1. Name Of The Medicinal Product
Quetiapine 25 mg Film-coated Tablets
2. Qualitative And Quantitative Composition
Each film-coated tablet contains 25 mg (as quetiapine hemifumarate).
Excipient (s):
Each 25 mg film-coated tablet contains 13.300 mg lactose monohydrate.
For a full list of excipients, see section 6.1
3. Pharmaceutical Form
Film-coated tablet
25mg tablets are pink coloured, round, biconvex, film-coated tablet, plain on both sides.
4. Clinical Particulars
4.1 Therapeutic Indications
Quetiapine tablet is indicated for the treatment of:
• Schizophrenia.
• Bipolar disorder, including:
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4.2 Posology And Method Of Administration
Quetiapine tablets can be administered, with or without food.
Adults
For the treatment of schizophrenia: Quetiapine tablets should be administered twice a daily. The total daily dose for the first 4 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 range 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 tablets should be administered twice a 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 per day by Day 6 should be in increments of no greater than 200 mg per day.
The dose may be adjusted depending on clinical response and tolerability of the individual patient, within the range of 200 to 800 mg per day. The usual effective dose is in the range of 400 to 800 mg per day.
For the treatment of depressive episodes in bipolar disorder: Quetiapine tablets 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 (see section 5.1). Individual patients may benefit from a 600 mg dose. 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. When treating depressive episodes in bipolar disorder, treatment should be initiated by physicians experienced in treating bipolar disorder.
For preventing recurrence in bipolar disorder: For prevention of recurrence of manic, depressive and mixed 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 may then be adjusted depending on clinical response and tolerability of the individual patient, within the range of 300 to 800 mg/day administered twice daily. It is important that the lowest effective dose is used for maintenance therapy.
Elderly
As with other antipsychotics, quetiapine tablets 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
Children and adolescents
Quetiapine tablets is not recommended for use in children and adolescents below 18 years of age, due to a lack of data to support use in this age group. The available evidence from placebo-controlled clinical trials is presented in sections 4.4, 4.8, 5.1 and 5.2
Renal impairment
Dosage adjustment is not necessary in patients with renal impairment.
Hepatic impairment
Quetiapine is extensively metabolised by the liver. Therefore, Quetiapine should be used with caution in patients with known hepatic impairment, especially during the initial dosing period. Patients with 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.
4.3 Contraindications
Quetiapine tablet is contra-indicated in patients who are hypersensitive to the active substance or to any of the excipients of this product.
Concomitant administration of cytochrome P450 3A4 inhibitors, such as HIV-protease inhibitors, azole-antifungal agents, erythromycin, clarithromycin and nefazodone, is contraindicated. (See also section 4.5).
4.4 Special Warnings And Precautions For Use
Children and adolescents (10 to 17 years of age)
Quetiapine tablet is not recommended for use in children and adolescents below 18 years of age, due to a lack of data to support use in this age group. Clinical trials have shown that in addition to the known safety profile identified in adults (see section 4.8 Undesirable effects), certain adverse events occurred at a higher frequency in children and adolescents compared to adults (increased appetite, elevations in serum prolactin, and extrapyramidal symptoms) 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 long-term safety implications of treatment on growth and maturation have not been studied beyond 26 weeks. Long-term implications for cognitive and behavioural development are not known.
In placebo-controlled clinical trials with children and adolescent patients, quetiapine 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 Undesirable effects).
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. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
In clinical studies of patients with major depressive episodes in bipolar disorder an increased risk of suicide-related events was observed in young adult patients less than 25 years of age who were treated with quetiapine as compared to those treated with placebo (3.0% vs. 0%, respectively).
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.
Somnolence
Quetiapine treatment has been associated with somnolence and related symptoms, such as sedation (see Section 4.8 Undesirable effects). In clinical trials for treatment of patients with bipolar depression, onset was usually within the first 3 days of treatment and was predominantly of mild to moderate intensity. Bipolar depression 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.
Cardiovascular disease
Quetiapine tablets should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension.
Quetiapine may induce orthostatic hypotension, especially during the initial dose-titration period. Dose reduction or more gradual titration should be considered if this occurs.
Seizures
In controlled clinical trials there was no difference in the incidence of seizures in patients treated with quetiapine or placebo. As with other antipsychotics, caution is recommended when treating patients with a history of seizures (see section 4.8 Undesirable effects).
Extrapyramidal symptoms
In placebo controlled clinical trials of 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 (see Section 4.8 Undesirable effects).
Tardive dyskinesia
Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic drugs including quetiapine. If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of quetiapine tablets should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment (see section 4.8 Undesirable effects).
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including quetiapine (see Section 4.8 Undesirable effects). 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
Severe neutropenia (neutrophil count <0.5 X 109/L) has been uncommonly reported in quetiapine tablets clinical trials. Most cases of severe neutropenia have occurred within a couple of months of starting therapy with quetiapine tablets. There is no apparent dose relationship. During post-marketing experience, resolution of leucopenia and/or neutropenia has followed cessation of therapy with quetiapine tablets. Possible risk factors for neutropenia include pre-existing low white cell count (WBC) and history of drug induced neutropenia. Quetiapine should be discontinued in patients with a neutrophil count <1.0 X 109/L. Patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 X 109/L). (See Section 5.1 Pharmacodynamic properties).
Interactions
See also Section 4.5 Interactions with other medicinal products and other forms of interaction.
Concomitant use of quetiapine with a strong hepatic enzyme inducer such as carbamazepine or phenytoin 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 removing 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).
Hyperglycaemia
Hyperglycaemia or exacerbation of pre-existing diabetes has been reported during treatment with quetiapine. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus (see also Section 4.8 Undesirable effects).
Lipids
Increases in triglycerides, LDL and total cholesterol, and decreases in HDL cholesterol have been observed in clinical trials with quetiapine (see Section 4.8 Undesirable effects). Lipid changes should be managed as clinically appropriate.
Metabolic Risk
Given the observed changes in weight, blood glucose (see hyperglycemia) and lipids seen in clinical studies, there may be possible worsening of the metabolic risk profile in individual patients, which should be managed as clinically appropriate (see also section 4.8).
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 (see Section 4.8) and in overdose (see Section 4.9). As with other antipsychotics, caution should be exercised when quetiapine is prescribed in patients with cardiovascular disease or family history of QT prolongation. Also, caution should be exercised when quetiapine is prescribed with medicines known to increase QTc interval, and concomitant neuroleptics, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia (see Section 4.5 Interaction with other medicinal products and other forms of interaction).
Acute Withdrawal reactions
Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and irritability have been described after abrupt cessation of quetiapine. Gradual withdrawal over a period of at least one to two weeks is advisable. (see section 4.8)
Elderly patients with dementia-related psychosis
Quetiapine is not approved for the treatment of patients with dementia-related psychosis.
An approximately 3-fold increased risk of cerebrovascular adverse events have been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. 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 risk factors for stroke.
In a meta-analysis of atypical antipsychotic drugs, it has been reported that elderly patients with dementia-related psychosis are at an increased risk of death compared to placebo. However 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 of a variety of causes that were consistent with expectations for this population. These data do not establish a causal relationship between quetiapine treatment and death in elderly patients with dementia.
Dysphagia
Dysphagia (see Section 4.8 Undesirable effects) has been reported with quetiapine. Quetiapine should be used with caution in patients at risk for aspiration pneumonia.
Venous thromboembolism
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with quetiapine and preventive measures undertaken.
Lactose
Quetiapine tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Additional information
Quetiapine data in combination with divalproex or lithium in acute moderate to severe manic episodes is limited; however, combination therapy was well tolerated (see section 4.8 Undesirable effects and 5.1 Pharmacodynamic properties). The data showed an additive effect at week 3
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Given the primary central nervous system effects of quetiapine, quetiapine should be used with caution in combination with other centrally acting drugs and alcohol.
Cytochrome P450 (CYP) 3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. In an interaction study in 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 take quetiapine together with grapefruit juice.
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 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 tablets therapy. Co-administration of quetiapine and phenytoin (another microsomal enzyme inducer) caused a greatly increased clearance of quetiapine by approx. 450%. 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 removing 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 also section 4.4 Special warnings and special precautions for use).
The pharmacokinetics of quetiapine were not significantly altered following co-administration with the antidepressants imipramine (a known CYP2D6 inhibitor) or fluoxetine (a known CYP3A4 and CYP2D6 inhibitor).
The pharmacokinetics of quetiapine were not significantly altered following co-administration with the antipsychotics risperidone or haloperidol. However co-administration of quetiapine tablets and thioridazine caused increases in the clearance of quetiapine by approx. 70%.
The pharmacokinetics of quetiapine were not altered following co-administration with cimetidine, a known P450 enzyme inhibitor.
The pharmacokinetics of lithium were not altered when co-administered with quetiapine tablets
The pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically relevant extent when co-administered.
Formal interaction studies with commonly used cardiovascular drugs have not been performed.
Caution should be exercised when quetiapine is used concomitantly with drugs known to cause electrolyte imbalance or to increase QTc interval.
4.6 Pregnancy And Lactation
The safety and efficacy of quetiapine tablets during human pregnancy have not been established. Up to now there are no indications for harmfulness in animal tests, possible effects on the foetal eye have not been examined, though. Therefore, quetiapine tablets should only be used during pregnancy if the benefits justify the potential risks. Following pregnancies in which quetiapine was used, neonatal withdrawal symptoms were observed.
The degree to which quetiapine is excreted into human milk is unknown. Women who are breast-feeding should therefore be advised to avoid breast-feeding while taking quetiapine tablets.
4.7 Effects On Ability To Drive And Use Machines
Given its primary central nervous system effects, quetiapine may interfere with activities requiring mental alertness and may cause somnolence. Therefore, patients should be advised not to drive or operate machinery, until individual susceptibility to this is known.
4.8 Undesirable Effects
The most commonly reported Adverse Drug Reactions (ADRs) with quetiapine tablets are somnolence, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension, and dyspepsia.
As with other antipsychotics, syncope, neuroleptic malignant syndrome, leucopenia, neutropenia and peripheral edema, have been associated with quetiapine tablets.
The incidences of ADRs associated with quetiapine tablets therapy, are tabulated below according to the format recommended by the Council for International Organizations of Medical Sciences (CIOMS III Working Group; 1995).
The frequencies of adverse events are ranked according to the following:
Very common (
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(1) See section 4.4
(2) Somnolence may occur, usually during the first two weeks of treatment and generally resolves with the continued administration of quetiapine .
(3) Asymptomatic elevations in serum transaminase (ALT, AST) or gamma-GT-levels have been observed in some patients administered quetiapine.
(4) As with other antipsychotics with alpha1 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 4.4 Special warnings and special precautions for use).
(5) Exacerbation of pre-existing diabetes has been reported in very rare cases.
(6) Calculation of frequency for these ADRs have been taken from post-marketing data only.
(7) Fasting blood glucose
(8) An increase in the rate of dysphagia with quetiapine vs. placebo was only observed in the clinical trials in bipolar depression.
(9) Based on >7% increase in body weight from baseline. Occurs predominantly during the early weeks of treatment.
(10) The following withdrawal symptoms have been observed most frequently in acute placebo-controlled, monotherapy clinical trials, which evaluated discontinuation symptoms: insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and irritability. The incidence of these reactions had decreased significantly after 1 week post-discontinuation.
(11) Triglycerides
(12) Cholesterol
(13) See text below.
(14) Platelets 9/L on at least one occasion.
(15) Based on clinical trial adverse event reports of blood creatine phosphokinase increase not associated with neuroleptic malignant syndrome.
(16) Prolactin levels (patients >18 years of age): >20μg/L (>869.56pmol/L) males; >30μg/L (>1304.34pmol/L) females at any time.
(17) May lead to falls.
(18) HDL cholesterol: <40 mg/dL (1.025mmol/L) males; <50 mg/dL (1.282mmol/L) females at any time.
(19) Incidence of patients who have a QTc shift from <450 msec to
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 (see section 4.4).
In short-term, placebo-controlled clinical trials in bipolar depression the aggregated incidence of extrapyramidal symptoms was 8.9% for quetiapine compared to 3.8% for placebo, though the incidence of the individual adverse events (eg, akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity) were generally low and did not exceed 4% in any treatment group.
In short-term, placebo-controlled clinical trials in schizophrenia and bipolar mania the aggregated incidence of extrapyramidal symptoms was similar to placebo (schizophrenia: 7.8% for quetiapine and 8.0% for placebo; bipolar mania: 11.2% for quetiapine and 11.4% for placebo).
Quetiapine tablets treatment was associated with small dose-related decreases in thyroid hormone levels, particularly total T4 and free T4. The reduction in total and free T4 was maximal within the first two to four weeks of quetiapine tablets treatment, with no further reduction during long-term treatment. In nearly all cases, cessation of quetiapine tablets treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment. Smaller decreases in total T3 and reverse T3 were seen only at higher doses. Levels of TBG were unchanged and in general, reciprocal increases in TSH were not observed, with no indication that quetiapine tablets causes clinically relevant hypothyroidism
Children and adolescents (10 to 17 years of age)
The same ADRs described above for adults should be considered for children and adolescents. The following table summarises ADRs that occur in a higher frequency category in children and adolescent patients (10-17 years of age) than in the adult population or ADRs that have not been identified in the adult population.
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(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 Institute of Health criteria) or increases>20mmHg for systolic or>10 mmHg for diastolic blood pressure at any time in two acute (3-6 weeks) placebo-controlled trials in children and adolescents.
(3) See Section 5.1.
(4) Note: The frequency is consistent to that observed in adults, but irritability might be associated with different clinical implications in children and adolescents as compared to adults.
4.9 Overdose
Fatal outcome has been reported in clinical trials following an acute overdose at 13.6 grams, and in post-marketing on doses as low as 6 grams of quetiapine tablets alone. However, survival has also been reported following acute overdoses of up to 30 grams.
In post-marketing experience, there have been very rare reports of overdose of quetiapine alone resulting in death or coma or QT-prolongation.
In general, reported signs and symptoms were those resulting from an exaggeration of the substance's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension.
Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose. (See Section 4.4 Special warnings and special precautions for use: Cardiovascular).
Management
There is no specific antidote to quetiapine. In cases of severe intoxication, 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. Whilst the prevention of absorption in overdose has not been investigated, gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.
Close medical supervision and monitoring should be continued until the patient recovers.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: antipsychotics
ATC code: N05A HO4
Mechanism of action
Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite, norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and norquetiapine exhibit affinity 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 (EPS) liability of Quetiapine compared to typical antispychotics. Additionally, norquetiapine has high affinity for the norepinephrine ransporter (NET). Quetiapine and norquetiapine also have high affinity at histaminergic and adrenergic α1 receptors, with a lower affinity at adrenergic α2 and serotonin 5HT1A receptors. Quetiapine has no appreciable affinity at cholinergic muscarinic or benzodiazepine receptors.
Pharmacodynamic effect
Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also blocks the action of dopamine agonists, measured either behaviourally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of D2-receptor blockade.
In pre-clinical tests predictive of EPS, quetiapine is unlike typical antipsychotics and has an atypical profile. Quetiapine does not produce dopamine D2-receptor supersensitivity after chronic administration. Quetiapine produces only weak catalepsy at effective dopamine D2-receptor blocking doses. Quetiapine demonstrates selectivity for the limbic system by producing depolarisation blockade of the mesolimbic but not the nigrostriatal dopamine-containing neurones following chronic administration. Quetiapine exhibits minimal dystonic liability in haloperidol-sensitised or drug-naive Cebus monkeys after acute and chronic administration. (See Section 4.8)
Clinical Efficacy
In three placebo-controlled clinical trials, in patients with schizophrenia, using variable doses of quetiapine, there were no differences between the quetiapine and placebo treatment groups in the incidence of EPS or concomitant use of anticholinergics. A placebo-controlled trial evaluating fixed doses of quetiapine across the range of 75 to 750 mg/day showed no evidence of an increase in EPS or the use of concomitant anticholinergics.
In four placebo-controlled clinical trials, evaluating doses of quetiapine up to 800 mg/day for the treatment of moderate to severe manic episodes, two each in monotherapy and as combination therapy to lithium or divalproex, there were no differences between the quetiapine and placebo treatment groups in the incidence of EPS or concomitant use of anticholinergics.
In placebo-controlled studies in elderly patients with dementia-related psychosis, the incidence of cerebrovascular adverse events per 100 patient years was not higher in quetiapine-treated patients than in placebo-treated patients.
In the treatment of moderate to severe manic episodes, quetiapine demonstrated superior efficacy to placebo in reduction of manic symptoms at 3 and 12 weeks, in two monotherapy trials. There are no data from long term studies to demonstrate quetiapine's effectiveness in preventing subsequent manic or depressive episodes. Quetiapine data in combination with divalproex or lithium in acute moderate to severe manic episodes at 3 and 6 weeks is limited; however, combination therapy was well tolerated. The data showed an additive effect at week 3. A second study did not demonstrate an additive effect at week 6.
The mean last week median dose of quetiapine in responders was approximately 600 mg/day and approximately 85% of the responders were in the dose range of 400 to 800 mg/day.
In 4 clinical trials with a duration of 8 weeks in patients with moderate to severe depressive episodes in bipolar I or bipolar II disorder, quetiapine IR 300 mg and 600 mg was significantly superior to placebo treated patients for the relevant outcome measures: mean improvement on the MADRS and for response defined as at least a 50% improvement in MADRS total score from baseline. There was no difference in magnitude of effect between the patients who received 300 mg Quetiapine IR and those who received 600 mg dose.
In the continuation phase in two of these studies, it was demonstrated that long-term treatment, of patients who responded on quetiapine IR 300 or 600 mg, was efficacious compared to placebo treatment with respect to depressive symptoms, but not with regard to manic symptoms.
In two recurrence prevention studies evaluating quetiapine in combination with mood stabilizers, in patients with manic, depressed or mixed mood episodes, the combination with Quetiapine was superior to mood stabilizers monotherapy in increasing the time to recurrence of any mood event (manic, mixed or depressed).
Quetiapine was administered twice-daily totalling 400 mg to 800 mg a day as combination therapy to lithium or valproate.
In one long-term study (up to 2 years treatment) evaluating recurrence prevention in patients with manic, depressed or mixed mood episodes quetiapine was superior to placebo in increasing the time to recurrence of any mood event (manic, mixed or depressed), in patients with bipolar I disorder. The number of patients with a mood event was 91 (22.5%) in the quetiapine group, 208 (51.5%) in the placebo group and 95 (26.1%) in the lithium treatment groups respectively. In patients who responded to quetiapine, when comparing continued treatment with quetiapine to switching to lithium, the results indicated that a switch to lithium treatment does not appear to be associated with an increased time to recurrence of a mood event.
Clinical trials have demonstrated that quetiapine is effective in schizophrenia and mania when given twice a day, although quetiapine has a pharmacokinetic half-life of approximately 7 hours. This is further supported by the data from a positron emis
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