PRODUCT MONOGRAPH

Pr (r)

SEROQUEL XR

quetiapine fumarate extended-release tablets 50, 200, 300 and 400 mg quetiapine (as quetiapine fumarate) Psychotropic Agent

AstraZeneca Canada Inc. 1004 Middlegate Road Mississauga, Ontario L4Y 1M4

www.astrazeneca.ca

Date of Revision: December 15, 2008

Submission Control Number: 124733

SEROQUEL XR(r) is a trade-mark of the AstraZeneca group of companies

Table of Contents

PRODUCT MONOGRAPH 1 PART I: HEALTH PROFESSIONAL INFORMATION 3 SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 12 DRUG INTERACTIONS. 21 DOSAGE AND ADMINISTRATION 24 OVERDOSAGE 26 ACTION AND CLINICAL PHARMACOLOGY 27 STORAGE AND STABILITY 29 DOSAGE FORMS, COMPOSITION AND PACKAGING 29 PART II: SCIENTIFIC INFORMATION 30 PHARMACEUTICAL INFORMATION 30 CLINICAL TRIALS 31 DETAILED PHARMACOLOGY 34 TOXICOLOGY 35 REFERENCES 43 PART III: CONSUMER INFORMATION 46

SEROQUEL XR(r)

quetiapine fumarate extended-release tablets 50, 200, 300 and 400 mg quetiapine (as quetiapine fumarate) Psychotropic Agent

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

*For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING

CONTRAINDICATIONS

SEROQUEL XR (quetiapine fumarate extended-release) is contraindicated in patients with a known hypersensitivity to this medication or any of its ingredients. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Increased Mortality in Elderly Patients with Dementia

Elderly patients with dementia treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of thirteen placebo controlled trials with various atypical antipsychotics (modal duration of 10 weeks) in these patients showed a mean 1.6 fold increase in death rate in the drug-related patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature (see WARNINGS AND PRECAUTIONS, Special Populations, Use in Geriatric Patients with Dementia).

General

Body Temperature Regulation:

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing SEROQUEL XR (quetiapine fumarate extended-release) for patients who will be experiencing conditions which may contribute to an elevation of core temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

Acute Withdrawal (discontinuation) Symptoms:

Acute discontinuation symptoms such as insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability, have been described after abrupt cessation of antipsychotic drugs including SEROQUEL XR. Gradual withdrawal over a period of at least one to two weeks is advisable. Symptoms usually resolved after 1 week post-discontinuation.

Carcinogenesis and Mutagenesis

For animal data, see Part II: TOXICOLOGY.

Cardiovascular

Hypotension and Syncope: As with other drugs that have high a1 adrenergic receptor blocking activity, SEROQUEL XR may induce orthostatic hypotension, dizziness, and sometimes syncope, especially during the initial dose titration period. In placebo-controlled SEROQUEL XR trials, there was little difference in the adverse reaction reporting rate of syncope in patients treated with SEROQUEL XR (0.3%, 4/1239) compared to patients on placebo (0.3%, 2/619). Syncope was reported in 1% (35/4083) of patients treated with SEROQUEL (quetiapine, immediate release formulation), compared with 0.3% (3/1006) on placebo, and 0.4% (2/527) on active control drugs. SEROQUEL XR should be used with caution in patients with known cardiovascular disease (e.g., history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or other conditions predisposing to hypotension (e.g., dehydration, hypovolemia and treatment with antihypertensive medications) (see OVERDOSAGE).

Cholesterol and Triglyceride Elevations:

In schizophrenia clinical trials, SEROQUEL XR treated patients had increases from baseline in mean cholesterol and triglycerides of 4% and 14%, respectively compared to decreases from baseline in mean cholesterol and triglycerides of 2% and 6% for placebo treated patients. In a 3-week bipolar mania clinical trial, SEROQUEL XR treated patients had increases from baseline in mean cholesterol and triglycerides of 2% and 20%, respectively compared to decreases in mean cholesterol and triglycerides of 2% and 5% for placebo-treated patients. In a bipolar depression clinical trial, SEROQUEL XR treated patients had decreases from baseline in mean cholesterol and increases from baseline in mean triglycerides of 2% and 11%, respectively compared to decreases in mean cholesterol and triglycerides of 3% and 2% for placebo-treated patients.

Very common (>=10%) cases of elevations in serum triglyceride levels (>=2.258 mmol/L on at least one occasion) and elevations in total cholesterol (predominantly LDL cholesterol) (>=6.2064 mmol/L on at least one occasion) have been observed during treatment with quetiapine in clinical trials (see ADVERSE REACTIONS). Lipid increases should be managed as clinically appropriate.

Endocrine and Metabolism

Hyperglycaemia: As with some other antipsychotics, hyperglycaemia and diabetes mellitus (including exacerbation of pre-existing diabetes, diabetic ketoacidosis, and diabetic coma including some fatal cases) in the aggregate have been reported rarely (>=0.01% - <0.1%) during the use of SEROQUEL in post-marketing experience, sometimes in patients with no reported history of hyperglycaemia (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions). Increases in blood glucose and hyperglycaemia, and occasional reports of diabetes, have been observed in clinical trials with quetiapine (see ADVERSE REACTIONS, Abnormal Hematologic and Clinical Chemistry Findings). Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycaemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycaemia- related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycaemia-related adverse events in patients treated with atypical antipsychotics are not available. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti- diabetic treatment despite discontinuation of the suspect drug. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.

Hyperprolactinemia:

An elevation of prolactin levels was not demonstrated in schizophrenia clinical trials with SEROQUEL XR as compared with placebo. In bipolar disorder clinical trials with SEROQUEL XR, elevation in prolactin levels occurred in 2.4% (7/288) of patients treated with SEROQUEL XR compared to 0.7% (2/300) of patients treated with placebo.

Increased prolactin levels with quetiapine were observed in rat studies. As is common with compounds which stimulate prolactin release, the administration of quetiapine resulted in an increase in the incidence of mammary neoplasms in rats. The physiological differences between rats and humans with regard to prolactin make the clinical significance of these findings unclear. To date, neither clinical nor epidemiological studies have shown an association between chronic administration of drugs that stimulate prolactin release, and mammary tumourigenesis. Tissue culture experiments, however, indicate that approximately one third of human breast cancers are prolactin dependent in vitro; a factor of potential importance if prescription of these drugs is contemplated in a patient with previously detected breast cancer. Possible manifestations associated with elevated prolactin levels are amenorrhea, galactorrhea, and menorrhagia. In the multiple fixed-dose schizophrenia clinical trial there were no differences in prolactin levels at study completion for SEROQUEL, across the recommended dose range, and placebo.

Hypothyroidism:

In SEROQUEL XR clinical trials, 0.5% (4/806) of patients on SEROQUEL XR compared to 0% (0/262) on placebo experienced decreased free thyroxine and 2.7% (21/786) on SEROQUEL XR compared to 1.2% (3/256) on placebo experienced increased TSH; however, no patients experienced a combination of clinically significant decreased free thyroxine and increased TSH. No patients had events of hypothyroidism.

In clinical trials, on average SEROQUEL was associated with about a 20% mean reduction in thyroxine levels (both total and free). Forty-two percent of SEROQUEL-treated patients showed at least a 30% reduction in total T4 and 7% showed at least a 50% reduction. Maximum reduction of thyroxine levels generally occurred during the first two to four weeks of treatment with SEROQUEL. These reductions were maintained without adaptation or progression during longer term treatment. Decreases in T4 were not associated with systematic changes in TSH or clinical signs or symptoms of hypothyroidism. Approximately 0.4% (12/2595) of patients treated with SEROQUEL experienced persistent increases in TSH, and 0.25% of patients were treated with thyroid replacement.

Weight Gain:

In 6-week placebo-controlled schizophrenia clinical trials, for patients treated with SEROQUEL XR mean weight gain was 1.77 kg (n=951) compared to 2.19 kg (n=414) in patients treated with SEROQUEL. For patients treated with placebo the mean weight gain was

0.26 kg (n=319). In a 3-week placebo-controlled bipolar mania clinical trial, for patients treated with SEROQUEL XR mean weight gain was 1.3 kg (n=151) compared to 0.1 kg (n=160) in patients treated with placebo. In an 8-week placebo-controlled bipolar depression clinical trial, for patients treated with SEROQUEL XR mean weight gain was 1.3 kg (n=137) compared to -0.2 kg (n=140) in patients treated with placebo.

Gastrointestinal

Antiemetic Effect:

Consistent with its dopamine antagonist effects, SEROQUEL XR may have an antiemetic effect. Such an effect may mask signs of toxicity due to overdosage of other drugs, or may mask symptoms of disease such as brain tumour or intestinal obstruction.

Hematologic

Neutropenia: Severe neutropenia (<0.5 x 109/L) has been uncommonly reported in quetiapine clinical trials. There was no apparent dose relationship. Possible risk factors for leucopenia and/or neutropenia include pre-existing low white cell count (WBC) and history of drug induced leucopenia and/or neutropenia. SEROQUEL XR should be discontinued in patients with a neutrophil count <1.0 x 109/L. These patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 x 109/L). (See ADVERSE REACTIONS, Abnormal Hematologic and Clinical Chemistry Findings and Post- Market Adverse Drug Reactions).

Hepatic

Hepatic Impairment:

Decreased clearance of SEROQUEL was observed in patients with mild hepatic impairment (see ACTIONS and CLINICAL PHARMACOLOGY, Special Populations and Conditions). No pharmacokinetic data are available for quetiapine in patients with moderate or severe hepatic impairment. However, should clinical judgement deem treatment with SEROQUEL XR necessary, the drug should be used with great caution in patients with moderate or severe hepatic impairment (see ACTIONS AND CLINICAL PHARMACOLOGY, Special Populations and Conditions and DOSAGE AND ADMINISTRATION).

Transaminase Elevations:

Asymptomatic, transient and reversible elevations in serum transaminases (primarily ALT) associated with SEROQUEL XR have been reported. The

proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of placebo-controlled trials ranged between 1% and 2% for SEROQUEL XR compared to 2% for placebo. During premarketing clinical trials, therapy with SEROQUEL was associated with elevation of hepatic transaminases, primarily ALT. Within a clinical trial database of 1892 SEROQUEL-treated schizophrenia patients, with baseline ALT levels <60 IU/L, 5.3% (101/1892) had treatment-emergent ALT elevations to >120 IU/L, 1.5% (29/1892) had elevations to >200 IU/L, and 0.2% (3/1892) had elevations to >400 IU/L. No patients had values in excess of 800 IU/L. None of the SEROQUEL-treated patients who had elevated transaminase values manifested clinical symptomatology associated with liver impairment. The majority of transaminase elevations were seen during the first two months of treatment. Most elevations were transient (80%) while patients continued on SEROQUEL therapy. Of the 101 SEROQUEL-treated patients whose enzyme levels increased to >120 IU/L, 40 discontinued treatment while their ALT values were still raised. In 114 SEROQUEL-treated patients whose baseline ALT was >90 IU/L, only 1 experienced an elevation to >400 IU/L. Precautions should be exercised when using SEROQUEL XR in patients with pre-existing hepatic disorders, in patients who are being treated with potentially hepatotoxic drugs, or if treatment-emergent signs or symptoms of hepatic impairment appear. For patients who have known or suspected abnormal hepatic function prior to starting SEROQUEL XR, standard clinical assessment, including measurement of transaminase levels is recommended. Periodic clinical reassessment with transaminase levels is recommended for such patients, as well as for patients who develop any signs and symptoms suggestive of a new onset liver disorder during SEROQUEL XR therapy.

Neurologic

Neuroleptic Malignant Syndrome (NMS):

Neuroleptic Malignant Syndrome is a potentially fatal symptom complex that has been reported in association with antipsychotic drugs, including SEROQUEL XR.

The clinical manifestations of NMS are hyperthermia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system pathology. The management of NMS should include immediate discontinuation of antipsychotic drugs, including SEROQUEL XR, and other drugs not essential to concurrent therapy; intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported.

Tardive Dyskinesia (TD) and Extrapyramidal Symptoms (EPS):

Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon estimates to predict which patients are likely to develop the syndrome.

In short-term placebo-controlled clinical trials in schizophrenia and bipolar mania, the aggregated incidence of EPS-related adverse events 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). In short-term placebo-controlled clinical trials in bipolar depression, the aggregated incidence of EPS-related adverse events was 8.9% for quetiapine compared to 3.8% for placebo. The incidence of individual EPS-related adverse events (e.g., akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity), however was generally low and did not exceed 4% for any individual adverse event. In long-term studies of schizophrenia and bipolar disorder the aggregated exposure adjusted incidence of treatment-emergent EPS was similar between quetiapine and placebo. The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of TD, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, SEROQUEL XR should be prescribed in a manner that is most likely to minimize the occurrence of TD. Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that is known to respond to antipsychotic drugs, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of TD appear in a patient on SEROQUEL XR, drug discontinuation should be considered. However, some patients may require treatment with SEROQUEL XR despite the presence of the syndrome.

Seizures:

In controlled clinical trials with SEROQUEL XR, there was no difference in the incidence of seizures in patients treated with SEROQUEL XR (0.1%, 1/1239) or placebo (0.5%, 3/619). Nevertheless, as with other antipsychotics, caution is recommended when treating patients with a history of seizures or with conditions associated with a lowered seizure threshold (see ADVERSE REACTIONS).

Potential Effect on Cognitive and Motor Performance:

Somnolence was a very commonly reported adverse event in patients treated with SEROQUEL XR, especially during the initial dose titration period. Since SEROQUEL XR may cause sedation and impair motor skill, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, until they are reasonably certain that therapy with SEROQUEL XR does not affect them adversely.

Ophthalmologic

Cataracts: The development of cataracts was observed in association with quetiapine treatment in chronic dog studies at 4 times the recommended human dose. Lens changes have also been observed in patients during long-term SEROQUEL treatment, but a causal relationship to SEROQUEL use has not been established. The possibility of lenticular changes during long-term use of SEROQUEL XR in man, thus can not be excluded at this time. Eye examinations (e.g., slit lamp exam) prior to or shortly after initiation of treatment with SEROQUEL XR and at 6 month intervals thereafter, are recommended. If clinically significant lens changes associated with SEROQUEL XR use are observed, discontinuation of SEROQUEL XR should be considered.

Psychiatric

Suicide/ suicidal thoughts or clinical worsening:

Depressive episodes are associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission of depression 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 addition to depressive episodes associated with bipolar disorder, depression may be co-morbid with schizophrenia.

Schizophrenia as well as manic episodes associated bipolar disorder, can also be associated with an increased risk of suicide-related events, and thus close supervision and appropriate clinical management of high risk patients should accompany drug therapy. Patients with a history of suicide-related events are also known to be at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. In a bipolar mania clinical trial with SEROQUEL XR, the incidence of treatment emergent suicidal ideation or suicidal behaviour, as measured by the Columbia Analysis of Suicidal Behaviour, was 1.3% for SEROQUEL XR treated patients and 3.8% for placebo-treated patients. In a bipolar depression clinical trial with SEROQUEL XR, the incidence of treatment emergent suicidal ideation or suicidal behaviour, as measured by the Columbia Analysis of Suicidal Behaviour, was 0.7% for SEROQUEL XR treated patients and 1.4% for placebo- treated patients.

Renal

There is little experience with SEROQUEL XR in patients with renal impairment, except in a low (subclinical) single dose study with SEROQUEL (see ACTIONS AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). SEROQUEL XR should thus be used with caution in patients with known renal impairment, especially during the initial dosing period (see DOSAGE AND ADMINISTRATION).

Special Populations

Pregnant Women:

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with SEROQUEL XR. The safety and efficacy of SEROQUEL XR during human pregnancy have not been established. Therefore, SEROQUEL XR should only be used during pregnancy if the expected benefits justify the potential risks.

Nursing Women:

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 SEROQUEL XR.

Pediatrics (< 18 years of age):

The safety and efficacy of SEROQUEL XR in children under the age of 18 years have not been established.

Geriatrics (>= 65 years of age):

The number of patients 65 years of age or over exposed to SEROQUEL XR during clinical trials was limited (n=68). When compared to younger patients the mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly subjects. In addition, as this population has more frequent hepatic, renal, central nervous system, and cardiovascular dysfunctions, and more frequent use of concomitant medication, caution should be exercised with the use of SEROQUEL XR in the elderly patient (see DOSAGE AND ADMINISTRATION).

Use in Geriatric Patients with Dementia:

Overall Mortality:

Elderly patients with dementia treated with atypical antipsychotic drugs showed increased mortality compared to placebo in a meta-analysis of 13 controlled trials of various atypical antipsychotic drugs. In two placebo-controlled trials with oral SEROQUEL in this population, the incidence of mortality was 5.5% for

SEROQUEL-treated patients compared to 3.2% for placebo-treated patients. SEROQUEL XR is not indicated in elderly patients with dementia.

Dysphagia:

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. SEROQUEL XR and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

DRUG INTERACTIONS

Drug-Drug Interactions

Given the primary central nervous system effects of quetiapine, SEROQUEL XR (quetiapine fumarate extended-release) should be used with caution in combination with other centrally acting drugs.

The Effect of SEROQUEL XR on Other Drugs

Alcohol:

SEROQUEL (quetiapine, immediate-release formulation) potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with psychotic disorders. Alcoholic beverages should be avoided while taking SEROQUEL XR.

Antihypertensive Agents:

Because of its potential for inducing hypotension, SEROQUEL XR may enhance the effects of certain antihypertensive agents.

Levodopa and Dopamine Agonists: As it exhibits in vitro dopamine antagonism, SEROQUEL XR may antagonize the effects of levodopa and dopamine agonists.

Lithium:

The single dose pharmacokinetics of lithium were not altered when coadministered with SEROQUEL.

Antipyrine:

SEROQUEL did not induce the hepatic enzyme systems involved in the metabolism of antipyrine.

Lorazepam

: SEROQUEL did not affect the single dose pharmacokinetics of lorazepam.

Divalproex:

Co-administration of SEROQUEL (150 mg bid) and divalproex (500 mg bid) increased the mean oral clearance and the mean maximum plasma concentration of total valproic acid (administered as divalproex) by 11%. These changes were not clinically relevant.

The Effect of Other Drugs on SEROQUEL XR

Hepatic Enzyme Inducers:

Concomitant use of SEROQUEL XR with hepatic enzyme inducers such as carbamazepine may substantially decrease systemic exposure to quetiapine. In a multiple dose trial in patients to assess the pharmacokinetics of SEROQUEL 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, and hence, in each patient, consideration for a higher dose of SEROQUEL XR, depending on clinical response, should be considered. It should be noted that the recommended maximum daily dose of SEROQUEL XR is 800 mg/day and continued treatment at higher doses should only be considered as a result of careful consideration of the benefit risk assessment for an individual patient.

Co-administration of SEROQUEL and another microsomal enzyme inducer, phenytoin, caused five-fold increases in the clearance of quetiapine. Increased doses of SEROQUEL XR may be required to maintain control of psychotic symptoms in patients co-administered SEROQUEL XR and phenytoin and other hepatic enzyme inducers (e.g., barbiturates, rifampicin, etc. ). The dose of SEROQUEL XR may need to be reduced if phenytoin or carbamazepine or other hepatic enzyme inducers are withdrawn and replaced with a non-inducer (e.g., sodium valproate). CYP 3A4 inhibitors: CYP 3A4 is the primary enzyme responsible for cytochrome P450- mediated metabolism of quetiapine. Thus, coadministration of compounds (such as ketoconazole, erythromycin, clarithromycin, diltiazem, verapamil, or nefazodone), which inhibit CYP 3A4, may increase the concentration of SEROQUEL XR. In a multiple-dose trial in healthy volunteers to assess the pharmacokinetics of SEROQUEL given before and during treatment with ketoconazole, co-administration of ketoconazole resulted in an increase in mean Cmax and AUC of quetiapine of 235% and 522%, respectively, with a corresponding decrease in mean oral clearance of 84%. The mean half-life of quetiapine increased from 2.6 to 6.8 hours, but the mean tmax was unchanged. Due to the potential for an interaction of a similar magnitude in a clinical setting, the dosage of SEROQUEL XR should be reduced during concomitant use of quetiapine and potent CYP3A4 inhibitors (such as azole antifungals, macrolide antibiotics, and protease inhibitors). Special consideration should be given in elderly and debilitated patients. The risk-benefit ratio needs to be considered on an individual basis in all patients.

Divalproex:

Co-administration of SEROQUEL (150 mg bid) and divalproex (500 mg bid) increased the mean maximum plasma concentration of quetiapine by 17% without changing the mean oral clearance.

Cimetidine:

In a clinical study examining the pharmacokinetics of SEROQUEL following coadministration with cimetidine, (a non-specific P450 enzyme inhibitor), no clinically significant interaction was observed.

Thioridazine:

Coadministration of thioridazine (200 mg b.i.d.) with SEROQUEL (300 mg b.i.d. ), increased the clearance of SEROQUEL by 65%.

Fluoxetine, Imipramine, Haloperidol, and Risperidone:

Fluoxetine (60 mg daily), imipramine (75 mg b.i.d. ), haloperidol (7.5 mg b.i.d. ), and risperidone (3 mg b.i.d.) did not significantly alter the steady state pharmacokinetics of SEROQUEL.

Drug-Food Interactions

SEROQUEL XR can be taken with or without food (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

SEROQUEL XR (quetiapine fumarate extended-release) tablets should be swallowed whole and not split, chewed or crushed. SEROQUEL XR can be administered with or without food (see ACTIONS AND CLINICAL PHARMACOLOGY, Pharmacokinetics). SEROQUEL XR should be administered once daily, generally in the evening.

Schizophrenia

Usual Dose: The titration rate, based on the clinical trials (see Part II: CLINICAL TRIALS) is shown in the table below.

The dose should be adjusted within the effective dose range of 400 mg to 800 mg per day, depending on the clinical response and tolerability of the patient. In a controlled clinical trial, the treatment effect size of 600 mg and 800 mg doses of SEROQUEL XR was greater than that of the 400 mg dose (see Part II: CLINICAL TRIALS). In schizophrenia, the safety of doses above 800 mg/day has not been evaluated. The need for continuing existing EPS medications should be re-evaluated periodically as SEROQUEL XR has not been associated with treatment-emergent EPS across the clinical dose range.

Bipolar Disorder

Bipolar Mania

Usual Dose: The titration rate, based on the clinical trial (see Part II: CLINICAL TRIALS) is shown in the table below.

The dose should be adjusted within the effective dose range of 400 mg to 800 mg per day, depending on the clinical response and tolerability of the patient. In bipolar mania, the safety of doses of above 800 mg/day has not been evaluated.

Bipolar Depression

Usual Dose: The titration rate, based on the clinical trial (see Part II: CLINICAL TRIALS) is shown in the table below.

The usual target dose is 300 mg/day. The dose may be further increased depending on the response and tolerability of the patient. The maximum dose is 600 mg/day. In SEROQUEL clinical trials antidepressant efficacy was demonstrated with SEROQUEL at both 300 mg/day and 600 mg/day, however no additional benefit was seen in the 600 mg group during short-term treatment. In bipolar depression, the safety of doses of quetiapine above 600 mg/day has not been evaluated.

Switching patients from SEROQUEL tablets to SEROQUEL XR tablets

For more convenient dosing, patients who are currently being treated with divided doses of SEROQUEL (quetiapine, immediate release formulation) may be switched to SEROQUEL XR at the equivalent total daily dose taken once daily. Individual dosage adjustments may be necessary.

Dosing Considerations in Special Populations

Elderly:

As with other antipsychotics, SEROQUEL XR should be used with caution in the elderly, especially during the initial dosing period. The rate of dose titration of SEROQUEL XR may need to be slower, and the daily therapeutic target dose lower, than that used in younger patients. In clinical trials, 68 patients, 65 years of age or over, were treated with SEROQUEL XR (see WARNINGS AND PRECAUTIONS, Special Populations). Given the limited experience with SEROQUEL XR in the elderly, and the higher incidence of concomitant illness and concomitant medication in this population, SEROQUEL XR should be used with caution. The mean plasma clearance of SEROQUEL was reduced by 30% to 50% in elderly subjects when compared to younger patients. Elderly patients should be started on the lowest available dose (i.e., 50 mg/day) of SEROQUEL XR. The dose can be increased in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerance of the individual patient.

Hepatic Impairment:

Quetiapine is extensively metabolized by the liver (see ACTIONS AND PHARMACOLOGY, Special Populations and Conditions). Therefore, SEROQUEL XR should be used with caution in patients with mild hepatic impairment, especially during the initial dosing period. Patients with mild hepatic impairment should be started on the lowest available dose (i.e., 50 mg/day) of SEROQUEL XR. The dose should be increased daily in increments of 50 mg/day to an effective dose, depending on the clinical response and

tolerance in the individual patient. No pharmacokinetic data are available for quetiapine in patients with moderate to severe hepatic impairment. However, should clinical judgement deem treatment with SEROQUEL XR necessary, the drug should be used with great caution in patients with moderate or severe hepatic impairment (see WARNINGS AND PRECAUTIONS, Hepatic and ACTIONS AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).

Renal Impairment:

As clinical experience is lacking, caution is advised (see WARNINGS AND PRECAUTIONS, Renal).

Missed Dose

SEROQUEL XR should be taken at the same time each day. If a previous days dose has been missed, administration should be resumed the next day at the normal administration time.

OVERDOSAGE

Experience

Clinical Trials:

One death has been reported in a clinical trial following an overdose of 13, 600 mg of quetiapine alone, however, survival has also been reported in acute overdoses of up to 30, 000 mg of quetiapine. Most patients who overdosed reported no adverse events or recovered fully from the reported events.

Post-Marketing:

In post-marketing experience, there have been cases of coma and death in patients taking a SEROQUEL (quetiapine, immediate-release formulation) overdose. The lowest reported dose associated with coma has been in a patient who took 5,000 mg and had a full recovery within 3 days. The lowest reported dose associated with a death was in a patient who took 6,000 mg.

Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension and Syncope).

Symptoms

In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects e.g., drowsiness and sedation, tachycardia and hypotension.

Treatment

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

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action and Pharmacodynamics

SEROQUEL XR (quetiapine fumarate extended-release), a dibenzothiazepine derivative, is a psychotropic agent. Quetiapine and the active plasma metabolite, N-desalkyl quetiapine interact with a broad range of neurotransmitter receptors. The extent to which the N-desalkyl quetiapine metabolite contributes to the pharmacological activity of SEROQUEL XR is not known. Quetiapine: Quetiapine exhibits affinity for brain serotonin 5HT2 and 5HT1A receptors (in vitro, Ki = 288 and 557 nM, respectively), and dopamine D1 and D2 receptors (in vitro, Ki = 558 and 531 nM, respectively). 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 psychotropic properties and low extrapyramidal symptoms (EPS) liability of quetiapine. Quetiapine also has high affinity for histamine H1 receptors (in vitro, Ki = 10 nM) and adrenergic a1 receptors (in vitro, Ki = 13 nM), with a lower affinity for adrenergic a2 receptors (in vitro, Ki = 782 nM), but no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors. N-desalkyl quetiapine: N-desalkyl quetiapine, similar to quetiapine, exhibits affinity for brain serotonin 5HT2 and dopamine D1 and D2 receptors. Additionally, like quetiapine, N- desalkyl quetiapine has high affinity at serotonin 5HT1 receptors, and histaminergic and adrenergic a1 receptors, with a lower affinity at adrenergic a2 receptors.

Pharmacokinetics

The pharmacokinetics of quetiapine and N-desalkyl quetiapine are linear within the clinical dose range. The kinetics of quetiapine are similar in men and women, and smokers and non- smokers. Absorption: Quetiapine is well absorbed following oral administration. SEROQUEL XR achieves peak plasma concentrations at approximately 6 hours after administration (Tmax). SEROQUEL XR displays dose-proportional pharmacokinetics for doses of up to 800 mg administered once daily. The maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) for SEROQUEL XR administered once daily are comparable to those achieved for the same total daily dose of SEROQUEL (quetiapine, immediate-release formulation) administered twice daily. Steady-state peak molar concentrations of the active metabolite N-desalkyl quetiapine are 35% of that observed for quetiapine. In a study (n=10) examining the effects of food on the bioavailability of quetiapine, a high-fat meal was found to produce statistically significant increases in the SEROQUEL XR Cmax and AUC of 44% to 52% and 20% to 22%, respectively, for the 50-mg and 300-mg tablets. In comparison, a light meal had no significant effect on the Cmax or AUC of quetiapine. This increase in exposure is not clinically significant, and therefore SEROQUEL XR can be taken with or without food.

Distribution:

Quetiapine has a mean apparent volume of distribution of 10+-4 L/kg, and is approximately 83% bound to plasma proteins.

Elimination and Metabolism:

The elimination half-life of quetiapine is approximately 6-7 hours upon multiple dosing within the proposed clinical dosage range. Quetiapine is extensively metabolized by the liver, with parent compound accounting for less than 5% of the dose in the urine and faeces, one week following the administration of radiolabelled quetiapine. Since quetiapine is extensively metabolised by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed in these patients. The elimination half-life of N-desalkyl quetiapine is approximately 12 hours. The average molar dose fraction of free quetiapine and the active human plasma metabolite N- desalkyl quetiapine is <5% excreted in the urine.

Major routes of metabolism of quetiapine involve oxidation of the alkyl side chain, hydroxylation of the dibenzothiazepine ring, sulphoxidation, and phase 2 conjugation. The principal human plasma metabolites are the sulfoxide, and the parent acid metabolite, neither of which are pharmacologically active.

In vitro

investigations established that CYP 3A4 is the primary enzyme responsible for cytochrome P450-mediated metabolism of quetiapine. N-desalkyl quetiapine is primarily formed and eliminated via CYP3A4.

Quetiapine and several of its metabolites (including N-desalkyl quetiapine) were found to be weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities in vitro. In vitro CYP inhibition is observed only at concentrations approximately 5 to 50-fold higher than those observed at a dose range of 300 to 800 mg/day in humans.

Special Populations and Conditions

Geriatrics (>= 65 years of age):

The mean clearance of quetiapine in the elderly is approximately 30 to 50% of that seen in adults aged 18-65 years (see WARNINGS AND PRECAUTIONS, Special Populations and DOSAGE AND ADMINISTRATION).

Hepatic Impairment: In 8 cirrhotic subjects with mild hepatic impairment, administration of a single 25 mg (sub-clinical) oral dose of SEROQUEL resulted in a 40% increase in both AUC and Cmax. Clearance of the drug decreased by 25% whereas t1/2 was elevated by nearly 45%. Therefore, SEROQUEL XR should be used with caution in patients with mild hepatic impairment, especially during the initial dosing period. No pharmacokinetic data are available for quetiapine in patients with moderate or severe hepatic impairment (see WARNINGS AND PRECAUTIONS, Hepatic and DOSAGE AND ADMINISTRATION). Renal Impairment: At single low (sub-clinical) doses, the mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m2). However, the individual clearance values remained within the range observed for healthy subjects (see WARNINGS AND PRECAUTIONS, Renal and DOSAGE AND ADMINISTRATION).

STORAGE AND STABILITY

SEROQUEL XR (quetiapine fumarate extended-release) should be stored between 15 - 30degC.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms and Packaging

SEROQUEL XR (quetiapine fumarate extended-release) is available as film-coated tablets containing quetiapine fumarate equivalent to 50 mg, 200 mg, 300 mg or 400 mg of quetiapine free base as follows: 50 mg quetiapine tablets are peach coloured, capsule-shaped, biconvex, intagliated with 'XR 50'on one side and plain on the other, available in high-density polyethylene (HDPE) bottles of 60 tablets. 200 mg quetiapine tablets are yellow, capsule-shaped, biconvex, intagliated with 'XR 200' on one side and plain on the other, available in HDPE bottles of 60 tablets. 300 mg quetiapine tablets are pale yellow, capsule-shaped, biconvex, intagliated with 'XR 300' on one side and plain on the other, available in HDPE bottles of 60 tablets. 400 mg quetiapine tablets are white, capsule-shaped, biconvex, intagliated with 'XR 400' on one side and plain on the other, available in HDPE bottles of 60 tablets.

Composition

SEROQUEL XR is available in 4 strengths containing 50, 200, 300 or 400 mg quetiapine per tablet (as quetiapine fumarate). The core of the tablet contains the excipients hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium citrate. The coating of the tablet contains hydroxypropyl methylcellulose, polyethylene glycol 400, red ferric oxide (50 mg tablets), titanium dioxide, and yellow ferric oxide (50, 200 and 300 mg tablets).