Ketilept® retard
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETILEPT® RETARD
Composition:
Active substance: quetiapine;
One prolonged-release coated tablet contains 57.56 mg, 172.680 mg, 230.24 mg, 345.36 mg, or 460.48 mg of quetiapine fumarate (corresponding to 50 mg, 150 mg, 200 mg, 300 mg, or 400 mg of quetiapine);
Excipients: methacrylic copolymer (type A), anhydrous lactose (spray-dried SD 250), crystalline maltose (Advantose 100), talc, magnesium stearate, vegetable origin;
Coating composition: methacrylic copolymer (type A), triethyl citrate (Citrofol).
Pharmaceutical form. Prolonged-release coated tablets.
Main physicochemical properties:
50 mg: white or almost white, round, biconvex tablets, engraved with the number "50" on one side;
150 mg: white or almost white, elongated, biconvex tablets, engraved with the number "150" on one side;
200 mg: white or almost white, elongated, biconvex tablets, engraved with the number "200" on one side;
300 mg: white or almost white, elongated, biconvex tablets, engraved with the number "300" on one side;
400 mg: white or almost white, oval, biconvex tablets, engraved with the number "400" on one side.
Pharmacotherapeutic group. Antipsychotic agents. ATC code N05A H04.
Pharmacological properties.
Pharmacodynamics.
Quetiapine is an atypical antipsychotic medicinal product. Quetiapine and its active plasma metabolite norquetiapine interact with multiple neurotransmitter receptors. Quetiapine and norquetiapine exhibit affinity for serotonergic (5HT2) and dopaminergic D1 and D2 receptors in the brain. This combination of receptor antagonism, with greater selectivity for 5HT2 receptors than for D2 receptors, is considered to contribute to the clinical antipsychotic effects and low propensity for extrapyramidal side effects of Ketilept® Retard compared to typical antipsychotic agents.
Quetiapine has no affinity for the norepinephrine transporter and low affinity for serotonergic 5HT1A receptors, whereas norquetiapine has high affinity for both. Inhibition by norquetiapine, as well as partial agonist activity at 5HT1A receptors, may contribute to the therapeutic efficacy of Ketilept® Retard as an antidepressant. Quetiapine and norquetiapine have high affinity for histaminergic receptors and alpha1-adrenergic receptors, and moderate affinity for alpha2-adrenergic receptors. Quetiapine has low or no affinity for muscarinic receptors, whereas norquetiapine has moderate to high affinity for several subtypes of muscarinic receptors.
Pharmacodynamic effects. 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 is well absorbed after oral administration. Peak plasma concentrations (Tmax) of quetiapine and norquetiapine are reached approximately 6 hours after administration of Ketilept® Retard. Steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of those of quetiapine.
The pharmacokinetics of quetiapine and norquetiapine are linear and dose-proportional up to 800 mg daily when administered once daily. When comparing equivalent total daily doses of Ketilept® Retard administered once daily and immediate-release quetiapine (immediate-release quetiapine fumarate) administered twice daily, the area under the plasma concentration–time curve (AUC) was similar, but the maximum plasma concentration (Cmax) was 13% lower at steady state. When comparing Ketilept® Retard with immediate-release quetiapine, the AUC of the metabolite norquetiapine was 18% lower.
In a study investigating the effect of food on the bioavailability of quetiapine, high-fat meals were shown to cause statistically significant increases in Cmax and AUC of Ketilept® Retard by approximately 50% and 20%, respectively. It cannot be excluded that the effect of high-fat meals on the bioavailability of the drug may be higher. Light meals have no significant effect on Cmax and AUC of quetiapine. Ketilept® Retard is recommended to be taken once daily at least one hour before a meal.
Distribution
Approximately 83% of quetiapine is bound to plasma proteins.
Metabolism
Quetiapine is extensively metabolized in the liver. Administration of radiolabeled quetiapine showed that less than 5% of quetiapine is excreted unchanged in urine or feces.
Elimination
The elimination half-lives of quetiapine and norquetiapine are approximately 7 and 12 hours, respectively. Approximately 73% of the radiolabeled dose is excreted in urine and 21% in feces.
In humans, 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 do not differ.
Elderly individuals
The mean clearance of quetiapine in elderly individuals is approximately 30–50% lower than in adults aged 18–65 years.
Renal impairment
The mean plasma clearance of quetiapine is reduced by approximately 25% in patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m²), although individual clearance values are within the range typical for healthy individuals.
Hepatic impairment
The mean plasma clearance of quetiapine is reduced by approximately 25% in patients with hepatic impairment (stable alcoholic cirrhosis). Since quetiapine is extensively metabolized in the liver, increased plasma levels are expected in patients with hepatic impairment. Dose adjustment may be required for such patients.
Clinical characteristics.
Indications.
Ketilept® Retard is indicated for the treatment of:
- schizophrenia, including prevention of recurrence in patients with stable schizophrenia who have been receiving maintenance therapy with quetiapine;
- bipolar disorder, specifically:
- treatment of moderate to severe manic episodes in bipolar disorder;
- treatment of severe depressive episodes in bipolar disorder;
- prevention of recurrence of illness in patients with bipolar disorder who have manic or depressive episodes responsive to quetiapine;
- as adjunctive therapy in severe depressive episodes in patients with major depressive disorder (MDD) who have had an inadequate response to antidepressant monotherapy. Prior to initiating therapy, the prescriber should carefully consider the safety profile of Ketilept® Retard.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients. Concomitant use of cytochrome P450 3A4 (CYP3A4) 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.
Since quetiapine primarily affects the central nervous system, Ketilept® Retard 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, due to an increased risk of developing serotonin syndrome, a potentially life-threatening condition (see section "Special warnings and precautions for use").
Cytochrome P450 (CYP) 3A4 is the primary enzyme responsible for quetiapine metabolism. In interaction studies in healthy volunteers, concomitant administration of quetiapine (25 mg) with ketoconazole (a 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 treatment with quetiapine.
In a multiple-dose pharmacokinetic study evaluating quetiapine administered before and during treatment with carbamazepine (a hepatic enzyme inducer), concomitant use of carbamazepine significantly increased quetiapine clearance. This increased clearance reduced systemic exposure to quetiapine (measured as AUC) to approximately 13% of exposure when quetiapine was administered alone, although a greater effect was observed in some patients. Due to this interaction, lower plasma concentrations may occur, potentially affecting the efficacy of Ketilept® Retard.
Concomitant administration of quetiapine and phenytoin (another microsomal enzyme inducer) resulted in an increase in quetiapine clearance by approximately 450%. Initiation of Ketilept® Retard therapy in patients receiving a hepatic enzyme inducer should only be considered if the physician judges that the benefit of Ketilept® Retard outweighs the risks associated with discontinuation of the hepatic enzyme inducer. It is important that any changes in the use of the inducer be made gradually. If necessary, the inducer should be replaced with a non-inducer (e.g., sodium valproate) (see section "Special warnings and precautions for use").
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. Concomitant administration of quetiapine and thioridazine resulted in an increase in quetiapine clearance by approximately 70%.
The pharmacokinetics of quetiapine were not altered when administered concomitantly with cimetidine.
The pharmacokinetics of lithium were not altered by concomitant administration with quetiapine.
In clinical trials comparing lithium plus Ketilept® Retard versus placebo plus Ketilept® Retard in adult patients with acute mania, increased incidence of extrapyramidal symptoms (particularly tremor), somnolence, and weight gain were observed in the lithium group compared to the placebo group.
No clinically significant changes in the pharmacokinetics of sodium valproate or quetiapine were observed when administered concomitantly. In a retrospective study involving children and adolescents receiving sodium valproate, quetiapine, or a combination of both, increased incidence of leukopenia and neutropenia was observed in the group receiving both medications compared to groups receiving either medication alone.
Interaction studies with cardiovascular medicinal products have not been conducted.
Caution should be exercised when administering quetiapine concomitantly with medicinal products that affect 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. It is recommended that questionable screening immunoassay results be confirmed using an appropriate chromatographic method.
Special precautions for use.
Since KetiLept® Retard is indicated for the treatment of schizophrenia, bipolar disorder, and adjunctive treatment of depressive episodes in patients with MDD, the safety profile of the medicinal product should be carefully considered with regard to the specific diagnosis established for the individual patient and the dose being taken.
Long-term efficacy and safety of adjunctive therapy in patients with MDD have not been evaluated; however, long-term efficacy and safety of monotherapy with the drug in adult patients have been studied.
Children
KetiLept® Retard is not recommended for use in children due to lack of data supporting its use in this age group. Clinical trial data for quetiapine have shown that, in addition to the known safety profile established in adults, the frequency of certain adverse events is higher in children than in adults (increased appetite, elevated serum prolactin levels, and extrapyramidal symptoms), and one adverse event not previously observed in trials involving adult patients has been identified (elevated blood pressure). In addition, 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 impact on cognitive and behavioral development is unknown.
During placebo-controlled clinical trials, quetiapine use in pediatric and adolescent patients was associated with an increased incidence of extrapyramidal symptoms (EPS) in patients treated for schizophrenia and bipolar mania (see section "Adverse reactions").
Suicide / suicidal thoughts or clinical worsening
Depression in bipolar disorder is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicide-related events). This risk persists until significant remission occurs. Since improvement may not occur during the first weeks of treatment or longer, patients should be closely monitored until such improvement occurs. According to general clinical experience, the risk of suicide increases in the early stages of improvement.
In addition, the potential risk of suicide-related events after abrupt discontinuation of quetiapine treatment should be considered.
Other psychiatric disorders for which KetiLept® Retard is prescribed are also associated with an increased risk of suicide-related events. Moreover, these disorders may coexist with depressive episodes.
When treating patients with other psychiatric disorders, the same precautions should be taken as when treating patients with major depressive episodes.
Patients with a history of suicide-related events or who exhibit significant levels of suicidal thinking prior to starting therapy are at higher risk of developing suicidal thoughts or attempting suicide and should be closely monitored during treatment. There is an increased risk of suicidal behavior in patients under 25 years of age. Close monitoring of patients, particularly those at high risk, should accompany pharmacological therapy, especially at the beginning of treatment and during subsequent dose adjustments. Patients (and their caregivers) should be advised to monitor for clinical worsening, suicidal behavior or thoughts, and changes in behavior, and to seek immediate medical attention if symptoms occur.
Reports indicate that patients under 25 years of age with major depressive episodes in bipolar disorders treated with quetiapine have an increased risk of suicide-related events. Similarly, there is a risk of suicide-related events in patients under 25 years of age with MDD who are taking quetiapine.
Somnolence
Treatment with quetiapine is associated with somnolence and similar symptoms such as sedation. In clinical trials, such symptoms in patients with bipolar depression typically occurred within the first 3 days of treatment and were predominantly mild to moderate in intensity. Patients with bipolar depression and patients with depressive episodes in MDD who experience somnolence may require monitoring for 2 weeks after onset of somnolence or until symptoms resolve, or discontinuation of treatment.
Orthostatic hypotension
Treatment with quetiapine has been associated with orthostatic hypotension and accompanying dizziness, which, similar to somnolence, usually occur during the dose titration period. These events may contribute to an increased frequency of accidental injuries (falls), particularly in elderly patients. Therefore, patients should be advised to exercise caution until they become accustomed to the possible effects of the medicinal product.
Cardiovascular disorders
KetiLept® Retard should be used with caution in patients with cardiovascular and cerebrovascular disorders or other conditions that may lead to arterial hypotension. Quetiapine may cause orthostatic hypotension, especially at the beginning of dose titration; therefore, dose reduction or more prolonged titration may be necessary in such cases.
Sleep apnea syndrome
Cases of sleep apnea syndrome have been reported in patients taking quetiapine. Quetiapine should be used with caution in patients who are concurrently taking central nervous system depressants and who have a history of or are at risk of developing sleep apnea. This includes, in particular, patients with excessive body weight/obesity and male patients.
Cardiomyopathy and myocarditis
Cases of cardiomyopathy and myocarditis have been reported in clinical trials and post-marketing studies (see section "Adverse reactions"). If cardiomyopathy or myocarditis is suspected in a patient, discontinuation of quetiapine treatment should be considered.
Seizures
During studies, there was no difference in the incidence of seizures between patients taking quetiapine and those in the placebo group. As with treatment with other antipsychotic agents, the drug should be prescribed with caution to patients with a history of seizures.
Extrapyramidal symptoms
The use of quetiapine is associated with an increased frequency of extrapyramidal symptoms (EPS) compared to placebo in patients receiving treatment for major depressive episodes associated with bipolar disorder and major depressive disorder.
The use of quetiapine has been associated with the development of akathisia, characterized by subjectively unpleasant or distressing restlessness and an urge to move, often accompanied by an inability to sit or stand still. These events are more commonly observed during the first few weeks of treatment. Increasing the dose in patients who develop such symptoms may be harmful.
Serotonin syndrome
Concomitant use of the medicinal product KetiLept® Retard and other serotonergic agents, 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 agents is clinically justified, careful monitoring of the patient is recommended, especially at the beginning of treatment and during dose increases. Symptoms of serotonin syndrome may include changes in mental status, autonomic instability, neuromuscular disturbances, and/or gastrointestinal symptoms.
If serotonin syndrome is suspected, dose reduction or discontinuation of therapy should be considered, depending on the severity of symptoms.
Tardive dyskinesia
If symptoms of tardive dyskinesia occur, the need for dose reduction or discontinuation of KetiLept® Retard should be considered. Symptoms of tardive dyskinesia may worsen or even emerge after discontinuation of therapy.
Malignant neuroleptic syndrome
Malignant neuroleptic syndrome may be associated with treatment with antipsychotics, including quetiapine. Clinical manifestations include hyperthermia, changes in mental status, muscle rigidity, autonomic instability, and elevated creatine phosphokinase levels. In such cases, treatment with KetiLept® Retard should be discontinued and appropriate treatment initiated.
Severe neutropenia and agranulocytosis
Severe neutropenia (neutrophil count < 0.5 × 10⁹/L) has been observed (rarely) during quetiapine use. Agranulocytosis (severe neutropenia with infection) has been reported infrequently in patients receiving quetiapine, particularly in the post-marketing period (including fatal cases). Most cases of severe neutropenia occurred within two months of starting quetiapine therapy. No clear dose relationship has been established. During the post-marketing period, normalization of leukopenia and/or neutropenia occurred after discontinuation of quetiapine. Risk factors for neutropenia include pre-existing leukopenia and drug-induced neutropenia in the patient's history. Cases of agranulocytosis have occurred in patients without risk factors. The possibility of developing neutropenia should be considered in patients with infection, even in the absence of risk factors, as well as in patients with fever of unknown origin, and appropriate clinical measures should be taken.
Quetiapine treatment should be discontinued if the neutrophil count in blood is < 1.0 × 10⁹/L. Patients should preferably be monitored for symptoms of infection, and neutrophil levels should be monitored until they exceed < 1.5 × 10⁹/L.
Interactions
See also section "Interaction with other medicinal products and other forms of interaction". Concomitant use of quetiapine with a potent hepatic enzyme inducer, such as carbamazepine or phenytoin, significantly reduces quetiapine plasma concentrations, which may compromise the effectiveness of quetiapine therapy. Treatment with KetiLept® Retard in patients receiving a hepatic enzyme inducer may only be initiated if the physician considers the benefit of using KetiLept® Retard to outweigh the risks of discontinuing the enzyme inducer. It is important that any changes in the use of the inducer occur gradually. If necessary, it should be replaced with a non-inducer (e.g., sodium valproate).
Effect on body weight
Weight gain has been reported during quetiapine treatment, which should be monitored and clinically managed when using antipsychotic agents.
Hyperglycemia
Hyperglycemia and/or development or exacerbation of diabetes mellitus, sometimes associated with ketoacidosis or coma, including several cases with fatal outcomes, have been observed rarely. In several cases, prior weight gain occurred, which may have contributed to these complications. Appropriate clinical monitoring should be performed according to current guidelines for the use of antipsychotic agents. Patients treated with any antipsychotic medicinal products, including quetiapine, should be monitored for symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes mellitus or risk factors for developing or worsening diabetes mellitus should have their glucose levels regularly checked. Body weight should be continuously monitored.
Lipids
Elevated levels of triglycerides, low-density lipoproteins (LDL), and total cholesterol, and decreased levels of high-density lipoprotein (HDL) cholesterol have been observed in clinical trials of quetiapine. Appropriate treatment should be initiated if lipid levels change.
Metabolic risk
Changes in body weight, blood glucose (see "Hyperglycemia"), and lipid levels in individual patients increase metabolic risk, which requires appropriate management.
Prolongation of QT interval
Quetiapine does not cause sustained increases in absolute QT intervals. However, QT interval prolongation has been observed in cases of overdose. As with other antipsychotics, caution should be exercised when prescribing quetiapine to patients with cardiovascular disorders and patients with a family history of prolonged QT interval. Caution should also be exercised when prescribing quetiapine with other medicinal products that prolong the QT interval, or with neuroleptics, especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalemia, or hypomagnesemia.
Severe skin adverse reactions
Very rare cases of severe skin adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, erythema multiforme, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal, have been reported during quetiapine treatment.
Severe skin adverse reactions are manifested by one or more symptoms: extensive skin rash, which may be accompanied by itching or pustules, exfoliative dermatitis, fever, lymphadenopathy, possible eosinophilia or neutrophilia. Most of these reactions occurred within 4 weeks after starting quetiapine treatment; some manifestations of DRESS syndrome occurred within 6 weeks after starting quetiapine treatment. If signs and symptoms suggestive of these severe skin reactions occur, quetiapine should be immediately discontinued and alternative treatment options considered.
Discontinuation of the drug
Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability have been described after abrupt discontinuation of quetiapine. Therefore, gradual discontinuation of the drug over a period of at least one to two weeks is recommended.
Elderly patients with psychosis associated with dementia
KetiLept® Retard is not recommended for the treatment of psychosis associated with dementia. In patients with dementia, use of some atypical antipsychotics has been associated with approximately a threefold increased risk of cardiovascular adverse events. The mechanism of this increased risk is unknown. An increased risk cannot be excluded with the use of other antipsychotics or in other patient groups. KetiLept® Retard should be used with caution in patients with risk factors for stroke.
According to meta-analysis data from studies of atypical antipsychotics, elderly patients with psychosis associated with dementia who take these drugs have an increased risk of mortality compared to placebo. In studies evaluating quetiapine in elderly patients with dementia, a causal relationship between quetiapine treatment and mortality has not been established.
Dysphagia
Dysphagia has been observed 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 the development of intestinal obstruction. Cases of constipation and intestinal obstruction (see section "Adverse reactions") have been reported with quetiapine use, including fatal cases in patients at higher risk of intestinal obstruction, including those receiving concomitant medications that reduce intestinal motility.
Venous thromboembolism
Cases of venous thromboembolism (VTE) have been observed during neuroleptic treatment. Since patients taking neuroleptics often have acquired risk factors for VTE, preventive measures should be taken.
Effect on liver
Treatment with KetiLept® Retard should be discontinued if jaundice develops.
Pancreatitis
Cases of pancreatitis have been reported during post-marketing use of quetiapine, although a causal relationship has not been established. Many of these patients had risk factors for pancreatitis, such as elevated triglyceride levels (see section "Special precautions for use"), gallstones, and alcohol consumption.
Cardiomyopathy and myocarditis
Cases of cardiomyopathy and myocarditis have been reported; however, a causal relationship with quetiapine use has not been established. The continued appropriateness of quetiapine use should be re-evaluated if cardiomyopathy or myocarditis is suspected.
Additional information
Data on the use of quetiapine in combination with divalproex or lithium in moderate to severe manic episodes are limited (see section "Adverse reactions"). These data indicate an additive effect by week 3 of treatment.
Lactose
KetiLept® Retard tablets contain lactose. This medicinal product should not be used in patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding.
The safety and efficacy of quetiapine use for treating pregnant women have not been established. Animal studies have not provided evidence of negative effects. Possible effects on fetal vision organs have not been studied. According to information from several pregnancies during which quetiapine was used, neonatal withdrawal symptoms were observed in newborns. Therefore, KetiLept® Retard may be prescribed during pregnancy only if the expected benefit justifies the potential risk. Newborns whose mothers took quetiapine during pregnancy have exhibited withdrawal symptoms.
Published reports indicate that quetiapine passes into human breast milk, although the extent of drug transfer into milk is unknown. Due to the lack of reliable data, a decision must be made whether to discontinue breastfeeding or discontinue quetiapine therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.
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. Adverse reactions observed in newborns include agitation, arterial hypertension, hypotension, tremor, somnolence, respiratory disorders, or feeding difficulties. Therefore, newborns should be closely monitored.
Ability to affect reaction speed when driving or operating machinery.
Since quetiapine primarily affects the central nervous system, patients are not recommended to drive or operate machinery until their individual sensitivity to this effect has been determined.
Method of Administration and Dosage
Different dosing regimens exist for each indication. Ensure that the patient is prescribed a dosage appropriate to their condition.
Ketylept® Retard should be administered once daily on an empty stomach. Tablets should be swallowed whole, without breaking, chewing, or crushing.
Treatment of schizophrenia and moderate to severe manic episodes in bipolar disorder
Ketylept® Retard should be taken at least 1 hour before food intake. The initial daily dose is 300 mg on day 1 and 600 mg on day 2. The recommended daily dose is 600 mg; however, if clinically justified, the dose may be increased up to 800 mg per day. The dose should be adjusted within the effective dose range of 400 mg to 800 mg daily, depending on clinical response and tolerability. No dose adjustment is necessary for maintenance therapy in schizophrenia.
Treatment of depressive episodes in bipolar disorder
Ketylept® Retard should be administered at bedtime. The total daily dose for 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. No additional benefit was observed with the 600 mg dose group compared to the 300 mg group (see section "Pharmacological Properties"). The 600 mg dose may be effective in some patients. Doses above 300 mg should be prescribed only by physicians experienced in treating bipolar disorder. For individual patients experiencing tolerability issues, consider reducing the dose to the minimum effective dose of 200 mg.
Prevention of relapse in bipolar disorder
To prevent subsequent manic, mixed, or depressive episodes in bipolar disorder, patients who responded to Ketylept® Retard during acute treatment should continue taking Ketylept® Retard at bedtime at the same dose. The dose of Ketylept® Retard may be adjusted within the range of 300 mg to 800 mg/day, depending on the patient's clinical response and tolerability. It is important to use the lowest effective doses for maintenance therapy.
Adjunctive treatment of major depressive episodes in MDD
Ketylept® Retard should be taken at bedtime. The initial daily dose is 50 mg on days 1 and 2, and 150 mg on days 3 and 4. In short-term adjunctive trials (with amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine), antidepressant effects were observed at doses of 150 and 300 mg/day, and at 50 mg/day in a short-term monotherapy study. The risk of adverse reactions increases with higher doses. Therefore, the physician should ensure that the lowest effective dose is used for treatment, starting at 50 mg/day. Increasing the dose from 150 to 300 mg/day should be based on patient assessment.
Switching from immediate-release quetiapine tablets
Patients currently receiving immediate-release quetiapine tablets may be switched to Ketylept® Retard at an equivalent total daily dose administered once daily. A dose titration period may be necessary to maintain clinical response.
Elderly patients
As with other antipsychotics and antidepressants, Ketylept® Retard should be used with caution in elderly patients, particularly at the beginning of treatment and during dose titration. A slower dose titration of Ketylept® Retard may be required, and the daily therapeutic dose may be lower than that used in younger patients. The mean plasma clearance of quetiapine was reduced by 30–50% in elderly subjects compared to younger patients. Treatment in elderly patients should begin at a dose of 50 mg/day. The dose may be gradually increased by 50 mg/day to achieve an effective dose, depending on clinical response and tolerability. Elderly patients with depressive episodes in MDD should start at 50 mg/day on days 1–3, increasing to 100 mg/day on day 4 and 150 mg/day on day 8. The lowest effective dose, starting at 50 mg/day, should be used. If, based on patient assessment, dose increase to 300 mg/day is required, this should not occur earlier than 22 days of treatment.
The safety and efficacy of Ketylept® Retard in patients over 65 years of age with depressive episodes in bipolar disorder have not been studied.
Renal impairment
No dose adjustment is required for patients with renal impairment.
Hepatic impairment
Quetiapine is extensively metabolized in the liver. Therefore, Ketylept® Retard should be used with caution in patients with hepatic impairment, particularly during the initial dose titration period. Treatment in patients with hepatic impairment should begin at a dose of 50 mg/day. The dose may be increased in 50 mg/day increments to achieve an effective dose, depending on the patient's clinical response and tolerability.
Children
Ketylept® Retard is not recommended for use in children due to lack of data supporting its use in this age group.
Overdose
Symptoms
In general, signs and symptoms of overdose were due to the exaggeration of known pharmacological effects, 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 severe cardiovascular disease have an increased risk of overdose effects (see section "Special Warnings and Precautions for Use").
Management of overdose
Survival has been reported following acute overdose of up to 30 g of quetiapine. Most patients either experienced adverse events or fully recovered. A fatal outcome has been reported after ingestion of 13.6 g of quetiapine. During post-marketing use, reports of quetiapine overdose leading to fatal outcome, coma, or QT interval prolongation have been very rare. In addition, the following events have been reported in quetiapine overdose: QT interval prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium, and/or agitation.
Patients with severe cardiovascular disease are at increased risk of overdose effects (see section "Special Warnings and Precautions for Use").
In general, the reported symptoms were due to the enhancement of known pharmacological effects of the drug, such as somnolence and sedation, tachycardia, and hypotension. There is no specific antidote for quetiapine. In severe cases, appropriate supportive measures and intensive therapy should be considered, including restoration and maintenance of airway patency, adequate oxygenation and ventilation, and monitoring and support of cardiovascular function. Published reports describe resolution of serious central nervous system (CNS) reactions, including coma and delirium, following intravenous administration of physostigmine (1–2 mg) with ECG monitoring.
In cases of persistent hypotension following quetiapine overdose, appropriate measures such as intravenous fluid administration and/or use of sympathomimetics should be taken. Adrenaline (epinephrine) and dopamine should be avoided, as stimulation of beta-adrenergic receptors may worsen hypotension in the presence of alpha-adrenergic blockade induced by quetiapine.
Since prevention of absorption has not been studied in overdose, consideration should be given to gastric lavage (after intubation if the patient is unconscious) and administration of activated charcoal with a laxative. Close medical supervision and monitoring should continue until full recovery.
Formation of gastric bezoars has been reported in overdose with extended-release quetiapine—appropriate diagnostic imaging is recommended to determine further management strategy. In some cases, endoscopic removal of the pharmacobezoar has been successful. Standard gastric lavage may be ineffective in removing the pharmacobezoar due to the sticky nature of the mass.
Close medical supervision and monitoring should continue until full recovery of the patient.
Adverse reactions
The most frequently reported adverse reactions (≥ 10%) during quetiapine use are somnolence, dizziness, headache, dry mouth, withdrawal symptoms (upon discontinuation), increased serum triglyceride levels, increased total cholesterol levels (predominantly LDL-cholesterol), decreased HDL-cholesterol levels, weight gain, decreased hemoglobin levels, and extrapyramidal symptoms.
As with other antipsychotics, quetiapine use has also been associated with weight gain, syncope, neuroleptic malignant syndrome, leukopenia, and peripheral edema.
The frequency of occurrence of the adverse reactions listed below during quetiapine treatment (Table 1) is defined according to the following classification: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated from available data).
Table 1
| Very common |
Common |
Uncommon |
Rare |
Very rare |
Frequency not known |
|
| Blood and lymphatic system disorders |
Decreased hemoglobin levels22 |
Leukopenia1,28, decreased neutrophil count, elevated eosinophil levels28 |
Thrombocytopenia13, anemia, neutropenia1, decreased platelet count13 |
Agranulocytosis26 |
||
| Immune system disorders |
Hypersensitivity (including skin allergic reactions) |
Anaphylactic reaction5 |
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| Endocrine disorders |
Hyperprolactinemia15, decreased total T424, decreased free T424, decreased total T324, increased TSH24 |
Decreased free T324, hypothyroidism22 |
Inappropriate secretion of antidiuretic hormone |
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| Metabolism and nutrition disorders |
Increased serum triglyceride levels10,30, increased total cholesterol (especially LDL cholesterol)11,30, decreased HDL cholesterol17,30, weight gain8,30 |
Increased appetite, increased blood glucose levels up to hyperglycemia6,30 |
Hypoglycemia19, diabetes mellitus1,5, worsening of pre-existing diabetes |
Metabolic syndrome29 |
||
| Psychiatric disorders |
Unusual dreams and nightmares, suicidal thoughts and suicidal behavior20 |
Sleepwalking and related phenomena such as sleep talking and sleep-related eating disorders |
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| Nervous system disorders |
Dizziness4,16, somnolence2,1, headache, extrapyramidal symptoms1,21 |
Dysarthria |
Seizures1, restless legs syndrome, tardive dyskinesia1,5, syncope4,16 |
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| Cardiac disorders |
Tachycardia4, palpitations24 |
QT interval prolongation1,12,18, bradycardia32 |
Cardiomyopathy and myocarditis |
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| Respiratory, thoracic and mediastinal disorders |
Dyspnea23 |
Rhinitis |
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| Eye disorders |
Blurred vision |
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| Vascular disorders |
Orthostatic hypotension4,16 |
Vein thromboembolism1 |
Stroke33 |
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| Renal and urinary disorders |
Urinary retention |
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| Gastrointestinal disorders |
Dry mouth |
Constipation, dyspepsia, vomiting25 |
Dysphagia7 |
Pancreatitis1, intestinal obstruction / volvulus |
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| Hepatobiliary disorders |
Elevated serum alanine aminotransferase (ALT)3, elevated gamma-glutamyltransferase levels3 |
Elevated serum aspartate transaminase (AST)3 |
Jaundice5, hepatitis |
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| Skin and subcutaneous tissue disorders |
Angioedema5, Stevens-Johnson syndrome5 |
Toxic epidermal necrolysis, erythema multiforme, acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), cutaneous vasculitis |
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| Musculoskeletal and connective tissue disorders |
Rhabdomyolysis |
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| Pregnancy, postpartum and perinatal conditions |
Drug withdrawal syndrome in newborns31 |
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| Reproductive system and breast disorders |
Sexual dysfunction |
Priapism, galactorrhea, breast swelling, menstrual disorders |
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| General disorders and administration site conditions |
Withdrawal symptoms (after discontinuation)1,9 |
Mild asthenia, peripheral edema, irritability, pyrexia |
Malignant neuroleptic syndrome1, hypothermia |
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| Investigations |
Elevated blood creatine phosphokinase levels14 |
(1) See section "Special precautions".
(2) Somnolence may occur, usually during the first two weeks of treatment and typically resolves with continued use of quetiapine.
(3) Asymptomatic elevations (more than 3 times the upper limit of normal) in serum transaminases (ALT, AST) or gamma-glutamyl transferase were observed in some patients during quetiapine treatment. These elevations were usually reversible with continued quetiapine therapy.
(4) Like other antipsychotic agents with α1-adrenergic receptor blocking activity, quetiapine frequently may induce orthostatic hypotension accompanied by dizziness, tachycardia, and in some patients, syncope, particularly during the initial dose titration period (see section "Special precautions").
(5) The frequency of adverse reactions is based solely on post-marketing data from the use of quetiapine immediate-release formulation.
(6) Fasting blood glucose ≥ 126 mg/dL (≥ 7.0 mmol/L) or non-fasting 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 treatment.
(9) Withdrawal symptoms most commonly reported in short-term placebo-controlled monotherapy clinical trials evaluating withdrawal symptoms: insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability. The frequency of these reactions markedly decreased within 1 week after discontinuation of treatment.
(10) Triglycerides ≥ 200 mg/dL (≥ 2.258 mmol/L) (patients aged > 18 years) or ≥ 150 mg/dL (≥ 1.694 mmol/L) (patients aged < 18 years) at least once during an examination.
(11) Cholesterol ≥ 240 mg/dL (≥ 6.2064 mmol/L) (patients aged > 18 years) or ≥ 200 mg/dL (≥ 5.172 mmol/L) (patients aged < 18 years) at least once during an examination. Increases in LDL cholesterol > 30 mg/dL (0.769 mmol/L) were very common. The mean change among patients with increases was 41.7 mg/dL (≥ 1.07 mmol/L).
(12) See text below.
(13) Platelets < 100 × 10⁹/L at least once.
(14) Based on clinical trial reports of adverse reactions, elevations in blood creatine phosphokinase levels are not associated with neuroleptic malignant syndrome.
(15) Prolactin levels (patients aged > 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) QT interval change from < 450 ms to ≥ 450 ms with an increase of ≥ 30 ms. In placebo-controlled trials with quetiapine, the mean change and frequency of patients shifting to a clinically significant level were similar in quetiapine and placebo groups.
(19) Shift from > 132 mmol/L to ≤ 132 mmol/L at least once during an examination.
(20) Cases of suicidal ideation and suicidal behavior were reported during treatment with prolonged-release quetiapine or immediately after discontinuation of treatment.
(21) See section "Pharmacodynamics".
(22) Decrease in hemoglobin levels to ≤ 13 g/dL (8.07 mmol/L) in males, ≤ 12 g/dL (7.45 mmol/L) in females at least once during an examination was observed in 11% of patients receiving quetiapine across all studies, including open-label extension studies. For these patients, the mean maximum decrease in hemoglobin at any time was 1.5 g/dL.
(23) These events often occurred in the context of tachycardia, dizziness, orthostatic hypotension, and/or underlying cardiac/respiratory disease.
(24) Based on deviation from normal baseline to potentially clinically significant value at any time after baseline in all studies. Deviations in total T4, free T4, total T3, and free T3 were < 0.8 × ULN (pmol/L); deviations in TSH were > 5 mIU/L at any time.
(25) Based on increased frequency of vomiting in elderly patients (≥ 65 years).
(26) Based on deviations in neutrophil count from ≥ 1.5 × 10⁹/L at baseline to < 0.5 × 10⁹/L at any time during treatment and on clinical trial data regarding patients with severe neutropenia (< 0.5 × 10⁹/L) and infection during the entire quetiapine treatment period.
(27) Based on deviations from normal baseline to potentially clinically significant value at any time in all studies. Deviation in eosinophil count was > 1 × 10⁹ cells/L at any time.
(28) Based on deviations from normal baseline to potentially clinically significant value at any time in all studies. Deviation in leukocyte count was ≤ 3 × 10⁹ cells/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 exhibited worsening of several metabolic factors negatively affecting body weight, blood glucose, and lipids.
(31) See section "Special precautions".
(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 prolonged QT interval, ventricular arrhythmia, sudden unexplained death, cardiac arrest, and torsade de pointes-type arrhythmia have been reported during treatment with neuroleptic medicinal products. These reactions are considered to be class-specific for this group of drugs.
Serious skin adverse reactions have been reported with quetiapine treatment, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).
Paediatric population
The adverse reactions listed above observed in adults also occur in children and adolescents.
Table 2 below summarizes adverse reactions with higher frequency in paediatric and adolescent patients (10–17 years) or those not observed in adult patients.
Adverse reactions are listed according to frequency.
Table 2
| Organ systems |
Very common (≥ 1/10) |
Common (≥ 1/100, <1/10) |
| Endocrine system |
Increased prolactin levels1 |
|
| Metabolism and nutrition |
Increased appetite |
|
| Nervous system |
Extrapyramidal symptoms3,4 |
Syncope |
| Respiratory, thoracic and mediastinal organs |
Rhinitis |
|
| Gastrointestinal tract |
Vomiting |
|
| General disorders and administration site reactions |
Agitation3 |
|
| Vascular system |
Increased blood pressure2 |
- 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 elevated > 100 µg/L.
- Based on deviations above clinically significant thresholds (adapted from criteria established by the U.S. National Institutes of Health) or increases > 20 mmHg in systolic or > 10 mmHg in diastolic blood pressure at any time, derived from short-term (3–6 weeks) placebo-controlled studies in children and adolescents.
- Frequency corresponds to that observed in adults; however, irritability may present with different clinical manifestations in children and adolescents compared to adults.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions. Store at temperatures not exceeding 30 °C. Keep out of reach of children.
Packaging. 10 tablets per blister. 6 blisters per cardboard package.
Prescription classification. Prescription only.
Manufacturer.
- Egis Pharmaceuticals PLC, Hungary.
- FARMATEN S.A., Greece.
- FARMATEN INTERNATIONAL S.A., Greece.
Manufacturer's address and site of operations.
- 118-120 Bekényföldi Street, Budapest 1165, Hungary.
- Dervenakion 6, Pallini Attica 15351, Greece.
- Industrial Park Sapes, Prefecture of Rodopi, Block No. 5, Rodopi 69300, Greece.