QUET is indicated for the treatment of schizophrenia (adults and adolescents aged 13 to 17
years),
Treatment of moderate to severe manic episodes in bipolar disorder (adults, children and
adolescents aged 10 to 17 years),
Treatment of major depressive episodes in bipolar disorder,
For preventing recurrence in bipolar disorder in patients whose manic or depressive episode has
responded to quetiapine treatment.
It is recommended that medication therapy for pediatric schizophrenia and bipolar disorder be
initiated only after a thorough diagnostic evaluation has been performed and careful
consideration given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolar disorder is indicated as part of a total treatment program
that often includes psychological, educational and social interventions.

QUET can be administered with or without food.
Frequency and duration of administration:
In adults:
For the treatment of schizophrenia: QUET should be administered twice a daily.
The total daily dose for the first 4 days of therapy is 50mg (Day 1), 100mg (Day 2), 200mg
(Day 3) and 300mg (Day 4).
From Day 4 onwards, the dose should be titrated to the usual effective dose range of 300 to
450mg quetiapine per day. Depending on the clinical response and tolerability of the individual
patient, the dose may be adjusted within the range 150 to 750mg per day.
Adolescents (13-17 years)
QUET should be administered twice daily. However, based on clinical response and tolerability
of the individual patient QUET may be administered three times daily where needed.
The total daily dose for the initial five days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg
(Day 3), 300 mg (Day 4) and 400 mg (Day 5).
After Day 5, the dose should be adjusted within the recommended dose range of 400 mg/day to
800 mg/day based on response and tolerability. Dosage adjustments should be in increments of
no greater than 100 mg/day. Efficacy was demonstrated with quetiapine at both 400 mg and 800
mg; however, no additional benefit was seen in the 800 mg group.
For the treatment of moderate to severe manic episodes in bipolar disorder:
QUET should be administered twice a daily. The total daily dose for the first four days of therapy
is 100mg (Day 1), 200mg (Day 2), 300mg (Day 3) and 400mg (Day 4). Further dosage
adjustments up to 800 mg per day by Day 6 should be in increments of no greater than 200mg
per day.
The dose may be adjusted depending on clinical response and tolerability of the individual
patient, within the range of 200 to 800mg quetiapine per day. The usual effective dose is in the
range of 400 to 800mg per day.
Children and Adolescents (10 to 17 years) (monotherapy) QUET should be administered twice daily. However, based on clinical response and tolerability
of the individual patient QUET may be administered three times daily where needed.
The total daily dose for the initial five days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg
(Day 3), 300 mg (Day 4) and 400 mg (Day 5).
After Day 5, the dose should be adjusted within the recommended dose range of 400 to 600
mg/day based on response and tolerability. Dosage adjustments should be in increments of no
greater than 100 mg/day. Efficacy was demonstrated with quetiapine at both 400 mg and 600 mg;
however, no additional benefit was seen in the 600 mg group.
For the treatment of depressive episodes in bipolar disorder
QUET should be administered once daily at bedtime. The recommended daily dose is 300 mg. The
total daily dose for the first four days of therapy is 50mg (Day 1), 100mg (Day 2), 200mg (Day 3) and 300mg (Day 4). No additional benefit was seen with the 600mg dose.
In clinical trials, no additional benefit was seen in the 600mg group compared to the 300mg group.
Individual patients may benefit from a 600mg dose. Doses greater than 300 mg should be initiated
by physicians experienced in treating bipolar disorder. In individual patients, in the event of
tolerance concerns, clinical trials have indicated that dose reduction to a minimum of 200mg could
be considered.
For preventing recurrence in bipolar disorder:
For prevention of recurrence of bipolar disorder, patients who have responded to QUET for acute
treatment of bipolar disorder should continue therapy with QUET at the same dose. QUET dose
may then be adjusted depending on clinical response and tolerability of the individual patient,
within the range of 300 to 800mg/day administered twice daily. It is important that the lowest
effective dose is used for maintenance therapy.
Method of administration:
Tablets orally administered are swallowed with a small amount of water

In a meta-analysis of atypical antipsychotic drugs, it has been reported that elderly patients with
dementia-related psychosis are at an increased risk of death compared to placebo. However in two
10-week placebo-controlled QUET studies in the same patient population (n=710; mean age: 83
years; range: 56-99 years) the incidence of mortality in QUET -treated patients was 5.5% versus
3.2% in the placebo group. The patients in these trials died from a variety of causes that were
consistent with expectations for this population. These data do not establish a causal relationship
between QUET treatment and death in elderly patients with dementia.
Suicide/suicidal thoughts or clinical worsening:
Depression in bipolar disorder is associated with an increased risk of suicidal thoughts, self-harm and
suicide (suicide-related events). This risk persists until significant remission occurs. As improvement
may not occur during the first few weeks or more of treatment, patients should be closely monitored
until such improvement occurs. It is general clinical experience that the risk of suicide may increase in
the early stages of recovery.
Other psychiatric conditions for which quetiapine is prescribed can also be associated with an
increased risk of suicide-related events. In addition, these conditions may be co-morbid with
major depressive disorder. The same precautions observed when treating patients with major
depressive disorder should therefore be observed when treating patients with other psychiatric
disorders.
Patients with a history of suicide-related events, or those exhibiting a significant degree of
suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal
thoughts or suicide attempts, and should receive careful monitoring during treatment.
An FDA meta-analysis of placebo-controlled clinical trials of antidepressant drugs in
approximately 4,400 children and adolescents and 77,000 adult patients with psychiatric
disorders showed an increased risk of suicidal behavior with antidepressants compared to
placebo in children, adolescents, and young adult patients less than 25 years old. This metaanalysis did not include trials involving quetiapine. (See Section 5.1 Pharmacodynamic
Properties).
In addition, physicians should consider the potential risk of suicide-related events after abrupt cessation
of quetiapine treatment, due to the known risk factors for the disease being treated.
Cardiovascular disease:
QUET should be used with caution in patients with known cardiovascular disease, cerebrovascular
disease, or other conditions predisposing to hypotension.
QUET may induce orthostatic hypotension, especially during the initial dose-titration period; this is
more common in elderly patients than in young patients. Seizures:
In controlled clinical trials there was no difference in the incidence of seizures in patients treated with
QUET or placebo. As with other antipsychotics, caution is recommended when treating patients with a
history of seizure.
Extrapyramidal symptoms:
In placebo-controlled clinical trials with patients treated for schizophrenia and bipolar mania, the
incidence of extrapyramidal symptoms was no different from that of placebo across the
recommended therapeutic dose range. In short-term, placebo-controlled clinical trials in adult
patients for bipolar depression, the incidence of extrapyramidal symptoms was higher in
quetiapine treated patients than in placebo treated patients (See Section 4.8 Undesirable Effects).
Tardive dyskinesia:
As with other antipsychotics, there is potential for QUET to cause tardive dyskinesia after longterm
treatment. If signs and symptoms of tardive dyskinesia appear, dose reduction or
discontinuation of QUET should be considered.
Severe Neutropenia:
Severe neutropenia (<0.5 X 109/L) has been uncommonly reported in QUET clinical trials. Most
cases of severe neutropenia have occurred within the first two of months of starting therapy with
QUET. There was no apparent dose relationship. Possible risk factors for neutropenia include
pre-existing low white cell count (WBC) and history of drug induced neutropenia. Quetiapine
should be discontinued in patients with a neutrophil count <1.0 X 109/L. These patients should be
observed for signs and symptoms of infection and neutrophil counts followed (until they exceed
1.5 X 109/L) (See Section 4.8 Undesirable Effects).
Lactose:
QUET contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this medicine 

Venous thromboembolism:
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since
patients treated with antipsychotics often present with acquired risk factors for VTE, all possible
risk factors for VTE should be identified before and during treatment with quetiapine and
preventive measures undertaken.
Hyperglycaemia:
Hyperglycemia or exacerbation of pre-existing diabetes have been reported during treatment with
quetiapine. Appropriate clinical monitoring is advisable in diabetic patients and in patients with
risk factors for the development of diabetes mellitus (See Section 4.8 Undesirable Effects).
Lipids:
Increases in triglycerides and cholesterol have been observed in clinical trials with quetiapine (See
Section 4.8 Undesirable Effects). Lipid increases should be managed as clinically appropriate.
Metabolic risk:
Given the observed changes in weight, blood glucose (see hyperglycaemia) and lipids seen in
clinical studies, there may be possible worsening of the metabolic risk profile in individual
patients, which should be managed as clinically appropriate (See Section 4.8).

Neuroleptic malignant syndrome:
Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including
QUET (see section 4.8 Undesirable Effects). Clinical manifestations include hyperthermia, altered
mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In
such an event, QUET should be discontinued and appropriate medical treatment given.
QT prolongation:
In clinical studies and when used in accordance with the Summary of Product Characteristics,
quetiapine was not associated with a persisting extension of the absolute QT interval. QT
prolongation was reported with quetiapine in overdose (see section 4.9 Overdose). Quetiapine
should not be used especially in the elderly, in patients with congenital prolonged QT syndrome,
congestive heart failure, cardiac hypertrophy, hypokalaemia and hypomagnesaemia and with other
drugs known to prolong the QTc interval (see section 4.5).
Acute withdrawal symptoms
Acute withdrawal symptoms including nausea, vomiting, and insomnia have been rarely described
after abrupt cessation of high doses of antipsychotic medicinal products. When therapy is
discontinued in such a way, symptoms of psychosis may recur; moreover, involuntary movement
disorders such as akathisia, dystonia and dyskinesia were also reported. Therefore, a gradual and
slow withdrawal is advisable.
Children and adolescents (10 to 17 years of age):
Although not all adverse reactions that have been identified in adult patients have been observed
in clinical trials of children and adolescent patients, the same warnings and precautions for use
that appear for adults should be considered for paediatrics. Changes in blood pressure and
thyroid function tests and increases in weight and prolactin levels have been observed and should
be managed as clinically appropriate (see section 4.8 Undesirable Effects).
Long-term safety data including growth, maturation, and behavioural development, beyond 26
weeks of treatment with QUET, is not available for children and adolescents 10 to 17 years for age 

Given the primary central nervous system effects of QUET it should be used with caution in
combination with other centrally acting medicinal products and alcohol.
The pharmacokinetics of lithium were not altered when co-administered with QUET.
Coadministration of valproate semisodium also known as Divalproex Sodium did not cause
clinically significant changes in pharmacokinetics of valproic acid and quetiapine. Valproate
semisodium is a stable compound comprised of 1:1 molar sodium valproate and valproic acid.
The pharmacokinetics of quetiapine were not significantly altered following co-administration
with the antipsychotics risperidone or haloperidol. However co-administration of QUET and
thioridazine caused increases in the clearance of quetiapine.
Quetiapine did not cause induction of hepatic enzyme systems which play role on antipyrine
metabolism. However, 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 (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 QUET, depending on
clinical response, should be considered. Continued treatment at higher doses should only be
considered as a result of careful consideration of the benefit risk assessment for an individual
patient. It should be noted that the recommended maximum daily dose of QUET is 600-800
mg/day depending on the indication (see section 4.2).
Co-administration of QUET and phenytoin (microsomal enzyme inducer) led to a greatly increased
clearance of quetiapine (approximately 450%). In patients co-administered QUET and phenytoin
or other hepatic enzyme inducers (e.g. barbiturates, rifampicin etc.), QUET therapy should only be
initiated if the physician considers that the benefits of such therapy outweigh the risks of
discontinuing the hepatic enzyme inducer treatment. It is important that any change in the inducer
treatment is gradual, and if required, inducer may be replaced with a non-inducing agent (eg
sodium valproate) (see also section 4.4).
CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of
quetiapine. In an interaction study in healthy subjects a co-administration of quetiapine (25mg)
and ketoconazole (CYP3A4 inhibitor) resulted in a factor 5 to 8 increase in the AUC of
quetiapine. On the basis of this, concomitant use of quetiapine with azole antifungals,
macrolide antibiotics and strong CYP3A4 inhibitors like protease inhibitors is contraindicated.
It is also not recommended to take quetiapine together with grapefruit juice. The
pharmacokinetics of quetiapine were not altered following co-administration with cimetidine, a
known P450 enzyme inhibitor. The pharmacokinetics of quetiapine were not significantly
altered following co-administration with the antidepressants imipramine (a known CYP 2D6
inhibitor) or fluoxetine (a known CYP 3A4 and CYP 2D6 inhibitor).There have been reports of false positive results in enzyme immunoassays for methadone and
tricyclic antidepressants in patients who have taken quetiapine. Confirmation of questionable
immunoassay screening results by an appropriate chromatographic technique is recommended. 1
Concomitant use of QUET with hepatic enzyme inducers such as carbamazepine may
substantially decrease systemic exposure to quetiapine. Depending on clinical response, higher
doses of QUET may need to be considered if QUET is used concomitantly with a hepatic
enzyme inducer.
During concomitant administration of medicines that are potent CYP3A4 inhibitors (such as
azole antifungals and macrolide antibiotics), plasma concentrations of quetiapine can be
significantly higher than observed in patients in clinical trials (See Section 5.2 Pharmacokinetic
propts.). As a consequence of this, lower doses of QUET should be used. 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

Pregnancy category is C
Women with childbearing potential/Contraception
The safety and efficacy of quetiapine during human pregnancy have not been established.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy,
embryonal/foetal development, parturition or postnatal development (See Section 5.3). It should
not be used unless necessary.
Pregnancy
There is no sufficient data on use of quetiapine to pregnant women.
Animal studies have shown reproductive toxicity (see Section 5.3)
Potential risk for humans is unknown.
Therefore, QUET should only be used during pregnancy if the benefits justify the potential risks.
Following pregnancies in which quetiapine was used, neonatal withdrawal symptoms were
observed.
Lactation
The degree to which quetiapine is excreted into human milk is unknown. Women who are breastfeeding
should therefore be advised to avoid breast-feeding while taking QUET.
Fertility
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.

Given its primary central nervous system effects, quetiapine may interfere with activities requiring
mental alertness. Therefore, patients should be advised not to drive or operate machinery, until
individual susceptibility to this is known.

The most commonly reported Adverse Drug Reactions (ADR) with quetiapine are somnolence,
dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension and
dyspepsia.
As with other antipsychotics, weight gain, syncope, neuroleptic malignant syndrome, leucopenia,
neutropenia and peripheral oedema have been associated with quetiapine. The incidences of
ADRs associated with quetiapine therapy, are tabulated below according to the format
recommended by the Council for International Organizations of Medical Sciences (CIOMS III
Working Group; 1995).
The frequencies of adverse events are ranked according to the following: Very common (>1/10),
common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000) and very
rare (<1/10,000).
Blood and lymphatic system disorders
Very common Decreased haemoglobin23
Common: Leucopenia27, decreased neutrophil count, eosinophils increased28
Uncommon: Thrombocytopenia, anaemia, platelet count decreased14
Unknown: Neutropenia Immune system disorders
Uncommon: Hypersensitivity (including allergic skin reactions)
Very rare: Anaphylactic reaction6
Endocrine disorders
Common: Hyperprolactinaemia16, decreases in total T4
25, decreases in free T4
25, decreases in total T3
25, increases in TSH 25
Uncommon Decreases in free T3 25, hypothyroidism22
Very rare: Inappropriate antidiuretic hormone secretion
Metabolism and nutritional disorders
Very common Elevations in serum triglyceride levels11,31, elevations in total
cholesterol (predominantly LDL cholesterol)12,31,
decreases in HDL cholesterol18,31, weight gain9,31
Common: Increased appetite, blood glucose increased to hyperglycaemic
levels 7,31
Uncommon: Hyponatraemia20, diabetes mellitus 1,5,6
Rare: Metabolic syndrome30
Psychiatric disorders Common: Abnormal dreams and nightmares, suicidal ideation and suicidal
behaviour21
Rare: Somnambulism and r related reactions such as sleep talking and
sleep related eating disorder
Nervous system disorders
Very common: Dizziness4, 17, somnolence2, 17, headache
Common: Syncope4, 17, extrapyramidal symptoms1, 22, dysarthria
Uncommon: Seizure1, restless legs syndrome, tardive dyskinesia1, 6
Cardiac disorders
Common: Tachycardia4, palpitations24
Uncommon QT prolongation 1,13, 19
Eye disorders
Common: Vision blurred Vascular disorders
Common: Orthostatic hypotension4, 17
Rare: Venous thromboembolism1
Respiratory, thoracic and mediastinal disorders
Common: Rhinitis, dyspnea24
Gastrointestinal disorders
Very common: Dry mouth
Common: Constipation, dyspepsia, vomiting26
Uncommon: Dysphagia1, 8
Rare Pancreatitis
Hepato-biliary disorders
Common Elevations in serum transaminases (ALT, AST)3, elevations in
gamma-GT levels3
Rare: Jaundice6, hepatitis
Skin and subcutaneous tissue disorders
Very rare: Angioedema6, Stevens-Johnson syndrome6
Pregnancy, puerperium and perinatal conditions Not known: Drug withdrawal syndrome neonatal (see section 4.6)
Musculoskeletal and connective tissue disorders
Very rare: Rhabdomyolysis
Reproductive system and breast disorders
Uncommon: Sexual dysfunction
Rare: Priapism, galactorrhoea, breast swelling, menstrual disorder
General disorders and administration site conditions
Very common: Withdrawal (discontinuation) symptoms1, 10
Common: Mild asthenia, peripheral oedema, irritability, pyrexia
Rare: Neuroleptic malignant syndrome1, hypothermia
Investigations

 Rare: Elevations in blood creatine phosphokinase 15

In clinical trials, survival has been reported following acute overdoses of up to 30 grams of
quetiapine. Most patients who overdosed reported no adverse events or recovered fully from the reported events. Death has been reported in a clinical trial following an overdose of 13.6 grams
of quetiapine alone.
In postmarketing experience, there have been very rare reports of overdose of quetiapine alone
resulting in death or coma.
In general, reported signs and symptoms were those resulting from an exaggeration of the known
pharmacological effects of the active substance, i.e., drowsiness and sedation, tachycardia and
hypotension.
Treatment of overdose
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.
In cases of quetiapine overdose, refractory hypotension should be treated with appropriate
measures such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine
should be avoided, since beta stimulation may worsen hypotension in the setting of quetiapineinduced
alpha blockade).9
Close medical supervision and monitoring should be continued until the patient recovers.

Pharmacotherapeutic group: Antipsychotics
ATC code: NO5A H04
Mechanism of action:
Quetiapine is an atypical antipsychotic agent interacting with a broad range of neurotransmitter
receptors. It has a greater affinity for serotonin (5HT2) receptors in brain than for dopamine D1
and D2 receptors. Quetiapine and norquetiapine also have high affinity at histaminergic and
adrenergic α1 receptors, with a lower affinity at adrenergic α2 receptors and serotonin 5HT1A
receptors; however, Quetiapine has no appreciable affinity at cholinergic muscarinic or
benzodiazepine receptors. Quetiapine is active in tests for antipsychotic activity, such as
conditioned avoidance.
Pharmacodynamic effects:
As a result of pre-clinical tests which examine the tendency for EPS by antipsychotics, it has
been shown that Quetiapine does not produce dopamine D2 receptor supersensitivity after
chronic administration. Quetiapine produces only weak catalepsy at effective dopamine D2
receptor blocking doses. Quetiapine demonstrates selectivity for the limbic system by producing
depolarisation blockade of the A10 mesolimbic but not the A9 nigrostriatal dopamine-containing
neurones following chronic administration. Quetiapine exhibits minimal dystonic liability in
haloperidol-sensitised or drug-naive monkeys after acute and chronic administration.
Clinical efficacy:
Clinical trials have demonstrated that QUET 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 800mg/day have not been evaluated.
Schizophrenia:
In clinical studies, QUET has been demonstrated to be effective on both positive and negative
symptoms of schizophrenia. In comparative clinical studies, it has been demonstrated that QUET
is as effective as standard antipsychotic drugs such as chlorpromazine and haloperidol.
Bipolar Mania:
In clinical trials, QUET has been shown to be effective as monotherapy or as adjunct therapy in
reducing manic symptoms in patients with bipolar mania. The mean last week median dose of
quetiapine in responders, was approximately 600 mg and approximately 85% of the responders
were in the dose range of 400 to 800 mg/day.
Bipolar Depression:
In four clinical trials, which included patients who are bipolar I, bipolar II and patients with and
without rapid cycling courses, quetiapine has been shown to be effective in patients with bipolar
depression at doses of 300 and 600 mg/day, however, no additional benefit was seen with the 600
mg dose during short-term treatment.
In all studies, quetiapine XR was superior to placebo in reduction of Montgomery-Asberg
Depression Scale (MADRS) total score. The antidepressant effect of quetiapine was significant
at Day 8 (Week 1) and was maintained through the end of the studies (Week 8).
Treatment with either quetiapine 300 or 600 mg at bedtime reduced depressive symptoms and
anxiety symptoms in patients with bipolar depression. There were fewer episodes of treatment
emergent mania with either dose of quetiapine than with placebo.
In 3 out of 4 studies, for the 300 mg and 600 mg dose group, statistically significant
improvements over placebo were seen in reductions in suicidal thinking as measured by MADRS item 10 and in 2 out of 3 studies, for the 300 mg dose group, overall quality of life and
satisfaction related to various areas of functioning, as measured using the Quality of Life
Enjoyment and Satisfaction Questionnaire (Q-LES-Q).
In two bipolar depression clinical trials, maintenance of antidepressant efficacy was established.
These trials included an 8-week placebo-controlled acute phase, followed by a placebocontrolled
continuation phase of at least 26 weeks but up to 52-weeks in duration. Patients were
required to be stable at the end of the acute phase in order to be in the randomized into the
continuation phase. In both trials, quetiapine was superior to placebo in increasing the time to
recurrence of any mood event (depressed, mixed or manic). The risk reduction from the pooled
trials was 49%. The risk of a mood event for quetiapine versus placebo was reduced by 41% for
the 300 mg dose and by 55% for the 600 mg dose.
Preventing recurrence in maintenance treatment of bipolar disorder:
The efficacy of quetiapine in the monotherapy treatment for recurrence prevention was
established in 1 placebo-controlled trial in 1226 patients who met DSM-IV criteria for Bipolar I
Disorder. The trial included patients whose most recent mood episode was manic, mixed, or
depressive, with or without psychotic features. In the open-label phase, patients were required to
be stabilised on quetiapine for a minimum of 4 weeks in order to be randomized. In the
randomization phase, patients either continued treatment with quetiapine (300 to 800 mg per day:
average dose 546 mg per day) or were to receive lithium or placebo for up to 104 weeks.
quetiapine was superior to placebo in increasing the time to recurrence of any mood event (manic, mixed, or depressive), the primary endpoint. The risk reductions were 74%, 73%, and
75% for mood, manic and depressive events, respectively.
The efficacy of quetiapine in the combination treatment for recurrence prevention was
established in 2 placebo-controlled trials in 1326 patients who met DSM-IV criteria for Bipolar I
Disorder. The trials included patients whose most recent mood episode was manic, mixed, or
depressive, with or without psychotic features. In the open-label phase, patients were required to
be stabilised on quetiapine in combination with mood stabilizer (lithium or valproate) for a
minimum of 12 weeks in order to be randomized. In the randomization phase, patients either
continued treatment with quetiapine (400 to 800 mg per day average dose 507 mg per day) in
combination with mood stabiliser or received placebo in combination with mood stabiliser for up
to 104 weeks. quetiapine was superior to placebo in increasing the time to recurrence of any
mood event (manic, mixed or depressive), the primary endpoint. The risk reductions were 70%,
67%, and 74% for mood, manic and depressive events, respectively.
Suicide/Suicidal thoughts or Clinical worsening:
In short-term placebo-controlled clinical trials across all indications and age groups, the incidence
of suicide related events was 0.8% (75/9238) for quetiapine and 0.8% (37/4745) for placebo.
In the trials of patients with schizophrenia, the incidence of suicide related events was 1.4%
(3/212) for quetiapine and 1.6% (1/62) for placebo in patients 18 to 24 years of age; 0.8%
(13/1663) for quetiapine and 1.1% (5/463) for placebo in patients  25 years of age; and 1.4%
(2/147) for quetiapine and 1.3% (1/75) for placebo in patients < 18 years of age.
In the trials of patients with bipolar mania, the incidence of suicide related events in was 0% for
both quetiapine (0/60) and placebo (0/58) in patients aged between 18 and 24; 1.2% or both
quetiapine (6/496) and placebo (6/503) in patients  25 years of age; 1.0% for quetiapine (2/193)
and 0% for placebo (0/90) in patients < 18 years of age.
In the trials of patients with bipolar depression the incidence of suicide related events was 3.0%
(7/233) for quetiapine and 0% (0/120) for placebo in patients aged between 18-24 and 1.8% for
both quetiapine (19/1616) and placebo (11/622) in patients ≥ 25 years of age. There have been no
trials conducted in patients <18 years of age with bipolar depression (See Section 4.4 Special
warnings and precautions for use).
Cataracts/lens opacities:
In a clinical trial to evaluate the cataractogenic potential of quetiapine (200-800 mg/day) versus
risperidone (2-8 mg) in patients with schizophrenia or schizoaffective disorder, the percentage of
patients with increased lens opacity grade (LOCS II Lens opacity grading system; nuclear
opacity, cortical and posterior subcapsular standards for LOCS II) was similar in respect of 2-
year event incidence, for patients with at least 21 months of exposure (See Section 5.3 Preclinical
safety data) 4.
Children and adolescents (10 to 17 years of age):
Bipolar Mania:
The efficacy of quetiapine in the acute treatment of manic episodes associated with bipolar I
disorder in children and adolescents (10 to 17 years of age) was demonstrated in a 3-week,
double-blind, placebo-controlled, multicenter trial. Patients who met DSM-IV diagnostic criteria
for a manic episode were randomized into one of three treatment groups: Quetiapine 400 mg/day
(n = 95), Quetiapine 600 mg/day (n = 98), or placebo (n = 91). Study medication was initiated at 50 mg/day and on day 2 increased to 100 mg/day (divided doses given two or three times daily).
Subsequently, the dose was titrated to a target dose of 400 mg/day or 600 mg/day using
increments of 100 mg/day, given in divided doses two or three times daily. The primary efficacy
variable was the mean change from baseline in total YMRS score.
Results of trial demonstrate that Quetiapine 400 mg/day and 600 mg/day were superior to
placebo. No additional benefit was seen with the 600 mg dose compared to 400 mg dose.
Schizophrenia:
The efficacy of quetiapine in the treatment of schizophrenia in adolescents (13–17 years of age)
was demonstrated in a 6-week, double-blind, placebo-controlled trial. Patients who met DSM-IV
diagnostic criteria for schizophrenia were randomized into one of three treatment groups:
quetiapine 400 mg/day (n = 73), quetiapine 800 mg/day (n = 74), or placebo (n = 75). Study
medication was initiated at 50 mg/day and on day 2 increased to 100 mg/per day (divided and
given two or three times per day). Subsequently, the dose was titrated to the target dose of 400
mg/day or 800 mg/day using increments of 100 mg/day, divided and given two or three times
daily. The primary efficacy variable was the mean change from baseline in total Positive and
Negative Syndrome Scale (PANSS).
Results of trial demonstrate that quetiapine at 400 mg/day and 800 mg/day was superior to
placebo. No additional benefit was seen with the 800 mg dose compared to 400 mg dose.
Weight gain in children and adolescents:
In one 6-week, placebo-controlled trial in adolescent patients (13-17 years of age) with
schizophrenia, the mean increase in body weight, was 2.0 kg in the quetiapine group and 0.4 kg
in the placebo group. Twenty one percent of quetiapine-treated patients and 7% of placebotreated
patients gained ≥ 7% of their body weight.
In one 3-week, placebo-controlled trial in children and adolescent patients (10-17 years of age)
with bipolar mania, the mean increase in body weight was 1.7 kg in the quetiapine group and 0.4
kg in the placebo group. Twelve percent of quetiapine-treated patients and 0% of placebo-treated
patients gained ≥ 7% of their body weight.
In the open-label study that enrolled patients from the above two trials, 63% of patients
(241/380) completed 26 weeks of therapy with quetiapine. After 26 weeks of treatment, the mean
increase in body weight was 4.4 kg. Forty five percent of 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 met this criterion after 26 weeks of
treatment.
Extrapryamidal symptoms in children and adolescent population:
In a short-term placebo-controlled monotherapy trial with quetiapine in adolescent patients (13-
17 years of age) with schizophrenia, the aggregated incidence of extrapyramidal symptoms was
12.9% for quetiapine and 5.3% for placebo, though the incidence of the individual adverse events
(e.g. akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor
hyperactivity, muscle rigidity, dyskinesia) did not exceed 4.1% in any treatment group. In a
short-term placebo-controlled monotherapy trial with quetiapine in children and adolescent
patients (10-17 years of age) with bipolar mania, the aggregated incidence of extrapyramidal
symptoms was 3.6% for quetiapine and 1.1% for placebo.

Absorption:
The bioavailability of quetiapine is not significantly affected by administration with food.
Quetiapine is well absorbed and extensively metabolised following oral administration.
Distribution:
Quetiapine is approximately 83% bound to plasma proteins. Steady-state peak molar
concentrations of the active metabolite norquetiapine are 35% of that observed for quetiapine.
The elimination half-life of quetiapine and norquetiapine are approximately 7 hours and 12
hours, respectively.
Clinical trials have demonstrated that quetiapine is effective in schizophrenia and mania when
given twice a day. 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.
Biotransformation:
In vitro investigations established that CYP3A4 is the primary enzyme responsible for cytochrome
P450 mediated metabolism of quetiapine.
Elimination:
The elimination half-life of quetiapine is approximately 7 hours.
Quetiapine is extensively metabolised by the liver, with parent compound accounting for less than
5% of unchanged drug-related material in the urine or faeces, following the administration of radio
labelled quetiapine. Approximately 73% of the radioactivity is excreted in the urine and 21% in the
faeces.
Linearity/Nonlinearity
The pharmacokinetics of quetiapine and norquetiapine are linear within the approved dosage
range. The pharmacokinetics of quetiapine is linear and there is no difference between men and
women as to the kinetics of quetiapine. The mean clearance of quetiapine in the elderly is
approximately 30 to 50% lower than that seen in adults aged 18 to 65 years.
Characteristics of patients
Age:
The mean clearance of quetiapine in the elderly was reduced approximately by 30 to 50%
compared to adults aged between 18 and 65 years.
Children and adolescents (10 to 17 years of age):
At steady-state the pharmacokinetics of the parent compound, in children and adolescents (10-17
years of age), were similar to adults. However, when adjusted for dose and weight, AUC and
Cmax of the parent compound were 41% and 39% lower, respectively, in children and
adolescents than in adults. For the active metabolite, norquetiapine, AUC and Cmax were 45%
and 31% higher, respectively, in children and adolescents than in adults. When adjusted for dose
and weight, the pharmacokinetics of the metabolite, norquetiapine, was similar between children
and adolescents and adults (See 4.2. Posology and method of administration). Renal impairment:
The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with
severe renal impairment (creatinine clearance less than 30 mL/min/1.73m2), but the individual
clearance values are within the range for normal subjects. The average molar dose fraction of
free quetiapine and the active human plasma metabolite norquetiapine is <5% excreted in the
urine.
Quetiapine is extensively metabolised by the liver with parent compound accounting for less than
5% of unchanged drug-related material in the urine or faeces, following the administration of
radiolabelled quetiapine. Approximately 73% of the radioactivity is excreted in the urine and
21% in the faeces.
Hepatic impairment:
The mean plasma clearance of quetiapine is reduced by approximately 25% in subjects with
hepatic impairment (stable alcoholic cirrhosis). 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 (see section 4.2). It should not be used in patients
with severe hepatic impairment.
Drug-drug interaction:
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 Cmax and AUC of quetiapine of 235% and 522%, respectively, with a
corresponding decrease in mean oral clearance of 84%. The mean half-life of quetiapine
increased from 2.6 to 6.8 hours, but the mean tmax was unchanged.
Quetiapine and several of its metabolites (including norquetiapine) 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 10 to 50 fold higher than those
observed at a dose range of 300 to 450 mg/day in humans. Based on these in vitro results, it is
unlikely that coadministration of quetiapine with other medicines will result in clinically
significant medicine inhibition of cytochrome P450 mediated metabolism of the other medicine.
In vitro investigations established that CYP3A4 is the primary enzyme responsible for
cytochrome P450 mediated metabolism of quetiapine. Norquetiapine is primarily formed and
eliminated via CYP3A4.

Acute toxicity studies:
Quetiapine has low acute toxicity. Findings in mice and rats after oral (500 mg/kg) or
intraperitoneal (100 mg/kg) dosing were typical of an effective neuroleptic agent and included
decreased motor activity, ptosis, loss of righting reflex, fluid around the mouth and convulsions.
Repeat-dose toxicity studies:
In multiple-dose studies in rats, dogs and monkeys, 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, and 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 Cynomolgus
monkeys dosed up to 225 mg/kg/day, nor in rodents. Monitoring in clinical studies did not reveal
drug-related corneal opacities in man. (See Section 5.1 Pharmacodynamic properties) 4.
No evidence of neutrophil reduction or agranulocytosis was seen in any of the toxicity studies.
Carcinogenicity studies
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.
Reproduction Studies
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 studies
Genetic toxicity studies with quetiapine show that it is not a mutagen or clastogen.

List of excipients
Dibasic calcium phosphate dihydrate
Lactose monohydrate
Povidone
Sodium starch glycolate
Magnesium stearate
Colloidal silicon dioxide
Microcrystalline cellulose
Sodium stearyl fumarate
Hydroxypropylmethylcellulose
Titanium dioxide (E 171)
Polyethylene glycol

Unknown

Store below 30ºC.

Opaque PVC/printed aluminum foil blister containing 10 film-coated tablets.
Each cardboard box contains 30 or 60 film coated tablets.
 

If applicable, unused products or waste materials must be disposed per “Legislation for Control
of Medical Wastes” and “Legislation for Control of Packages and Package Wastes