quetiapine do not differ between men and women.

Elderly.

The mean clearance of quetiapine in the elderly is 30−50% lower than that seen in adults aged 18 to 65 years.

Patients with renal impairment.

The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with the severe renal impairment (creatinine clearance less than 30 ml/min/1.73m²), but the individual clearance values are within the range for normal subjects.

Patients with hepatic impairment.

The mean quetiapine plasma clearance decreases by approximately 25% in persons with the known hepatic impairment (stable alcohol cirrhosis). As quetiapine is extensively metabolized by the liver, elevated plasma levels are expected in the population with the hepatic impairment. Dose adjustments may be necessary in these patients.

Clinical particulars.

Indications.

Treatment of schizophrenia.

Treatment of bipolar disorders, including:

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

− for the treatment of major depressive episodes in bipolar disorder.

For the prevention of recurrence of manic or depressed episodes in patients with bipolar disorder who previously responded to quetiapine treatment.

Contraindications.

Hypersensitivity to any component of this medicinal product.

Concomitant administration 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.

Given the primary central nervous system effects of quetiapine, this product should be used with caution in combination with other centrally acting medicinal products and alcohol.

Caution should be exercised treating patients receiving other medications with the anti-cholinergic (muscarinic) effects.

Cytochrome P450 (CYP) 3A4 is the enzyme that is primarily responsible for the cytochrome P450 mediated metabolism of quetiapine. In an interaction study in the healthy volunteers, concomitant administration of quetiapine (dosage of 25 mg) with ketoconazole, a CYP3A4 inhibitor, caused a 5- to 8-fold increase in the AUC of quetiapine. On the basis of this, concomitant use of quetiapine with CYP3A4 inhibitors is contraindicated. It is also not recommended to consume grapefruit juice while on quetiapine therapy.

In a multiple dose trial in patients to assess the pharmacokinetics of quetiapine given before and during treatment with carbamazepine (a known hepatic enzyme inducer), co-administration of carbamazepine significantly increased the clearance of quetiapine. This increase in clearance reduced the systemic quetiapine exposure (as measured by AUC) to an average of 13% of the exposure during administration of quetiapine alone; although a greater effect was seen in some patients. As a consequence of this interaction, lower plasma concentrations can occur, which could affect the efficacy of quetiapine therapy.

Co-administration of quetiapine and phenytoin (hepatic microsomal enzyme inducer) caused the increased clearance of quetiapine by 450%. In patients receiving a hepatic enzyme inducer, initiation of quetiapine treatment should only occur if the benefits of quetiapine outweigh the risks of discontinuation of the hepatic enzyme inducer. It is important that any change in the inducer is gradual, and if required, replaced with a non-inducer (e.g. sodium valproate), see section “Special warnings and precautions for use”.

The pharmacokinetics of quetiapine were not significantly altered by co-administration of the antidepressants imipramine (a known CYP 2D6 inhibitor) or fluoxetine (a known CYP 3A4 and CYP 2D6 inhibitor).

The pharmacokinetics of quetiapine were not significantly altered by co-administration of the antipsychotics risperidone or haloperidol. Concomitant use of quetiapine and thioridazine caused an increased clearance of quetiapine by approximately 70%.

The pharmacokinetics of quetiapine were not altered following co-administration with cimetidine.

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

The pharmacokinetics of sodium valproate and quetiapine were not altered when co-administered. A retrospective study in the children and adolescents who received valproate, quetiapine, or both, found a higher incidence of leucopenia and neutropenia in the combination group versus the monotherapy groups.

Formal interaction studies with commonly used cardiovascular products have not been performed. Caution should be exercised when quetiapine is used concomitantly with the medical products known to cause electrolyte imbalance or to increase QT interval.

There have been reports of the false positive results in enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine. Confirmation of questionable immunoassay screening results by the appropriate chromatographic technique is recommended.

Special warnings and precautions for use.

As quetiapine has several indications, the safety profile should be considered with respect to the individual patient's diagnosis and the dose being administered.

Pediatric population.

Quetiapine is not recommended for use in children and adolescents below 18 years of age, due to a lack of data to support the use in this age group. Clinical trials with quetiapine have shown that in addition to the known safety profile identified in adults, certain adverse events occurred at a higher frequency in children and adolescents compared to adults (increased appetite, elevations in serum prolactin, vomiting, rhinitis and syncope), or may have different implications for children and adolescents (extrapyramidal symptoms and irritability) and one was identified that has not been previously seen in adult studies (increases in blood pressure). Changes in thyroid function tests have also been observed in children and adolescents.

Furthermore, the delayed implications of treatment with quetiapine on growth and maturation have not been studied beyond 26 weeks. Long-term implications for cognitive and behavioral development are not known.

In placebo-controlled clinical trials in children and adolescent patients, quetiapine was associated with the increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia and bipolar mania (see section “Undesirable effects”).

Suicide/suicidal thoughts or clinical worsening.

Depression is associated with the increased risk of suicidal thoughts, self-harm and suicide (suicide related events and manifestations). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement is observed. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

 

In addition, physicians should consider the potential risk of suicide-related events after abrupt cessation of quetiapine treatment, due to the known risk factors for the disease being treated.

Other psychiatric conditions for which quetiapine is prescribed can also be associated with the increased risk of suicide related events and manifestations. In addition, these conditions may be co-morbid with the major depressive episodes. The same precautions observed when treating patients with major depressive episodes should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of the suicide related events and manifestations, or those exhibiting a significant degree of suicidal ideation prior to the commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo controlled clinical trials of antidepressant drugs in the adult patients with psychiatric disorders showed an increased risk of suicidal behavior with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany the drug therapy especially in the early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behavior or thoughts and unusual changes in behavior and to seek medical advice immediately if these symptoms are present.

In shorter-term placebo controlled clinical studies of patients with major depressive episodes in bipolar disorder an increased risk of suicide related events was observed in the young adult patients (younger than 25 years of age) who were treated with quetiapine as compared to those treated with placebo (3.0% vs. 0%, respectively).

In clinical studies of patients with major depressive disorder (MDD) the incidence of suicide related events and manifestations observed in young adult patients (younger than 25 years of age) was 2.1% (3/144) for quetiapine and 1.3% (1/75) for placebo. A population retrospective analysis of quetiapine used in the treatment of patients with MDD showed an increased risk of self-harm and suicide in patients aged 25 to 64 years without a history of self-harm during use of quetiapine with other antidepressants.

Metabolic risk.

Given the observed risk for worsening of their metabolic profile, including changes in weight, blood glucose and lipids, which was seen in clinical studies, patient metabolic parameters should be assessed at the time of treatment initiation and changes in these parameters should be regularly controlled during the course of treatment. Worsening in these parameters should be managed as clinically appropriate.

Extrapyramidal symptoms.

In placebo controlled clinical trials in the adult patients quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major depressive episodes in bipolar disorder and major depressive disorder.

The use of quetiapine has been associated with the development of akathisia, characterized by the subjectively unpleasant or distressing restlessness and need to move often accompanied by the inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Tardive dyskinesia.

If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of quetiapine should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment (see section “Undesirable effects”).

Somnolence and dizziness.

Quetiapine treatment has been associated with somnolence and related symptoms, such as sedation. In clinical trials for treatment of patients with bipolar depression and MDD, onset was usually within the first three days of treatment and was predominantly of mild to moderate intensity. Patients experiencing somnolence of severe intensity may require more frequent contact for a minimum of 2 weeks from onset of somnolence, or until symptoms improve and treatment discontinuation may need to be considered.

Orthostatic hypotension.

Quetiapine treatment has been associated with orthostatic hypotension and related dizziness which, like somnolence has onset usually during the initial dose titration period. These events could increase the occurrence of accidental injury (fall), especially in the elderly population. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects or impact of the medicinal product.

Quetiapine should be used with caution in patients with the known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension. Dose reduction or more gradual titration should be considered if orthostatic hypotension occurs, especially in patients with the underlying cardiovascular disease.

Sleep apnea syndrome.

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

Seizures.

There was no difference in the incidence of seizures in patients treated with quetiapine or placebo. No data is available about the incidence of seizures in patients with a history of seizure disorder. As with other antipsychotics, caution is recommended when treating patients with a history of seizures (see section “Undesirable effects”).

Neuroleptic malignant syndrome.

Neuroleptic malignant syndrome has been associated with the antipsychotic treatment, including quetiapine. Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event, quetiapine should be discontinued and appropriate medical treatment given.

Severe neutropenia and agranulocytosis.

Severe neutropenia (neutrophil count < 0.5 × 10⁹/L) has been reported in quetiapine clinical trials. Most cases of the severe neutropenia have occurred within a couple of months of starting therapy with quetiapine. There was no apparent dose relationship. During post-marketing experience, some cases were fatal. Possible risk factors include pre-existing low white blood cell (WBC) count and history of drug induced neutropenia. However, some cases occurred in patients without the pre-existing risk factors. Quetiapine should be discontinued in patients with neutrophil count < 1.0 × 10⁹/L. Patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 × 10⁹/L).

Neutropenia should be considered in patients presenting with the infection and fever, especially in the absence of obvious predisposing factors, in particular fever of unknown origin and should be managed as clinically appropriate.

Patients should be advised to immediately report the appearance of signs/symptoms consistent with agranulocytosis or infection (e.g. fever, weakness, lethargy, or sore throat) at any time during quetiapine therapy. Such patients should have a WBC count and an absolute neutrophil count (ANC) performed promptly, especially in the absence of predisposing factors.

 

Anti-cholinergic (muscarinic) syndrome.

Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes which may explain the anti-cholinergic (muscarinic) syndrome. This contributes to the adverse drug reactions reflecting anti-cholinergic effects when quetiapine is used concomitantly with other medicinal products having anti-cholinergic effects, and in the setting of overdose. Quetiapine should be used with caution in patients receiving medicinal products having anti-cholinergic (muscarinic) effects.

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

Concomitant use of hepatic enzyme inducers.

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

Concomitant use of quetiapine with a strong hepatic enzyme inducer such as carbamazepine or phenytoin substantially decreases quetiapine plasma concentrations, which could affect the efficacy of quetiapine therapy. In patients receiving a hepatic enzyme inducer, initiation of quetiapine treatment should only occur if the physician considers that the benefits of quetiapine outweigh the risks of discontinuation of the hepatic enzyme inducer. It is important that any change in the inducer is gradual, and if required, replaced with a non-inducer (e.g. sodium valproate).

Increased weight.

Weight gain has been reported in patients who have been treated with quetiapine, and should be monitored and managed as clinically appropriate and in accordance with the utilized antipsychotic guidelines.

Hyperglycemia.

Hyperglycemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been reported rarely, including some fatal cases. In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with the utilized antipsychotic guidelines. Patients treated with any antipsychotic agent including quetiapine, should be observed for signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of the glucose control. Weight should be monitored regularly.

Lipids.

Increases in triglycerides, LDL and total cholesterol, and decreases in HDL cholesterol have been observed in the clinical trials with quetiapine. Lipid changes should be managed as clinically appropriate.

QT prolongation.

In clinical trials and use in accordance with the SPC, quetiapine was not associated with a persistent increase in absolute QT intervals. In post-marketing, QT prolongation was reported with quetiapine at the therapeutic doses and in overdose. As with other antipsychotics, caution should be exercised when quetiapine is prescribed in patients with the cardiovascular disease or family history of QT prolongation. Also, caution should be exercised when quetiapine is prescribed either with medicinal products known to increase QT interval or with concomitant neuroleptics, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalemia or hypomagnesemia (see section “Interaction with other medicinal products and other forms of interaction”.

 

Cardiomyopathy and myocarditis.

Cardiomyopathy and myocarditis have been reported in the clinical trials and during the post-marketing experience (see section “Undesirable effects”).

In patients with suspected cardiomyopathy or myocarditis discontinuation of quetiapine should be considered.

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), erythema multiforme (EM) and drug reaction with eosinophilia and systemic symptoms (DRESS) which can be life-threatening or fatal have been reported very rarely with quetiapine treatment.

SCARs commonly present with one or more of the following symptoms: extensive cutaneous rash, exfoliative dermatitis, fever, lymphadenopathy and possible eosinophilia or neutrophilia. Most of these reactions occurred within 4 weeks after initiation of quetiapine therapy, some DRESS reactions occurred within 6 weeks after initiation of quetiapine therapy. If signs and symptoms suggestive of these severe skin reactions appear, quetiapine should be withdrawn immediately and alternative treatment should be considered.

Withdrawal.

Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability have been described after abrupt cessation of quetiapine. Therefore, gradual withdrawal over a period of at least one to two weeks is advisable (see section “Undesirable effects”).

Elderly patients with dementia-related psychosis.

Quetiapine is not approved for the treatment of dementia-related psychosis. An approximately 3‒fold increased risk of cerebrovascular adverse events has been observed when some atypical antipsychotics were used. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Quetiapine should be used with caution in patients with the risk factors for stroke.

In a meta-analysis of atypical antipsychotics, it has been reported that elderly patients with the dementia-related psychosis are at the increased risk of death compared to placebo. In two 10-week placebo-controlled quetiapine studies in the same patient population (n = 710); mean age: 83 years; range: 56–99 years) the incidence of mortality in quetiapine treated patients was 5.5% versus 3.2% in the placebo group. The patients in these trials died from a variety of causes that were consistent with expectations for this population.

Elderly patients with Parkinson's disease.

A population-based retrospective study of quetiapine for the treatment of patients with MDD, showed the increased risk of death during the use of quetiapine in patients aged > 65 years. This association was not present when patients with parkinsonism were removed from the analysis. Caution should be exercised if quetiapine is prescribed to this patient group.

Hepatic effects.

Quetiapine should be discontinued if jaundice develops.

Dysphagia.

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

Constipation and intestinal obstruction.

Constipation represents a risk factor for the intestinal obstruction. Constipation and intestinal obstruction have been reported with quetiapine. This includes fatal reports in the patients who are at higher risk of intestinal obstruction, including those that are receiving multiple concomitant medications that decrease intestinal motility and may not report symptoms of constipation.

 

Patients with intestinal obstruction/ileus should be managed with close monitoring and urgent care.

Venous thromboembolism.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with the acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with quetiapine and preventive measures undertaken.

Pancreatitis.

Pancreatitis has been reported. Among the marketing reports, while not all cases were confounded by risk factors, many patients had factors which are known to be associated with pancreatitis such as increased triglycerides, gallstones, and alcohol consumption.

Additional information.

Quetiapine data in combination with divalproex or lithium in the acute moderate to severe manic episodes is limited; however, combination therapy was well tolerated. The data showed an additive effect at week 3 of treatment.

Misuse and abuse.

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

Important information about excipients.

This medicinal product contains lactose. Therefore, patients with the rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Also, this medicinal product contains sunset yellow FCF (E 110) dye, which may cause the allergic reactions.

Pregnancy and breastfeeding.

Pregnancy.

First trimester.

The moderate amount of published data from exposed pregnancies (i.e. between 300‒1000 pregnancy outcomes), including individual reports do not suggest the increased risk of malformations due to treatment with quetiapine. However, based on all available data, a definite conclusion cannot be drawn. Therefore, quetiapine should only be used during pregnancy if the benefits justify the potential risks.

Third trimester.

Neonates exposed to antipsychotics (including quetiapine) during the third trimester of pregnancy are at risk of the adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertension, hypotension, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.

Breastfeeding.

Based on the limited data from the published reports on quetiapine excretion into human breast milk, excretion of quetiapine at the therapeutic doses appears to be inconsistent. Due to lack of robust data, a decision must be made whether to discontinue breastfeeding or to discontinue quetiapine therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

 

Fertility.

The effects of quetiapine on the human fertility have not been assessed. Effects related to elevated prolactin levels were seen in rats, although these are not directly relevant to humans.

Effects on ability to drive and use machines.

Given its primary central nervous system effects, quetiapine may interfere with the activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery, until individual susceptibility to this is known.

Posology and method of administration.

The medicinal product can be administered with or without food..

For the treatment of schizophrenia

Quetiapine-Darnitsa should be administered twice daily. The total daily dose for the first four days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). From Day 4 onwards, the dose should be titrated to the usual effective dose of 300 to 450 mg/day. Depending on the clinical response and tolerability of the individual patient, the dose may be adjusted within the range 150 to 750 mg/day.

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

Quetiapine-Darnitsa should be administered twice daily. The total daily dose for the first four days of therapy is 100 mg (Day 1), 200 mg (Day 2), 300 mg (Day 3) and 400 mg (Day 4). Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day.

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

For the treatment of major depressive episodes in bipolar disorder

Quetiapine-Darnitsa should be administered once daily at bedtime. The total daily dose for the first four days of therapy 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. In clinical trials, no additional benefit was seen in the 600 mg group compared to the 300 mg group. Individual patients may benefit from a 600 mg dose. Doses higher than 300 mg should be initiated by physicians experienced in treating bipolar disorder. In individual patients, in the event of tolerance concerns, clinical trials have indicated that dose reduction to a minimum of 200 mg could be considered.

For preventing recurrence of manic or depressive episodes in bipolar disorder in patients who have responded to quetiapine

For preventing recurrence of the manic, mixed or depressive episodes in bipolar disorder, patients who have responded to quetiapine for acute treatment of bipolar disorder should continue therapy at the same dose. The dose of Quetiapine-Darnitsa may be adjusted depending on the clinical response and tolerability of the individual patient, within the range of 300 to 800 mg/day. It is important that the lowest effective dose is used for maintenance therapy.

Elderly

As with other antipsychotics, Quetiapine-Darnitsa should be used with caution in the elderly, especially during the initial dosing period. The rate of dose titration may need to be slower, and the daily therapeutic dose lower, than that used in younger patients, depending on the clinical response and tolerability of the individual patient. The mean plasma clearance of quetiapine was reduced by 30–50% in elderly subjects when compared to younger patients.

 

Efficacy and safety have not been evaluated in patients over 65 years with depressive episodes in the framework of bipolar disorder.

Patients with renal impairment

Dosage adjustment is not necessary in patients with the 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 the known hepatic impairment, especially during the initial dosing period. Patients with the known hepatic impairment should be started with 25 mg/day. The dosage should be increased daily with increments of 25–50 mg/day until an effective dosage, depending on the clinical response and tolerability of the individual patient.

Pediatric population.

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

Overdose.

Symptoms.

The reported signs and symptoms were those resulting from an exaggeration of the active substance's known pharmacological effects, i.e. drowsiness and sedation, tachycardia, hypotension and anti-cholinergic effects. Overdose could lead to the QT-prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium and/or agitation, coma and death. Patients with the pre-existing severe cardiovascular disease may be at the increased risk of the effects of overdose (see section “Special warnings and precautions for use”).

Management.

There is no specific antidote.

In cases of the severe signs of overdose, the possibility of multiple drug involvement should be considered, and intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.

Based on public literature, patients with delirium and agitation and a clear anti-cholinergic syndrome may be treated with physostigmine, 1‒2 mg (under continuous ECG monitoring). This is not recommended as the standard treatment, because of the potential negative effect of physostigmine on cardiac conductance. Physostigmine may be used if there are no ECG aberrations. Do not use physostigmine in case of dysrhythmias, any degree of heart block or QRS-widening.

In cases of quetiapine overdose, refractory hypotension should be treated with the appropriate measures such as intravenous fluids and/or sympathomimetic agents. Epinephrine and dopamine should be avoided, since beta stimulation may worsen hypotension in the setting of quetiapine-induced alpha blockade.

Whilst the prevention of absorption in overdose has not been investigated, gastric lavage can be indicated and if possible performed within one hour of ingestion (after intubation, if patient is unconscious). The administration of activated charcoal together with a laxative should be considered.

 

In case of a quetiapine extended-release overdose gastric bezoar formation has been reported and appropriate diagnostic imaging is recommended to further guide patient management.

Endoscopic pharmacobezoar removal has been performed successfully in some cases.

Close medical supervision and monitoring should be continued until the patient recovers.

Undesirable effects.

The most commonly reported events with quetiapine are somnolence, dizziness, dry mouth, headache, withdrawal syndrome, elevations in serum triglyceride levels, elevations in serum total cholesterol, weight gain, decreased hemoglobin and extrapyramidal symptoms.

As with other antipsychotics, weight gain, syncope, neuroleptic malignant syndrome, leucopenia and peripheral edema have been associated with quetiapine.

All adverse events are ranked according to the system organ class and depending on the report frequencies: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), not known (cannot be estimated from the available data).

Eye disorders: common — vision blurred.

Respiratory, thoracic and mediastinal disorder: common — dyspnea²³; uncommon — rhinitis.

Gastrointestinal disorders: very common — dry mouth; common — constipation, dyspepsia, vomiting²⁵; uncommon — dysphagia⁷; very rare — pancretitus¹, intestinal obstruction, ileus.

Hepato-biliary disorders: common — elevations in transaminases (alanine aminotransferase³, gamma-glutamyl transferase³); uncommon — elevations in aspartate aminotransferase³; very rare — jaundice⁵, hepatitis.

Renal and urinary disorders: uncommon — urinary retention.

Endocrine disorders: common — hyperprolactinemia¹⁵, decreases in total Т4²⁴, decreases in free Т4²⁴, decreases in total Т3²⁴, increases in TSH²⁴; uncommon — decreases in free Т3²⁵, hypothyreosis; hypothyroidism²¹; very rare — inappropriate antidiuretic hormone secretion .

Metabolism and nutritional disorders: very common — elevations in serum triglyceride levels^10,30, elevations in total cholesterol (predominantly LDL cholesterol)^11,30, decrease in HDL cholesterol^7,30, weight gain^8,30; common — increased appetite, blood glucose increased to hyperglycemic levels^6,30; uncommon — hyponatremia¹⁹, diabetes mellitus^1,5, exacerbation of pre-existing diabetes; very rare — metabolic syndrome²⁹.

Nervous system disorders: very common — dizziness^4,16, somnolence^2,16, headache, extrapyramidal symptoms^1,21; common — dysarthria; uncommon — seizure¹, restless legs syndrome, tardive dyskinesia^1,5, syncope^4,16.

Psychiatric disorders: common — abnormal dreams and nightmares, suicidal ideation and suicidal behaviour²⁰; very rare — somnambulism and related reactions such as sleep talking and sleep related eating disorder.

Cardiovascular disorders: common — tachycardia⁴, palpitations²³, orthostatic hypotensio^4,16; uncommon — QT prolongation^1,12,18, bradycardia³²; very rare — venous thromboembolism¹; not known — stroke³³, cardiomyopathy and myocarditis.

Blood and lymphatic system disorders: very common — decreased hemoglobin²²; common — leucopenia^1,28, decreased neutrophil count, eosinophils increase²⁷; uncommon — neutropenia¹, thrombocytopenia, anemia, platelet count decreased¹³; very rare — agranulocytosis²⁶.

 

Immune system disorders: uncommon — hypersensitivity (including allergic skin reactions); very rare — anaphylactic reaction⁵.

Skin and subcutaneous tissue disorders: very rare — angizedema⁵, Stevens-Johnson syndrome⁵; not known — toxic epidermal necrolysis, erythema multiforme, drug rash 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 swelling, menstrual disorder.

Pregnancy, puerperium and perinatal conditions: not known — drug withdrawal syndrome neonatal³¹.

General disorders: very common — withdrawal (discontinuation) symptoms^1,9; common — mild asthenia, peripheral edema, irritability, pyrexia; very rare — neuroleptic malignant syndrome¹, hypothermia.

Investigations: very rare — elevations in blood creatine phosphokinase⁷.

Notes:

1 – See section “Special warnings and precautions for use”.

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

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

4 – As with other antipsychotics with α1-adrenergic blocking activity, quetiapine may commonly induce orthostatic hypotension, associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period.(see section “Special warnings and precautions for use”).

5− Calculation of frequency for these adverse drug reactions have been taken from post-marketing data only with the immediate release formulation of quetiapine.

6 – Fasting blood glucose ≥ 126 mg/dL (≥ 7.0 mmol/L) or a non-fasting blood glucose ≥ 200 mg/dL (≥ 11.1 mmol/L) on at least one occasion.

7 – An increase in the rate of dysphagia with quetiapine vs. placebo was only observed in the clinical trials in bipolar depression.

8 – Based on > 7% increase in body weight from baseline. Occurs predominantly during the early weeks of treatment in adults.

9 – The following withdrawal symptoms have been observed most frequently in acute placebo-controlled, monotherapy clinical trials, which evaluated discontinuation symptoms: insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability. The incidence of these reactions had decreased significantly after 1 week post-discontinuation.

10 – Triglycerides ≥ 200 mg/dL (≥ 2.258 mmol/L) (patients ≥ 18 years of age) or ≥ 150 mg/dL (≥ 1.694 mmol/L) (patients < 18 years of age) on at least one occasion.

11 – Cholesterol ≥ 240 mg/dL (≥ 6.2064 mmol/L) (patients ≥ 18 years of age) or ≥ 200 mg/dL (≥ 5.172 mmol/L) (patients < 18 years of age) on at least one occasion. An increase in LDL cholesterol of ≥ 30 mg/dL (≥ 0.769 mmol/L) has been very commonly observed. Mean change among patients who had this increase was 41.7 mg/dL (≥ 1.07 mmol/L).

12 – See text below.

13 – Platelets ≤ 100 × 10⁹/L on at least one occasion.

14 – Based on clinical trial adverse event reports of blood creatine phosphokinase increase not associated with neuroleptic malignant syndrome.

15 – Prolactin levels (patients > 18 years of age): > 20 μg/L (> 869.56 pmol/L) males; > 30 μg/L (> 1304.34 pmol/L) females at any time.

16 – May lead to falls.

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

18 – incidence of patients who have a QTc shift from < 450 msec to ≥ 450 msec with a ≥ 30 msec increase. In placebo-controlled trials with quetiapine the mean change and the incidence of patients who have a shift to thea clinically significant level is similar between quetiapine and placebo.

19 – Shift from > 132 mmol/L to ≤ 132 mmol/L on at least one occasion.

20 – Cases of suicidal ideation and suicidal behavior have been reported during quetiapine therapy or early after treatment discontinuation (see sections “Special warnings and precautions for use” and “Pharmaceutical particulars”).

21 – see section “Pharmaceutical particulars”.

22 – Decreased hemoglobin to ≤ 13 g/dL (8.07 mmol/L) males, ≤ 12 g/dL (7.45 mmol/L) females on at least one occasion occurred in 11% of quetiapine patients in all trials including open label extensions. For these patients, the mean maximum decrease in hemoglobin at any time was –1.50 g/dL.

23 – These reports often occurred in the setting of tachycardia, dizziness, orthostatic hypotension and/or underlying cardiac/respiratory disease.

24 – Based on shifts from normal baseline to potentially clinically important value at any time post-baseline in all trials. Shifts in total T₄, free T₄, total T₃ and free T₃ are defined as < 0.8 × LLN (pmol/L) and shift in TSH is > 5 mIU/L at any time.

25 – Based upon the increased rate of vomiting in elderly patients (≥ 65 years of age).

26 – Based on shift in neutrophils from ≥ 1.5 × 10⁹L at baseline to < 0.5 × 10⁹/L at any time during treatment.

27 – Based on shifts from normal baseline to potentially clinically important value at any time post-baseline in all trials. Shifts in eosinophils are defined as > 1 × 10⁹/L at any time.

28 – Based on shifts from normal baseline to potentially clinically important value at any time post-baseline in all trials. Shifts in WBC are defined as ≤ 3 × 10⁹/L at any time.

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

30 – In some patients, a worsening of more than one of the metabolic factors of weight, blood glucose and lipids was observed in clinical studies.

31 – See section “Pregnancy and breastfeeding”.

32 – May occur at or near initiation of treatment and be associated with hypotension and/or syncope. Frequency based on adverse event reports of bradycardia and related events in all clinical trials with quetiapine.

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

Cases of QT prolongation, ventricular arrhythmia, sudden unexplained death, cardiac arrest and torsades de pointes have been reported with the use of neuroleptics and are considered class effects.

Severe cutaneous adverse reactions (SCARs), 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.

Pediatric population

The same adverse drug reactions (ADRs) described above for adults should be considered for children. The ADRs with higher frequency in this age group of patients or ADRs that have not been identified in the adult population.

Endocrine disorders: very common — elevations in prolactin¹.

Metabolism and nutritional disorders: very common — increased appetite.

Nervous system disorders: very common — extrapyramidal symptoms³; common – syncope.

Vascular disorders: very common — increases in blood pressure².

Respiratory disorders: common — rhinitis.

Gastrointestinal disorders: very common — vomiting.

General disorders: common — irritability.

Notes:

1 – Prolactin levels (patients < 18 years of age): > 20 μg/L (> 869.56 pmol/L) males; > 26 μg/L (> 1130.428 pmol/L) females at any time. Less than 1% of patients had an increase to a prolactin level > 100 μg/L.

2 – Based on shifts above clinically significant thresholds (adapted from the National Institutes of Health criteria) or increases > 20 mm Hg for systolic or > 10 mm Hg for diastolic blood pressure at any time in two acute (3−6 weeks) placebo-controlled trials in children and adolescents.

3 – The frequency is consistent to that observed in adults, but might be associated with different clinical implications in children and adolescents as compared to adults.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions in the post-marketing surveillance period is very important. It allows monitoring of the benefit/risk balance of the medicinal products. Healthcare professionals are asked to report any suspected adverse reactions via the national Reporting System.

 

Shelf life. 3 years.

Storage conditions.

Store in the original package at temperature not more than 25°С.

Keep out of reach of children.

Packaging. Each blister contains 10 tablets; each cardboard box contains 3 blisters.

Legal classification. On prescription.

Manufacturer.

Genepharm S.A.

Manufacturer address and place of activity.

18 km Marathon Avenue, Pallini Attiki, 15351, Greece.

Applicant.

PJSC Pharmaceutical Company Darnitsa.

Applicant address and place of activity.

Boryspilska str. 13, Kyiv, 02093, Ukraine.

Date of last review. February 10, 2022