Nu-Quetiapine Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Schizophrenia

NU-QUETIAPINE (quetiapine) is indicated for the management of the manifestations of schizophrenia. The antipsychotic efficacy of quetiapine was established in short-term (6-week) controlled inpatient trials (see Part II: CLINICAL TRIALS). The efficacy of quetiapine in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials of patients with manifestations of schizophrenia.

Bipolar Disorder – Mania

NU-QUETIAPINE is indicated as monotherapy for the acute management of manic episodes associated with bipolar disorder.

The efficacy of quetiapine in bipolar disorder - mania was established in two 12-week clinical trials of bipolar patients (see Part II: CLINICAL TRIALS). The safety and effectiveness of quetiapine for long-term use, and for prophylactic use in bipolar disorder has not been evaluated.

Geriatrics (> 65 years of age)

NU-QUETIAPINE is not indicated in elderly patients with dementia. See WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions Box and Special Populations.

Pediatrics (< 18 years of age)

The safety and efficacy of NU-QUETIAPINE in children under the age of 18 years have not been established.

CONTRAINDICATIONS

NU-QUETIAPINE (quetiapine) 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: Although not reported with quetiapine disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing NU-QUETIAPINE 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 quetiapine. 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 α₁ adrenergic receptor blocking activity, quetiapine may induce orthostatic hypotension, dizziness, and sometimes syncope, especially during the initial dose titration period. Syncope was reported in 1% (23/2371) of patients treated with quetiapine, compared with 0% (0/404) on placebo, and 0.4% (2/527) on active control drugs. The risk of hypotension and syncope may be reduced by more gradual titration to the target dose (see DOSAGE AND ADMINISTRATION).

Quetiapine 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 short-term placebo-controlled schizophrenia trials, quetiapine-treated patients showed mean increases from baseline in cholesterol and triglyceride of 11% and 17%, respectively, compared to mean decreases in the placebo-treated patients. LDL cholesterol was not measured in these trials.

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 quetiapine 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 hyperglycaemiarelated 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 antidiabetic 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: Elevation of prolactin levels was not seen in clinical trials with quetiapine, although increased prolactin levels were observed in rat studies with this compound. 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 quetiapine, across the recommended dose range, and placebo.

Hypothyroidism: Clinical trials in schizophrenia demonstrated that quetiapine is associated with a dose-related decrease in total and free thyroxine (T₄). On average quetiapine was associated with about a 20% mean reduction in thyroxine levels (both total and free). Forty-two percent of quetiapine-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 quetiapine. 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 quetiapine (schizophrenia and bipolar studies combined) experienced persistent increases in TSH, and 0.25% of patients were treated with thyroid replacement.

Weight Gain: In controlled schizophrenia clinical trials (up to 6 weeks), mean weight gain was approximately 2.3 kg compared to a mean weight gain of 0.1 kilograms in patients taking placebo (n=427). In open-label extension trials, after 9 to 13 weeks of quetiapine monotherapy, the mean weight increase was 1.58 kg (n=170). After 53 to 78 weeks of treatment, the mean weight increase was 1.98 kg (n=137). These data are obtained from uncontrolled, open-label trials; the relevance of these findings to clinical practice is unknown. Weight change over time appeared to be independent of quetiapine dose (see ADVERSE REACTIONS). In the acute placebo-controlled bipolar mania clinical trials (up to 12 weeks) mean weight gain in patients taking quetiapine was 1.8 kg compared to a mean weight loss of 0.1 kg in patients taking placebo. In patients completing the entire 12 weeks of treatment mean weight gain in patients taking quetiapine was 2.8 kg.

Gastrointestinal

Antiemetic Effect: Consistent with its dopamine antagonist effects, quetiapine 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. Quetiapine 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 quetiapine was observed in patients with mild hepatic impairment (see ACTIONS and CLINICAL PHARMACOLOGY, Special Populations and Conditions). Patients with mild hepatic impairment should be started on 25 mg/day. The dose should be increased daily in increments of 25 to 50 mg/day to an effective dose, depending on the clinical response and tolerability in the individual patient. No pharmacokinetic data are available for any dose of quetiapine in patients with moderate or severe hepatic impairment. However, should clinical judgement deem treatment with quetiapine 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: During premarketing clinical trials, therapy with quetiapine was associated with elevation of hepatic transaminases, primarily ALT. Within a clinical trial database of 1892 quetiapine-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 quetiapine -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 quetiapine therapy. Of the 101 quetiapine-treated patients whose enzyme levels increased to >120 IU/L, 40 discontinued treatment while their ALT values were still raised. In 114 quetiapine–treated patients whose baseline ALT was >90 IU/L, only 1 experienced an elevation to >400 IU/L.

In the bipolar disorder - mania trials, the proportions of patients with transaminase elevations of > 3 times the upper limits of the normal reference range, was approximately 1% for both quetiapine-treated and placebo-treated patients.

Precautions should be exercised when using quetiapine 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 quetiapine, 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 quetiapine 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 quetiapine.

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 quetiapine, 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.

It has been hypothesized that agents with a lower EPS liability may also have a lower liability to produce TD. In schizophrenia and bipolar mania placebo-controlled clinical trials with quetiapine, the incidence of EPS was not statistically significantly different than placebo across the recommended therapeutic dose range. This may predict that quetiapine has less potential than standard antipsychotic agents to induce TD in schizophrenia and bipolar mania patients (see ADVERSE REACTIONS).

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, quetiapine 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 quetiapine, drug discontinuation should be considered. However, some patients may require treatment with quetiapine despite the presence of the syndrome.

Seizures: In controlled schizophrenia clinical trials, there was no difference in the incidence of seizures in patients treated with quetiapine or placebo (incidence of 0.4% or 3 events per 100 patient years in patients given quetiapine, compared with 0.5% or 6.9 events per 100 patient years for placebo). 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 commonly reported adverse event in patients treated with quetiapine, especially during the initial dose titration period. Since quetiapine 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 quetiapine therapy 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 quetiapine treatment, but a causal relationship to quetiapine use has not been established. The possibility of lenticular changes during long-term use of quetiapine 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 quetiapine and at 6 month intervals thereafter, are recommended. If clinically significant lens changes associated with quetiapine use are observed, discontinuation of quetiapine should be considered.

Psychiatric

Suicide: The possibility of suicide or attempted suicide is inherent in bipolar disorder and schizophrenia, and thus close supervision and appropriate clinical management of high-risk patients should accompany drug therapy.

Renal

There is little experience with quetiapine in patients with renal impairment, except in a low (subclinical) single dose study (see ACTIONS AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). Quetiapine 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 quetiapine. The safety and efficacy of quetiapine during human pregnancy have not been established. Therefore, quetiapine 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 quetiapine.

Pediatrics (< 18 years of age): The safety and efficacy of quetiapine 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, with schizophrenia or related disorders, exposed to quetiapine, during clinical trials was limited (n=38). 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 quetiapine 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 quetiapine in this population, the incidence of mortality was 5.5% for quetiapine-treated patients compared to 3.2% for placebo-treated patients.

Quetiapine 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. Quetiapine and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

ADVERSE REACTIONS

The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Clinical Trial Adverse Drug Reactions

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The figures cited, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence in the populations studied.

Adverse Events Associated with Discontinuation

Short-Term Placebo-Controlled Clinical Trials:

Schizophrenia: Overall, 3.9% of quetiapine treated patients (n=510) discontinued treatment due to adverse events compared with 2.9% of placebo-treated patients (n=206). Somnolence, the single most common adverse event leading to withdrawal from quetiapine treatment, led to the withdrawal of four quetiapine-treated patients and no placebo-treated patients. Postural hypotension, hypotension, and/or tachycardia led to withdrawal of 1.8% of quetiapine-treated subjects, compared to 0.5% of placebo-treated subjects.

Bipolar Disorder - Mania: Discontinuations due to adverse events were similar for quetiapine (5.7%) and placebo (5.1%).

Combined Short- and Long-term Controlled Trial Database in Schizophrenia:

In a premarketing controlled clinical trial database of 1710 quetiapine-treated patients, 5% discontinued due to an adverse event. Somnolence was the single most common adverse event leading to withdrawal of 24 patients from quetiapine, and was the only adverse event leading to withdrawal that occurred in more than 1% of patients. Cardiovascular adverse events (e.g., postural hypotension, hypotension, tachycardia, dizziness) accounted for 20% of all subject withdrawals from quetiapine treatment. Sixteen (0.9%) quetiapine-treated subjects were withdrawn due to elevated liver enzymes. Four quetiapine-treated subjects were withdrawn because of leucopenia. Two of these subjects had at least one clinically significant, non-baseline low neutrophil count. Two quetiapine-treated subjects were withdrawn from the trial because of suspected neuroleptic malignant syndrome (NMS).

Commonly Observed Adverse Events in Short-Term Placebo-Controlled Clinical Trials Schizophrenia: The following treatment-emergent adverse events, derived from Table 1, commonly occurred during acute therapy with quetiapine (incidence of at least 5%, and an incidence at least 5% higher than that observed with placebo): somnolence, dizziness, dry mouth, postural hypotension, and elevated ALT levels.

Bipolar Disorder - Mania: In the bipolar mania studies, the following treatment-emergent adverse events commonly occurred during acute therapy with quetiapine (incidence of at least 5%, and an incidence at least 5% higher than that observed with placebo): somnolence, dry mouth, and weight gain.

Incidence of Adverse Events in Placebo-Controlled Clinical Trials

Certain portions of the discussion below relating to objective or numeric safety parameters are derived from studies in patients with schizophrenia and have not been duplicated for bipolar mania trials. However, this information is also generally applicable to bipolar mania. Table 1 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy (up to 6 weeks) of schizophrenia in 1% or more of patients treated with quetiapine (doses of 150 mg/day or more) where the incidence in patients treated with quetiapine was greater than the incidence in placebo-treated patients.

Table 1 Adverse Events Reported For At Least 1% Of Quetiapine-Treated

Subjects (Dose ≥ 150 mg/day) And For A Higher Percentage Of Quetiapine-Treated Subjects Than Subjects Who received Placebo In Short-Term, Placebo-Controlled Schizophrenia Phase II-III Trials

* Subjects may have had more than one adverse event. Other Adverse Events

Weight Gain: During acute therapy (up to 6 weeks) in placebo-controlled schizophrenia clinical trials, mean weight gain in patients taking quetiapine was 2.3 kilograms compared to a mean weight gain of 0.1 kilograms in patients taking placebo. In open-label extension trials with quetiapine monotherapy, mean weight gain after 9 to 13 weeks was 1.58 kg, after 14 to 26 weeks, 0.26 kg, after 27 to 39 weeks, 1.66 kg, after 40 to 52 weeks, -1.53 kg and after 53 to 78 weeks, 1.98 kg (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism). In the acute placebo-controlled bipolar mania clinical trials (up to 12 weeks) mean weight gain in patients taking quetiapine was 1.8 kg compared to a mean weight loss of 0.1 kg in patients taking placebo. In patients completing the entire 12 weeks of treatment mean weight gain in patients taking quetiapine was 2.8 kg.

Seizures: There have been uncommon reports (≥0.1% - <1%) of seizures in patients administered quetiapine, although the frequency was no greater than that observed in patients administered placebo in controlled clinical trials (see WARNINGS AND PRECAUTIONS, Neurologic).

Restless Legs Syndrome: There have been uncommon cases of restless legs syndrome in patients administered quetiapine.

Priapism: There have been rare reports (≥0.01% - <0.1%) of priapism in patients administered quetiapine.

Somnolence: Somnolence may occur, usually during the first two weeks of treatment, which generally resolves with the continued administration of quetiapine.

Neuroleptic Malignant Syndrome: As with other antipsychotics, rare cases of neuroleptic malignant syndrome have been reported in patients treated with quetiapine (see WARNINGS AND PRECAUTIONS, Neurologic).

Vital Signs: As with other antipsychotics with α1 adrenergic blocking activity, quetiapine may induce postural hypotension, associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose titration period (see WARNINGS AND PRECAUTIONS, Cardiovascular). In placebo-controlled clinical trials in schizophrenia, postural hypotension was reported with an incidence of 8% in quetiapine-treated patients compared to 2% in placebo-treated patients. Quetiapine was associated with a mean baseline to endpoint increase in heart rate of 3.9 beats per minute, compared to 1.6 beats per minute among placebo-treated patients.

Peripheral Edema: As with other antipsychotic agents, common cases (≥1% - <10%) of peripheral edema have been reported in patients treated with quetiapine.

Mild Asthenia: As with other antipsychotic agents, common cases of mild asthenia have been reported in patients treated with quetiapine.

Hypersensitivity: Uncommon cases of hypersensitivity including angioedema have been reported.

ECG Changes: Between group comparisons for pooled placebo-controlled trials revealed no statistically significant quetiapine /placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals. However, the proportions of patients meeting the criteria for tachycardia were compared in four 3- to 6-week-placebo-controlled clinical trials for the treatment of schizophrenia revealing a 1% (4/399) incidence for quetiapine compared to 0.6% (1/156) incidence for placebo. Quetiapine use was associated with a mean increase in heart rate, assessed by ECG, of 7 beats per minute compared to a mean increase of 1 beat per minute among placebo patients. This slight tendency to tachycardia may be related to quetiapine's potential for inducing orthostatic changes (see WARNINGS AND PRECAUTIONS, Cardiovascular). In bipolar disorder - mania trials the proportion of patients meeting the criteria for tachycardia was 0.5% (1/192) for quetiapine compared to 0% (0/178) for placebo.

Extrapyramidal Symptoms (EPS): Table 2 enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms in a short-term acute phase clinical trial in patients with schizophrenia comparing five fixed doses of quetiapine with placebo (n = ~ 50 patients per group), as assessed by: 1) spontaneous complaints of parkinsonism (extrapyramidal syndrome, hypertonia, tremor and cogwheel rigidity), or akathisia; 2) Simpson-Angus scores (mean change from baseline); and 3) use of anticholinergic medication to treat emergent EPS.

Table 2 Treatment-Emergent Extrapyramidal Symptoms, Assessed by Spontaneous

Reports, Simpson Scale, And Incidence of Anticholinergic Use

*Patients may have had more than one Parkinsonism adverse event

There were no differences between the quetiapine and placebo treatment groups in the incidence of EPS or concomitant use of anticholinergics and no evidence of dose-related increase in EPS or in the use of concomitant anticholinergics across the dose range of 75 – 750 mg/day.

In 2 bipolar disorder - mania placebo-controlled clinical trials using variable doses of quetiapine, there were no differences between the quetiapine and placebo treatment groups in the incidence of EPS, as assessed by Simpson-Angus total scores and Barnes Akathisia rating scale, spontaneous complaints of EPS and the use of concomitant anticholinergic medications to treat EPS.

Blurred Vision: There have been common cases of blurred vision in patients administered quetiapine.

Dysphagia: There have been uncommon cases of dysphagia in patients administered quetiapine.

Dysarthria: There have been uncommon cases of dysarthria in patients administered quetiapine.

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 quetiapine. Gradual withdrawal over a period of at least one to two weeks is advisable. Symptoms usually resolved after 1 week post-discontinuation.

Abnormal Hematologic and Clinical Chemistry Findings

As with other antipsychotics, common cases of leucopenia and/or neutropenia have been observed in patients administered quetiapine. Uncommon cases of eosinophilia have been observed.

In all placebo-controlled monotherapy clinical trials among patients with a baseline neutrophil count ≥ 1.5 x 10⁹ /L, the incidence of at least one occurrence of neutrophil count <1.5 x 10⁹ /L was 1.72% in patients treated with quetiapine, compared to 0.73% in placebo-treated patients. In clinical trials conducted prior to a protocol amendment for discontinuation of patients with treatment-emergent neutrophil count <1.0 x 10⁹/L, among patients with a baseline neutrophil count ≥1.5 x 10⁹/L, the incidence of at least one occurrence of neutrophil count <0.5 x 10⁹/L was 0.21% in patients treated with quetiapine and 0% in placebo treated patients and the incidence ≥0.5 - <1.0 x 10⁹/L was 0.75% in patients treated with quetiapine and 0.11% in placebo-treated patients. (See WARNINGS AND PRECAUTIONS, Hematologic).

Asymptomatic elevations in serum transaminases (AST, ALT) or gamma-GT levels have been observed in some patients administered quetiapine. These elevations were usually reversible on continued quetiapine treatment (see WARNINGS AND PRECAUTIONS, Hepatic).

Quetiapine 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 2 to 4 weeks of quetiapine treatment, with no further reduction during long-term treatment. There was no evidence of clinically significant changes in TSH concentration over time. In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T₄, irrespective of the duration of treatment (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism). 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 and there was no indication that quetiapine causes clinically relevant hypothyroidism.

Hyperglycaemia: Blood glucose increases to hyperglycaemic levels (fasting blood glucose ≥7.0 mmol/L or a non fasting blood glucose ≥11.1 mmol/L on at least one occasion) have been observed commonly (≥1% - <10%) with quetiapine in clinical trials.

In 2 long-term bipolar maintenance placebo-controlled adjunct clinical trials, mean exposure 213 days for quetiapine (646 patients) and 152 days for placebo (680 patients), the exposure-adjusted rate of any increased blood glucose level (≥7.0 mmol/L) for patients more than 8 hours since a meal was 18.0 per 100 patient years for quetiapine (10.7% of patients) and 9.5 for placebo per 100 patient years (4.6% of patients).

In short-term (12 weeks duration or less) placebo-controlled clinical trials (3342 treated with quetiapine and 1490 treated with placebo), the percent of patients who had a fasting blood glucose ≥7.0 mmol/L or a non fasting blood glucose ≥11.1 mmol/L was 3.5% for quetiapine and 2.1% for placebo.

In a 24 week trial (active-controlled, 115 patients treated with quetiapine) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at week 24 the incidence of a treatment-emergent post-glucose challenge glucose level ≥11.1 mmol/L was 1.7% and the incidence of a fasting treatment-emergent blood glucose level ≥7.0 mmol/L was 2.6%. (See WARNINGS AND PRECAUTIONS, Endocrine and Metabolism).

Cholesterol and Triglyceride Elevations: 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 WARNINGS AND PRECAUTIONS, Cardiovascular). Lipid increases should be managed as clinically appropriate.

In one 24-week clinical trial, where LDL cholesterol was directly measured as opposed to calculated, there was a slight mean increase in total cholesterol in patients administered quetiapine, which was driven by increases in LDL cholesterol. The mean LDL level increased at Week 24 by 10% in patients administered quetiapine, which was statistically significant. The total cholesterol/HDL ratio did not change significantly during therapy with quetiapine. Furthermore, triglycerides did not increase significantly nor did HDL cholesterol decrease during therapy. (See WARNINGS AND PRECAUTIONS, Cardiovascular).

Post-Market Adverse Drug Reactions

During post-marketing experience, leucopenia and/or neutropenia have been reported during quetiapine treatment. Resolution of leucopenia and/or neutropenia has followed cessation of therapy with quetiapine. Possible risk factors for leucopenia and/or neutropenia include pre-existing low white cell count and history of drug induced leucopenia and/or neutropenia. (See WARNINGS AND PRECAUTIONS, Hematologic).

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 quetiapine, sometimes in patients with no reported history of hyperglycaemia. (See WARNINGS AND PRECAUTIONS, Endocrine and Metabolism).

Anaphylactic reactions have been reported very rarely in post-marketing reports, including a case with a fatal outcome, possibly related to quetiapine treatment. The reporting rate of anaphylaxis associated with quetiapine use, which is generally accepted to be an underestimate due to underreporting, does not exceed the background incidence rate estimates. Estimates of the background incidence rate (all cause) of severe life-threatening anaphylaxis in the general population range between 80 and 210 cases per million person-years, and the incidence rate of drug-induced anaphylaxis is reported to be 16 cases per million person-years.

In addition, the all cause fatal anaphylaxis rate is reported to be one per million person-years while the drug-induced fatal anaphylaxis is estimated to be 0.3 cases per million person-years. If a patient develops anaphylaxis after treatment with quetiapine, the drug should be discontinued and an alternative treatment started.

DRUG INTERACTIONS

Drug-Drug Interactions

Given the primary central nervous system effects of quetiapine, quetiapine should be used with caution in combination with other centrally acting drugs.

The Effect of Quetiapine on Other Drugs

Alcohol: Quetiapine potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with psychotic disorders. Alcoholic beverages should be avoided while taking quetiapine.

Antihypertensive Agents: Because of its potential for inducing hypotension, quetiapine may enhance the effects of certain antihypertensive agents.

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

Lithium: The single dose pharmacokinetics of lithium were not altered when coadministered with quetiapine.

Antipyrine: Quetiapine did not induce the hepatic enzyme systems involved in the metabolism of antipyrine.

Lorazepam: Quetiapine did not affect the single dose pharmacokinetics of lorazepam.

Divalproex: Co-administration of quetiapine (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 Quetiapine

Hepatic Enzyme Inducers: Concomitant use of quetiapine 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 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, and hence, in each patient, consideration for a higher dose of quetiapine, depending on clinical response, should be considered. It should be noted that the recommended maximum daily dose of NU-QUETIAPINE 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 quetiapine and another microsomal enzyme inducer, phenytoin, caused five-fold increases in the clearance of quetiapine. Increased doses of quetiapine may be required to maintain control of psychotic symptoms in patients co-administered quetiapine and phenytoin and other hepatic enzyme inducers (e.g., barbiturates, rifampicin, etc.).

The dose of quetiapine 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 quetiapine. In a multiple-dose trial in healthy volunteers to assess the pharmacokinetics of quetiapine given before and during treatment with ketoconazole, co-administration of ketoconazole resulted in an increase in mean C_max 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 t_max was unchanged. Due to the potential for an interaction of a similar magnitude in a clinical setting, the dosage of quetiapine should be reduced during concomitant use of quetiapine and potent CYP 3A4 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 quetiapine (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 quetiapine 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 quetiapine (300 mg b.i.d.), increased the clearance of quetiapine 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 quetiapine.

Drug-Food Interactions

Quetiapine can be administered with or without food.

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

Schizophrenia:

The usual starting dose of NU-QUETIAPINE (quetiapine) is 25 mg b.i.d., titrated with increments of 25-50 mg b.i.d. per day, as tolerated, to a target dose of 300 mg/day given b.i.d. within four to seven days.

Further dosage adjustments may be indicated depending on the clinical response and tolerability in the individual patient. Dosage adjustments should generally occur at intervals of not less than 2 days, as steady state for quetiapine would not be achieved for approximately 1-2 days in the typical patient. When adjustments are necessary, dose increments/decrements of 25-50 mg b.i.d. are recommended.

NU-QUETIAPINE can be administered with or without food (see ACTIONS AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Clinical trials suggest that the usual effective treatment dose will be in the range of 300-600 mg/day (see Part II: CLINICAL TRIALS). However, some patients may require as little as 150 mg/day. 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 quetiapine has not been associated with treatment-emergent EPS across the clinical dose range.

Bipolar Disorder – Mania:

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

Dosage adjustments should be made depending on the clinical response and tolerability in the individual patient.

Approximately 85% of patients responded between 400 and 800 mg/day, while over 50% of patients responded between 600 and 800 mg/day (the average median dose for responders during the last week of treatment was approximately 600 mg/day). The safety of doses above 800 mg/day has not been evaluated.

Dosing Considerations in Special Populations

Elderly: In clinical trials, 38 patients with schizophrenia or related disorders, 65 years of age or over, were treated with quetiapine (see WARNINGS AND PRECAUTIONS, Special Populations). Given the limited experience with quetiapine in the elderly, and the higher incidence of concomitant illness and concomitant medication in this population, NU-QUETIAPINE should be used with caution. The mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly subjects when compared to younger patients. The rate of dose titration may thus need to be slower, and the daily therapeutic target dose lower, than that used in younger patients.

Hepatic Impairment: Quetiapine is extensively metabolized by the liver (see ACTIONS AND PHARMACOLOGY, Special Populations and Conditions). Therefore, NU-QUETIAPINE 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 25 mg/day. The dose should be increased daily in increments of 25 to 50 mg/day to an effective dose, depending on the clinical response and tolerance in the individual patient. No pharmacokinetic data are available for any dose of quetiapine in patients with moderate to severe hepatic impairment. However, should clinical judgement deem treatment with NU-QUETIAPINE 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

If a dose is missed by only a few hours, take it as soon as possible. If most of the day has passed since the missed dose, skip that dose and wait until next scheduled dose. Never take two doses at once.

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 quetiapine 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.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action and Pharmacodynamics

Quetiapine, a dibenzothiazepine derivative, is an antipsychotic 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 quetiapine 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 antipsychotic 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 α1 receptors (in vitro, Ki = 13 nM), with a lower affinity for adrenergic α2 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 α1 receptors, with a lower affinity at adrenergic α2 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 nonsmokers.

Absorption: Quetiapine is well absorbed following oral administration. In studies with radiolabelled drug, approximately 73% of the total radioactivity is recovered in the urine and 21% in the faeces over a period of one week. The bioavailability of quetiapine is marginally affected by administration with food, with C_max and AUC values increased by 25% and 15%, respectively. Peak plasma concentrations of quetiapine generally occur within 2 hours after oral administration. Steady-state peak molar concentrations of the active metabolite N-desalkyl quetiapine are 35% of that observed for quetiapine.

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. 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.

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.

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 quetiapine resulted in a 40% increase in both AUC and C_max. Clearance of the drug decreased by 25% whereas t_½ was elevated by nearly 45%. Therefore, quetiapine should be used with caution in patients with mild hepatic impairment, especially during the initial dosing period. No pharmacokinetic data are available for any dose of 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

NU-QUETIAPINE should be stored at controlled room temperature 15 - 30°C (59-86°F).

DOSAGE FORMS, COMPOSITION AND PACKAGING

NU-QUETIAPINE Tablets 25 mg: Each peach, round, biconvex, film-coated tablet, engraved “APO” on one side, “QUE” over “25” on the other side contains 25 mg quetiapine as quetiapine fumarate. Available in bottles of 100 and 500 tablets and in blister packages of 30 tablets.

NU-QUETIAPINE Tablets 100 mg: Each yellow, round, biconvex, film-coated tablet, engraved “APO” on one side, “QUE” over “100” on the other side contains 100 mg quetiapine as quetiapine fumarate. Available in bottles of 100 and 500 tablets and in blister packages of 30 tablets.

NU-QUETIAPINE Tablets 200 mg: Each white, round, biconvex, film-coated tablet, engraved “APO” on one side, “QUE” over “200” on the other side contains 200 mg quetiapine as quetiapine fumarate. Available in bottles of 100 and 500 tablets and in blister packages of 30 tablets.

NU-QUETIAPINE Tablets 300 mg: Each white, capsule shaped, biconvex film-coated tablet, engraved “APO” on one side “QUE300” on the other side contains 300 mg quetiapine as quetiapine fumarate. Available in bottles of 100 and 500 tablets and in blister packages of 30 tablets.

In addition to quetiapine fumarate, each tablet contains the excipients colloidal silicon dioxide, croscarmellose sodium, ethylcellulose 7FP, fumaric acid, hydroxypropyl cellulose type LF, hydroxypropyl methylcellulose 2910 E5, magnesium stearate, polyethylene glycol 8000, red ferric oxide (25 mg only), titanium dioxide, yellow ferric oxide (25 mg and 100 mg only).

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Common Name: Quetiapine Fumarate

Chemical Name: 1) Ethanol, 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy] -, (E)-2-butenedioate (2:1)

1. 2) 2-[2-(4-Dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]ethanol fumarate (2:1)

Molecular formula and molecular weight:

Quetiapine: C₂₁H₂₅N₃O₂S, 383.51

Quetiapine fumarate: (C₂₁H₂₅N₃O₂S)₂·C₄H₄O₄, 883.09

Structural Formula:

N

S

N

N

O OH

2

. ^O

O HO

OH

Physicochemical properties: A white to off-white crystalline powder

pKa: Quetiapine: pK_a1 3.3; pK_a2 6.8

Fumaric Acid: pK_a1 3.03; pH_a2 4.54

Partition Coefficient: Log P = 0.45 (Octanol/Water)

Melting point: Quetiapine fumarate: 172-173°C (Crystals from ethanol).

CLINICAL TRIALS

Comparative Bioavailability Studies

A randomized, single-dose, double-blinded, two-way crossover comparative bioavailability study, conducted under fasting conditions, was performed on healthy male and female volunteers. The rate and extent of absorption of quetiapine was measured and compared following a single oral dose (1 x 25 mg) of NU-QUETIAPINE (quetiapine fumarate) or SEROQUEL^® tablets. The results from measured data from a total of 31 volunteers (20 males and 11 females) are summarized in the following table.

Other Studies

Schizophrenia

The efficacy of quetiapine in the short-term management of schizophrenia was demonstrated in 3 short-term (6-week) controlled trials of inpatients who met a DSM-III-R diagnosis of schizophrenia. The results of the trials follow:

1. 1.

   In a 6-week, placebo-controlled trial (n=361) involving 5 fixed doses of quetiapine (75,

   150, 300, 600 and 750 mg/day on a t.i.d. schedule), the 4 highest doses of quetiapine were generally superior to placebo on the BPRS total score, the BPRS psychosis cluster and the CGI severity score, with the maximal effect seen at 300 mg/day, and the effects of doses of 150 to 750 were generally indistinguishable. Quetiapine, at a dose of 300 mg/day, was superior to placebo on the SANS.

2. 2. In a 6-week, placebo-controlled trial (n=286) involving titration of quetiapine in high (up to 750 mg/day on a t.i.d. schedule) and low (up to 250 mg/day on a t.i.d. schedule) doses, only the high dose quetiapine group (mean dose, 500 mg/day) was generally superior to placebo on the BPRS total score, the BPRS psychosis cluster, the CGI severity score and the SANS.
3. 3. In a 6-week dose and dose regimen comparison trial (n=618) involving two fixed doses of quetiapine (450 mg/day on both b.i.d. and t.i.d. schedules and 50 mg/day on a b.i.d. schedule), only the 450 mg/day (225 mg b.i.d. schedule) dose group was generally superior to the 50 mg/day (25 mg b.i.d.) quetiapine dose group on the BPRS total score, the BPRS psychosis cluster, the CGI severity score, and on the SANS.

Clinical trials have demonstrated that quetiapine is effective 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 emission tomography (PET) study which identified that for quetiapine, 5HT₂ and D₂ receptor occupancy is maintained for up to 12 hours. The safety and efficacy of doses greater than 800 mg/day have not been evaluated.

Bipolar Disorder – Mania

The efficacy of quetiapine in the treatment of manic episodes was established in two 12 week placebo-controlled monotherapy trials in patients who met DSM-IV criteria for Bipolar I disorder. These trials included patients with or without psychotic features and excluded patients with rapid-cycling and mixed episodes. There were from 95 to 107 patients per treatment group in each study.

The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), and these studies included patients with a wide range of baseline YMRS scores (i.e. 18 to 58). The primary outcome in these trials was change from baseline in the YMRS total score at Day 21.

In the two 12-week trials comparing quetiapine to placebo, quetiapine was significantly superior to placebo in reducing manic symptoms. Of those patients with a clinical response, 87% received doses of quetiapine between 400 and 800 mg per day; in the two individual studies, 52% and 81% of responders received doses between 600 and 800 mg per day (b.i.d. dosing). DETAILED PHARMACOLOGY

Quetiapine is a multiple receptor antagonist. It exhibits affinity for brain serotonin 5HT_1A and 5HT₂ receptors (IC_50s=717 and 148 nM, respectively), and dopamine D₁ and D₂ receptors (IC_50s=1268 and 329 nM, respectively). Quetiapine has lower affinity for dopamine D₂ receptors, than serotonin 5HT₂ receptors. Quetiapine also has high affinity at histamine H₁ receptors (IC₅₀=30 nM) and adrenergic α₁ receptors (IC₅₀=94 nM), with a lower affinity at adrenergic α₂ receptors (IC₅₀=271 nM), but no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors (IC_50s>5000 nM). N-desalkyl quetiapine is an active human plasma metabolite. Similar to quetiapine, it exhibits affinity for brain serotonin 5HT₂ and dopamine D₁ and D₂ receptors. Additionally, N-desalkyl quetiapine has high affinity at serotonin 5HT₁ receptors, and histaminergic and adrenergic α₁ receptors, with a lower affinity at adrenergic α₂ receptors.

Quetiapine is active in pharmacologic tests for antipsychotic activity, such as conditioned avoidance in primates. It also reverses the actions of dopamine agonists measured either behaviourally or electrophysiologically in mice, rats, cats and monkeys. Quetiapine also elevates levels of the dopamine metabolites homovanillic acid (HVA) and 3,4 dihydroxyphenylalanine (DOPAC) in brain, which are considered to be neurochemical indices of dopamine D₂ receptor blockade. The extent to which the N-desalkyl quetiapine metabolite contributes to the pharmacological activity of quetiapine in humans is not known.

In preclinical tests predictive of EPS, quetiapine is unlike standard 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 depolarization blockade of the A10 mesolimbic but not the A9 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. The results of these tests predict that quetiapine should have minimal EPS liability.

Pharmacology of Metabolites

Quetiapine and several of its metabolites (including N-desalkyl quetiapine) have been tested in vitro for their affinity for 5HT₂, D₁ and D₂ receptors, and in vivo animal models. The major metabolites, parent acid and sulfoxide, are pharmacologically inactive in plasma. The 7- hydroxy and 7-hydroxy N-dealkylated metabolites are pharmacologically active with in vitro binding comparable to or greater than that for parent compound. The peak plasma concentrations for the 7-hydroxy and 7-hydroxy N-dealkylated metabolites account for approximately only 5% and 2% of that of quetiapine at steady state, respectively.

TOXICOLOGY

Thyroid

Quetiapine caused a dose-related increase in pigment deposition in thyroid gland in rat toxicity studies which were 4 weeks in duration or longer and in a mouse 2 year carcinogenicity study. Doses were 10-250 mg/kg in rats, 75-750 mg/kg in mice; these doses are 0.1-3.0, and 0.1-4.5 times the maximum recommended human dose (on a mg/m² basis), respectively. Pigment deposition was shown to be irreversible in rats. The identity of the pigment could not be determined, but was found to be co-localized with quetiapine in thyroid gland follicular epithelial cells. The functional effects and the relevance of this finding to human risk are unknown.

Cataracts

In dogs receiving quetiapine for 6 or 12 months, but not for 1 month, focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mg/kg, or 4 times the maximum recommended human dose on a mg/m² basis. This finding may be due to inhibition of cholesterol biosynthesis by quetiapine. Quetiapine caused a dose related reduction in plasma cholesterol levels in repeat-dose dog and monkey studies; however, there was no correlation between plasma cholesterol and the presence of cataracts in individual dogs. The appearance of delta-8-cholestanol in plasma is consistent with inhibition of a late stage in cholesterol biosynthesis in these species. There also was a 25% reduction in cholesterol content of the outer cortex of the lens observed in a special study in quetiapine treated female dogs. Drug-related cataracts have not been seen in any other species; however, in a 1-year study in monkeys, a striated appearance of the anterior lens surface was detected in 2/7 females at a dose of 225 mg/kg or 5.5 times the maximum recommended human dose on a mg/m² basis.

Acute Toxicity

Single dose studies were conducted in mice and rats by the oral and intraperitoneal routes and in dogs by the oral route. The principal clinical signs in mice, rats and dogs of decreased motor activity, ptosis, loss of righting reflex, tremors, ataxia, prostration and convulsions were consistent with the pharmacological activity of the drug. The lowest oral doses causing lethality were 250 mg/kg in mouse and 500 mg/kg in rat; no deaths occurred at the highest oral dose tested (750 mg/kg) in dogs. The highest parenteral non-lethal doses were 100 mg/kg in both mouse and rat.

Subacute/Chronic Toxicity

In multiple dose studies in rats, dogs and monkeys (refer to Table 3 for individual study details) anticipated central nervous system effects of an antipsychotic drug were observed with quetiapine (e.g., sedation at lower doses and tremor, convulsions or prostration at higher exposures).

Hyperprolactinaemia, induced through the dopamine D₂ receptor antagonist activity of quetiapine or its metabolites, varied between species, but was most marked in the rat. A range of effects consequent to this were seen in the 12 month study including mammary hyperplasia, increased pituitary weight, decreased uterine weight and enhanced growth of females.

Reversible morphological and functional effects on the liver, consistent with hepatic enzyme induction, were seen in mouse, rat and monkey.

Thyroid follicular cell hypertrophy and concomitant changes in plasma thyroid hormone levels occurred in rat and monkey.

Pigmentation of a number of tissues, particularly the thyroid, was not associated with any morphological or functional effects.

Transient increases in heart rate, unaccompanied by an effect on blood pressure, occurred in dogs.

Posterior triangular cataracts seen after 6 months in dogs at 100 mg/kg/day were consistent with inhibition of cholesterol biosynthesis in the lens. No cataracts were observed in cynomolugus monkeys dosed up to 225 mg/kg/day, or in rodents. Monitoring in clinical studies did not reveal drug-related corneal opacities in man.

No evidence of neutrophil reduction or agranulocytosis was seen in any of the toxicity studies.

Carcinogenicity

Results from the 2 year carcinogenicity studies performed in mice and rats (and mouse sighting studies) are summarized in Table 4.

In the rat study (doses 0, 20, 75 and 250 mg/kg/day) the incidence of mammary adenocarcinomas was increased at all doses in female rats, consequential to prolonged hyperprolactinaemia.

In male rat (250 mg/kg/day) and mouse (250 and 750 mg/kg/day), there was an increased incidence of thyroid follicular cell benign adenomas, consistent with known rodent-specific mechanisms resulting from enhanced hepatic thyroxine clearance.

Table 3 Principal Multiple Dose Toxicity Studies With Quetiapine

Table 3 Principal Multiple Dose Toxicity Studies With Quetiapine

Table 4 Carcinogenicity (And Mouse Sighting) Studies With Quetiapine

Reproduction and Teratology

Results from the individual reproduction and teratology studies, performed with quetiapine in rats and rabbits, are summarized in Table 5.

Effects related to elevated prolactin levels (marginal reduction in male fertility and pseudopregnancy, protracted periods of diestrus, increased precoital interval and reduced pregnancy rate) were seen in rats, although these are not directly relevant to humans because of species differences in hormonal control of reproduction.

Quetiapine had no teratogenic effects.

Mutagenicity

Genetic toxicity studies with quetiapine show that it is not a mutagen or a clastogen. There was no evidence of mutagenic potential in reverse (Salmonella typhimurium and E. coli) or forward point mutation (CHO-HGPRT) assays or in two assays for chromosomal aberrations (human peripheral blood lymphocyte clastogenesis assay and the rat bone marrow erythrocyte micronucleus assay).

Table 5 Reproduction And Teratology Studies With Quetiapine

Table 5 Reproduction And Teratology Studies With Quetiapine

M = Male, F = Female

d6 = day 6 gestation, day of sperm positive smear (rats)/day of mating (rabbits) = day 0 gestation d16 = day 16 gestation, day of mating = day 1 gestation

d17 = day 17 gestation, day of sperm positive smear = day 1 gestation

d6 pp = day 6 post partum, day of parturition = day 1 post partum

d8 pp = day 8 post partum, day of littering = day 1 post partum

d21 pp = day 21 post partum, day of littering = day 1 post partum

d24 pp = day 24 post partum, day of littering = day 1 post partum

(pp = post partum)

REFERENCES

1. 1)

   Arvanitis LA, Miller BG, Seroquel Trial 13 Study Group. Multiple fixed doses of

   'Seroquel' (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. Biol Psychiatry 1997;42:233-46.

2. 2) Borison RL, Arvanitis LA, Miller BG, Study-Group. ICI 204,636, an atypical antipsychotic: efficacy and safety in a multicenter, placebo-controlled trial in patients with schizophrenia. J Clin Psychopharmacol 1996;16(2):158-69.
3. 3) Casey DE. 'Seroquel' (quetiapine): preclinical and clinical findings of a new atypical antipsychotic. Exp Opin Invest Drugs 1996;5(8):939-57.
4. 4) Emsley RA, Raniwalla J, Bailey PJ, Jones AM. A comparison of the effects of quetiapine (‘Seroquel’) and haloperidol in schizophrenic patients with a history of and a demonstrated partial response to conventional antipsychotic treatment. International Clinical Pharmacology 2000; 15(3):121-31.
5. 5) Fabre LF, Arvanitis L, Pultz J, Jones VM, Malick JB, Slotnick VB. ICI 204,636, a novel atypical antipsychotic: early indication of safety and efficacy in patients with chronic and subchronic schizophrenia. Clin Ther 1995;17(3):366-78.
6. 6) Goldstein JM, Litwin LC, Sutton EB and Malick JB. Seroquel: electrophysiological profile of a potential atypical antipsychotic. Psychopharmacology 1993;112(2-3):293-8.
7. 7) Hamner MB, Arvanitis LA, Miller BG, Link CGG, Hong WW. Plasma prolactin in schizophrenia subjects treated with SeroquelTM (ICI 204,636). Psychopharmacology Bull 1996;32(1):107-10.
8. 8) Migler BM, Warawa EJ and Malick JB. Seroquel: behavioural effects in conventional and novel tests for atypical antipsychotic drug. Psychopharmacology 1993;112(2-3):299-307.
9. 9) Peuskens J, Link CGG. A comparison of quetiapine and chlorpromazine in the treatment of schizophrenia. Acta Psychiatr Scand 1997;96:265-73.
10. 10) Pinninti NR, Mago R, Townsend J, Doghramji K. Periodic restless legs syndrome associated with quetiapine use: a case report. J Clin Psychopharmacol. 2005 Dec;25(6):617-8.
11. 11)

    Pullen RH, Palermo KM and Curtis MA. Determination of an antipsychotic agent (ICI

    204,636) and its 7-hydroxy metabolite in human plasma by high-performance liquid chromatography and gas chromatography-mass spectrometry. J Chromatogr Biomed Appl 1992;573(1):49-57.

12. 12) Saller CF, Salama AI. Seroquel: biochemical profile of a potential atypical antipsychotic. Psychopharmacology 1993;112(2-3):285-92.
13. 13) Small JG, Hirsch SR, Arvanitis LA, Miller BG, Link CG. Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Arch Gen Psychiatry 1997;54:549-57.
14. 14) Swerdlow NR, Zisook D, Taaid N. Seroquel (ICI 204,636) restores prepulse inhibition of acoustic startle in apomorphine-treated rats: similarities to clozapine. Psychopharmacology 1994;114(4):675-8.
15. 15)

    Wetzel H, Szegedi A, Hain C, Weisner J, Schlegel S and Benkert O. Seroquel (ICI

    204,636), putative "atypical" antipsychotic, in schizophrenia with positive symptomatology: results of an open clinical trial and changes of neuroendocrinological and EEG parameters. Psychopharmacology 1995;119(2):231-8.

16. 16)

    Product Monograph –SEROQUEL^® (quetiapine fumarate) tablets, AstraZeneca Canada

    Inc., Date of Revision: May 21, 2008 Control No.: 120108.