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QUETIAPINE 100MG FILM-COATED TABLET

Active substance(s): QUETIAPINE FUMARATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Quetiapine 100mg Film-coated Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 100mg quetiapine (as fumarate)
Excipient(s) with known effect:
Each film-coated tablet contains lactose monohydrate.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Film-coated Tablet
White coloured, round tablets debossed with ‘Q3’ on one side and plain on the other
side

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Quetiapine 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.
4.2

Posology and method of administration

Different dosing schedules exist for each indication. It must therefore be ensured that
patients receive clear information on the appropriate dosage for their condition.
Quetiapine can be administered with or without food.
Adults:
For the treatment of schizophrenia
For the treatment of schizophrenia, Quetiapine should be administered twice a day.
The total daily dose for the first 4 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, Quetiapine
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 per day by Day 6 should be in increments of
no greater than 200 mg per day.
The dose may be adjusted depending on clinical response and tolerability of the
individual patient, within the range of 200 to 800 mg per day. The usual effective dose
is in the range of 400 to 800 mg per day.
For the treatment of major depressive episodes in bipolar disorder
Quetiapine 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 the 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.

Older people
As with other antipsychotics, Quetiapine should be used with caution in older people,
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% to 50% in older people when
compared to younger patients.
Efficacy and safety have not been evaluated in patients over 65 years with depressive
episodes in the framework of bipolar disorder.
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. 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, Quetiapine should be
used with caution in patients with known hepatic impairment, especially during the
initial dosing period. Patients with hepatic impairment should be started with 25
mg/day. The dosage can 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.
4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients of this product, as
listed in section 6.1.
Concomitant administration of cytochrome P450 3A4 inhibitors, such as HIVprotease inhibitors, azole-antifungal agents, erythromycin, clarithromycin and
nefazodone, is contraindicated. (See also section 4.5).
4.4

Special warnings and precautions for use

As Quetiapine 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 and 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).
Metabolic Risk

Given the observed risk for worsening of their metabolic profile, including changes in
weight, blood glucose (see hyperglycemia) 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 older people 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.
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 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 quetiapine therapy. Such patients should have a WBC count
and an absolute neutrophil count (ANC) performed promptly, especially in the
absence of predisposing factors.

Interactions
See also 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 Section 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
Undesirable effects). 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 older people, 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.
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).
Older people 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 antipsychotic, it has been reported that older people
with dementia-related psychosis are at an increased risk of death compared to placebo.
However 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 of a variety of causes that were consistent with
expectations for this population. These data do not establish a causal relationship
between Quetiapine treatment and death in older people with dementia.
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 Undesirable
effects). 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 the post marketing
experience. Among the 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
This medicinal product contains lactose monohydrate. Patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption should not take this medicine.
4.5

Interaction with other medicinal products and other forms of interaction

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.
Cytochrome P450 (CYP) 3A4 is the enzyme that is primarily responsible for
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 CYP2D6 inhibitor) or
fluoxetine (a known CYP3A4 and CYP2D6 inhibitor).
The pharmacokinetics of quetiapine were not significantly altered following coadministration of the antipsychotics risperidone or haloperidol. Concomitant use of
Quetiapine and thioridazine caused an increased in the clearance of quetiapine by
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.
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 group.

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.
4.6

Fertility, pregnancy and lactation

Pregnancy
First trimester
The moderate amount of published data from exposed pregnancies (i.e. between 3001000 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.
Breastfeeding
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 breastfeeding 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 preclinical data).
4.7

Effects on ability to drive and use machines

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

4.8

Undesirable effects

The most commonly reported Adverse Drug Reactions (ADRs) with Quetiapine (≥
10%) are somnolence, dizziness, 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) and very rare (<1/10,000), not known (cannot be estimated from
the available data)
SOC

Very
Common

Common

Uncommon

Rare

Very Rare

Not known

1,

Blood and
lymphatic
system
disorders

Decreased
haemoglobin2
2

Leucopenia
28
, decreased
neutrophil
count,
eosinophils
increased27

Agranulocytosis

Neutropenia

26

1

Hypersensitivit
y (including
allergic skin
reactions)

Anaphylacti
c reaction 5

Hyperprolactin
aemia15,
decreases in
total T4 24,
decreases in
free T4 24,
decreases in
total T3 24,
increases in
TSH 24

Decreases in
free T3 24,
Hypothyroidism21

Inappropriat
e
antidiuretic
hormone
secretion

Increased
appetite,
blood glucose
increased to
hyperglycaemi
c levels 6, 30

Hyponatraemia
19
, Diabetes
Mellitus 1,5

Exacerbatio
n of preexisting
diabetes

Immune
system
disorders

Endocrine
disorders

Metabolism
and
nutritional
disorders

Thrombocytop
enia,
Anaemia,
platelet count
decreased13

Elevations in
serum
triglyceride
levels 10,30
Elevations in
total
cholesterol
(predominant

Metabolic
syndrome29

SOC

Very
Common
ly LDL
cholesterol)

Common

Uncommon

Rare

11,30

Decreases in
HDL
cholesterol
17,30

Weight gain
8,30

Abnormal
dreams and
nightmares,
Suicidal
ideation and
suicidal
behaviour20

Psychiatric
disorders

Nervous
system
disorders

Dizziness 4,
16
,
somnolence

Seizure 1,
Restless legs
syndrome,
Tardive
dyskinesia 1, 5,
Syncope 4,16

2,16

headache,
Extrapyramid
al symptoms1,

Somnambulism
and related
reactions such
as sleep talking
and sleep
related eating
disorder

Dysarthria

21

Tachycardia 4,
Palpitations23

Cardiac
disorders

QT
prolongation
1,12, 18

Bradycardia32
Eye
Disorders

Vision blurred
Orthostatic
hypotension

Vascular
disorders

4,16

Respiratory,
thoracic and
mediastinal
disorder
Gastrointestinal
disorders

Hepatobiliary
disorders

Venous
thromboembolism1

Dyspnoea

Dry mouth

23

Rhinitis

Constipation,
dyspepsia,
vomiting 25

Dysphagia7

Pancreatitis1,
Intestinal
obstruction/Ileu
s

Elevations in
serum alanine
aminotransfera
se (ALT)3,
Elevations in
gamma-GT
levels3

Elevations in
serum aspartate
aminotransfera
se (AST) 3

Jaundice5,
Hepatitis

Very Rare

Not known

SOC

Very
Common

Common

Uncommon

Rare

Musculoskele
tal and
connective
tissue
disorders
Renal and
urinary
disorders

Not known

Angioedema
5
StevensJohnson
syndrome5

Skin and
subcutaneous
tissue
disorders

Very Rare

Toxic
Epidermal
Necrolysis,
Erythema
Multiforme

Rhabdomyol
ysis

Urinary
retention
Drug
withdrawal
syndrome
neonatal 31

Pregnancy,
puerperium
and perinatal
conditions
Reproductive
system and
breast
disorders
General
disorders and
administratio
n site
conditions

Sexual
dysfunction

Withdrawal
(discontinuati
on)
symptoms 1,9

Mild asthenia,
peripheral
oedema,
irritability,
pyrexia

Priapism,
galactorrhoea,
breast swelling,
menstrual
disorder
Neuroleptic
malignant
syndrome 1,
hypothermia
Elevations in
blood creatine
phosphokinase

Investigation
s

14

(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 > 3X 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 ADRs have been taken from post-marketing
data only.
(6) Fasting blood glucose ≥126mg/dL (≥7.0mmol/L) or a non fasting blood glucose
≥200mg/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 (≥2.258mmol/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 ≥240mg/dL (≥6.2064mmol/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 ≥30mg/dL (≥0.769 mmol/L) has been very commonly
observed. Mean change among patients who had this increase was 41.7mg/dL
(≥1.07mmol/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): >20μg/L (>869.56 pmol/L) males;
>30μg/L (>1304.34 pmol/L) females at any time.
(16) May lead to falls.
(17) HDL cholesterol: <40 mg/dL (1.025mmol/L) males; <50 mg/dL (1.282mmol/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 XR 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 hemoglobin 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 older people (≥65 years of age).
(26) Shift in neutrophils from ≥1.5 x 109/L at baseline to <0.5 x 109/L at any time
during treatment.
(27) Based on shifts from normal baseline to potentially clinically important value at
anytime post-baseline in all trials. Shifts in eosinophils are defined as >1x 109 cells/L
at any time.
(28) Based on shifts from normal baseline to potentially clinically important value at
anytime post-baseline in all trials. Shifts in WBCs are defined as ≤ 3X109 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 (Fertility, pregnancy and lactation)
(32) May occur at or near initiation of treatment and be associated with hypotension
and/or syncope. Frequency based on adverse 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 very rarely 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 adolescents 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).
SOC
Endocrine disorders
Metabolism and nutritional
disorders
Nervous system disorders
Vascular disorders
Respiratory, thoracic and
mediastinal disorders
Gastrointestinal disorders
General disorders and
administration site conditions

Very common
Elevations in prolactin1
Increased appetite

Common

Extrapyramidal
symptoms3, 4
Increases in blood
pressure2

Syncope

Rhinitis
Vomiting
Irritability3

1. Prolactin levels (patients < 18 years of age): >20 ug/L (>869.56
pmol/L) males; >26 ug/L (>1130.428 pmol/L) females at any time.
Less than 1% of patients had an increase to a prolactin level >100
ug/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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9

Overdose

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 and hypotension.
Overdose could lead to QT-prolongation, seizures, status epilepticus,
rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium, and/or
agitation.
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 delerium and agitation and a clear
anticholinergic 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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antipsychotics
Therapeutic classification: 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 dopamine D2 receptors which is believed to
contribute to the clinical antipsychotic properties and low extrapyramidal side effect
(EPS) liability of Quetiapine compared to typical antipsychotics. Quetiapine and
norquetiapine have no appreciable affinity at benzodiazepine receptors but high
affinity at histaminergic and adrenergic alpha1 receptors, moderate affinity at
adrenergic alpha2 receptors and moderate to high affinity at several muscarinic
receptors. Inhibition of NET and partial agonist action at 5HT1A sites by
norquetiapine may contribute to Seroquel’s therapeutic efficacy as an antidepressant.
Pharmacodynamic effect:
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 depolarization blockade of the
mesolimbic but not the nigrostriatal dopamine-containing neurons following chronic
administration. Quetiapine exhibits minimal dystonic liability in haloperidolsensitised 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 Quetiapine and
placebo treatment groups in the incidence of EPS or concomitant use of
anticholinergics. 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 anticholinergics. 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 disorders

In four placebo controlled clinical trials, evaluating doses of Quetiapine 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 Quetiapine and placebo treatment groups in the incidence of
EPS or concomitant use of anticholinergics.
In the treatment of moderate to severe manic episodes, Quetiapine 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
Quetiapines’s effectiveness in preventing subsequent manic or depressive episodes.
Quetiapine 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 Quetiapine in responders was approximately 600
mg/day and approximately 85% of the responders were in the dose range of 400 to
800 mg per 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, Quetiapine 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 Quetiapine 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 Quetiapine 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 Quetiapine in combination with mood
stabilizers, in patients with manic, depressed or mixed mood episodes, the
combination with Quetiapine was superior to mood stabilizers monotherapy in
increasing the time to recurrence of any mood event (manic, mixed or depressed).
Quetiapine 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 Quetiapine versus placebo and
Quetiapine 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 Quetiapine 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 shortterm, 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
Quetiapine and 3.2% for placebo. In a short-term placebo-controlled monotherapy
trial in older people with major depressive disorder, the aggregated incidence of
extrapyramidal symptoms was 9.0% for Quetiapine 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.

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 older people 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 short-term, placebo-controlled clinical trials in bipolar depression the aggregated
incidence of extrapyramidal symptoms was 8.9% for quetiapine compared to 3.8% for
placebo, though the incidence of the individual adverse events were generally low and
did not exceed 4% in any treatment group. 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).
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 T 4 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 Quetiapine (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 Quetiapine (4%) compared with risperidone (10%), for patients with
at least 21 months of exposure.
Paediatric population
Clinical efficacy
The efficacy and safety of Quetiapine 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 6week 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
Quetiapine were excluded. Treatment with Quetipaine 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 Quetiapine 400 mg/day and –6.56 for
Quetiapine 600 mg/day. Responder rates (YMRS improvement ≥50%) were 64% for
Quetiapine 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 Quetiapine 400 mg/day and –9.29 for
Quetiapine 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 quetiapine 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 pediatric 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 12.5% vs. 6% 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
posttreatment 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 Quetiapine
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.
5.2

Pharmacokinetic properties

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.
Older people
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.
5.3

Preclinical safety data

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 cynomologus
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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Intragranular
Calcium hydrogen phosphate (Dihydrate),
Lactose monohydrate,
Microcrystalline cellulose,
Povidone (PVP K30),
Extragranular
Sodium starch glycollate (Type A),
Magnesium stearate,
Film coating material composition
Opadry OY-S-58910 White containing:
Hypromellose 5cP (E464)
Titanium dioxide (E171)
Macrogol /PEG 400
Talc (E553b)

6.2

Incompatibilities
Not applicable

6.3

Shelf life
3 years

6.4

Special precautions for storage
This medicinal product does not require any special storage condition.

6.5

Nature and contents of container
Blister pack of PVC/PE/PVdC/Al
Or
Blister pack of PVC/ACLAR
Pack sizes: 6, 20, 30, 50, 60 and 100
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements
Any unused product or waste material should be disposed of in accordance
with local requirements

7

MARKETING AUTHORISATION HOLDER
Ranbaxy (UK) Ltd.,
Building 4, Chiswick Park,
566 Chiswick High Road,
London, W4 5YE
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 14894/0542

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
17/08/2010

10

DATE OF REVISION OF THE TEXT
24/11/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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