Seroquel is indicated for:

•  treatment of schizophrenia.
•  treatment of bipolar disorder:

- For the treatment of moderate to severe manic episodes in bipolar disorder
- For the treatment of major depressive episodes in bipolar disorder
- For the prevention of recurrence of manic or depressed episodes in patients with
bipolar disorder who previously responded to quetiapine treatment.

Different dosing schedules exist for each indication. It must therefore be ensured
that patients receive clear information on the appropriate dosage for their condition.
Seroquel can be administered with or without food.

Adults
For the treatment of schizophrenia
For the treatment of schizophrenia, Seroquel should be administered twice a day.
The total daily dose for the first four days of therapy is 50 mg (Day 1), 100 mg
(Day 2), 200 mg (Day 3) and 300 mg (Day 4) From Day 4 onwards, the dose
should be titrated to the usual effective dose of 300 to 450 mg/day. Depending on
the clinical response and tolerability of the individual patient, the dose may be
adjusted within the range 150 to 750 mg/day.

For the treatment of moderate to severe manic episodes in bipolar disorder
For the treatment of manic episodes associated with bipolar disorder, Seroquel
should be administered twice a day. The total daily dose for the first four days of
therapy is 100 mg (Day 1), 200 mg (Day 2), 300 mg (Day 3) and 400 mg (Day 4).
Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of
no greater than 200 mg/day.

The dose may be adjusted depending on clinical response and tolerability of the
individual patient, within the range of 200 to 800 mg/day. The usual effective dose
is in the range of 400 to 800 mg/day.

For the treatment of major depressive episodes in bipolar disorder
Seroquel should be administered once daily at bedtime. The total daily dose for the
first four days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and
300 mg (Day 4). The recommended daily dose is 300 mg. In clinical trials, no
additional benefit was seen in the 600 mg group compared to the 300 mg group (see section 5.1).

Individual patients may benefit from a 600 mg dose. 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 200 mg could be considered.

For preventing recurrence in bipolar disorder
For preventing recurrence of manic, mixed or depressive episodes in bipolar
disorder, patients who have responded to quetiapine for acute treatment of bipolar
disorder should continue therapy at the same dose. The dose may be adjusted
depending on clinical response and tolerability of the individual patient, within the
range of 300 to 800 mg/day administered twice daily. It is important that the lowest
effective dose is used for maintenance therapy.

Elderly
As with other antipsychotics, Seroquel should be used with caution in the elderly,
especially during the initial dosing period. The rate of dose titration may need to be
slower, and the daily therapeutic dose lower, than that used in younger patients,
depending on the clinical response and tolerability of the individual patient. The
mean plasma clearance of quetiapine was reduced by 30 - 50% in elderly subjects
when compared to younger patients.
Efficacy and safety has not been evaluated in patients over 65 years with depressive
episodes in the framework of bipolar disorder.

Paediatric population
Seroquel is not recommended for use in children and adolescents below 18 years of
age, due to a lack of data to support use in this age group. The available evidence
from placebo-controlled clinical trials is presented in sections 4.4, 4.8, 5.1 and 5.2.
Renal impairment
Dosage adjustment is not necessary in patients with renal impairment.
Hepatic impairment
Quetiapine is extensively metabolised by the liver. Therefore, Seroquel should be
used with caution in patients with known hepatic impairment, especially during the
initial dosing period. Patients with known hepatic impairment should be started
with 25 mg/day. The dosage should be increased daily with increments of 25 - 50
mg/day until an effective dosage, depending on the clinical response and
tolerability of the individual patient.

As Seroquel has several indications, the safety profile should be considered with
respect to the individual patient’s diagnosis and the dose being administered.
Paediatric population
Quetiapine is not recommended for use in children and adolescents below 18 years
of age, due to a lack of data to support use in this age group. Clinical trials with
quetiapine have shown that in addition to the known safety profile identified in
adults (see section 4.8), certain adverse events occurred at a higher frequency in
children and adolescents compared to adults (increased appetite, elevations in
serum prolactin, vomiting, rhinitis and syncope), or may have different implications
for children and adolescents (extrapyramidal symptoms and irritability) and one
was identified that has not been previously seen in adult studies (increases in blood
pressure). Changes in thyroid function tests have also been observed in children and
adolescents.
Furthermore, the long-term safety implications of treatment with quetiapine on
growth and maturation have not been studied beyond 26 weeks. Long-term
implications for cognitive and behavioural development are not known.
In placebo-controlled clinical trials with children and adolescent patients,
quetiapine was associated with an increased incidence of extrapyramidal symptoms
(EPS) compared to placebo in patients treated for schizophrenia, bipolar mania and
bipolar depression (see section 4.8).
Suicide/suicidal thoughts or clinical worsening
Depression in bipolar disorder is associated with an increased risk of suicidal
thoughts, self-harm and suicide (suicide-related events). This risk persists until
significant remission occurs. As improvement may not occur during the first few
weeks or more of treatment, patients should be closely monitored until such
improvement occurs. It is general clinical experience that the risk of suicide may
increase in the early stages of recovery.

In 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.
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 episodes. The same
precautions observed when treating patients with major depressive episodes 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. A meta analysis of placebo controlled clinical trials of
antidepressant drugs in adult patients with psychiatric disorders showed an 

increased risk of suicidal behaviour with antidepressants compared to placebo in
patients less than 25 years old.
Close supervision of patients and in particular those at high risk should accompany
drug therapy especially in early treatment and following dose changes. Patients
(and caregivers of patients) should be alerted about the need to monitor for any
clinical worsening, suicidal behaviour or thoughts and unusual changes in
behaviour and to seek medical advice immediately if these symptoms present.
In shorter-term placebo controlled clinical studies of patients with major depressive
episodes in bipolar disorder an increased risk of suicide-related events was
observed in young adult patients (younger than 25 years of age) who were treated
with quetiapine as compared to those treated with placebo (3.0% vs. 0%,
respectively).

A population-based retrospective study of quetiapine
for the treatment of patients with major depressive
disorder showed an increased risk of self-harm and
suicide in patients aged 25 to 64 years without a
history of self-harm during use of quetiapine with
other antidepressants.

Metabolic risk
Given the observed risk for worsening of their metabolic profile, including changes
in weight, blood glucose (see hyperglycaemia) and lipids, which was seen in
clinical studies, patients’ metabolic parameters should be assessed at the time of
treatment initiation and changes in these parameters should be regularly controlled
for during the course of treatment. Worsening in these parameters should be
managed as clinically appropriate (see also section 4.8).
Extrapyramidal symptoms
In placebo controlled clinical trials of adult patients quetiapine was associated with
an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in
patients treated for major depressive episodes in bipolar disorder (see sections 4.8
and 5.1).
The use of quetiapine has been associated with the development of akathisia,
characterised by a subjectively unpleasant or distressing restlessness and need to
move often accompanied by an inability to sit or stand still. This is most likely to
occur within the first few weeks of treatment. In patients who develop these
symptoms, increasing the dose may be detrimental.
Tardive dyskinesia
If signs and symptoms of tardive dyskinesia appear, dose reduction or
discontinuation of quetiapine should be considered. The symptoms of tardive
dyskinesia can worsen or even arise after discontinuation of treatment (see section
4.8).
Somnolence and dizziness
Quetiapine treatment has been associated with somnolence and related symptoms,
such as sedation (see section 4.8). In clinical trials for treatment of patients with
bipolar depression, onset was usually within the first 3 days of treatment and was
predominantly of mild to moderate intensity. Patients experiencing somnolence of
severe intensity may require more frequent contact for a minimum of 2 weeks from
onset of somnolence, or until symptoms improve and treatment discontinuation
may need to be considered.

Orthostatic hypotension
Quetiapine treatment has been associated with orthostatic hypotension and related
dizziness (see section 4.8) which, like somnolence has onset usually during the
initial dose-titration period. This could increase the occurrence of accidental injury
(fall), especially in the elderly population. Therefore, patients should be advised to
exercise caution until they are familiar with the potential effects of the medication.
Quetiapine should be used with caution in patients with known cardiovascular
disease, cerebrovascular disease, or other conditions predisposing to hypotension.
Dose reduction or more gradual titration should be considered if orthostatic
hypotension occurs, especially in patients with underlying cardiovascular disease.
Sleep apnoea syndrome
Sleep apnoea syndrome has been reported in patients using quetiapine. In patients
receiving concomitant central nervous system depressants and who have a history
of or are at risk for sleep apnoea, such as those who are overweight/obese or are
male, quetiapine should be used with caution.
Seizures
In controlled clinical trials there was no difference in the incidence of seizures in
patients treated with quetiapine or placebo. No data is available about the incidence
of seizures in patients with a history of seizure disorder. As with other
antipsychotics, caution is recommended when treating patients with a history of
seizures (see section 4.8).
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome has been associated with antipsychotic treatment,
including quetiapine (see section 4.8). Clinical manifestations include
hyperthermia, altered mental status, muscular rigidity, autonomic instability, and
increased creatine phosphokinase. In such an event, quetiapine should be
discontinued and appropriate medical treatment given.
Severe neutropenia and agranulocytosis
Severe neutropenia (neutrophil count <0.5 x 109/L) has been reported in quetiapine
clinical trials. Most cases of severe neutropenia have occurred within a couple of
months of starting therapy with quetiapine. There was no apparent dose
relationship. During post-marketing experience, some cases were fatal. Possible
risk factors for neutropenia include pre-existing low white blood cell count (WBC)
and history of drug induced neutropenia. However, some cases occurred in patients
without pre-existing risk factors. Quetiapine should be discontinued in patients with
a neutrophil count <1.0 x 109/L. Patients should be observed for signs and
symptoms of infection and neutrophil counts followed (until they exceed
1.5 x 109/L) (see section 5.1).
Neutropenia should be considered in patients presenting with infection or fever,
particularly in the absence of obvious predisposing factor(s), and should be
managed as clinically appropriate.
Patients should be advised to immediately report the appearance of signs/symptoms
consistent with agranulocytosis or infection (e.g. fever, weakness, lethargy, or sore

throat) at any time during Seroquel therapy. Such patients should have a WBC
count and an absolute neutrophil count (ANC) performed promptly, especially in
the absence of predisposing factors.
Anti-cholinergic (muscarinic) effects
Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity
for several muscarinic receptor subtypes. This contributes to ADRs reflecting anticholinergic
effects when quetiapine is used at recommended doses, when used
concomitantly with other medications having anti-cholinergic effects, and in the
setting of overdose. Quetiapine should be used with caution in patients receiving
medications having anti-cholinergic (muscarinic) effects. Quetiapine should be
used with caution in patients with a current diagnosis or prior history of urinary
retention, clinically significant prostatic hypertrophy, intestinal obstruction or
related conditions, increased intraocular pressure or narrow angle glaucoma (see
sections 4.5, 4.8, 5.1 and 4.9).
Interactions
See section 4.5.
Concomitant use of quetiapine with a strong hepatic enzyme inducer such as
carbamazepine or phenytoin substantially decreases quetiapine plasma
concentrations, which could affect the efficacy of quetiapine therapy. In patients
receiving a hepatic enzyme inducer, initiation of quetiapine treatment should only
occur if the physician considers that the benefits of quetiapine outweigh the risks of
removing the hepatic enzyme inducer. It is important that any change in the inducer
is gradual, and if required, replaced with a non-inducer (e.g. sodium valproate).
Weight
Weight gain has been reported in patients who have been treated with quetiapine,
and should be monitored and managed as clinically appropriate as in accordance
with utilised antipsychotic guidelines (see sections 4.8 and 5.1).
Hyperglycaemia
Hyperglycaemia and/or development or exacerbation of diabetes occasionally
associated with ketoacidosis or coma has been reported rarely, including some fatal
cases (see section 4.8). In some cases, a prior increase in body weight has been
reported which may be a predisposing factor. Appropriate clinical monitoring is
advisable in accordance with utilised antipsychotic guidelines. Patients treated with
any antipsychotic agent including quetiapine, should be observed for signs and
symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and
weakness) and patients with diabetes mellitus or with risk factors for diabetes
mellitus should be monitored regularly for worsening of glucose control. Weight
should be monitored regularly.
Lipids
Increases in triglycerides, LDL and total cholesterol, and decreases in HDL
cholesterol have been observed in clinical trials with quetiapine (see section 4.8).
Lipid changes should be managed as clinically appropriate.

QT prolongation
In clinical trials and use in accordance with the SPC, quetiapine was not associated
with a persistent increase in absolute QT intervals. In post-marketing, QT
prolongation was reported with quetiapine at the therapeutic doses (see section 4.8)
and in overdose (see section 4.9). As with other antipsychotics, caution should be
exercised when quetiapine is prescribed in patients with cardiovascular disease or
family history of QT prolongation. Also, caution should be exercised when
quetiapine is prescribed either with medicines known to increase QT interval or
with concomitant neuroleptics, especially in the elderly, in patients with congenital
long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or
hypomagnesaemia (see section 4.5).
Cardiomyopathy and myocarditis
Cardiomyopathy and myocarditis have been reported in clinical trials and during
the post-marketing experience, however, a causal relationship to quetiapine has not
been established. Treatment with quetiapine should be reassessed in patients with
suspected cardiomyopathy or myocarditis.

Severe Cutaneous Adverse Reactions :
Severe cutaneous adverse reactions (SCARs),
including Stevens-Johnson syndrome (SJS), toxic
epidermal necrolysis (TEN) and drug reaction with
eosinophilia and systemic symptoms (DRESS) which
can be life-threatening or fatal have been reported
very rarely with quetiapine treatment. SCARs
commonly present as a combination of the
following symptoms: extensive cutaneous rash or
exfoliative dermatitis, fever, lymphadenopathy and
possible eosinophilia. If signs and symptoms
suggestive of these severe skin reactions appear,
quetiapine should be withdrawn immediately and
alternative treatment should be considered.

Withdrawal
Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhoea,
vomiting, dizziness and irritability have been described after abrupt cessation of
quetiapine. Gradual withdrawal over a period of at least one to two weeks is
advisable (see section 4.8).
Elderly patients with dementia-related psychosis
Quetiapine is not approved for the treatment of dementia-related psychosis.
An approximately 3-fold increased risk of cerebrovascular adverse events has been
seen in randomised placebo controlled trials in the dementia population with some
atypical antipsychotics. The mechanism for this increased risk is not known. An
increased risk cannot be excluded for other antipsychotics or other patient
populations. Quetiapine should be used with caution in patients with risk factors for
stroke.
In a meta-analysis of atypical antipsychotics, it has been reported that elderly
patients with dementia-related psychosis are at an increased risk of death compared
to placebo. In two 10-week placebo-controlled quetiapine studies in the same
patient population (n=710); mean age: 83 years; range: 56-99 years) the incidence
of mortality in quetiapine treated patients was 5.5% versus 3.2% in the placebo
group. The patients in these trials died from a variety of causes that were consistent
with expectations for this population.

Elderly patients with Parkinson’s disease (PD)/parkinsonism
A population-based retrospective study of quetiapine for the treatment of patients with
MDD, showed an increased risk of death during use of quetiapine in patients aged >65
years. This association was not present when patients with PD were removed from the
analysis. Caution should be exercised if quetiapine is prescribed to elderly patients with
PD.

Dysphagia
Dysphagia (see section 4.8) has been reported with quetiapine. Quetiapine should
be used with caution in patients at risk for aspiration pneumonia.
Constipation and intestinal obstruction
Constipation represents a risk factor for intestinal obstruction. Constipation and
intestinal obstruction have been reported with quetiapine (see section 4.8). This
includes fatal reports in patients who are at higher risk of intestinal obstruction,

including those that are receiving multiple concomitant medications that decrease
intestinal motility and/or may not report symptoms of constipation. Patients with
intestinal obstruction/ileus should be managed with close monitoring and urgent
care.
Venous thromboembolism (VTE)
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.
Pancreatitis
Pancreatitis has been reported in clinical trials and during post marketing
experience. Among post marketing reports, while not all cases were confounded by
risk factors, many patients had factors which are known to be associated with
pancreatitis such as increased triglycerides (see section 4.4), gallstones, and alcohol
consumption.
Additional information
Quetiapine data in combination with divalproex or lithium in acute moderate to
severe manic episodes is limited; however, combination therapy was well tolerated
(see section 4.8 and 5.1). The data showed an additive effect at week 3.
Lactose
Seroquel tablets contain lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should
not take this medicine.
Misuse and abuse
Cases of misuse and abuse have been reported. Caution may be needed when
prescribing quetiapine to patients with a history of alcohol or drug abuse.

Given the primary central nervous system effects of quetiapine, quetiapine should
be used with caution in combination with other centrally acting medicinal products
and alcohol.
Caution should be exercised treating patients receiving other medications having
anti-cholinergic (muscarinic) effects (see section 4.4).
Cytochrome P450 (CYP) 3A4 is the enzyme that is primarily responsible for the
cytochrome P450 mediated metabolism of quetiapine. In an interaction study in
healthy volunteers, concomitant administration of quetiapine (dosage of 25 mg)
with ketoconazole, a CYP3A4 inhibitor, caused a 5- to 8-fold increase in the AUC
of quetiapine. On the basis of this, concomitant use of quetiapine with CYP3A4
inhibitors is contraindicated. It is also not recommended to consume grapefruit
juice while on quetiapine therapy.

In a multiple dose trial in patients to assess the pharmacokinetics of quetiapine
given before and during treatment with carbamazepine (a known hepatic enzyme
inducer), co-administration of carbamazepine significantly increased the clearance
of quetiapine. This increase in clearance reduced systemic quetiapine exposure (as
measured by AUC) to an average of 13% of the exposure during administration of
quetiapine alone; although a greater effect was seen in some patients. As a
consequence of this interaction, lower plasma concentrations can occur, which
could affect the efficacy of quetiapine therapy. Co-administration of quetiapine and
phenytoin (another microsomal enzyme inducer) caused a greatly increased
clearance of quetiapine by approx. 450%. In patients receiving a hepatic enzyme
inducer, initiation of quetiapine treatment should only occur if the physician
considers that the benefits of quetiapine outweigh the risks of removing the hepatic
enzyme inducer. It is important that any change in the inducer is gradual, and if
required, replaced with a non-inducer (e.g. sodium valproate) (see section 4.4).
The pharmacokinetics of quetiapine were not significantly altered by coadministration
of the antidepressants imipramine (a known CYP 2D6 inhibitor) or
fluoxetine (a known CYP 3A4 and CYP 2D6 inhibitor).
The pharmacokinetics of quetiapine were not significantly altered by coadministration
of the antipsychotics risperidone or haloperidol. Concomitant use of
quetiapine and thioridazine caused an increased clearance of quetiapine with
approx. 70%.
The pharmacokinetics of quetiapine were not altered following co-administration
with cimetidine.
The pharmacokinetics of lithium were not altered when co-administered with
quetiapine.
In a 6-week, randomised, study of lithium and Seroquel XL versus placebo and
Seroquel XL in adult patients with acute mania, a higher incidence of
extrapyramidal related events (in particular tremor), somnolence, and weight gain
were observed in the lithium add-on group compared to the placebo add-on group
(see section 5.1).
The pharmacokinetics of sodium valproate and quetiapine were not altered to a
clinically relevant extent when co-administered. A retrospective study of children
and adolescents who received valproate, quetiapine, or both, found a higher
incidence of leucopenia and neutropenia in the combination group versus the
monotherapy groups.
Formal interaction studies with commonly used cardiovascular medicinal products
have not been performed.
Caution should be exercised when quetiapine is used concomitantly with medicinal
products known to cause electrolyte imbalance or to increase QT interval.
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.

Pregnancy
First trimester
The moderate amount of published data from exposed pregnancies (i.e. between
300-1000 pregnancy outcomes), including individual reports and some
observational studies do not suggest an increased risk of malformations due to
treatment. However, based on all available data, a definite conclusion cannot be
drawn. Animal studies have shown reproductive toxicity (see section 5.3).
Therefore, quetiapine should only be used during pregnancy if the benefits justify
the potential risks.
Third trimester
Neonates exposed to antipsychotics (including quetiapine) during the third trimester
of pregnancy are at risk of adverse reactions including extrapyramidal and/or
withdrawal symptoms that may vary in severity and duration following delivery.
There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence,
respiratory distress, or feeding disorder. Consequently, newborns should be
monitored carefully.
Breast-feeding
Based on very limited data from published reports on quetiapine excretion into
human breast milk, excretion of quetiapine at therapeutic doses appears to be
inconsistent. Due to lack of robust data, a decision must be made whether to
discontinue breast-feeding or to discontinue Seroquel therapy taking into account
the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
The effects of quetiapine on human fertility have not been assessed. Effects related
to elevated prolactin levels were seen in rats, although these are not directly
relevant to humans (see section 5.3).

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 (ADRs) with quetiapine
(≥10%) are somnolence, dizziness, headache, dry mouth, withdrawal
(discontinuation) symptoms, elevations in serum triglyceride levels, elevations in
total cholesterol (predominantly LDL cholesterol), decreases in HDL cholesterol,
weight gain, decreased haemoglobin and extrapyramidal symptoms.
The incidences of ADRs associated with quetiapine therapy, are tabulated below
(Table 1) according to the format recommended by the Council for International
Organizations of Medical Sciences (CIOMS III Working Group; 1995).

Table 1      ADRs associated with quetiapine therapy

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), very rare (<1/10,000) and not known (cannot be estimated from the available data).

1.     See section 4.4.

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

3.     Asymptomatic elevations (shift from normal to >3 x ULN at any time) in serum transaminase (ALT, AST) or gamma-GT levels have been observed in some patients administered quetiapine. These elevations were usually reversible on continued quetiapine treatment.

4.     As with other antipsychotics with alpha1 adrenergic blocking activity, quetiapine may commonly induce orthostatic hypotension, associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period. (see section 4.4).

5.     Calculation of Frequency for these ADR’s have been taken from post-marketing data only.

6.     Fasting blood glucose ≥126 mg/dL (≥7.0 mmol/L) or a non-fasting blood glucose ≥200 mg/dL (≥11.1 mmol/L) on at least one occasion.

7.     An increase in the rate of dysphagia with quetiapine vs. placebo was only observed in the clinical trials in bipolar depression.

8.     Based on >7% increase in body weight from baseline. Occurs predominantly during the early weeks of treatment in adults.

9.     The following withdrawal symptoms have been observed most frequently in acute placebo- controlled, monotherapy clinical trials, which evaluated discontinuation symptoms: insomnia,

nausea, headache, diarrhoea, vomiting, dizziness, and irritability. The incidence of these reactions had decreased significantly after 1 week post-discontinuation.

10.   Triglycerides ≥200 mg/dL (≥2.258 mmol/L) (patients ≥18 years of age) or ≥150 mg/dL (≥1.694 mmol/L) (patients <18 years of age) on at least one occasion.

11.   Cholesterol ≥240 mg/dL (≥6.2064 mmol/L) (patients ≥18 years of age) or ≥200 mg/dL

(≥5.172 mmol/L) (patients <18 years of age) on at least one occasion. An increase in LDL cholesterol of ≥30 mg/dL (≥0.769 mmol/L) has been very commonly observed. Mean change among patients who had this increase was 41.7 mg/dL (≥1.07 mmol/L).

12.   See text below.

13.   Platelets ≤100 x 109/L on at least one occasion.

14.   Based on clinical trial adverse event reports of blood creatine phosphokinase increase not associated with neuroleptic malignant syndrome.

15.   Prolactin levels (patients >18 years of age): >20 μg/L (>869.56 pmol/L) males; >30 μg/L (>1304.34 pmol/L) females at any time.

16.   May lead to falls.

17.   HDL cholesterol: 40 mg/dL (1.025 mmol/L) males; 50 mg/dL (1.282 mmol/L) females at any time.

18.   Incidence of patients who have a QTc shift from <450 msec to ≥450 msec with a ≥30 msec

increase. In placebo-controlled trials with quetiapine the mean change and the incidence of patients who have a shift to a clinically significant level is similar between quetiapine and placebo.

19.   Shift from >132 mmol/L to ≤132 mmol/L on at least one occasion.

20.   Cases of suicidal ideation and suicidal behaviours have been reported during quetiapine therapy or early after treatment discontinuation (see sections 4.4 and 5.1).

21.   See section 5.1.

22.   Decreased haemoglobin to ≤13 g/dL (8.07 mmol/L) males, ≤12 g/dL (7.45 mmol/L) females on at least one occasion occurred in 11% of quetiapine patients in all trials including open label extensions. For these patients, the mean maximum decrease in haemoglobin at any time was –

1.50 g/dL.

23.   These reports often occurred in the setting of tachycardia, dizziness, orthostatic hypotension and/or underlying cardiac/respiratory disease.

24.   Based on shifts from normal baseline to potentially clinically important value at any time post- baseline in all trials. Shifts in total T4, free T4, total T3 and free T3 are defined as <0.8 x LLN (pmol/L) and shift in TSH is > 5 mIU/L at any time.

25.   Based upon the increased rate of vomiting in elderly patients (≥65 years of age).

26.   Based on shift in neutrophils from > =1.5 x 109L at baseline to <0.5 x 109/L at any time during treatment and based on patients with severe neutropenia (<0.5 x 109/L) and infection during all quetiapine clinical trials (see section 4.4).

27.   Based on shifts from normal baseline to potentially clinically important value at any time post- baseline in all trials. Shifts in eosinophils are defined as >1 x 109 cells/L at any time.

28.   Based on shifts from normal baseline to potentially clinically important value at any time post- baseline in all trials. Shifts in WBCs are defined as ≤3 x 109 cells/L at any time.

29.   Based on adverse event reports of metabolic syndrome from all clinical trials with quetiapine.

30.   In some patients, a worsening of more than one of the metabolic factors of weight, blood glucose and lipids was observed in clinical studies (see section 4.4).

31.   See section 4.6

32.   May occur at or near initiation of treatment and be associated with hypotension and/or syncope. Frequency based on adverse event reports of bradycardia and related events in all

clinical trials with quetiapine.

33. Based on one retrospective non-randomised
epidemiological study.

Cases of QT prolongation, ventricular arrhythmia, sudden unexplained death, cardiac arrest and torsades de pointes have been reported with the use of neuroleptics and are considered class effects.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome
(SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic
symptoms (DRESS) have been reported in association with quetiapine treatment.

Paediatric population

The same ADRs described above for adults should be considered for children and adolescents. The following table summarises ADRs that occur in a higher

frequency category in children and adolescent patients (10-17  years of age) than in the adult population or ADRs that have not been identified in the adult population.

Table 2      ADRs in children and adolescents associated with quetiapine therapy that occur in a higher frequency than adults, or not identified in the adult population

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).

1.  Prolactin levels (patients < 18 years of age): >20 μg/L (>869.56 pmol/L) males; >26 μg/L (>1130.428 pmol/L) females at any time. Less than 1% of patients had an increase to a prolactin level >100 μg/L.

2.  Based on shifts above clinically significant thresholds (adapted from the National Institutes of Health criteria) or increases >20 mmHg for systolic or >10 mmHg for diastolic blood pressure at any time in two acute (3-6 weeks) placebo-controlled trials in children and adolescents.

3.  Note: The frequency is consistent to that observed in adults, but might be associated with different clinical implications in children and adolescents as compared to adults.

4.  See section 5.1.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via The National

Pharmacovigilance and Drug Safety Centre (NPC)

Table 1      ADRs associated with quetiapine therapy

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), very rare (<1/10,000) and not known (cannot be estimated from the available data).

1.     See section 4.4.

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

3.     Asymptomatic elevations (shift from normal to >3 x ULN at any time) in serum transaminase (ALT, AST) or gamma-GT levels have been observed in some patients administered quetiapine. These elevations were usually reversible on continued quetiapine treatment.

4.     As with other antipsychotics with alpha1 adrenergic blocking activity, quetiapine may commonly induce orthostatic hypotension, associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period. (see section 4.4).

5.     Calculation of Frequency for these ADR’s have been taken from post-marketing data only.

6.     Fasting blood glucose ≥126 mg/dL (≥7.0 mmol/L) or a non-fasting blood glucose ≥200 mg/dL (≥11.1 mmol/L) on at least one occasion.

7.     An increase in the rate of dysphagia with quetiapine vs. placebo was only observed in the clinical trials in bipolar depression.

8.     Based on >7% increase in body weight from baseline. Occurs predominantly during the early weeks of treatment in adults.

9.     The following withdrawal symptoms have been observed most frequently in acute placebo- controlled, monotherapy clinical trials, which evaluated discontinuation symptoms: insomnia,

nausea, headache, diarrhoea, vomiting, dizziness, and irritability. The incidence of these reactions had decreased significantly after 1 week post-discontinuation.

10.   Triglycerides ≥200 mg/dL (≥2.258 mmol/L) (patients ≥18 years of age) or ≥150 mg/dL (≥1.694 mmol/L) (patients <18 years of age) on at least one occasion.

11.   Cholesterol ≥240 mg/dL (≥6.2064 mmol/L) (patients ≥18 years of age) or ≥200 mg/dL

(≥5.172 mmol/L) (patients <18 years of age) on at least one occasion. An increase in LDL cholesterol of ≥30 mg/dL (≥0.769 mmol/L) has been very commonly observed. Mean change among patients who had this increase was 41.7 mg/dL (≥1.07 mmol/L).

12.   See text below.

13.   Platelets ≤100 x 109/L on at least one occasion.

14.   Based on clinical trial adverse event reports of blood creatine phosphokinase increase not associated with neuroleptic malignant syndrome.

15.   Prolactin levels (patients >18 years of age): >20 μg/L (>869.56 pmol/L) males; >30 μg/L (>1304.34 pmol/L) females at any time.

16.   May lead to falls.

17.   HDL cholesterol: 40 mg/dL (1.025 mmol/L) males; 50 mg/dL (1.282 mmol/L) females at any time.

18.   Incidence of patients who have a QTc shift from <450 msec to ≥450 msec with a ≥30 msec

increase. In placebo-controlled trials with quetiapine the mean change and the incidence of patients who have a shift to a clinically significant level is similar between quetiapine and placebo.

19.   Shift from >132 mmol/L to ≤132 mmol/L on at least one occasion.

20.   Cases of suicidal ideation and suicidal behaviours have been reported during quetiapine therapy or early after treatment discontinuation (see sections 4.4 and 5.1).

21.   See section 5.1.

22.   Decreased haemoglobin to ≤13 g/dL (8.07 mmol/L) males, ≤12 g/dL (7.45 mmol/L) females on at least one occasion occurred in 11% of quetiapine patients in all trials including open label extensions. For these patients, the mean maximum decrease in haemoglobin at any time was –

1.50 g/dL.

23.   These reports often occurred in the setting of tachycardia, dizziness, orthostatic hypotension and/or underlying cardiac/respiratory disease.

24.   Based on shifts from normal baseline to potentially clinically important value at any time post- baseline in all trials. Shifts in total T4, free T4, total T3 and free T3 are defined as <0.8 x LLN (pmol/L) and shift in TSH is > 5 mIU/L at any time.

25.   Based upon the increased rate of vomiting in elderly patients (≥65 years of age).

26.   Based on shift in neutrophils from > =1.5 x 109L at baseline to <0.5 x 109/L at any time during treatment and based on patients with severe neutropenia (<0.5 x 109/L) and infection during all quetiapine clinical trials (see section 4.4).

27.   Based on shifts from normal baseline to potentially clinically important value at any time post- baseline in all trials. Shifts in eosinophils are defined as >1 x 109 cells/L at any time.

28.   Based on shifts from normal baseline to potentially clinically important value at any time post- baseline in all trials. Shifts in WBCs are defined as ≤3 x 109 cells/L at any time.

29.   Based on adverse event reports of metabolic syndrome from all clinical trials with quetiapine.

30.   In some patients, a worsening of more than one of the metabolic factors of weight, blood glucose and lipids was observed in clinical studies (see section 4.4).

31.   See section 4.6

32.   May occur at or near initiation of treatment and be associated with hypotension and/or syncope. Frequency based on adverse event reports of bradycardia and related events in all

clinical trials with quetiapine.

Cases of QT prolongation, ventricular arrhythmia, sudden unexplained death, cardiac arrest and torsades de pointes have been reported with the use of neuroleptics and are considered class effects.

Paediatric population

The same ADRs described above for adults should be considered for children and adolescents. The following table summarises ADRs that occur in a higher

frequency category in children and adolescent patients (10-17  years of age) than in the adult population or ADRs that have not been identified in the adult population.

Table 2      ADRs in children and adolescents associated with quetiapine therapy that occur in a higher frequency than adults, or not identified in the adult population

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).

1.  Prolactin levels (patients < 18 years of age): >20 μg/L (>869.56 pmol/L) males; >26 μg/L (>1130.428 pmol/L) females at any time. Less than 1% of patients had an increase to a prolactin level >100 μg/L.

2.  Based on shifts above clinically significant thresholds (adapted from the National Institutes of Health criteria) or increases >20 mmHg for systolic or >10 mmHg for diastolic blood pressure at any time in two acute (3-6 weeks) placebo-controlled trials in children and adolescents.

3.  Note: The frequency is consistent to that observed in adults, but might be associated with different clinical implications in children and adolescents as compared to adults.

4.  See section 5.1.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via The National

Pharmacovigilance and Drug Safety Centre (NPC)

To report any side effects:

Saudi Arabia:

- The National Pharmacovigilance and Drug Safety Centre (NPC)

oSFDA Call Center: 19999

o E-mail: npc.drug@sfda.gov.sa

o E-mail: npc.drug@sfda.gov.sa

Other GCC states:

-    Please contact the relevant competent authority.

Symptoms

In general, reported signs and symptoms were those resulting from an exaggeration of the active substance’s known pharmacological effects, i.e. drowsiness and sedation, tachycardia, hypotension and anti-cholinergic effects.

Overdose could lead to QT-prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium and/or agitation, coma and death. Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose. (see section 4.4, Orthostatic hypotension).

Management of overdose

There is no specific antidote to quetiapine. In cases of severe signs, 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.

Based on public literature, patients with delirium and agitation and a clear anti- cholinergic syndrome may be treated with physostigmine, 1-2 mg (under continuous ECG monitoring).  This is not recommended as standard treatment, because of potential negative effect of physostigmine on cardiac conductance. Physostigmine may be used if there are no ECG aberrations. Do not use  physostigmine in case of dysrhythmias, any degree of heart block or QRS- widening.

Whilst the prevention of absorption in overdose has not been investigated, gastric lavage can be indicated in severe poisonings and if possible to perform within one hour of ingestion. The administration of activated charcoal should be considered.

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 quetiapine-induced alpha blockade.

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

Pharmacotherapeutic group: Antipsychotics, ATC code: N05A H04

Mechanism of action

Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite, norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and norquetiapine exhibit affinity for brain serotonin (5HT2) and dopamine D1- and D2- receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT2 relative to D2- receptors, which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal side effect (EPS) liability of Seroquel compared to typical antipsychotics. Quetiapine

and norquetiapine have no appreciable affinity at benzodiazepine receptors but high affinity at histaminergic and adrenergic alpha1 receptors and moderate affinity at adrenergic alpha2 receptors. Quetiapine also has low or no affinity for muscarinic receptors, while norquetiapine has moderate to high affinity at several muscarinic receptors, which may explain anti-cholinergic (muscarinic) effects. Inhibition of NET and partial agonist action at 5HT1A sites by norquetiapine may contribute to Seroquel’s therapeutic efficacy as an antidepressant.

Pharmacodynamic effects

Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also blocks the action of dopamine agonists, measured either behaviourally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of D2-receptor blockade.

In pre-clinical tests predictive of EPS, quetiapine is unlike typical antipsychotics and has an atypical profile. Quetiapine does not produce dopamine D2 receptor supersensitivity after chronic administration. Quetiapine produces only weak catalepsy at effective dopamine D2 receptor blocking doses. Quetiapine demonstrates selectivity for the limbic system by producing depolarisation

blockade of the mesolimbic but not the nigrostriatal dopamine-containing neurones following chronic administration. Quetiapine exhibits minimal dystonic liability in 

haloperidol-sensitised or drug-naive Cebus monkeys after acute and chronic administration (see section 4.8).

Clinical efficacy:

Schizophrenia

In three placebo-controlled clinical trials, in patients with schizophrenia, using variable doses of quetiapine, there were no differences between the Seroquel and placebo treatment groups in the incidence of EPS or concomitant use of anti- cholinergics. A placebo-controlled trial evaluating fixed doses of quetiapine across the range of 75 to 750 mg/day showed no evidence of an increase in EPS or the use of concomitant anti-cholinergics. The long-term efficacy of Seroquel IR in prevention of schizophrenic relapses has not been verified in blinded clinical trials. In open label trials, in patients with schizophrenia, quetiapine was effective in maintaining the clinical improvement during continuation therapy in patients who showed an initial treatment response, suggesting some long-term efficacy.

Bipolar disorder

In four placebo-controlled clinical trials, evaluating doses of Seroquel up to

800 mg/day for the treatment of moderate to severe manic episodes, two each in monotherapy and as combination therapy to lithium or divalproex, , there were no differences between the Seroquel and placebo treatment groups in the incidence of EPS or concomitant use of anti-cholinergics.

In the treatment of moderate to severe manic episodes, Seroquel demonstrated superior efficacy to placebo in reduction of manic symptoms at 3 and 12 weeks, in two monotherapy trials. There are no data from long-term studies to demonstrate Seroquel’s effectiveness in preventing subsequent manic or depressive episodes. Seroquel data in combination with divalproex or lithium in acute moderate to severe manic episodes at 3 and 6 weeks is limited; however, combination therapy was well tolerated. The data showed an additive effect at week 3. A second study did not demonstrate an additive effect at week 6.

The mean last week median dose of Seroquel in responders was approximately

600 mg/day and approximately 85% of the responders were in the dose range of

400 to 800 mg/day.

In 4 clinical trials with a duration of 8 weeks in patients with moderate to severe depressive episodes in bipolar I or bipolar II disorder, Seroquel IR 300 mg and

600 mg was significantly superior to placebo treated patients for the relevant

outcome measures: mean improvement on the MADRS and for response defined as

at least a 50% improvement in MADRS total score from baseline. There was no difference in magnitude of effect between the patients who received 300 mg Seroquel IR and those who received 600 mg dose.

In the continuation phase in two of these studies, it was demonstrated that long- term treatment, of patients who responded on Seroquel IR 300 or 600 mg, was efficacious compared to placebo treatment with respect to depressive symptoms, but not with regard to manic symptoms.

In two recurrence prevention studies evaluating Seroquel in combination with mood stabilizers, in patients with manic, depressed or mixed mood episodes, the 

combination with Seroquel was superior to mood stabilizers monotherapy in increasing the time to recurrence of any mood event (manic, mixed or depressed). Seroquel was administered twice-daily totalling 400 mg to 800 mg a day as combination therapy to lithium or valproate.

In a 6-week, randomised, study of lithium and Seroquel XL versus placebo and Seroquel XL in adult patients with acute mania, the difference in YMRS mean improvement between the lithium add-on group and the placebo add-on group was

2.8 points and the difference in % responders (defined as 50% improvement from baseline on the YMRS) was 11% (79% in the lithium add-on group vs. 68% in the placebo add-on group).

In one long-term study (up to 2 years treatment) evaluating recurrence prevention in patients with manic, depressed or mixed mood episodes quetiapine was superior to placebo in increasing the time to recurrence of any mood event (manic, mixed or depressed), in patients with bipolar I disorder. The number of patients with a mood event was 91 (22.5%) in the quetiapine group, 208 (51.5%) in the placebo group

and 95 (26.1%) in the lithium treatment groups respectively. In patients who responded to quetiapine, when comparing continued treatment with quetiapine to

switching to lithium, the results indicated that a switch to lithium treatment does

not appear to be associated with an increased time to recurrence of a mood event.

Clinical trials have demonstrated that Seroquel is effective in schizophrenia and mania when given twice a day, although quetiapine has a pharmacokinetic half-life of approximately 7 hours. This is further supported by the data from a positron emission tomography (PET) study, which identified that for quetiapine, 5HT2- and D2-receptor occupancy are maintained for up to 12 hours. The safety and efficacy of doses greater than 800 mg/day have not been evaluated.

Clinical safety

In short-term, placebo-controlled clinical trials in schizophrenia and bipolar mania the aggregated incidence of extrapyramidal symptoms was similar to placebo (schizophrenia: 7.8% for quetiapine and 8.0% for placebo; bipolar mania: 11.2% for quetiapine and 11.4% for placebo). Higher rates of extrapyramidal symptoms were seen in quetiapine treated patients compared to those treated with placebo in short-term, placebo-controlled clinical trials in MDD and bipolar depression. In

short-term, placebo-controlled bipolar depression trials the aggregated incidence of extrapyramidal symptoms was 8.9% for quetiapine compared to 3.8% for placebo. In short-term, placebo-controlled monotherapy clinical trials in major depressive disorder the aggregated incidence of extrapyramidal symptoms was 5.4% for

Seroquel XL and 3.2% for placebo. In a short-term placebo-controlled monotherapy trial in elderly patients with major depressive disorder, the aggregated incidence of extrapyramidal symptoms was 9.0% for Seroquel XL and 2.3% for placebo. In both bipolar depression and MDD, the incidence of the individual adverse events (eg, akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness,

muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity)

did not exceed 4% in any treatment group.

In short-term, fixed-dose (50mg/d to 800 mg/d), placebo-controlled studies

(ranging from 3 to 8 weeks), the mean weight gain for quetiapine-treated patients

ranged from 0.8 kg for the 50 mg daily dose to 1.4 kg for the 600 mg daily dose (with lower gain for the 800 mg daily dose), compared to 0.2 kg for the placebo treated patients.  The percentage of quetiapine treated patients who gained ≥7% of body weight ranged from 5.3% for the 50 mg daily dose to 15.5% for the 400 mg daily dose (with lower gain for the 600 and 800 mg daily doses), compared to 3.7% for placebo treated patients.

A 6-week, randomised, study of lithium and Seroquel XL versus placebo and Seroquel XL in adult patients with acute mania indicated that the combination of Seroquel XL with lithium leads to more adverse events (63% versus 48% in Seroquel XL in combination with placebo). The safety results showed a higher incidence of extrapyramidal symptoms reported in 16.8% of patients in the lithium add-on group and 6.6% in the placebo add-on group, the majority of which consisted of tremor, reported in 15.6% of the patients in the lithium add-on group and 4.9% in the placebo add-on group. The incidence of somnolence was higher in the Seroquel XL with lithium add-on group (12.7%) compared to the Seroquel XL with the placebo add-on group (5.5%). In addition, a higher percentage of patients treated in the lithium add-on group (8.0%) had weight gain (≥7%) at the end of treatment compared to patients in the placebo add-on group (4.7%).

Longer term relapse prevention trials had an open label period (ranging from 4 to

36 weeks) during which patients were treated with quetiapine, followed by a randomized withdrawal period during which patients were randomized to quetiapine or placebo. For patients who were randomized to quetiapine, the mean weight gain during the open label period was 2.56 kg, and by week 48 of the randomized period, the mean weight gain was 3.22 kg, compared to open label baseline. For patients who were randomized to placebo, the mean weight gain

during the open label period was 2.39 kg, and by week 48 of the randomized period the mean weight gain was 0.89 kg, compared to open label baseline.

In placebo-controlled studies in elderly patients with dementia-related psychosis, the incidence of cerebrovascular adverse events per 100 patient years was not higher in quetiapine-treated patients than in placebo-treated patients.

In all short-term placebo-controlled monotherapy trials in patients with a baseline neutrophil count ≥1.5 x 109/L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 x 109/L, was 1.9% in patients treated with quetiapine compared to 1.5% in placebo-treated patients. The incidence of shifts to >0.5-<1.0 x 109/L was the same (0.2%) in patients treated with quetiapine as with placebo- treated patients. In all clinical trials (placebo-controlled, open-label, active

comparator) in patients with a baseline neutrophil count ≥1.5 x 109/L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 x 109/L was 2.9% and to <0.5 x 109/L was 0.21% in patients treated with quetiapine.

Quetiapine treatment was associated with dose-related decreases in thyroid hormone levels.  The incidences of shifts in TSH was 3.2% for quetiapine versus

2.7% for placebo. The incidence of reciprocal, potentially clinically significant shifts of both T3 or T4 and TSH in these trials were rare, and the observed changes

in thyroid hormone levels were not associated with clinically symptomatic hypothyroidism.

The reduction in total and free T4 was maximal within the first six weeks of quetiapine treatment, with no further reduction during long-term treatment. For about 2/3 of 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.

Cataracts/lens opacities

In a clinical trial to evaluate the cataractogenic potential of Seroquel (200-

800 mg/day) versus risperidone (2-8 mg/day) in patients with schizophrenia or schizoaffective disorder, the percentage of patients with increased lens opacity grade was not higher in Seroquel (4%) compared with risperidone (10%), for patients with at least 21 months of exposure.

Paediatric population

Clinical efficacy

The efficacy and safety of Seroquel was studied in a 3-week placebo controlled study for the treatment of mania (n= 284 patients from the US, aged 10-17). About

45% of the patient population had an additional diagnosis of ADHD. In addition, a

6-week placebo controlled study for the treatment of schizophrenia (n = 222 patients, aged 13-17) was performed. In both studies, patients with known lack of response to Seroquel were excluded. Treatment with Seroquel was initiated at

50 mg/day and on day 2 increased to 100 mg/day; subsequently the dose was titrated to a target dose (mania 400-600 mg/day; schizophrenia 400-800 mg/day) using increments of 100 mg/day given two or three times daily.

In the mania study, the difference in LS mean change from baseline in YMRS total score (active minus placebo) was –5.21 for Seroquel 400 mg/day and –6.56 for Seroquel 600 mg/day. Responder rates (YMRS improvement ≥50%) were 64% for Seroquel 400 mg/day, 58% for 600 mg/day and 37% in the placebo arm.

In the schizophrenia study, the difference in LS mean change from baseline in

PANSS total score (active minus placebo) was –8.16 for Seroquel 400 mg/day and

–9.29 for Seroquel 800 mg/day. Neither low dose (400 mg/day) nor high dose regimen (800 mg/day) quetiapine was superior to placebo with respect to the percentage of patients achieving response, defined as ≥30% reduction from baseline in PANSS total score. Both in mania and schizophrenia higher doses resulted in numerically lower response rates.

In a third short-term placebo-controlled monotherapy trial with Seroquel XL in children and adolescent patients (10-17 years of age) with bipolar depression, efficacy was not demonstrated.

No data are available on maintenance of effect or recurrence prevention in this age group.

Clinical safety

In the short-term paediatric trials with quetiapine described above, the rates of EPS in the active arm vs. placebo were 12.9% vs. 5.3% in the schizophrenia trial, 3.6% vs. 1.1% in the bipolar mania trial, and 1.1% vs. 0% in the bipolar depression trial. The rates of weight gain ≥ 7% of baseline body weight in the active arm vs. placebo were 17% vs. 2.5% in the schizophrenia and bipolar mania trials, and 13.7% vs.

6.8% in the bipolar depression trial. The rates of suicide related events in the active arm vs. placebo were 1.4% vs. 1.3% in the schizophrenia trial, 1.0% vs. 0% in the bipolar mania trial, and 1.1% vs. 0% in the bipolar depression trial. During an extended post treatment follow-up phase of the bipolar depression trial, there were two additional suicide related events in two patients; one of these patients was on quetiapine at the time of the event.

Long-term safety

A 26-week open-label extension to the acute trials (n=380 patients), with Seroquel flexibly dosed at 400- 800 mg/day, provided additional safety data. Increases in blood pressure were reported in children and adolescents and increased appetite, extrapyramidal symptoms and elevations in serum prolactin were reported with higher frequency in children and adolescents than in adult patients (see sections 4.4 and 4.8). With respect to weight gain, when adjusting for normal growth over the longer term, an increase of at least 0.5 standard deviation from baseline in Body Mass Index (BMI) was used as a measure of a clinically significant change; 18.3% of patients who were treated with quetiapine for at least 26 weeks met this criterion.

Absorption

Quetiapine is well absorbed and extensively metabolised following oral administration. The bioavailability of quetiapine is not significantly affected by administration with food. Steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of that observed for quetiapine.

The pharmacokinetics of quetiapine and norquetiapine are linear across the approved dosing range.

Distribution

Quetiapine is approximately 83% bound to plasma proteins.

Biotransformation

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. 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.

Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces.

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 5 to 50 fold higher than those observed at a dose range of 300 to

800 mg/day in humans. Based on these in vitro results, it is unlikely that co-

administration of quetiapine with other drugs will result in clinically significant drug inhibition of cytochrome P450 mediated metabolism of the other drug. From animal studies it appears that quetiapine can induce cytochrome P450 enzymes. In a specific interaction study in psychotic patients, however, no increase in the cytochrome P450 activity was found after administration of quetiapine.

Elimination

The elimination half lives of quetiapine and norquetiapine are approximately 7 and

12 hours, respectively. The average molar dose fraction of free quetiapine and the

active human plasma metabolite norquetiapine is <5% excreted in the urine.

Special populations

Gender

The kinetics of quetiapine do not differ between men and women.

Elderly

The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than that seen in adults aged 18 to 65 years.

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.

Hepatic impairment

The mean quetiapine plasma clearance decreases with approx. 25% in persons with

known hepatic impairment (stable alcohol cirrhosis). As quetiapine is extensively metabolised by the liver, elevated plasma levels are expected in the population with hepatic impairment. Dose adjustments may be necessary in these patients (see

section 4.2).

Paediatric population

Pharmacokinetic data were sampled in 9 children aged 10-12 years old and 12 adolescents, who were on steady-state treatment with 400 mg quetiapine twice daily. At steady-state, the dose-normalised plasma levels of the parent compound, quetiapine, in children and adolescents (10-17 years of age) were in general similar to adults, though Cmax in children was at the higher end of the range observed in adults. The AUC and Cmax for the active metabolite, norquetiapine, were higher, approximately 62% and 49% in children (10-12 years), respectively and 28% and

14% in adolescents (13-17 years), respectively, compared to adults.

There was no evidence of genotoxicity in a series of in vitro and in vivo genotoxicity studies. In laboratory animals at a clinically relevant exposure level the following deviations were seen, which as yet have not been confirmed in long- term clinical research:

In rats, pigment deposition in the thyroid gland has been observed; in cynomolgus monkeys thyroid follicular cell hypertrophy, a lowering in plasma T3 levels, decreased haemoglobin concentration and a decrease of red and white blood cell count have been observed; and in dogs lens opacity and cataracts. (For cataracts/lens opacities, see section 5.1).

In an embryofetal toxicity study in rabbits the foetal incidence of carpal/tarsal flexure was increased. This effect occurred in the presence of overt maternal effects such as reduced body weight gain. These effects were apparent at maternal

exposure levels similar or slightly above those in humans at the maximal therapeutic dose. The relevance of this finding for humans is unknown.

In a fertility study in rats, marginal reduction in male fertility and pseudopregnancy, protracted periods of diestrus, increased precoital interval and reduced pregnancy rate were seen. These effects are related to elevated prolactin levels and not directly relevant to humans because of species differences in hormonal control of reproduction

Core

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Coating

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Blisters:

Tablet Strength                   Carton (pack)

contents

Blisters

                                                  6 tablets                      1 blister of 6 tablets 

25 mg tablets                       20 tablets                    2 blisters of 10 tablets

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                                              60 tablets                       6 blisters of 10 tablets
                                                                                       12 blisters of 5 tablets

                                              100 tablets                     10 blisters of 10 tablets

100 mg, and 200 mg tablets 300 mg tablets    

                                            10 tablets                       1 blister of 10 tablets

                                            20 tablets                    2 blisters of 10 tablets

                                           30 tablets                     3 blisters of 10 tablets

                                           50 tablets                     10 blisters of 5 tablets
                                                                                  5 blisters of 10 tablets

                                          60 tablets                     6 blisters of 10 tablets

                                         90 tablets                      9 blisters of 10 tablets

                                        100 tablets                     10 blisters of 10 tablets

                                        120 tablets                      12 blisters of 10 tablets (300 mg tablets only)

                                        180 tablets                      18 blisters of 10 tablets (300 mg tablets only)

                                        240 tablets                     24 blisters of 10 tablets (300 mg tablets only)

Not all pack sizes may be marketed.

No special requirements.