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PSYQUET XL 150 MG PROLONGED-RELEASE TABLETS

Active substance(s): QUETIAPINE FUMARATE / QUETIAPINE FUMARATE / QUETIAPINE FUMARATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Psyquet XL 150 mg prolonged-release tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Psyquet XL 150 mg contains 150 mg quetiapine (as quetiapine fumarate)
Excipient with known effect: 42 mg lactose (anhydrous) per tablet
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Prolonged-release tablet
150mg: a white to off white, oblong biconvex tablet, 13.6 mm in length, 6.6
mm in width and 4.2 mm in thickness, engraved with “150” on one side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Psyquet XL 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 associated with bipolar
disorder
- For the prevention of recurrence of manic or depressed episodes in
patients with bipolar disorder who previously responded to quetiapine
treatment.


add-on treatment of major depressive episodes in patients with Major Depressive
Disorder (MDD) who have had sub-optimal response to antidepressant
monotherapy (see Section 5.1). Prior to initiating treatment, clinicians should
consider the safety profile of quetiapine (see Section 4.4).

4.2

Posology and method of administration

Posology
Different dosing schedules exist for each indication. It must therefore be ensured that
patients receive clear information on the appropriate dosage for their condition.
Adults:
For the treatment of schizophrenia and moderate to severe manic episodes in
bipolar disorder
Psyquet XL should be administered at least one hour before a meal. The daily dose at
the start of therapy is 300 mg on Day 1 and 600 mg on Day 2. The recommended
daily dose is 600 mg, however if clinically justified the dose may be increased to 800
mg daily. The dose should be adjusted within the effective dose range of 400 mg to
800 mg per day, depending on the clinical response and tolerability of the patient. For
maintenance therapy in schizophrenia no dosage adjustment is necessary.
For the treatment of major depressive episodes in bipolar disorder
Psyquet XL should be administered 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 Psyquet XL for acute treatment of bipolar disorder
should continue on Psyquet XL at the same dose administered at bedtime. Psyquet XL
dose can be adjusted depending on clinical response and tolerability of the individual
patient within the dose range of 300 mg to 800 mg/day. It is important that the lowest
effective dose is used for maintenance therapy.
For add-on treatment of major depressive episodes in MDD:
Psyquet XL should be administered prior to bedtime. The daily dose at the start of
therapy is 50 mg on Day 1 and 2, and 150 mg on Day 3 and 4. Antidepressant effect
was seen at 150 and 300 mg/day in short-term trials as add-on therapy (with
amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine,
sertraline and venlafaxine - see Section 5.1) and at 50 mg/day in short-term
monotherapy trials.
There is an increased risk of adverse events at higher doses. Clinicians should
therefore ensure that the lowest effective dose, starting with 50 mg/day, is used for
treatment. The need to increase the dose from 150 to 300 mg/day should be based on
individual patient evaluation.
Switching from Quetiapine immediate-release tablets:

For more convenient dosing, patients who are currently being treated with divided
doses of immediate release Quetiapine tablets may be switched to Psyquet XL at the
equivalent total daily dose taken once daily.
Individual dosage adjustments may be necessary.
Older people:
As with other antipsychotics and antidepressants, Psyquet XL should be used with
caution in the elderly, especially during the initial dosing period. The rate of dose
titration of Psyquet XL may need to be slower, and the daily therapeutic dose lower,
than that used in younger patients. The mean plasma clearance of quetiapine was
reduced by 30% to 50% in elderly patients when compared to younger patients.
Elderly patients should be started on 50 mg/day. The dose can be increased in
increments of 50 mg/day to an effective dose, depending on the clinical response and
tolerability of the individual patient.
In elderly patients with major depressive episodes in MDD, dosing should begin with
50 mg/day on Days 1- 3, increasing to 100 mg/day on Day 4 and 150 mg/day on Day
8. The lowest effective dose, starting from 50 mg/day should be used. Based on
individual patient evaluation, if dose increase to 300 mg/day is required this should
not be prior to Day 22 of treatment.
Efficacy and safety has not been evaluated in patients over 65 years with depressive
episodes in the framework of bipolar disorder.
Paediatric Population
Psyquet XL 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 metabolized by the liver. Therefore, Psyquet XL should be
used with caution in patients with known hepatic impairment, especially during the
initial dosing period. Patients with hepatic impairment should be started on 50
mg/day. The dose can be increased in increments of 50 mg/day to an effective dose,
depending on the clinical response and tolerability of the individual patient.
Method of administration
Psyquet XL should be administered once daily, without food. The tablets should be
swallowed whole and not split, chewed or crushed.
4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients 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 section 4.5).

4.4

Special warnings and precautions for use

As Psyquet XL has several indications, the safety profile should be considered with
respect to the individual patient’s diagnosis and the dose being administered.
Long-term efficacy and safety in patients with MDD has not been evaluated as add-on
therapy, however long-term efficacy and safety has been evaluated in adult patients as
monotherapy (see Section 5.1).
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 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 adults patients (younger than 25 years of age) who were treated with
quetiapine as compared to those treated with placebo (3.0% vs. 0%, respectively). In
clinical studies of patients with MDD the incidence of suicide-related events observed
in young adult patients (younger than 25 years of age) was 2.1% (3/144) for
quetiapine and 1.3% (1/75) for placebo.
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, patient’s 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 and major depressive
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 and major depressive disorder, 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.
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 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
utilized 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.
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 randomized 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.
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 from 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 elderly patients 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 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:
Psyquet XL prolonged-release tablets contain lactose. 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
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 coadministration with cimetidine.
The pharmacokinetics of lithium were not altered when co-administered with
quetiapine.
In a 6-week, randomised, study of lithium and quetiapine versus placebo and
quetiapine 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 addon 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.

4.6

Fertility, Pregnancy and lactation
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.
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 breast-feeding or to discontinue quetiapine 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. 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, headache, 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), very rare (<1/10,000) and not known (cannot be
estimated from the available data).

SOC
Blood and
lymphatic
system
disorders

Very
Common
Decreased
haemoglobi
n22

Immune
system
disorders

Endocrine
disorders

Metabolism
and
nutritional
disorders

Elevations
in serum
triglyceride
levels 10,30
Elevations
in total
cholesterol
(predomina
ntly LDL
cholesterol)

Common
Leucopenia
1, 28
,
decreased
neutrophil
count,
eosinophils
increased27

Uncommo
n:
Thrombocy
topenia,
Anaemia,
platelet
count
decreased13

Rare
Agranulocy
tosis26

Hypersensit
ivity
(including
allergic skin
reactions)
Hyperprola Decreases
ctinemia15, in free T324,
decreases in Hypothyroi
total T424,
dism21
decreases in
free T424,
decreases in
total T324,
increases in
TSH 24
Hyponatrae Metabolic
Increased
mia 19,
syndrome29
appetite,
blood
Diabetes
glucose
Mellitus 1,5
increased to
hyperglycae
mic levels 6,
30

11,30

Decreases in
HDL
cholesterol
17,30
, Weight
gain 8,30
Psychiatric
disorders

Abnormal
dreams and
nightmares,
Suicidal
ideation and
suicidal
behaviour20

Very Rare

Somnambul
ism and
related
reactions
such as
sleep
talking and
sleep
related
eating

Not known
Neutropeni
a1

Anaphylacti
c reaction5

Inappropria
te
antidiuretic
hormone
secretion

Exacerbatio
n of preexisting
diabetes

disorder
Nervous
system
disorders

4,

Dizziness
Dysarthria
16
,
somnolence
2, 16
,
headache,
Extrapyrami
dal
symptoms1, 21

1

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

Cardiac
disorders

Tachycardi
a 4,
Palpitations
23

QT
prolongatio
n 1,12, 18,
Bradycardia
32

Eye
Disorders
Vascular
disorders

Vision
blurred
Orthostatic
hypotension

Venous
thromboem
bolism1

4, 16

Respiratory
, thoracic
and
mediastinal
disorder
Gastrointes
tinal
disorders
Hepatobiliary
disorders

Dyspnoea 23 Rhinitis

Dry mouth

Constipatio
n,
dyspepsia,
vomiting25
Elevations
in serum
alanine
aminotransf
erase
(ALT)3
Elevations
in gammaGT levels3

Dysphagia7 Pancreatitis
1
, Intestinal
obstruction/
Ileus
Elevations
Jaundice5,
in serum
Hepatitis
aspartate
aminotransf
erase
(AST)3

Skin and
subcutaneo
us tissue
disorders

Angioedem
a5, StevensJohnson
syndrome5

Musculoske
letal and
connective
tissue
disorders
Renal and

Rhabdomyo
lysis

Urinary

Toxic
Epidermal
Necrolysis,
Erythema
Multiforme

urinary
disorders
Pregnancy,
puerperium
and
perinatal
conditions
Reproductiv
e system
and breast
disorders

General
disorders
and
administrati
on site
conditions
Investigatio
ns

retention
Drug
withdrawal
syndrome
neonatal31
Sexual
dysfunction

Withdrawal
(discontinu
ation)
symptoms 1,
9

Mild
asthenia,
peripheral
oedema,
irritability,
pyrexia

Priapism,
galactorrho
ea, breast
swelling,
menstrual
disorder
Neuroleptic
malignant
syndrome 1,
hypothermi
a

Elevations
in blood
creatine
phosphokin
ase14

(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 ADR’s have only been taken from
postmarketing data with the immediate release formulation of quetiapine.
(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 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 anytime 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 10^9/L at baseline to <0.5 x
10^9/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 anytime post-baseline in all trials. Shifts in eosinophils are defined as
>1x 10^9 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 ≤
3X10^9 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 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

Very Common

Common
1

Elevations in prolactin
Metabolism and nutritional Increased appetite
disorders
Nervous system disorders Extrapyramidal symptoms

Syncope

3, 4

Vascular disorders
Respiratory, thoracic and
mediastinal disorders
Gastrointestinal disorders
General disorders and
administration site
conditions

Increases in blood
pressure2
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, 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 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 QRSwidening.
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; Diazepines, oxazepines,
thiazepines and oxepines.
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 undesirable effect (EPS) liability of
quetiapine compared to typical antispychotics. Additionally, norequetiapine
has high affinity for the norepinephrine transporter (NET). Quetiapine and
norquetiapine have no appreciable affinity at benzodiazepine receptors but
high affinity at histaminergic and adrenergic α1- receptors, moderate affinity at
adrenergic α2 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 quetiapine XR’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
The efficacy of quetiapine in the treatment of schizophrenia was demonstrated
in one 6-week placebo-controlled trial in patients who met DSM-IV criteria
for schizophrenia, and one active-controlled quetiapine immediate release-toquetiapine XR switching study in clinically stable outpatients with
schizophrenia.
The primary outcome variable in the placebo-controlled trial was change from
baseline to final assessment in the PANSS total score. quetiapine XR 400
mg/day, 600 mg/day and 800 mg/day were associated with statistically
significant improvements in psychotic symptoms compared to placebo. The
effect size of the 600 mg and 800 mg doses was greater than that of the 400
mg dose. In the 6 week active-controlled switching study the primary outcome
variable was the proportion of patients who showed lack of efficacy, ie, who
discontinued study treatment due to lack of efficacy or whose PANSS total
score increased 20% or more from randomization to any visit. In patients
stabilised on quetiapine immediate release 400 mg to 800 mg, efficacy was
maintained when patients were switched to an equivalent daily dose of
quetiapine XR given once daily.
In a long-term study in stable schizophrenic patients who had been maintained
on quetiapine XR for 16 weeks, quetiapine XR was more effective than
placebo in preventing relapse. The estimated risks of relapse after 6 months
treatments was 14.3% for the quetiapine XR treatment group compared to
68.2% for placebo. The average dose was 669 mg. There were no additional
safety findings associated with treatment with quetiapine XR for up to 9
months (median 7 months). In particular, reports of adverse events related to
EPS and weight gain did not increase with longer-term treatment with
quetiapine XR.
Bipolar Disorder
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. The efficacy of quetiapine XR was
further demonstrated with significance versus placebo in an additional 3 week
study. quetiapine XR was dosed in the range of 400 to 800 mg/day and the
mean dose was approximately 600 mg/day. 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.
In a clinical trial, in patients with depressive episodes in bipolar I or bipolar II
disorder, 300 mg/day quetiapine XR showed superior efficacy to placebo in
reduction of MADRS total score.
In 4 additional clinical trials with quetiapine, 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 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 addon group vs. 68% in the placebo add-on group).
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 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.
Major depressive episodes in MDD
Two short-term (6 week) studies enrolled patients who had shown an
inadequate response to at least one antidepressant. Quetiapine XR 150 mg and
300 mg/day, given as add-on treatment to ongoing antidepressant therapy
(amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine,
paroxetine, sertraline or venlafaxine) demonstrated superiority over
antidepressant therapy alone in reducing depressive symptoms as measured by
improvement in MADRS total score (LS mean change vs. placebo of 2-3.3
points).
Long-term efficacy and safety in patients with MDD has not been evaluated as
add-on therapy, however long-term efficacy and safety has been evaluated in
adult patients as monotherapy (see below).

The following studies were conducted with quetiapine XR as monotherapy
treatment, however quetiapine XR is only indicated for use as add-on therapy:
In three out of four short term (up to 8 weeks) monotherapy studies, in patients
with major depressive disorder, quetiapine XR 50 mg, 150 mg and 300
mg/day demonstrated superior efficacy to placebo in reducing depressive
symptoms as measured by improvement in the Montgomery-Åsberg
Depression Rating Scale (MADRS) total score (LS mean change vs. placebo
of 2-4 points).
In a monotherapy relapse prevention study, patients with depressive episodes
stabilised on open-label quetiapine XR treatment for at least 12 weeks were
randomised to either quetiapine XR once daily or placebo for up to 52 weeks.
The mean dose of quetiapine XR during the randomised phase was 177
mg/day. The incidence of relapse was 14.2% for quetiapine XR treated
patients and 34.4% for placebo-treated patients.
In a short-term (9 week) study non-demented elderly patients (aged 66 to 89
years) with major depressive disorder, quetiapine XR dosed flexibly in the
range of 50 mg to 300 mg/day demonstrated superior efficacy to placebo in
reducing depressive symptoms as measured by improvement in MADRS total
score (LS mean change vs placebo -7.54). In this study patients randomised to
quetiapine XR received 50 mg/day on Days 1- 3, the dose could be increased
to 100 mg/day on Day 4, 150 mg/day on Day 8 and up to 300 mg/day
depending on clinical response and tolerability. The mean dose of quetiapine
XR was 160 mg/day. Other than the incidence of extrapyramidal symptoms
(see section 4.8 and ‘Clinical Safety’ below) the tolerability of quetiapine XR
once daily in elderly patients was comparable to that seen in adults (aged 1865 years). The proportion of randomized patients over 75 years of age was
19%.
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 quetiapine XR 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
quetiapine XR 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 quetiapine versus placebo and
quetiapine in adult patients with acute mania indicated that the combination of
quetiapine with lithium leads to more adverse events (63% versus 48% in
quetiapine 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 quetiapine with lithium add-on group (12.7%)
compared to the quetiapine 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 quetiapine (200800 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.
Children and adolescents (10 to 17 years of age)
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 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 quetiapine were excluded. Treatment
with quetiapine 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 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
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 following oral administration. quetiapine XR
achieves peak quetiapine and norquetiapine plasma concentrations at
approximately 6 hours after administration (Tmax). 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 and doseproportional for doses up to 800 mg administered once daily. When quetiapine
XR administered once daily is compared to the same total daily dose of
immediate-release quetiapine fumarate (quetiapine immediate release)
administered twice daily, the area under the plasma concentration-time curve

(AUC) is equivalent, but the maximum plasma concentration (Cmax) is 13%
lower at steady state. When quetiapine XR is compared to quetiapine
immediate release, the norquetiapine metabolite AUC is 18% lower.
In a study examining the effects of food on the bioavailability of quetiapine, a
high-fat meal was found to produce statistically significant increases in the
quetiapine XR Cmax and AUC of approximately 50% and 20% respectively.,
It cannot be excluded that the effect of a high fat meal on the formulation may
be larger. In comparison, a light meal had no significant effect on the Cmax or
AUC of quetiapine. It is recommended that quetiapine XR is taken once daily
without food.
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.
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. Approximately 73% of a radiolabelled drug was
excreted in the urine and 21% in the faeces with less than 5% of the total
radioactivity representing unchanged drug-related material. 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 pharmacokinetics of quetiapine does 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/1.73 m2), but the individual clearance values are within the range for
normal subjects.
Hepatic impairment:
The mean quetiapine plasma clearance decreases with approximately 25% in
persons with known hepatic impairment (stable alcoholcirrhosis). 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-normalized 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.
No information is available for quetiapine XR in children and adolescents.

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
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 embryofoetal 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
Core
Methacrylic acid – ethyl acrylate copolymer (1:1), type A
Lactose anhydrous
Magnesium stearate
Crystalline Maltose
Talc
Coating
Methacrylic acid – ethyl acrylate copolymer (1:1), type A
Triethyl Citrate

6.2

Incompatibilities
Not applicable.

6.3

Shelf life

3 years
HDPE bottle
The shelf life is not affected after opening the bottle.
6.4

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

6.5

Nature and contents of container

A cardboard box containing the appropriate number of white opaque PVC/PCTFEAluminium foil blisters and an instruction leaflet.

White opaque HDPE bottle with child resistant polypropylene screw cap and
induction seal liner.

The pack sizes for the blisters are: 10, 30, 50, 56, 60 and 100 tablets.
The pack sizes for the bottles are: 60 and 120 tablets.
The pack size of 120 tablets is limited for hospital use and dose dispensing.
Not all pack sizes may be marketed.
6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Sandoz Limited
Frimley Business Park,
Frimley,
Camberley,
Surrey,
GU16 7SR,
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 04416/1471

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
09/12/2014

10

DATE OF REVISION OF THE TEXT
23/03/2016

Expand Transcript

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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