Instructions Ketilept film-coated tablets 200 mg bottle No. 30
Composition
active ingredient: quetiapine;
1 tablet contains 28.78 mg, 115.13 mg and 230.26 mg of quetiapine fumarate, corresponding to 25 mg, or 100 mg or 200 mg of quetiapine;
excipients: microcrystalline cellulose, lactose monohydrate, sodium starch glycolate (type A), povidone, magnesium stearate, colloidal anhydrous silicon dioxide;
shell composition: Opadry II 33G28523 white (hypromellose, titanium dioxide (E 171), lactose monohydrate, macrogol, triacetin); Opadry II 33G24283 pink (for 200 mg tablets) (hypromellose, titanium dioxide (E 171), lactose monohydrate, macrogol, triacetin, red iron oxide (E 172), yellow iron oxide (E 172)).
Dosage form
Film-coated tablets.
Main physicochemical properties:
25 mg tablets: white or almost white, round biconvex tablets, film-coated, engraved with the stylized letter “E” on one side and the number “201” on the other side of the tablet, odorless or almost odorless;
100 mg tablets: white or almost white, round biconvex tablets, film-coated, engraved with the stylized letter “E” and the number “202” on one side of the tablet, odorless or almost odorless;
200 mg tablets: dark pink, round, biconvex, film-coated tablets, engraved with a stylized letter “E” and the number “204” on one side of the tablet, odorless or almost odorless.
Pharmacotherapeutic group
Antipsychotics. Quetiapine. ATC code. N05A H04.
Pharmacological properties
Mechanism of action.
Quetiapine is an atypical antipsychotic drug that antagonizes brain neurotransmitter receptors. Quetiapine and the active human plasma metabolite norquetiapine interact with different types of neurotransmitter receptors.
Quetiapine and norquetiapine have affinity for serotonin (5HT1A and 5HT2), dopamine (D1 and D2), histamine (H1) and adrenergic (α1 and α2) receptors; it has a higher affinity for 5HT2 receptors than for D1 and D2 receptors. It is this combination of receptor antagonism with greater selectivity for 5HT2 receptors over D2 receptors that is thought to contribute to the clinical antipsychotic effects and low propensity for extrapyramidal side effects of Quetiapine compared to typical antipsychotics.
Quetiapine and norquetiapine also have high affinity for histaminergic (H1) and α1-adrenergic receptors, lower affinity for α2 receptors, but no appreciable affinity for muscarinic cholinergic or benzodiazepine receptors, whereas norquetiapine has moderate to high affinity for several muscarinic receptor subtypes, which may account for its anticholinergic (muscarinic) effects.
Norquetiapine (NET) inhibition, as well as partial agonist action at 5HT1A receptors, may contribute to the therapeutic efficacy of Ketilept® as an antidepressant.
The mechanism of action of quetiapine, like other antipsychotics, is unknown.
The drowsiness caused by quetiapine can be explained by its high affinity for histamine (H1) receptors.
Similarly, orthostatic hypotension during quetiapine administration may be explained by its high affinity for α1-adrenergic receptors.
Pharmacodynamics.
Quetiapine is known to be active in tests of antipsychotic activity, such as conditioned avoidance.
Quetiapine blocks the agonistic effect on dopamine, as confirmed by the results of behavioral or electrophysiological studies, and also increases the concentration of dopamine metabolites, a neurochemical expression of D2 receptor blockade.
It is known that in preclinical studies, during which the tendency to develop extrapyramidal symptoms was tested, quetiapine had an atypical activity profile and differed from standard antipsychotic drugs.
Quetiapine did not lead to excessive sensitivity of dopamine D2 receptors after long-term use.
It is known that quetiapine, at doses effective for dopamine D2 receptor blockade, caused only mild catalepsy.
Quetiapine has been shown to be selective for the limbic system after chronic administration, as demonstrated by its ability to block depolarization in A10 mesolimbic neurons, but not in A9 nigrostriatal neurons, which contain dopamine.
Clinical safety
It is known that treatment with quetiapine may cause a decrease in thyroid hormone levels, and this effect is dose-dependent.
Cataract
It is known that in a clinical trial evaluating the cataractogenic potential of quetiapine (200-800 mg/day) versus risperidone (2-8 mg/day) in patients with schizophrenia or schizoaffective disorder, the percentage of patients with increased lens opacity was not higher in the group of patients taking quetiapine (4%) compared to those receiving risperidone (10%) when using the drug for at least 21 months.
There is evidence that in placebo-controlled studies in elderly patients with dementia-related psychosis, the incidence of cardiovascular adverse events per 100 patient-years in the quetiapine group was no higher than in patients receiving placebo.
Pharmacokinetics.
After oral administration, quetiapine is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations are achieved within 1.5 hours. Food intake affects the bioavailability of quetiapine.
At steady state, the maximum molar concentration of the active metabolite norquetiapine is 35% of the concentration of quetiapine.
The pharmacokinetics of quetiapine and norquetiapine are linear within the approved dose range.
Distribution
Approximately 83% of the drug is bound to plasma proteins.
Metabolism
Quetiapine is extensively metabolized in the liver; the main routes of its biotransformation are sulfoxidation and oxidation. The use of radiolabeled quetiapine has shown that less than 5% of quetiapine is not metabolized and is excreted unchanged in the urine or feces.
In vitro studies have shown that the major enzyme involved in the cytochrome P450-mediated metabolism of quetiapine is CYP3A4. The major metabolites formed in the body do not have significant pharmacological activity.
Breeding
Clinical studies have shown that quetiapine is effective when administered twice daily. Although quetiapine has a half-life of almost 7 hours, positron emission tomography (PET) data show that 5HT2 and D2 receptor occupancy is maintained for up to 12 hours after a single dose of quetiapine.
Following a single oral dose of 14C-labeled quetiapine, less than 5% of the administered dose is excreted unchanged, indicating that quetiapine is extensively metabolized in the liver. Approximately 73% of the radiolabel is excreted in the urine and 21% in the feces.
Special populations.
Sex
The pharmacokinetics of quetiapine do not differ between women and men.
The pharmacokinetics of quetiapine are linear in the therapeutic dose range and are not significantly affected by gender or race.
Elderly patients
In elderly subjects, the mean clearance of quetiapine is approximately 30-50% lower than in adult patients aged 18-65 years.
Patients with renal impairment
In severe renal insufficiency (creatinine clearance less than 30 ml/min per 1.73 m2) and hepatic insufficiency (alcoholic cirrhosis), the average plasma clearance of quetiapine is reduced by approximately 25%.
Patients with hepatic impairment
In patients with liver damage (compensated alcoholic cirrhosis), the average plasma clearance of quetiapine is reduced by approximately 25%. Since quetiapine is extensively metabolized in the liver, plasma concentrations of quetiapine may be increased in patients with impaired liver function, and therefore dose adjustment may be required for this group of patients (see section 4.2).
Children
Pharmacokinetic data are available in children receiving 400 mg quetiapine twice daily. At therapeutic doses, quetiapine parent compound levels in children and adolescents (10–17 years) were generally similar to those in adults, although Cmax was higher in children than in adults. The AUC and Cmax for norquetiapine were higher, approximately 62% and 49% in children (10–12 years), and 28% and 14% in adolescents (13–17 years), respectively, compared to adults.
Indication
Treatment of schizophrenia.
Treatment of bipolar disorder, including:
moderate to severe manic episodes associated with bipolar disorder;
major depressive episodes associated with bipolar disorder.
Prevention of relapse in patients with bipolar disorder whose manic episodes were treated with quetiapine.
Contraindication
Hypersensitivity to any of the components of the drug;
concomitant use of cytochrome P450 3A4 inhibitors, such as HIV protease inhibitors, azole antifungals, erythromycin, clarithromycin and nefazodone (see section "Interaction with other medicinal products and other types of interactions").
Interaction with other medicinal products and other types of interactions
Given that quetiapine primarily acts on the central nervous system, Ketilept® should be used with caution in combination with other drugs with similar effects and with alcohol.
Quetiapine should be used with caution with serotonergic drugs such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs) or tricyclic antidepressants, as the risk of developing serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4).
The drug should be prescribed with caution to patients receiving other drugs with anticholinergic (muscarinic) effects (see section "Special instructions").
Cytochrome P450 (CYP) 3A4 is the enzyme primarily responsible for the metabolism of quetiapine. In an interaction study in healthy volunteers, co-administration of quetiapine (25 mg) with ketoconazole (a CYP 3A4 inhibitor) resulted in an increase in AUC
In a multiple-dose study to evaluate the pharmacokinetics of quetiapine administered before and during treatment with carbamazepine (a hepatic enzyme inducer), concomitant use of carbamazepine significantly increased quetiapine clearance. This increase in clearance reduced systemic exposure to quetiapine (as measured by AUC) to a level that was on average 13% of that seen with quetiapine alone, although some patients had a greater effect. This interaction may result in lower plasma concentrations, which may affect the efficacy of Ketilept® therapy. Concomitant use of quetiapine and phenytoin (another microsomal enzyme inducer) resulted in an increase in quetiapine clearance of approximately 450%. Ketilept® therapy should only be initiated in patients receiving a hepatic enzyme inducer if the physician considers that the benefits of Ketilept® outweigh the risks associated with discontinuation of the hepatic enzyme inducer. It is important that any changes in the dose of the inducer should be gradual. If necessary, it should be replaced by 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 use of antidepressants such as imipramine (a known CYP 2D6 inhibitor) or fluoxetine (a known CYP 3A4 and CYP 2D6 inhibitor).
The pharmacokinetics of quetiapine are not significantly altered by co-administration with risperidone or haloperidol. Co-administration of quetiapine and thioridazine results in an increase in quetiapine clearance by approximately 70%.
The pharmacokinetics of quetiapine were not altered when co-administered with cimetidine.
The pharmacokinetics of lithium were not altered when co-administered with quetiapine.
There is evidence that in a 6-week randomized trial comparing the combination of lithium with quetiapine and placebo with quetiapine in adult patients with acute mania, an increased incidence of extrapyramidal events (especially tremor), somnolence, and weight gain was observed in the lithium-added group compared to the placebo-added group.
There were no clinically significant changes in the pharmacokinetics of sodium valproate and quetiapine when co-administered. In a retrospective study of children and adolescents receiving sodium valproate, quetiapine, or a combination of these drugs, an increase in the incidence of leukopenia and neutropenia was observed in the group receiving both drugs compared to the groups receiving these drugs separately.
No interaction studies with cardiovascular drugs have been conducted.
Caution should be exercised when administering quetiapine concomitantly with drugs that disrupt electrolyte balance or prolong the QT interval.
Cases of false-positive enzyme immunoassay results for methadone and tricyclic antidepressants have been reported in patients taking quetiapine. It is recommended that equivocal screening immunoassay results be verified by an appropriate chromatographic method.
Application features
Since Ketilept® is indicated for the treatment of schizophrenia, bipolar disorder and concomitant treatment of depressive episodes in patients with MDD, the safety profile of the drug should be carefully considered in light of the individual patient's diagnosis and the dose being taken.
Children
Quetiapine is not recommended for use in children and adolescents under 18 years of age due to the lack of data to support its use in this age group. Clinical trials of quetiapine have shown that, in addition to the known safety profile established in adults (see section 4.8), the frequency of some adverse events is higher in children than in adults (increased appetite, increased serum prolactin levels and extrapyramidal symptoms), and one event not previously observed in studies involving adult patients (increased blood pressure) has also been identified. In addition, changes in thyroid function tests have been observed in children and adolescents.
It should also be noted that the delayed effects of Ketilept® treatment on growth and puberty have not been studied beyond 26 weeks. The long-term effects on cognitive and behavioral development are unknown.
In placebo-controlled clinical trials in children and adolescents, quetiapine treatment was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia and bipolar mania (see section 4.8).
Suicide/suicidal thoughts or clinical worsening
In addition, the potential risk of suicide-related events following abrupt discontinuation of quetiapine should be considered due to known risk factors for the condition being treated.
Other psychiatric conditions for which Ketilept® is prescribed may also be associated with an increased risk of suicide-related events. In addition, these conditions may occur concurrently with depressive episodes.
When treating patients with other psychiatric disorders, the same precautions should be taken as when treating patients with severe depressive episodes.
Patients with a history of suicide-related events or who demonstrate a significant level of suicidal ideation prior to initiation of therapy are 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 antidepressants in adult patients with psychiatric disorders has shown an increased risk of suicidal behavior in patients under 25 years of age.
Close monitoring of patients, particularly those at high risk, should accompany drug therapy, especially at the beginning of treatment and during subsequent dose changes. Patients (and caregivers of patients) should be advised to monitor for clinical worsening, suicidal behaviour or thoughts, and unusual changes in behaviour and to seek medical advice immediately if symptoms develop.
In short-term placebo-controlled studies in patients with major depressive episodes in bipolar disorder, an increased risk of suicide-related events was observed in young patients (under 25 years of age) treated with quetiapine compared to those treated with placebo (3.0% vs. 0%, respectively).
Extrapyramidal symptoms
In placebo-controlled trials, quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major depressive episodes associated with bipolar disorder and major depressive disorder (see section 4.8).
Quetiapine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still. These events are more likely to occur during the first few weeks of treatment. Increasing the dose in patients who develop these symptoms may be harmful to them.
Tardive dyskinesia
If signs and symptoms of tardive dyskinesia appear, consideration should be given to reducing the dose or discontinuing Ketilept®. Symptoms of tardive dyskinesia may worsen and even recur after discontinuation of therapy (see section 4.8).
Drowsiness and dizziness
Quetiapine treatment has been associated with somnolence and related symptoms such as sedation (see section 4.8). In clinical trials in patients with bipolar depression, these symptoms typically occurred within the first 3 days of treatment and were mostly mild to moderate in intensity. For patients with bipolar depression and patients with depressive episodes in MDD who develop somnolence, observation may be necessary for 2 weeks after the onset of somnolence or until symptoms resolve, or discontinuation of treatment may be considered.
Orthostatic hypotension
Quetiapine treatment has been associated with orthostatic hypotension and associated dizziness in some patients (see section 4.8), which, like somnolence, usually occurs during the dose titration period. These events may contribute to an increased incidence of accidental injury (falls), particularly in the elderly. Therefore, patients should be advised to exercise caution until they are familiar with the possible effects of the medicinal product.
Sleep apnea syndrome
There have been reports of sleep apnea syndrome in patients taking quetiapine, therefore, Ketilept® should be used with caution in overweight/obese patients, male patients, and patients receiving concomitant antidepressant therapy.
Cardiovascular diseases
Ketilept® should be used with caution in patients with known cardiovascular and cerebrovascular diseases or other conditions that may lead to arterial hypotension.
Quetiapine may cause orthostatic hypotension, especially at the beginning of dose titration, therefore, in such cases, a dose reduction or longer titration is necessary.
Cardiomyopathy and myocarditis
Cardiomyopathy and myocarditis have been reported in clinical trials and during post-marketing surveillance (see section 4.8). If cardiomyopathy or myocarditis is suspected in a patient, discontinuation of quetiapine should be considered.
There was no difference in the incidence of seizures between patients taking quetiapine and those taking placebo in the studies. There are no data on the incidence of seizures in patients with a history of epilepsy. As with other antipsychotics, caution is recommended when prescribing the drug to patients with a history of seizures (see section "Adverse reactions").
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome may be associated with treatment with antipsychotics, including quetiapine. Clinical manifestations include hyperthermia, altered mental status, muscle rigidity, autonomic instability, and elevated creatine phosphokinase levels. In such cases, Ketilept® should be discontinued and appropriate treatment initiated.
Serotonin syndrome
Concomitant use of Ketilept® and other serotonergic drugs, such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and 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 types of interactions”).
If concomitant treatment with other serotonergic drugs is clinically warranted, close monitoring of the patient is recommended, especially at the beginning of treatment and when the dose is increased. Symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular disorders and/or gastrointestinal symptoms.
If serotonin syndrome is suspected, dose reduction or discontinuation of therapy should be considered, depending on the severity of symptoms.
Severe neutropenia and agranulocytosis
Severe neutropenia (neutrophil count <0.5x109/L) was uncommonly observed in clinical trials with quetiapine. Agranulocytosis (severe neutropenia with infection) has been reported rarely in patients treated with quetiapine in clinical trials and in the post-marketing setting (including fatal cases). The majority of cases of severe neutropenia occurred within two months of initiating quetiapine therapy. No clear dose relationship was established. During the post-marketing period, recovery of leukopenia and/or neutropenia occurred after discontinuation of quetiapine. Possible risk factors for neutropenia include pre-existing low white blood cell (WBC) counts and a history of drug-induced neutropenia. However, some cases have occurred in patients without pre-existing risk factors. It is recommended to discontinue quetiapine treatment if the blood neutrophil count falls below 1.0 x 109/l. Signs and symptoms of infection should be monitored and neutrophil counts should be monitored until they exceed <1.5 x 109/l (see section 4.8).
The possibility of neutropenia in patients with an existing infection despite the absence of risk factors, as well as in patients with fever of unknown origin, should be considered and appropriate clinical measures should be taken.
Patients should be advised to report promptly any signs/symptoms suggestive of agranulocytosis or infection (such as fever, malaise, lethargy, or sore throat) at any time during treatment with Ketilept®. These patients should have a WBC count and absolute neutrophil count (ANC) performed promptly, especially in the absence of predisposing factors.
Anticholinergic (muscarinic) syndrome
Norquetiapine, the active metabolite of quetiapine, has moderate to high affinity for several subtypes of muscarinic receptors, which may explain the anticholinergic (muscarinic) syndrome. This contributes to the occurrence of adverse reactions reflecting anticholinergic effects when quetiapine is used concomitantly with other drugs that have anticholinergic effects in overdose. Quetiapine should be used with caution in patients receiving drugs that have anticholinergic (muscarinic) effects. Quetiapine should be used with caution in patients with urinary retention, significant prostatic hypertrophy, intestinal obstruction, increased intraocular pressure or narrow-angle glaucoma (see sections “Interaction with other medicinal products and other forms of interaction”, “Adverse reactions”, “Pharmacodynamic properties”, “Overdose”).
Interactions
See also section “Interaction with other medicinal products and other types of interactions”.
Concomitant use of quetiapine with a potent hepatic enzyme inducer such as carbamazepine or phenytoin significantly reduces quetiapine plasma concentrations, which may impair the efficacy of quetiapine therapy. Treatment with Ketilept® in patients receiving a hepatic enzyme inducer should only be initiated if the physician considers that the benefits of using Ketilept® outweigh the risks of withdrawing the hepatic enzyme inducer. It is important that any changes in the use of the inducer are gradual. If necessary, it should be replaced by a non-inducer (e.g. sodium valproate).
Weight gain has been reported during treatment with quetiapine, which should be monitored and managed clinically when using antipsychotic medications.
Hyperglycemia
Hyperglycaemia and/or development or exacerbation of diabetes mellitus have occasionally been associated with ketoacidosis or coma, which have been reported rarely, including a few cases with fatal outcomes (see section 4.8). A few cases have been reported with a prior increase in body weight, which may be a contributing factor. Appropriate clinical monitoring is advisable in accordance with existing guidelines for the use of antipsychotics. Patients treated with any antipsychotic medicinal product, including quetiapine, should be observed for signs and symptoms of hyperglycaemia (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 glucose control. Weight should be monitored regularly.
Lipids
Increases in triglycerides, LDL-C and total cholesterol, and decreases in HDL-C have been observed in clinical trials with quetiapine (see section 4.8). If lipid levels change, appropriate treatment should be administered.
Metabolic risk
Given the identified risk of worsening of the metabolic profile, including changes in body weight, glucose levels (see "Hyperglycemia") and blood lipids, observed during clinical studies, it is necessary to assess the patient's metabolic parameters at the beginning of treatment and monitor changes in these parameters regularly during the course of treatment. Deterioration of these parameters should be corrected taking into account clinical feasibility.
QT prolongation
In clinical trials and when used according to the Instructions for Medical Use, quetiapine did not cause a sustained increase in absolute QT intervals. However, prolongation of the QT interval has been observed with overdose. As with other antipsychotics, caution should be exercised when prescribing quetiapine to patients with cardiovascular disease or a family history of prolonged QT. Caution should also be exercised when prescribing quetiapine with other drugs known to prolong the QT interval or when used concomitantly with neuroleptics, especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalemia or hypomagnesemia (see section "Interaction with other drugs").
Cardiomyopathy and myocarditis
Cardiomyopathy and myocarditis have been reported in clinical trials and during the post-marketing period, however, a causal relationship to quetiapine has not been established. The use of quetiapine in patients with suspected cardiomyopathy or myocarditis should be re-evaluated.
Severe skin adverse reactions
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported very rarely with quetiapine. SCARs typically present as a combination of the following symptoms: widespread skin rash or exfoliative dermatitis, fever, lymphadenopathy, and possible eosinophilia. If signs and symptoms suggestive of these severe cutaneous reactions occur, quetiapine should be discontinued immediately and alternative treatment considered.
Discontinuation of the drug
Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhoea, vomiting, dizziness and irritability have been reported following abrupt discontinuation of quetiapine. Therefore, gradual withdrawal over a period of at least one to two weeks is recommended (see section 4.8).
Elderly patients with Parkinson's disease (XII)/parkinsonism
A large retrospective analysis of quetiapine in patients with PD showed an increased risk of death with quetiapine in patients >65 years of age. This finding was not confirmed when data from patients with Parkinson's disease were excluded from the analysis. Caution should be exercised when quetiapine is prescribed to elderly patients with PD.
Ketilept® is not recommended for the treatment of psychosis associated with dementia.
A meta-analysis of atypical antipsychotics has shown that elderly patients with dementia-related psychosis are at increased risk of death compared with placebo. However, in two 10-week placebo-controlled trials of quetiapine in the same population (n=710, mean age 83 years, range 56-99 years), the mortality rate in quetiapine-treated patients was 5.5% compared with 3.2% in the placebo group. Mortality in the studies was due to a variety of causes, as expected for this patient population. These data do not establish a causal relationship between quetiapine treatment and mortality in patients with dementia.
Dysphagia
Dysphagia has been reported with quetiapine. Quetiapine should be used with caution in patients at risk of aspiration pneumonia (see section 4.8).
Constipation and intestinal obstruction
Constipation is a risk factor for intestinal obstruction. Cases of constipation and intestinal obstruction have been reported with quetiapine (see section 4.8). These reports include fatal cases in patients at increased risk of intestinal obstruction, including those receiving concomitant medications that reduce intestinal motility and/or medications that may not have been reported to cause symptoms of constipation.
Venous thromboembolism (VTE)
Cases of venous thromboembolism (VTE) have been reported with the use of neuroleptics. Since patients taking neuroleptics often have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with quetiapine and preventive measures should be taken.
Pancreatitis
Cases of pancreatitis have been reported in clinical trials and during post-marketing use, but a causal relationship has not been established. In the post-marketing reports, many patients had factors known to be associated with pancreatitis, such as increased triglycerides (see section 4.4, sub-section Lipids), gallstones and alcohol consumption.
Additional information
Data on the use of quetiapine in combination with divalproex or lithium in moderate to severe manic episodes are limited; however, the combination therapy was well tolerated (see sections 4.8 and 5.1). These data showed an additive effect by the third week of treatment.
Lactose
Ketilept® tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Ketilept® 25 mg contains 4 mg of lactose monohydrate in 1 tablet.
Ketilept® 100 mg contains 16 mg of lactose monohydrate in 1 tablet.
Ketilept® 200 mg contains 32 mg of lactose monohydrate in 1 tablet.
Misuse and abuse
Cases of misuse and abuse have been reported. Quetiapine should be prescribed with caution to patients with a history of alcohol or drug abuse.
Use during pregnancy or breastfeeding
Pregnancy
First trimester
The safety and efficacy of quetiapine in pregnant women have not been established. There is currently no evidence of adverse effects in animal studies. The potential effects on fetal vision have not been studied. Neonatal withdrawal symptoms have been reported in newborns from several pregnancies exposed to quetiapine. Therefore, Ketilept® should be used during pregnancy only if the potential benefit justifies the potential risk. Withdrawal symptoms have been observed in newborns whose mothers took quetiapine during pregnancy.
Third trimester
Newborns whose mothers took antipsychotic drugs (including quetiapine) in the third trimester are at risk of developing
