DRUG INTERACTIONS

7 The risks of using quetiapine in combination with other drugs have not been extensively evaluated in systematic studies.

Given the primary CNS effects of quetiapine, caution should be used when it is taken in combination with other centrally acting drugs.

Quetiapine potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with selected psychotic disorders, and alcoholic beverages should be avoided while taking quetiapine fumarate tablets.

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

Quetiapine may antagonize the effects of levodopa and dopamine agonists.

The use of quetiapine should be avoided in combination with drugs known to increase QT interval, and caution should be exercised when quetiapine is used in combination with drugs known to cause electrolyte imbalance [ see Warnings and Precautions (5.12)].

There have been literature reports suggesting false positive results in urine enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine.

Caution should be exercised in the interpretation of positive urine drug screen results for these drugs, and confirmation by alternative analytical technique (e.g.

chromatographic methods) should be considered.

P450 3A Inhibitors: May decrease the clearance of quetiapine.

Lower doses of quetiapine may be required.

( 7.1 ) Hepatic Enzyme Inducers: May increase the clearance of quetiapine.

Higher doses of quetiapine may be required with phenytoin or other inducers.

( 7.1 ) Centrally Acting Drugs: Caution should be used when quetiapine is used in combination with other CNS acting drugs.

( 7 ) Antihypertensive Agents: Quetiapine may add to the hypotensive effects of these agents.

( 7 ) Levodopa and Dopamine Agents: Quetiapine may antagonize the effect of these drugs.

( 7 ) Drugs known to cause electrolyte imbalance or increase QT interval: Caution should be used when quetiapine is used concomitantly with these drugs.

( 7 ) Interference with Urine Drug Screens: False positive urine drug screens using immunoassays for methadone or tricyclic antidepressants (TCAs) in patients taking quetiapine have been reported.

( 7 ).

7.1 The Effect of Other Drugs on Quetiapine Phenytoin: Coadministration of quetiapine (250 mg three times daily) and phenytoin (100 mg three times daily) increased the mean oral clearance of quetiapine by 5-fold.

Increased doses of quetiapine may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other hepatic enzyme inducers (e.g., carbamazepine, barbiturates, rifampin, glucocorticoids).

Caution should be taken if phenytoin is withdrawn and replaced with a non-inducer (e.g., valproate) [see Dosage and Administration (2)].

Divalproex: Coadministration of quetiapine (150 mg twice daily) and divalproex (500 mg twice daily) increased the mean maximum plasma concentration of quetiapine at steady state by 17% without affecting the extent of absorption or mean oral clearance.

Thioridazine: Thioridazine (200 mg twice daily) increased the oral clearance of quetiapine (300 mg twice daily) by 65%.

Cimetidine: Administration of multiple daily doses of cimetidine (400 mg three times daily for 4 days) resulted in a 20% decrease in the mean oral clearance of quetiapine (150 mg three times daily).

Dosage adjustment for quetiapine is not required when it is given with cimetidine.

P450 3A Inhibitors: Coadministration of ketoconazole (200 mg once daily for 4 days), a potent inhibitor of cytochrome P450 3A, reduced oral clearance of quetiapine by 84%, resulting in a 335% increase in maximum plasma concentration of quetiapine.

Caution (reduced dosage) is indicated when quetiapine is administered with ketoconazole and other inhibitors of cytochrome P450 3A (e.g., itraconazole, fluconazole, erythromycin, and protease inhibitors).

Fluoxetine, Imipramine, Haloperidol, and Risperidone: Coadministration of fluoxetine (60 mg once daily), imipramine (75 mg twice daily), haloperidol (7.5 mg twice daily), or risperidone (3 mg twice daily) with quetiapine (300 mg twice daily) did not alter the steady-state pharmacokinetics of quetiapine.

7.2 Effect of Quetiapine on Other Drugs Lorazepam: The mean oral clearance of lorazepam (2 mg, single dose) was reduced by 20% in the presence of quetiapine administered as 250 mg three times daily dosing.

Divalproex: The mean maximum concentration and extent of absorption of total and free valproic acid at steady state were decreased by 10 to 12% when divalproex (500 mg twice daily) was administered with quetiapine (150 mg twice daily).

The mean oral clearance of total valproic acid (administered as divalproex 500 mg twice daily) was increased by 11% in the presence of quetiapine (150 mg twice daily).

The changes were not significant.

Lithium: Concomitant administration of quetiapine (250 mg three times daily) with lithium had no effect on any of the steady-state pharmacokinetic parameters of lithium.

Antipyrine: Administration of multiple daily doses up to 750 mg/day (on a three times daily schedule) of quetiapine to subjects with selected psychotic disorders had no clinically relevant effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites.

These results indicate that quetiapine does not significantly induce hepatic enzymes responsible for cytochrome P450 mediated metabolism of antipyrine.

OVERDOSAGE

10 10.1 Human Experience In clinical trials, survival has been reported in acute overdoses of up to 30 grams of quetiapine.

Most patients who overdosed experienced no adverse reactions or recovered fully from the reported reactions.

Death has been reported in a clinical trial following an overdose of 13.6 grams of quetiapine alone.

In general, reported signs and symptoms were those resulting from an exaggeration of the drugs known pharmacological effects, ie, drowsiness and sedation, tachycardia and hypotension.

Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose [see Warnings and Precautions (5)].

One case, involving an estimated overdose of 9600 mg, was associated with hypokalemia and first degree heart block.

In post-marketing experience, there were cases reported of QT prolongation with overdose.

There were also very rare reports of overdose of quetiapine alone resulting in death or coma.

10.2 Management of Overdosage In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation.

Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.

The possibility of obtundation, seizure or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

If antiarrhythmic therapy is administered, disopyramide, procainamide and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with acute overdosage of quetiapine.

Similarly it is reasonable to expect that the alpha-adrenergic-blocking properties of bretylium might be additive to those of quetiapine, resulting in problematic hypotension.

There is no specific antidote to quetiapine.

Therefore, appropriate supportive measures should be instituted.

The possibility of multiple drug involvement should be considered.

Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of quetiapine-induced alpha blockade).

In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.

Close medical supervision and monitoring should continue until the patient recovers.

DESCRIPTION

11 Quetiapine fumarate is a psychotropic agent belonging to a chemical class, the dibenzothiazepine derivatives.

The chemical designation is 2-[2-(4-dibenzo [b,f] [1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate (2:1) (salt).

It is present in tablets as the fumarate salt.

All doses and tablet strengths are expressed as milligrams of base, not as fumarate salt.

Its molecular formula is C 42 H 50 N 6 O 4 S 2 •C 4 H 4 O 4 and it has a molecular weight of 883.11 (fumarate salt).

The structural formula is: Quetiapine fumarate is a white to off-white crystalline powder which is moderately soluble in water.

Quetiapine fumarate tablets are supplied for oral administration as 25 mg (round, peach), 50 mg (round, white), 100 mg (round, yellow), 200 mg (round, white), 300 mg (capsule-shaped, white), and 400 mg (capsule-shaped, yellow) tablets.

Inactive ingredients are croscarmellose sodium, colloidal silicon dioxide, fumaric acid, ethylcellulose, magnesium stearate, hypromellose, hydroxylpropyl cellulose, polyethylene glycol, and titanium dioxide.

The 25 mg tablets also contain red ferric oxide and yellow ferric oxide and the 100 mg and 400 mg tablets contain only yellow ferric oxide.

Chemical Structure- Quetiapine Fumarate

CLINICAL STUDIES

14 14.1 Schizophrenia Adults The efficacy of quetiapine in the treatment of schizophrenia was established in 3 short-term (6 week) controlled trials of inpatients with schizophrenia who met DSM III-R criteria for schizophrenia.

Although a single fixed dose haloperidol arm was included as a comparative treatment in one of the three trials, this single haloperidol dose group was inadequate to provide a reliable and valid comparison of quetiapine and haloperidol.

Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia.

The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients.

A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.

The results of the trials follow: In a 6 week, placebo-controlled trial (n=361) involving 5 fixed doses of quetiapine fumarate (75 mg/day, 150 mg/day, 300 mg/day, 600 mg/day and 750 mg/day given in divided doses three times per day), the 4 highest doses of quetiapine fumarate tablets 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 mg/day to 750 mg/day were generally indistinguishable.

In a 6 week, placebo-controlled trial (n=286) involving titration of quetiapine fumarate in high (up to 750 mg/day given in divided doses three times per day) and low (up to 250 mg/day given in divided doses three times per day) doses, only the high dose quetiapine fumarate group (mean dose, 500 mg/day) was superior to placebo on the BPRS total score, the BPRS psychosis cluster, and the CGI severity score.

In a 6 week dose and dose regimen comparison trial (n=618) involving two fixed doses of quetiapine fumarate(450 mg/day given in divided doses both twice daily and three times daily and 50 mg/day given in divided doses twice daily), only the 450 mg/day (225 mg given twice daily) dose group was superior to the 50 mg/day (25 mg given twice daily) quetiapine fumarate dose group on the BPRS total score, the BPRS psychosis cluster, and the CGI severity score.

Examination of population subsets (race, gender, and age) did not reveal any differential responsiveness on the basis of race or gender, with an apparently greater effect in patients under the age of 40 years compared to those older than 40.

The clinical significance of this finding is unknown.

Adolescents (ages 13-17) Clinical trial information in patients (13 to 17 years of age) with schizophrenia is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for such use in those adolescent patients.

14.2 Bipolar Disorder Manic Episodes Adults The efficacy of quetiapine fumarate in the acute treatment of manic episodes was established in 3 placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder with manic episodes.

These trials included patients with or without psychotic features and excluded patients with rapid cycling and mixed episodes.

Of these trials, 2 were monotherapy (12 weeks) and 1 was adjunct therapy (3 weeks) to either lithium or divalproex.

Key outcomes in these trials were change from baseline in the Young Mania Rating Scale (YMRS) score at 3 and 12 weeks for monotherapy and at 3 weeks for adjunct therapy.

Adjunct therapy is defined as the simultaneous initiation or subsequent administration of quetiapine fumarate with lithium or divalproex.

The primary rating instrument used for assessing manic symptoms in these trials was YMRS, an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score).

The results of the trials follow: Monotherapy The efficacy of quetiapine fumarate in the acute treatment of bipolar mania was established in 2 placebo-controlled trials.

In two 12-week trials (n=300, n=299) comparing quetiapine fumarate to placebo, quetiapine fumarate was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12.

The majority of patients in these trials taking quetiapine fumarate were dosed in a range between 400 mg/day and 800 mg per day.

Adjunct Therapy In this 3-week placebo-controlled trial, 170 patients with bipolar mania (YMRS > 20) were randomized to receive quetiapine fumarate or placebo as adjunct treatment to lithium or divalproex.

Patients may or may not have received an adequate treatment course of lithium or divalproex prior to randomization.

Quetiapine fumarate was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score.

The majority of patients in this trial taking quetiapine fumarate tablets were dosed in a range between 400 mg/day and 800 mg per day.

In a similarly designed trial (n=200), quetiapine fumarate was associated with an improvement in YMRS scores but did not demonstrate superiority to placebo, possibly due to a higher placebo effect.

Children and Adolescents (ages 10-17) Clinical trial use information in patients (10 to 17 years of age) with bipolar mania is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients.

Depressive Episodes Adults The efficacy of quetiapine fumarate for the acute treatment of depressive episodes associated with bipolar disorder was established in 2 identically designed 8-week, randomized, double-blind, placebo-controlled studies (N=1045).

These studies included patients with either bipolar I or II disorder and those with or without a rapid cycling course.

Patients randomized to quetiapine fumarate were administered fixed doses of either 300 mg or 600 mg once daily.

The primary rating instrument used to assess depressive symptoms in these studies was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10 item clinician-rated scale with scores ranging from 0 to 60.

The primary endpoint in both studies was the change from baseline in MADRS score at week 8.

In both studies, quetiapine fumarate was superior to placebo in reduction of MADRS score.

Improvement in symptoms, as measured by change in MADRS score relative to placebo, was seen in both studies at Day 8 (week 1) and onwards.

In these studies, no additional benefit was seen with the 600 mg dose.

For the 300 mg dose group, statistically significant improvements over placebo were seen in overall quality of life and satisfaction related to various areas of functioning, as measured using the Q-LES-Q(SF).

Maintenance Treatment as an Adjunct to Lithium or Divalproex The efficacy of quetiapine fumarate in the maintenance treatment of bipolar I disorder was established in 2 placebo-controlled trials in patients (n=1326) who met DSM-IV criteria for bipolar I disorder.

The trials included patients whose most recent episode was manic, depressed, or mixed, with or without psychotic features.

In the open-label phase, patients were required to be stable on quetiapine fumarate plus lithium or divalproex for at least 12 weeks in order to be randomized.

On average, patients were stabilized for 15 weeks.

In the randomization phase, patients continued treatment with lithium or divalproex and were randomized to receive either quetiapine fumarate (administered twice daily totaling 400 mg/day to 800 mg/day) or placebo.

Approximately 50% of the patients had discontinued from the quetiapine fumarate group by day 280 and 50% of the placebo group had discontinued by day 117 of double-blind treatment.

The primary endpoint in these studies was time to recurrence of a mood event (manic, mixed or depressed episode).

A mood event was defined as medication initiation or hospitalization for a mood episode; YMRS score ≥ 20 or MADRS score ≥ 20 at 2 consecutive assessments; or study discontinuation due to a mood event.

In both studies, quetiapine fumarate was superior to placebo in increasing the time to recurrence of any mood event.

The treatment effect was present for increasing time to recurrence of both manic and depressed episodes.

The effect of quetiapine fumarate was independent of any specific subgroup (assigned mood stabilizer, sex, age, race, most recent bipolar episode, or rapid cycling course).

HOW SUPPLIED

16 /STORAGE AND HANDLING 25 mg Tablets : Peach, round, biconvex, film coated tablets.

Engraved with ‘APO’ on one side and “QUE’ over ‘25’ on the other side.

They are supplied as follows: Bottles of 100 (NDC 60429-371-01) Bottles of 1000 (NDC 60429-371-10) 50 mg Tablets : White, round, biconvex, film coated tablets.

Engraved with ‘APO’ on one side and ‘QUE’ over ‘50’ on the other side.

They are supplied as follows: Bottles of 100 (NDC 60429-372-01) Bottles of 1000 (NDC 60429-372-10) 100 mg Tablets : Yellow, round, biconvex film coated tablets.

Engraved with ‘APO’ on one side and ‘QUE’ over ‘100’ on the other side.

They are supplied as follows: Bottles of 100 (NDC 60429-373-01) Bottles of 1000 (NDC 60429-373-10) 200 mg Tablets : White, round, biconvex, film coated tablets.

Engraved ‘APO’ on one side and ‘QUE’ over ‘200’ on the other side.

They are supplied as follows: Bottles of 100 (NDC 60429-374-01) Bottles of 1000 (NDC 60429-374-10) 300 mg Tablets : White, capsule-shaped, biconvex, film coated tablets.

Engraved ‘APO’ on one side and ‘QUE300’ on the other side.

They are supplied as follows: Bottles of 60 (NDC 60429-375-60) 400 mg Tablets : Yellow, capsule-shaped, biconvex, film coated tablets.

Engraved ‘APO’ on one side and ‘QUE 400’ on the other side.

They are supplied as follows: Bottles of 100 (NDC 60429-376-01) Storage Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15 to 30ºC (59 to 86ºF) [See USP Controlled Room Temperature].

RECENT MAJOR CHANGES

Warnings and Precautions, Hyperglycemia ( 5.4 ), 1/2011 Warnings and Precautions, Hyperlipidemia ( 5.5 ), 1/2011 Warnings and Precautions, Weight Gain ( 5.6 ), 1/2011 Warnings and Precautions, QT Prolongation ( 5.12 ), 6/2011 Warnings and Precautions, Hypothyroidism ( 5.14 ), 1/2011 Warnings and Precautions, Withdrawal ( 5.23 ), 5/2010

GERIATRIC USE

8.5 Geriatric Use Of the approximately 3700 patients in clinical studies with quetiapine, 7% (232) were 65 years of age or over.

In general, there was no indication of any different tolerability of quetiapine in the elderly compared to younger adults.

Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to quetiapine, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period in the elderly.

The mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly patients when compared to younger patients [ see Clinical Pharmacology (12) and Dosage and Administration (2)].

DOSAGE FORMS AND STRENGTHS

3 25 mg tablets 50 mg tablets 100 mg tablets 200 mg tablets 300 mg tablets 400 mg tablets 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, and 400 mg ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action The mechanism of action of quetiapine, as with other drugs having efficacy in the treatment of schizophrenia and bipolar disorder, is unknown.

However, it has been proposed that the efficacy of quetiapine in schizophrenia and its mood stabilizing properties in bipolar depression and mania are mediated through a combination of dopamine type 2 (D 2 ) and serotonin type 2 (5HT 2 ) antagonism.

Antagonism at receptors other than dopamine and 5HT 2 with similar receptor affinities may explain some of the other effects of quetiapine.

Quetiapine’s antagonism of histamine H 1 receptors may explain the somnolence observed with this drug.

Quetiapine’s antagonism of adrenergic α 1 receptors may explain the orthostatic hypotension observed with this drug.

INDICATIONS AND USAGE

1 Quetiapine Fumarate Tablets is an atypical antipsychotic indicated for the: Treatment of schizophrenia ( 1.1 ) • Adults: Efficacy was established in three 6 week clinical trials in patients with schizophrenia ( 14.1 ) Acute treatment of manic episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex ( 1.2 ) Adults: Efficacy was established in two 12 week monotherapy trials and in one 3 week adjunctive trial in patients with manic episodes associated with bipolar I disorder ( 14.2 ) Acute treatment of depressive episodes associated with bipolar disorder ( 1.2 ) Adults: Efficacy was established in two 8 week trials in patients with bipolar I or II disorder ( 14.2 ) Maintenance treatment of bipolar I disorder as an adjunct to lithium or divalproex ( 1.2 ) Adults: Efficacy was established in two maintenance trials in adults ( 14.2 ) 1.1 Schizophrenia Quetiapine fumarate tablets are indicated for the treatment of schizophrenia.

The efficacy of quetiapine fumarate tablets in schizophrenia was established in three 6 week trials in adults.

The effectiveness of quetiapine fumarate tablets for the maintenance treatment of schizophrenia has not been systematically evaluated in controlled clinical trials [see Clinical Studies (14.1)].

Pediatric use information in patients (13 to 17 years of age) with schizophrenia is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for use in those adolescent patients.

1.2 Bipolar Disorder Quetiapine fumarate tablets are indicated for the acute treatment of manic episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex.

Efficacy was established in two 12 week monotherapy trials in adults, in one 3 week adjunctive trial in adults [ see Clinical Studies (14.2)].

Quetiapine fumarate tablets are indicated as monotherapy for the acute treatment of depressive episodes associated with bipolar disorder.

Efficacy was established in two 8 week monotherapy trials in adult patients with bipolar I and bipolar II disorder [ see Clinical Studies (14.2)].

Quetiapine fumarate tablets are indicated for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex.

Efficacy was established in two maintenance trials in adults.

The effectiveness of quetiapine fumarate tablets as monotherapy for the maintenance treatment of bipolar disorder has not been systematically evaluated in controlled clinical trials [ see Clinical Studies (14.2)].

Pediatric use information in patients (10 to 17 years of age) with bipolar mania is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for use in those pediatric patients.

1.3 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder Pediatric use information in patients (13 to 17 years of age) with schizophrenia, and patients (10 to 17 years of age) with bipolar mania is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for use in those patients.

PEDIATRIC USE

8.4 Pediatric Use In general, the adverse reactions observed in children and adolescents during the clinical trials were similar to those in the adult population with few exceptions.

Increases in systolic and diastolic blood pressure occurred in children and adolescents and did not occur in adults.

Orthostatic hypotension occurred more frequently in adults (4 to 7%) compared to children and adolescents (< 1%).

Schizophrenia Safety and effectiveness of quetiapine in pediatric patients less than 13 years of age with schizophrenia have not been established.

Maintenance The safety and effectiveness of quetiapine in the maintenance treatment of bipolar disorder has not been established in pediatric patients less than 18 years of age.

The safety and effectiveness of quetiapine in the maintenance treatment of schizophrenia has not been established in any patient population, including pediatric patients.

Bipolar Mania Safety and effectiveness of quetiapine in pediatric patients less than 10 years of age with bipolar mania have not been established.

Bipolar Depression Safety and effectiveness of quetiapine in pediatric patients less than 18 years of age with bipolar depression have not been established.

Pediatric use information in patients (13 to 17 years of age) with schizophrenia, and patients (10 to 17 years of age) with bipolar mania is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for such use in those patients.

PREGNANCY

8.1 Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of quetiapine use in pregnant women.

In limited published literature, there were no major malformations associated with quetiapine exposure during pregnancy.

In animal studies, embryo-fetal toxicity occurred.

Quetiapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

There are limited published data on the use of quetiapine for treatment of schizophrenia and other psychiatric disorders during pregnancy.

In a prospective observational study, 21 women exposed to quetiapine and other psychoactive medications during pregnancy delivered infants with no major malformations.

Among 42 other infants born to pregnant women who used quetiapine during pregnancy, there were no major malformations reported (one study of 36 women, 6 case reports).

Due to the limited number of exposed pregnancies, these postmarketing data do not reliably estimate the frequency or absence of adverse outcomes.

When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no increase in the incidence of major malformations in fetuses at doses up to 2.4 times the maximum recommended human dose for schizophrenia (MRHD, 800 mg/day on a mg/m 2 basis); however, there was evidence of embryo-fetal toxicity.

In rats, delays in skeletal ossification occurred at 0.6 and 2.4 times the MRHD and in rabbits at 1.2 and 2.4 times the MRHD.

At 2.4 times the MRHD, there was an increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses and decreased fetal weights in both species.

Maternal toxicity (decreased body weights and/or death) occurred at 2.4 times the MRHD in rats and at 0.6 to 2.4 times the MRHD (all doses) in rabbits.

In a peri/postnatal reproductive study in rats, no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 0.01, 0.12, and 0.24 times the MRHD.

However, in a preliminary peri/postnatal study, there were increases in fetal and pup death, and decreases in mean litter weight at 3.0 times the MRHD.

Non-Teratogenic Effects Neonates exposed to antipsychotic drugs (including quetiapine), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates.

These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Quetiapine fumarate tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

8.3 Nursing Mothers Quetiapine was excreted into human milk.

It is recommended that women receiving quetiapine fumarate tablets should not breastfeed.

In published case reports, the level of quetiapine in breast milk ranged from undetectable to 170 μg/L.

The estimated infant dose ranged from 0.09% to 0.43% of the weight-adjusted maternal dose.

Based on a limited number (N=8) of mother/infant pairs, calculated infant daily doses range from less than 0.01 mg/kg (at a maternal daily dose up to 100 mg quetiapine) to 0.1 mg/kg (at a maternal daily dose of 400 mg).

BOXED WARNING

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks) largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.

Over the course of a typical 10 week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

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.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality.

The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

Quetiapine fumarate tablets are not approved for the treatment of patients with dementia-related psychosis [ see Warnings and Precautions (5.1)].

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See Full Prescribing Information for complete boxed warning.

Antipsychotic drugs are associated with an increased risk of death ( 5.1 ) Quetiapine is not approved for elderly patients with Dementia-Related Psychosis ( 5.1 )

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Atypical antipsychotic drugs, including quetiapine, are associated with an increased risk of death; causes of death are variable.

( 5.1 ) Suicidality and Antidepressant Drugs: Increased the risk of suicidal thinking and behavior in children, adolescents and young adults taking antidepressants for major depressive disorder and other psychiatric disorders.

( 5.2 ) Neuroleptic Malignant Syndrome (NMS): Manage with immediate discontinuation and close monitoring.

( 5.3 ) Hyperglycemia and Diabetes Mellitus (DM): Ketoacidosis, hyperosmolar coma and death have been reported in patients treated with atypical antipsychotics, including quetiapine.

Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

When starting treatment, patients with diabetes or risk factors for diabetes should undergo blood glucose testing before and during treatment.

( 5.4 ) Hyperlipidemia: Undesirable alterations in lipids have been observed.

Increases in total cholesterol, LDL-cholesterol and triglycerides and decreases in HDL-cholesterol have been reported in clinical trials.

Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically during treatment.

( 5.5 ) Weight Gain: Patients should receive regular monitoring of weight.

( 5.6 ) Tardive Dyskinesia: Discontinue if clinically appropriate.

( 5.7 ) Orthostatic Hypotension: Associated dizziness, tachycardia and syncope may occur especially during the initial dose titration period.

( 5.8 ) Increased Blood Pressure in Children and Adolescents: Blood pressure should be measured at the beginning of, and periodically during treatment in children and adolescents.

( 5.9 ) Leukopenia, Neutropenia and Agranulocytosis have been reported with atypical antipsychotics including quetiapine fumarate tablets.

Patients with a pre-existing low white cell count (WBC) or a history of leukopenia/neutropenia should have complete blood count (CBC) monitored frequently during the first few months of treatment and should discontinue quetiapine fumarate at the first sign of a decline in WBC in absence of other causative factors.

( 5.10 ) Cataracts: Lens changes have been observed in patients during long-term quetiapine treatment.

Lens examination is recommended when starting treatment and at 6 month intervals during chronic treatment.

( 5.11 ) • QT Prolongation: Post-marketing case show increases in QT interval in patients who overdosed on quetiapine, in patients with concomitant illness, and in patients taking medicines know to cause electrolyte imbalance or increase QT interval.

Avoid use with drugs that increase the QT interval and in patients with risk factors for prolonged QT interval.

( 5.12 ) Suicide: The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder, and close supervision of high risk patients should accompany drug therapy.

( 5.21 ) See Full Prescribing Information for additional WARNINGS and PRECAUTIONS .

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Quetiapine fumarate tablets are not approved for the treatment of patients with dementia-related psychosis ( see Boxed Warning ).

5.2 Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.

Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.

The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.

There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.

There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.

The risk differences (drug vs.

placebo), however, were relatively stable within age strata and across indications.

These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1: Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18–24 5 additional cases Decreases Compared to Placebo 25–64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials.

There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.

However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.

Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers.

Such monitoring should include daily observation by families and caregivers.

Prescriptions for quetiapine fumarate tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder.

It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.

Whether any of the symptoms described above represent such a conversion is unknown.

However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

It should be noted that quetiapine fumarate tablets are approved for use in treating adult bipolar depression.

5.3 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including quetiapine fumarate.

Rare cases of NMS have been reported with quetiapine fumarate.

Clinical manifestations of NMS are hyperpyrexia, 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.

The diagnostic evaluation of patients with this syndrome is complicated.

In arriving at a diagnosis, it is important to exclude 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 (EPS).

Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available.

There is no general agreement about specific pharmacological treatment regimens for 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.

5.4 Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including quetiapine.

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 hyperglycemia-related adverse reactions is not completely understood.

However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.

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.

Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing.

In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose and lipids was observed in clinical studies.

Changes in these parameters should be managed as clinically appropriate.

Adults: Table 2: Fasting Glucose — Proportion of Patients Shifting to ≥ 126 mg/dL in Short-Term (≤ 12 weeks) Placebo-Controlled Studies Laboratory Analyte Category Change (At Least Once) from Baseline Treatment Arm N Patients n (%) Fasting Glucose Normal to High (<100 mg/dL to ≥ 126 mg/dL) Quetiapine 2907 71 (2.4%) Placebo 1346 19 (1.4%) Borderline to High (≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL) Quetiapine 572 67 (11.7%) Placebo 279 33 (11.8%) In a 24 week trial (active-controlled, 115 patients treated with quetiapine fumarate) 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 ≥ 200 mg/dL was 1.7% and the incidence of a fasting treatment-emergent blood glucose level ≥ 126 mg/dL was 2.6%.

The mean change in fasting glucose from baseline was 3.2 mg/dL and mean change in 2 hour glucose from baseline was -1.8 mg/dL for quetiapine.

In 2 long-term placebo-controlled randomized withdrawal clinical trials for bipolar maintenance, mean exposure of 213 days for quetiapine (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 mg/dL for quetiapine and –0.05 mg/dL for placebo.

The exposure-adjusted rate of any increased blood glucose level (≥ 126 mg/dL) for patients more than 8 hours since a meal (however, some patients may not have been precluded from calorie intake from fluids during fasting period) was 18.0 per 100 patient years for quetiapine (10.7% of patients; n=556) and 9.5 for placebo per 100 patient years (4.6% of patients; n=581).

Children and Adolescents: In a placebo-controlled quetiapine monotherapy study of adolescent patients (13 to 17 years of age) with schizophrenia (6 weeks duration), the mean change in fasting glucose levels for quetiapine (n=138) compared to placebo (n=67) was -0.75 mg/dL versus -1.70 mg/dL.

In a placebo controlled quetiapine monotherapy study of children and adolescent patients (10 to 17 years of age) with bipolar mania (3 weeks duration), the mean change in fasting glucose level for quetiapine (n=170) compared to placebo (n=81) was 3.62 mg/dL versus -1.17 mg/dL.

No patient in either study with a baseline normal fasting glucose level (<100 mg/dL) or a baseline borderline fasting glucose level (≥100 mg/dL and <126 mg/dL) had a treatment-emergent blood glucose level of ≥126 mg/dL.

5.5 Hyperlipidemia Undesirable alterations in lipids have been observed with quetiapine use.

Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using quetiapine is recommended.

In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose and lipids was observed in clinical studies.

Changes in these parameters should be managed as clinically appropriate.

Adults: Table 3 shows the percentage of adult patients with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline by indication in clinical trials with quetiapine fumarate.

Table 3: Percentage of Adult Patients with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication Laboratory Analyte Indication Treatment Arm N Patients n (%) Total Cholesterol ≥ 240 mg/dL Schizophrenia 6 weeks duration Quetiapine Fumarate 137 24 (18%) Placebo 92 6 (7%) Bipolar Depression 8 weeks duration Quetiapine Fumarate 463 41 (9%) Placebo 250 15 (6%) Triglycerides ≥200 mg/dL Schizophrenia Quetiapine Fumarate 120 26 (22%) Placebo 70 11 (16%) Bipolar Depression Quetiapine Fumarate 436 59 (14%) Placebo 232 20 (9%) LDL-Cholesterol ≥ 160 mg/dL Schizophrenia Quetiapine Fumarate na Parameters not measured in the quetiapine fumarate registration studies for schizophrenia.

Lipid parameters also were not measured in the bipolar mania registration studies.

na Placebo na na Bipolar Depression Quetiapine Fumarate 465 29 (6%) Placebo 256 12 (5%) HDL-Cholesterol ≤ 40 mg/dL Schizophrenia Quetiapine Fumarate na na Placebo na na Bipolar Depression Quetiapine Fumarate 393 56 (14%) Placebo 214 29 (14%) Children and Adolescents: Table 4 shows the percentage of children and adolescents with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline in clinical trials with quetiapine fumarate.

Table 4: Percentage of Children and Adolescents with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels Laboratory Analyte Indication Treatment Arm N Patients n (%) Total Cholesterol ≥ 200 mg/dL Schizophrenia 13-17 years, 6 weeks duration Quetiapine Fumarate 107 13 (12%) Placebo 56 1 (2%) Bipolar Mania 10-17 years, 3 weeks duration Quetiapine Fumarate 159 16 (10%) Placebo 66 2 (3%) Triglycerides ≥150 mg/dL Schizophrenia Quetiapine Fumarate 103 17 (17%) Placebo 51 4 (8%) Bipolar Mania Quetiapine Fumarate 149 32 (22%) Placebo 60 8 (13%) LDL-Cholesterol ≥ 130 mg/dL Schizophrenia Quetiapine Fumarate 112 4 (4%) Placebo 60 1 (2%) Bipolar Mania Quetiapine Fumarate 169 13 (8%) Placebo 74 4 (5%) HDL-Cholesterol ≤ 40 mg/dL Schizophrenia Quetiapine Fumarate 104 16 (15%) Placebo 54 10 (19%) Bipolar Mania Quetiapine Fumarate 154 16 (10%) Placebo 61 4 (7%) 5.6 Weight Gain Increases in weight have been observed in clinical trials.

Patients receiving quetiapine should receive regular monitoring of weight [ see Patient Counseling Information (17)].

In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose and lipids was observed in clinical studies.

Changes in these parameters should be managed as clinically appropriate.

Adults: In clinical trials with quetiapine fumarate the following increases in weight have been reported.

Table 5: Proportion of Patients with Weight Gain ≥7% of Body Weight (Adults) Vital Sign Indication Treatment Arm N Patients n (%) Weight Gain ≥7% of Body Weight Schizophrenia up to 6 weeks duration Quetiapine Fumarate 391 89 (23%) Placebo 206 11 (6%) Bipolar Mania (monotherapy) up to 12 weeks duration Quetiapine Fumarate 209 44 (21%) Placebo 198 13 (7%) Bipolar Mania (adjunct therapy) up to 3 weeks duration Quetiapine Fumarate 196 25 (13%) Placebo 203 8 (4%) Bipolar Depression up to 8 weeks duration Quetiapine Fumarate 554 47 (8%) Placebo 295 7 (2%) Children and Adolescents: In two clinical trials with quetiapine fumarate, one in bipolar mania and one in schizophrenia, reported increases in weight are included in the table below.

Table 6: Proportion of Patients with Weight Gain ≥7% of Body Weight (Children and Adolescents) Vital Sign Indication Treatment Arm N Patients n (%) Weight Gain ≥7% of Body Weight Schizophrenia : 6 weeks duration Quetiapine Fumarate 111 23 (21%) Placebo 44 3 (7%) Bipolar Mania : 3 weeks duration Quetiapine Fumarate 157 18 (12%) Placebo 68 0 (0%) The mean change in body weight in the schizophrenia trial was 2.0 kg in the quetiapine fumarate group and -0.4 kg in the placebo group and in the bipolar mania trial it was 1.7 kg in the quetiapine fumarate group and 0.4 kg in the placebo group.

In an open-label study that enrolled patients from the above two pediatric trials, 63% of patients (241/380) completed 26 weeks of therapy with quetiapine fumarate.

After 26 weeks of treatment, the mean increase in body weight was 4.4 kg.

Forty-five percent of the patients gained ≥ 7% of their body weight, not adjusted for normal growth.

In order to adjust for normal growth over 26 weeks an increase of at least 0.5 standard deviation from baseline in BMI was used as a measure of a clinically significant change; 18.3% of patients on Quetiapine fumarate met this criterion after 26 weeks of treatment.

When treating pediatric patients with quetiapine fumarate for any indication, weight gain should be assessed against that expected for normal growth.

5.7 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including quetiapine.

Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.

Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia 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 or may even arise after discontinuation of treatment.

There is no known treatment for established cases of tardive dyskinesia, 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 fumarate should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.

Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) 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 tardive dyskinesia appear in a patient on quetiapine fumarate, drug discontinuation should be considered.

However, some patients may require treatment with quetiapine fumarate despite the presence of the syndrome.

5.8 Orthostatic Hypotension Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α1-adrenergic antagonist properties.

Syncope was reported in 1% (28/3265) of the patients treated with quetiapine fumarate, compared with 0.2% (2/954) on placebo and about 0.4% (2/527) on active control drugs.

Orthostatic hypotension, dizziness, and syncope may lead to falls.

Quetiapine fumarate should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications) [ see Adverse Reactions (6.2)].

The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 25 mg twice daily [ see Dosage and Administration (2)].

If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.

5.9 Increases in Blood Pressure in Children and Adolescents In placebo-controlled trials in children and adolescents with schizophrenia (6 week duration) or bipolar mania (3 week duration), the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 15.2% (51/335) for quetiapine fumarate and 5.5% (9/163) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 40.6% (136/335) for quetiapine fumarate and 24.5% (40/163) for placebo.

In the 26 week open-label clinical trial, one child with a reported history of hypertension experienced a hypertensive crisis.

Blood pressure in children and adolescents should be measured at the beginning of, and periodically during treatment.

5.10 Leukopenia, Neutropenia and Agranulocytosis In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including quetiapine fumarate.

Agranulocytosis (including fatal cases) has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white cell count (WBC) and history of drug induced leukopenia/neutropenia.

Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue quetiapine fumarate at the first sign of a decline in WBC in absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur.

Patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) should discontinue quetiapine fumarate and have their WBC followed until recovery [ see Adverse Reactions (6.2)].

5.11 Cataracts The development of cataracts was observed in association with quetiapine treatment in chronic dog studies [ see Nonclinical Toxicology, Animal Toxicology (13.2)].

Lens changes have also been observed in adults, children and adolescents during long-term quetiapine treatment, but a causal relationship to quetiapine use has not been established.

Nevertheless, the possibility of lenticular changes cannot be excluded at this time.

Therefore, examination of the lens by methods adequate to detect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6-month intervals during chronic treatment.

5.12 QT Prolongation In clinical trials quetiapine was not associated with a persistent increase in QT intervals.

However, the QT effect was not systematically evaluated in a thorough QT study.

In post marketing experience, there were cases reported of QT prolongation in patients who overdosed on quetiapine [see Overdosage (10.1)], in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval [see Drug Interactions (7)].

The use of quetiapine should be avoided in combination with other drugs that are known to prolong QTc including Class 1A antiarrythmics (e.g., quinidine, procainamide) or Class III antiarrythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone).

Quetiapine should also be avoided in circumstances that may increase the risk of occurrence of torsade de pointes and/or sudden death including (1) a history of cardiac arrhythmias such as bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

Caution should also be exercised when quetiapine is prescribed in patients with increased risk of QT prolongation (e.g.

cardiovascular disease, family history of QT prolongation, the elderly, congestive heart failure and heart hypertrophy).

5.13 Seizures During clinical trials, seizures occurred in 0.5% (20/3490) of patients treated with quetiapine fumarate compared to 0.2% (2/954) on placebo and 0.7% (4/527) on active control drugs.

As with other antipsychotics, quetiapine fumarate should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia.

Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

5.14 Hypothyroidism Adults: Clinical trials with quetiapine demonstrated a dose-related decreases in thyroid hormone levels.

The reduction in total and free thyroxine (T4) of approximately 20% at the higher end of the therapeutic dose range was maximal in the first six weeks of treatment and maintained without adaptation or progression during more chronic therapy.

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.

About 0.7% (26/3489) of quetiapine patients did experience TSH increases in monotherapy studies.

Some patients with TSH increases needed replacement thyroid treatment.

In the mania adjunct studies, where quetiapine was added to lithium or divalproex, 12% (24/196) of quetiapine-treated patients compared to 7% (15/203) of placebo-treated patients had elevated TSH levels.

Of the quetiatpine-treated patients with elevated TSH levels, 3 had simultaneous low free T4 levels.

In all quetiapine trials, the incidence of potentially clinically significant shifts in thyroid hormones and TSH were*: decrease in free T4, 2.0% (357/17513); decrease in total T4, 4.0% (75/1861); decrease in free T3, 0.4% (53/13766); decrease in total T3, 2.0% (26/1312), and increase in TSH, 4.9% (956/19412).

In eight patients, where TBG was measured, levels of TBG were unchanged.

Table 7 shows the incidence of these shifts in short-term placebo-controlled clinical trials.

Table 7: Incidence of potentially clinically significant shifts in thyroid hormone levels and TSH in short term placebo-controlled clinical trials Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline.

Shifts in total T 4 , free T 4 , total T 3 and free T 3 are defined as 5 mIU/L at any time.

Total T 4 Free T 4 Total T 3 Free T 3 TSH Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo 3.4 % (37/1097) 0.6% (4/651) 0.7% (52/7218) 0.1% (4/3668) 0.5% (2/369) 0.0% (0/113) 0.2% (11/5673) 0.0% (1/2679) 3.2% (240/7587) 2.7% (105/3912) In short-term placebo-controlled monotherapy trials, the incidence of reciprocal, potentially clinically significant shifts in T 3 and TSH was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for T 4 and TSH the shifts were 0.1% (7/6154) for quetiapine versus 0.0% (1/3007) for placebo.

Generally, these changes in thyroid hormone levels were of no clinical significance.

Children and Adolescents: In acute placebo-controlled trials in children and adolescent patients with schizophrenia (6 week duration) or bipolar mania (3 week duration), the incidence of shifts to potentially clinically important thyroid function values at any time for quetiapine treated patients and placebo-treated patients for elevated TSH was 2.9% (8/280) vs.

0.7% (1/138), respectively and for decreased total thyroxine was 2.8% (8/289) vs.

0% (0/145, respectively).

Of the quetiapine treated patients with elevated TSH levels, 1 had simultaneous low free T4 level at end of treatment.

5.15 Hyperprolactinemia Adults: During clinical trials with quetiapine, the incidence of shifts in prolactin levels to a clinically significant value occurred in 3.6% (158/4416) of patients treated with quetiapine compared to 2.6% (51/1968) on placebo.

Children and Adolescents: In acute placebo-controlled trials in children and adolescent patients with bipolar mania (3 week duration) or schizophrenia (6 week duration), the incidence of shifts in prolactin levels to a clinically significant value (>20 µg/L males; > 26 µg/L females at any time) was 13.4% (18/134) for quetiapine compared to 4% (3/75) for placebo in males and 8.7% (9/104) for quetiapine compared to 0% (0/39) for placebo in females.

Like other drugs that antagonize dopamine D2 receptors, quetiapine elevates prolactin levels in some patients and the elevation may persist during chronic administration.

Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion.

This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients.

Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer.

As is common with compounds which increase prolactin release, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in carcinogenicity studies conducted in mice and rats.

Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive [ see Carcinogenesis, Mutagenesis, Impairment of Fertility (13.1)].

5.16 Transaminase Elevations Asymptomatic, transient and reversible elevations in serum transaminases (primarily ALT) have been reported.

In schizophrenia trials in adults, the proportions of patients with transaminase elevations of > 3 times the upper limits of the normal reference range in a pool of 3 to 6 week placebo-controlled trials were approximately 6% (29/483) for quetiapine fumarate compared to 1% (3/194) for placebo.

In acute bipolar mania trials in adults, the proportions of patients with transaminase elevations of > 3 times the upper limits of the normal reference range in a pool of 3 to 12 week placebo-controlled trials were approximately 1% for both quetiapine fumarate (3/560) and placebo (3/294).

These hepatic enzyme elevations usually occurred within the first 3 weeks of drug treatment and promptly returned to pre-study levels with ongoing treatment with quetiapine fumarate.

In bipolar depression trials, the proportions of patients with transaminase elevations of > 3 times the upper limits of the normal reference range in two 8 week placebo-controlled trials was 1% (5/698) for quetiapine fumarate and 2% (6/347) for placebo.

5.17 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse event reported in patients treated with quetiapine fumarate especially during the 3-5 day period of initial dose-titration.

In schizophrenia trials, somnolence was reported in 18% (89/510) of patients on quetiapine fumarate compared to 11% (22/206) of placebo patients.

In acute bipolar mania trials using quetiapine fumarate as monotherapy, somnolence was reported in 16% (34/209) of patients on quetiapine fumarate compared to 4% of placebo patients.

In acute bipolar mania trials using quetiapine fumarate as adjunct therapy, somnolence was reported in 34% (66/196) of patients on quetiapine fumarate compared to 9% (19/203) of placebo patients.

In bipolar depression trials, somnolence was reported in 57% (398/698) of patients on quetiapine fumarate compared to 15% (51/347) of placebo patients.

Since quetiapine fumarate has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that quetiapine fumarate therapy does not affect them adversely.

Somnolence may lead to falls.

5.18 Priapism One case of priapism in a patient receiving quetiapine fumarate has been reported prior to market introduction.

While a causal relationship to use of quetiapine fumarate has not been established, other drugs with alpha-adrenergic blocking effects have been reported to induce priapism, and it is possible that quetiapine fumarate may share this capacity.

Severe priapism may require surgical intervention.

5.19 Body Temperature Regulation Although not reported with quetiapine fumarate, disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents.

Appropriate care is advised when prescribing quetiapine fumarate tablets for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

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

5.21 Suicide The possibility of a suicide attempt is inherent in bipolar disorder and schizophrenia; close supervision of high risk patients should accompany drug therapy.

Prescriptions for quetiapine fumarate should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.

In two 8 week clinical studies in patients with bipolar depression (N=1048), the incidence of treatment emergent suicidal ideation or suicide attempt was low and similar to placebo (quetiapine fumarate 300 mg, 6/350, 1.7%; quetiapine fumarate 600 mg, 9/348, 2.6%; Placebo, 7/347, 2.0%).

5.22 Use in Patients with Concomitant Illness Clinical experience with quetiapine fumarate in patients with certain concomitant systemic illnesses is limited [ see Pharmacokinetics (12.3)].

Quetiapine fumarate has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease.

Patients with these diagnoses were excluded from premarketing clinical studies.

Because of the risk of orthostatic hypotension with quetiapine fumarate, caution should be observed in cardiac patients [ see Warnings and Precautions (5.8)].

5.23 Withdrawal Acute withdrawal symptoms, such as insomnia, nausea, and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including quetiapine fumarate.

In short-term placebo-controlled, monotherapy clinical trials with quetiapine fumarate extended-release tablets that included a discontinuation phase which evaluated discontinuation symptoms, the aggregated incidence of patients experiencing one or more discontinuation symptoms after abrupt cessation was 12.1% (241/1993) for quetiapine fumarate extended-release tablets and 6.7% (71/1065) for placebo.

The incidence of the individual adverse events (i.e., insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability) did not exceed 5.3% in any treatment group and usually resolved after 1 week post-discontinuation.

Gradual withdrawal is advised.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION [see Medication Guide] Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with quetiapine fumarate tablets and should counsel them in its appropriate use.

A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for quetiapine fumarate tablets.

The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents.

Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.

The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking quetiapine fumarate tablets.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at increased risk of death compared with placebo.

Quetiapine is not approved for elderly patients with dementia-related psychosis [ see Warnings and Precautions (5.1)].

Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down.

Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt.

Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [ see Warnings and Precautions (5.2)].

Neuroleptic Malignant Syndrome (NMS) Patients should be advised to report to their physician any signs or symptoms that may be related to NMS.

These may include muscle stiffness and high fever [ see Warnings and Precautions (5.3)].

Hyperglycemia and Diabetes Mellitus Patients should be aware of the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus.

Patients who are diagnosed with diabetes, those with risk factors for diabetes, or those that develop these symptoms during treatment should have their blood glucose monitored at the beginning of and periodically during treatment [ see Warnings and Precautions (5.4)].

Hyperlipidemia Patients should be advised that elevations in total cholesterol, LDL–cholesterol and triglycerides and decreases in HDL-cholesterol may occur.

Patients should have their lipid profile monitored at the beginning of and periodically during treatment [ see Warnings and Precautions (5.5)].

Weight Gain Patients should be advised that they may experience weight gain.

Patients should have their weight monitored regularly [ see Warnings and Precautions (5.6)].

Orthostatic Hypotension Patients should be advised of the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing, which may lead to falls), especially during the period of initial dose titration, and also at times of re-initiating treatment or increases in dose [ see Warnings and Precautions (5.8)].

Increased Blood Pressure in Children and Adolescents Blood pressure should be measured at the beginning of, and periodically during, treatment [ see Warnings and Precautions (5.9)].

Leukopenia/Neutropenia Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should be advised that they should have their CBC monitored while taking quetiapine fumarate tablets [see Warnings and Precautions (5.10)].

Interference with Cognitive and Motor Performance Patients should be advised of the risk of somnolence or sedation (which may lead to falls), especially during the period of initial dose titration.

Patients should be cautioned about performing any activity requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating machinery, until they are reasonably certain quetiapine therapy does not affect them adversely.

Patients should limit consumption of alcohol during treatment with quetiapine [see Warnings and Precautions (5.17)].

Heat Exposure and Dehydration Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.19).] Concomitant Medication As with other medications, patients should be advised to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs [see Warnings and Precautions (5.22)] Pregnancy and Nursing Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Patients should be advised not to breast feed if they are taking quetiapine [ see Use in Specific Populations (8.1) and (8.3)].

Need for Comprehensive Treatment Program Pediatric use information in patients (13 to 17 years of age) with schizophrenia, and patients (10 to 17 years of age) with bipolar mania is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for such use in those patients.

Manufactured by: Apotex Inc.

Toronto, Ontario Canada M9L 1T9 Manufactured for: Apotex Corp.

Weston, Florida USA 33326 Marketed/Packaged by: GSMS Inc.

Camarillo, CA 93012 Revised: July 2011

DOSAGE AND ADMINISTRATION

2 Quetiapine fumarate tablets can be taken with or without food.

Quetiapine fumarate tablets can be taken with or without food.

Indication Dosing Instructions After initial dosing, adjustments can be made upwards or downwards, if necessary, within the dose range depending upon the clinical response and tolerance of the patient.

Recommended Dose/Dose Range Schizophrenia-Adults (2.1) Day 1: 25 mg twice daily.

Increase in increments of 25 mg to 50 mg divided two or three times on Days 2 and 3 to range of 300 to 400 mg by Day 4.

Further adjustments can be made in increments of 25 to 50 mg twice a day, in intervals of not less than 2 days.

150 to 750 mg/day Bipolar Mania- Adults Monotherapy or as an adjunct to lithium or divalproex (2.2) Day 1: Twice daily dosing totaling 100 mg.

Day 2: Twice daily dosing totaling 200 mg.

Day 3: Twice daily dosing totaling 300 mg.

Day 4: Twice daily dosing totaling 400 mg.

Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day.

400 to 800 mg/day Bipolar Depression- Adults Administer once daily at bedtime.

Day 1: 50 mg.

Day 2: 100 mg.

Day 3: 200 mg.

Day 4: 300 mg.

300 mg/day Bipolar I Disorder Maintenance Therapy- Adults Administer twice daily totaling 400 to 800 mg/day as adjunct to lithium or divalproex.

Generally, in the maintenance phase, patients continued on the same dose on which they were stabilized.

2.1 Schizophrenia Adults Dose Selection—Quetiapine fumarate tablets should generally be administered with an initial dose of 25 mg twice daily, with increases in total daily dose of 25 mg to 50 mg divided in two or three doses on the second and third day, as tolerated, to a total dose range of 300 mg to 400 mg daily by the fourth day.

Further dosage adjustments, if indicated, should generally occur at intervals of not less than 2 days, as steady-state for quetiapine fumarate tablets would not be achieved for approximately 1 to 2 days in the typical patient.

When dosage adjustments are necessary, dose increments/decrements of 25 mg to 50 mg divided twice daily are recommended.

Most efficacy data with quetiapine fumarate tablets were obtained using three times daily dosing regimens, but in one controlled trial 225 mg given twice per day was also effective.

Efficacy in schizophrenia was demonstrated in a dose range of 150 mg/day to 750 mg/day in the clinical trials supporting the effectiveness of quetiapine fumarate tablets.

In a dose response study, doses above 300 mg/day were not demonstrated to be more efficacious than the 300 mg/day dose.

In other studies, however, doses in the range of 400 mg/day to 500 mg/day appeared to be needed.

The safety of doses above 800 mg/day has not been evaluated in clinical trials.

Maintenance Treatment —The effectiveness of quetiapine fumarate tablets for longer than 6 weeks has not been evaluated in controlled clinical trials.

While there is no body of evidence available to answer the question of how long the patient treated with quetiapine fumarate tablets should be maintained, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission.

Patients should be periodically reassessed to determine the need for maintenance treatment.

Adolescents (13-17 years) Pediatric dosing information in patients (13 to 17 years of age) with schizophrenia is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for such use in those adolescent patients.

2.2 Bipolar Disorder Adults Acute Treatment of Manic Episodes in Bipolar I Disorder Dose Selection —When used as monotherapy or adjunct therapy (with lithium or divalproex), quetiapine fumarate tablets should be initiated in twice daily doses totaling 100 mg/day on Day 1, increased to 400 mg/day on Day 4 in increments of up to 100 mg/day in twice daily divided doses.

Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day.

Data indicate that the majority of patients responded between 400 mg/day to 800 mg/day.

The safety of doses above 800 mg/day has not been evaluated in clinical trials.

Acute Treatment of Depressive Episodes in Bipolar Disorder Dose Selection —Quetiapine fumarate tablets should be administered once daily at bedtime to reach 300 mg/day by Day 4.

Recommended Dosing Schedule Day Day 1 Day 2 Day 3 Day 4 Quetiapine Fumarate Tablets 50 mg 100 mg 200 mg 300 mg In the clinical trials supporting effectiveness, the dosing schedule was 50 mg, 100 mg, 200 mg and 300 mg/day for Days 1 to 4 respectively.

Patients receiving 600 mg increased to 400 mg on Day 5 and 600 mg on Day 8 (Week 1).

Antidepressant efficacy was demonstrated with quetiapine fumarate tablets at both 300 mg and 600 mg; however, no additional benefit was seen in the 600 mg group.

Maintenance Treatment of Bipolar I Disorder Maintenance of efficacy in bipolar I disorder was demonstrated with quetiapine fumarate tablets (administered twice daily totaling 400 to 800 mg per day) as adjunct therapy to lithium or divalproex.

Generally, in the maintenance phase, patients continued on the same dose on which they were stabilized during the stabilization phase Children and Adolescents (10 to 17 years) Pediatric dosing information in patients (10 to 17 years of age) with bipolar mania is approved for AstraZeneca Pharmaceuticals LP’s quetiapine fumarate drug product labeling.

However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients.

2.3 Dosing in Special Populations Consideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions [ see Clinical Pharmacology (12)].

When indicated, dose escalation should be performed with caution in these patients.

Patients with hepatic impairment should be started on 25 mg/day.

The dose should be increased daily in increments of 25 mg/day to 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient.

2.4 Reinitiation of Treatment in Patients Previously Discontinued Although there are no data to specifically address reinitiation of treatment, it is recommended that when restarting patients who have had an interval of less than one week off quetiapine fumarate tablets, titration of quetiapine fumarate tablets is not required and the maintenance dose may be reinitiated.

When restarting therapy of patients who have been off quetiapine fumarate tablets for more than one week, the initial titration schedule should be followed.

2.5 Switching from Antipsychotics There are no systematically collected data to specifically address switching patients with schizophrenia from antipsychotics to quetiapine fumarate tablets, or concerning concomitant administration with antipsychotics.

While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others.

In all cases, the period of overlapping antipsychotic administration should be minimized.

When switching patients with schizophrenia from depot antipsychotics, if medically appropriate, initiate quetiapine fumarate tablets therapy in place of the next scheduled injection.

The need for continuing existing EPS medication should be re-evaluated periodically.