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QUETHARTIC XL 400 MG PROLONGED-RELEASE TABLETS

Active substance(s): QUETIAPINE FUMARATE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Quethartic XL 400 mg prolonged-release tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Quethartic XL 400 mg contains 400 mg quetiapine (as quetiapine fumarate)
Excipient: 128mg lactose monohydrate per tablet
For the full list of excipients, see Section 6.1.

3

PHARMACEUTICAL FORM
Prolonged-release tablet
Quethartic XL 400 mg tablets are peach, bi-convex, capsule shaped, coated tablets, of
dimension about 20.5 mm x 9.3 mm, debossed “AI005” on one side and plain on
other side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Quethartic XL prolonged-release tablet 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

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 Quethartic XL (see Section 4.4).

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.

Posology
Adults:
For the treatment of schizophrenia and moderate to severe manic episodes in bipolar
disorder
Quethartic XL prolonged-release tablet should be administrated 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
Quethartic XL prolonged-release tablet 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 quetiapine for acute treatment of bipolar disorder
should continue on Quethartic XL prolonged-release tablet at the same dose
administered at bedtime. Quethartic 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
Quethartic XL prolonged-release tablet 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 addon 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 Quethartic XL
prolonged-release tablet at the equivalent total daily dose taken once daily. Individual
dosage adjustments may be necessary
Elderly:
As with other antipsychotics and antidepressants, quetiapine should be used with
caution in the elderly, especially during the initial dosing period. The rate of dose
titration of quetiapine 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:
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 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:
Quethartic XL prolonged-release tablet 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 quetiapine 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 addon 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 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). 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.
Sleep apnoea syndrome:
Sleep apnoea syndrome has been reported in patients using quetiapine. In patients
receiving concomitant central nervous system depressants and who have a history of
or are at risk for sleep apnoea, such as those who are overweight/obese or are male,
quetiapine should be used with caution.
Seizures:
In controlled clinical trials there was no difference in the incidence of seizures in
patients treated with quetiapine or placebo. No data is available about the incidence of
seizures in patients with a history of seizure disorder. As with other antipsychotics,
caution is recommended when treating patients with a history of seizures (see
Section 4.8).
Neuroleptic Malignant Syndrome:
Neuroleptic malignant syndrome has been associated with antipsychotic treatment,
including quetiapine (see Section 4.8). Clinical manifestations include hyperthermia,
altered mental status, muscular rigidity, autonomic instability, and increased creatine
phosphokinase. In such an event, quetiapine should be discontinued and appropriate
medical treatment given.
Severe Neutropenia and agranulocytosis:

Severe neutropenia (neutrophil count <0.5 X 109/L) has been reported in quetiapine
clinical trials. Most cases of severe neutropenia have occurred within a couple of
months of starting therapy with quetiapine. There was no apparent dose relationship.
During post-marketing experience, some cases were fatal. Possible risk factors for
neutropenia include pre-existing low white blood cell count (WBC) and history of
drug induced neutropenia. However, some cases occurred in patients without preexisting 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.
Anti-cholinergic (muscarinic) effects:
Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for
several muscarinic receptor subtypes. This contributes to ADRs reflecting anticholinergic effects when quetiapine is used at recommended doses, when used
concomitantly with other medications having anti-cholinergic effects, and in the
setting of overdose. Quetiapine should be used with caution in patients receiving
medications having anti-cholinergic (muscarinic) effects. Quetiapine should be used
with caution in patients with a current diagnosis or prior history of urinary retention,
clinically significant prostatic hypertrophy, intestinal obstruction or related
conditions, increased intraocular pressure or narrow angle glaucoma. (See Sections
4.5, 4.8, 5.1, and 4.9.)
Interactions:
See 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 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 utilized 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.)
Elderly patients with dementia-related psychosis:
Quetiapine is not approved for the treatment of dementia-related psychosis.
An approximately 3-fold increased risk of cerebrovascular adverse events has been
seen in randomised placebo controlled trials in the dementia population with some
atypical antipsychotics. The mechanism for this increased risk is not known. An
increased risk cannot be excluded for other antipsychotics or other patient
populations. Quetiapine should be used with caution in patients with risk factors for
stroke.
In a meta-analysis of atypical antipsychotics, it has been reported that elderly patients
with dementia-related psychosis are at an increased risk of death compared to
placebo. In two 10-week placebo controlled quetiapine studies in the same patient
population (n=710; mean age: 83 years; range: 56-99 years) the incidence of
mortality in quetiapine treated patients was 5.5% versus 3.2% in the placebo
group. The patients in these trials died from a variety of causes that were consistent
with expectations for this population.
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:
Quethartic 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.
Misuse and Abuse:
Cases of misuse and abuse have been reported. Caution may be needed when
prescribing quetiapine to patients with a history of alcohol or drug abuse.

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

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

Caution should be exercised when quetiapine is used concomitantly with medicinal
products known to cause electrolyte imbalance or to increase QT interval.
There have been reports of false positive results in enzyme immunoassays for
methadone and tricyclic antidepressants in patients who have taken quetiapine.
Confirmation of questionable immunoassay screening results by an appropriate
chromatographic technique is recommended.

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.

Breast-feeding
Based on very limited data from published reports on quetiapine excretion into human
breast milk, excretion of quetiapine at therapeutic doses appears to be inconsistent.
Due to lack of robust data, a decision must be made whether to discontinue breastfeeding or to discontinue quetiapine therapy taking into account the benefit of
breastfeeding 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, dizziness, headache, dry mouth, withdrawal
(discontinuation) symptoms, elevations in serum triglyceride levels, elevations in
total cholesterol (predominantly LDL cholesterol), decreases in HDL cholesterol,
weight gain, decreased haemoglobin and extrapyramidal symptoms.
The incidences of ADRs associated with quetiapine therapy, are tabulated below
(Table 1) according to the format recommended by the Council for International
Organizations of Medical Sciences (CIOMS III Working Group 1995).

Table 1 ADRs associated with quetiapine therapy
The frequencies of adverse events are ranked according to the following: Very
common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare
(≥1/10,000, <1/1000), very rare (<1/10,000), and not known (cannot be estimated
from the available data).

SOC

Very Common

Blood and
Decreased
lymphatic system haemoglobin22
disorders
Immune system
disorders
Endocrine
disorders

Common

Uncommon
1,28

Leucopenia ,
decreased neutrophil
count, eosinophils
increased27

Rare
1

Very Rare
26

Neutropenia ,
Agranulocytosis
Thrombocytopenia,
Anaemia, platelet count
decreased13
Hypersensitivity
(including allergic skin
reactions)

Anaphylactic
reaction5

Hyperprolactinaemia15 Decreases in free T3 24,
, decreases in total
Hypothyroidism21
24
T4 , decreases in free
T4 24, decreases in total
T3 24, increases in
TSH 24

Inappropriate
antidiuretic
hormone
secretion

Not known

Metabolism and
nutritional
disorders

Elevations in serum
triglyceride
levels 10,30
Elevations in total
cholesterol
(predominantly
LDL
cholesterol)11,30
Decreases in HDL
cholesterol17,30,
Weight gain 8,30

Psychiatric
disorders

Increased appetite,
blood glucose
increased to
hyperglycaemic
levels6, 30

Hyponatraemia19,
Diabetes Mellitus1,5
Exacerbation of preexisting diabetes

Abnormal dreams and
nightmares, Suicidal
ideation and suicidal
behaviour20

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

Cardiac disorders

Tachycardia 4,
Palpitations23

QT prolongation1,12, 18
Bradycardia32

Eye-disorders

Vision blurred

Vascular
disorders

Orthostatic
hypotension 4,16

Respiratory,
thoracic and
mediastinal
disorder

Dyspnoea 23

Gastrointestinal
disorders

Dizziness 4, 16,
somnolence2,16,
headache,
Extrapyramidal
symptoms1, 21

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

Dysarthria

Nervous system
disorders

Dry mouth

Hepato-biliary
disorders

Metabolic
syndrome29

Venous
thromboembolism1
Rhinitis

Constipation,
Dysphagia7
dyspepsia, vomiting25

Pancreatitis1,
Intestinal
obstruction/ Ileus

Elevations in serum
alanine
aminotransferase
(ALT)3,
Elevations in gammaGT levels3

Jaundice5
Hepatitis

Elevations in serum
aspartate
aminotransferase
(AST) 3

Skin and
subcutaneous
tissue disorders

Angioedema5,Ste Toxic
vens-Johnson
Epidermal
syndrome5
Necrolysis,
Erythema
Multiforme

Musculoskeletal
and connective
tissue disorders

Rhabdomyolysis

Renal and urinary
disorders

Urinary retention

Pregnancy,
puerperium and
perinatal
conditions

Drug
withdrawal
syndrome
neonatal31

Reproductive
system and breast
disorders
General disorders Withdrawal
and
(discontinuation)
administration
symptoms 1,9
site conditions
Investigations

Sexual dysfunction

Mild asthenia,
peripheral oedema,
irritability, pyrexia

Priapism,
galactorrhoea,
breast swelling,
menstrual disorder
Neuroleptic
malignant
syndrome 1,
hypothermia
Elevations in
blood creatine
phosphokinase14

(1) See Section 4.4.
(2) Somnolence may occur, usually during the first two weeks of treatment and
generally resolves with the continued administration of quetiapine.
(3) Asymptomatic elevations (shift from normal to ≥3 X ULN at any time) in serum
transaminase (ALT, AST) or gamma-GT levels have been observed in some
patients administered quetiapine. These elevations were usually reversible on
continued quetiapine treatment.
(4) As with other antipsychotics with alpha1 adrenergic blocking activity, quetiapine
may commonly induce orthostatic hypotension, associated with dizziness, tachycardia
and, in some patients, syncope, especially during the initial dose-titration period. (see
Section 4.4).
(5) Calculation of Frequency for these ADR's have only been taken from
postmarketing data with the immediate release formulation of quetiapine.
(6) Fasting blood glucose ≥126mg/dL (≥ 7.0 mmol/L) or a non fasting blood glucose
≥200mg/dL (≥ 11.1 mmol/L) on atleast one occasion.
(7) An increase in the rate of dysphagia with quetiapine vs. placebo was only
observed in the clinical trials in bipolar depression.
(8) Based on >7% increase in body weight from baseline. Occurs predominantly
during the early weeks of treatment in adults.
(9) The following withdrawal symptoms have been observed most frequently in acute
placebo-controlled, monotherapy clinical trials, which evaluated discontinuation
symptoms: insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and
irritability. The incidence of these reactions
had decreased significantly after 1
week post-discontinuation.
(10) Triglycerides ≥200 mg/dL (≥2.258 mmol/L) (patients ≥18 years of age) or ≥150
mg/dL (≥1.694 mmol/L) (patients <18 years of age) on at least one occasion.
(11) Cholesterol ≥240 mg/dL (≥6.2064 mmol/L) (patients ≥18 years of age) or ≥200
mg/dL (≥5.172 mmol/L) (patients <18 years of age) on at least one occasion. An
increase in LDL cholesterol of ≥30 mg/dL (≥0.769 mmol/L) has been very commonly
observed. Mean change among patients who had this increase was 41.7 mg/dL (≥1.07
mmol/L).
(12) See text below.

(13) Platelets ≤100 x 109/L on at least one occasion.
(14) Based on clinical trial adverse event reports of blood creatine phosphokinase
increase not associated with neuroleptic malignant syndrome.
(15) Prolactin levels (patients >18 years of age): >20 μg/L (>869.56 pmol/L) males;
>30 μg/L (>1304.34 pmol/L) females at any time.
(16) May lead to falls.
(17) HDL cholesterol: <40 mg/dL (1.025 mmol/L) males; <50 mg/dL (1.282 mmol/L)
females at any time.
(18) Incidence of patients who have a QTc shift from <450 msec to ≥450 msec with a
≥30 msec increase. In placebo controlled trials with quetiapine the mean change and
the incidence of patients who have a shift to a clinically significant level is similar
between quetiapine and placebo.
(19) Shift from >132 mmol/L to ≤132 mmol/L on at least one occasion.
(20) Cases of suicidal ideation and suicidal behaviours have been reported during
quetiapine therapy or early after treatment discontinuation (see Sections 4.4 and 5.1).
(21) See Section 5.1.
(22) Decreased haemoglobin to ≤13 g/dL (8.07 mmol/L) males, ≤12 g/dL (7.45
mmol/L) females on at least one occasion occurred in 11% of quetiapine patients in
all trials including open label extensions. For these patients, the mean maximum
decrease in haemoglobin at any time was -1.50 g/dL.
(23) These reports often occurred in the setting of tachycardia, dizziness, orthostatic
hypotension
and/or underlying cardiac/respiratory disease.
(24) Based on shifts from normal baseline to potentially clinically important value at
any time post-baseline in all trials. Shifts in total T4, free T4, total T3 and free T3 are
defined as <0.8 X LLN (pmol/L) and shift in TSH is >5 mIU/L at any time.
(25) Based upon the increased rate of vomiting in elderly patients (≥65 years of age).
(26) Based on shift in neutrophils from > = 1.5 x 109/L at baseline to <0.5 x 109/L at
any time during treatment and based on patients with severe neutropenia (<0.5 x
109/L) and infection during all quetiapine clinical trials (see Section 4.4).

(27) Based on shifts from normal baseline to potentially clinically important value at
any time post-baseline in all trials. Shifts in eosinophils are defined as ≥1 x 109 cells/L
at any time.
(28) Based on shifts from normal baseline to potentially clinically important value at
any time post-baseline in all trials. Shifts in WBCs are defined as ≤3 x 109 cells/L at
any time.
(29) Based on adverse event reports of metabolic syndrome from all clinical trials
with quetiapine.
(30) In some patients, a worsening of more than one of the metabolic factors of
weight, blood glucose and lipids was observed in clinical studies (see Section 4.4)
(31) See Section 4.6.
(32) May occur at or near initiation of treatment and be associated with hypotension
and/or syncope. Frequency based on adverse event reports of bradycardia and related
events in all clinical trials with quetiapine.
Cases of QT prolongation, ventricular arrhythmia, sudden unexplained death, cardiac
arrest and torsades de pointes have been reported with the use of neuroleptics and are
considered class effects.

Paediatric population
The same ADRs described above for adults should be considered for children and
adolescents. The following table summarises ADRs that occur in a higher frequency
category in children and 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
Very Common
Common
1
Endocrine disorders
Elevations in prolactin
Metabolism and nutritional disorders Increased appetite
Nervous system disorders
Extrapyramidal symptoms3, Syncope

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 μg/L (>869.56 pmol/L) males;
>26 μg/L (>1130.428 pmol/L) females at any time. Less than 1% of patients had an
increase to a prolactin level >100 μg/L.
(2) Based on shifts above clinically significant thresholds (adapted from the National
Institutes of Health criteria) or increases >20 mmHg for systolic or >10 mmHg for
diastolic blood pressure at any time in two acute (3-6 weeks) placebo-controlled trials
in children and adolescents.
(3) Note: The frequency is consistent to that observed in adults, but might be
associated with different clinical implications in children and adolescents as
compared to adults.
(4) See Section 5.1.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the MHRA Yellow Card Scheme, website: 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, hypotension and anti-cholinergic effects.
Overdose could lead to QT-prolongation, seizures, status epilepticus, rhabdomyolysis,
respiratory depression, urinary retention, confusion, delirium and/or agitation, coma
and death. Patients with pre-existing severe cardiovascular disease may be at an
increased risk of the effects of overdose. (see Section 4.4, Orthostatic Hypotension).

Management of overdose
There is no specific antidote to quetiapine. In cases of severe signs, the possibility of
multiple drug involvement should be considered, and intensive care procedures are
recommended, including establishing and maintaining a patent airway, ensuring
adequate oxygenation and ventilation, and monitoring and support of the
cardiovascular system.
Based on public literature, patients with 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; Diazepines, oxazepines and thiazepines
ATC code: N05A H04

Mechanism of action:
Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human
plasma metabolite, norquetiapine interact with a broad range of neurotransmitter
receptors. Quetiapine and norquetiapine exhibit affinity for brain serotonin (5HT2)
and dopamine D1- and D2-receptors. It is this combination of receptor antagonism
with a higher selectivity for 5HT2 relative to D2-receptors, which is believed to

contribute to the clinical antipsychotic properties and low extrapyramidal side effect
(EPS) liability of quetiapine compared to typical antipsychotics. Quetiapine and
norquetiapine have no appreciable affinity at benzodiazepine receptors but high
affinity at histaminergic and adrenergic alpha1 receptors and moderate affinity at
adrenergic alpha2 receptors Quetiapine also has low affinity for muscarinic receptors,
while norquetiapine has moderate to high affinity at several muscarinic receptors,
which may explain anti-cholinergic (muscarinic) effects. Inhibition of NET and
partial agonist action at 5HT1A sites by norquetiapine may contribute to quetiapine
fumarate’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 haloperidolsensitised or drug-naïve Cebus monkeys after acute and chronic administration. (See
Section 4.8.)

Clinical efficacy and Safety:
Schizophrenia
The efficacy of quetiapine prolonged-release 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 prolonged-release 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 prolonged-release
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, i.e, who discontinued study
treatment due to lack of efficacy or whose PANSS total score increased 20% or more
from randomisation 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 prolonged-release given once daily.
In a long-term study in stable schizophrenic patients who had been maintained on
quetiapine prolonged-release for 16 weeks, quetiapine prolonged-release was more
effective than placebo in preventing relapse. The estimated risks of relapse after 6
months treatments was 14.3% for the quetiapine prolonged-release 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 prolonged-release
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
prolonged-release.
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 prolonged-release was further
demonstrated with significance versus placebo in an additional 3 week study.
Quetiapine prolonged-release was dosed in the range of 400 to 800 mg/day and
themean 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 prolonged-release 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 immediate release 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 immediate release 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 immediate release 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 prolonged-releaseversus
placebo and quetiapine prolonged-release 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.
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 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 addon therapy, however long-term efficacy and safety has been evaluated in adult
patients as monotherapy (see below).
The following studies were conducted with quetiapine prolonged-release as
monotherapy treatment, however quetiapine prolonged-release 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 prolonged-release 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 prolonged-release treatment for at least 12 weeks
were randomised to either quetiapine prolonged-release once daily or placebo for up

to 52 weeks. The mean dose of quetiapine prolonged-release during the randomised
phase was 177 mg/day. The incidence of relapse was 14.2% for quetiapine prolongedreleasetreated 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 prolonged-release 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 prolongedrelease 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 prolonged-release was 160 mg/day.
Other than the incidence of extrapyramidal symptoms (see Section 4.8 and 'Clinical
Safety' below) the tolerability of quetiapine prolonged-release once daily in elderly
patients was comparable to that seen in adults (aged 18-65 years). The proportion of
randomised 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 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 prolonged-release and 3.2% for placebo. In a short-term placebocontrolled monotherapy trial in elderly patients with major depressive disorder, the
aggregated incidence of extrapyramidal symptoms was 9.0% for quetiapine
prolonged-release 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 (50 mg/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 prolonged-release versus
placebo and quetiapine prolonged-release in adult patients with acute mania indicated
that the combination of quetiapine prolonged-release with lithium leads to more

adverse events (63% versus 48% in quetiapine prolonged-release 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 prolonged-release 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 randomised
withdrawal period during which patients were randomised to quetiapine or placebo.
For patients who were randomised to quetiapine, the mean weight gain during the
open label period was 2.56 kg, and by week 48 of the randomised period, the mean
weight gain was 3.22 kg, compared to open label baseline. For patients who were
randomised to placebo, the mean weight gain during the open label period was 2.39
kg, and by week 48 of the randomised 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 incidence of shifts in TSH was 3.2 % for quetiapine versus 2.7 % for
placebo. The incidences 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 (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 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 prolongedrelease in children and adolescent patients (10-17 years of age) with bipolar
depression, efficacy was not demonstrated.
No data are available on maintenance of effect or recurrence prevention in this age
group.
Clinical safety
In the short-term paediatric trials with quetiapine described above, the rates of EPS in
the active arm vs. placebo were 12.9% vs. 5.3% in the schizophrenia trial, 3.6% vs.
1.1% in the bipolar mania trial, and 1.1% vs. 0% in the bipolar depression trial. The
rates of weight gain ≥ 7% of baseline body weight in the active arm vs. placebo were
17% vs. 2.5% in the schizophrenia and bipolar mania trials, and 13.7 % vs. 6.8% in
the bipolar depression trial. The rates of suicide related events in the active arm vs.

placebo were 1.4% vs. 1.3% in the schizophrenia trial, 1.0% vs. 0% in the bipolar
mania trial, and 1.1% vs. 0% in the bipolar depression trial. During an extended 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 following oral administration. Quetiapine prolongedrelease tablet 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
prolonged-release tablet 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 prolonged-release tablet 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 highfat meal was found to produce statistically significant increases in the quetiapine 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 prolonged-release tablet 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
Elderly
The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower
than that seen in adults aged 18 to 65 years.
Renal impairment

The mean plasma clearance of quetiapine was reduced by approximately 25% in
subjects with severe renal impairment (creatinine clearance less than 30 ml/min/1.73
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 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.
No information is available for quetiapine prolonged-release 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 embryo foetal 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
Tablet core:
Cellulose, Microcrystalline
Lactose monohydrate
Sodium citrate
Hypromellose
Magnesium Stearate
Film coat:
Hypromellose
Macrogol 400
Titanium Dioxide (E171)

6.2

Incompatibilities
Not applicable

6.3

Shelf life
2 years

6.4

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

6.5

Nature and contents of container
PVC-Aclar/Aluminium blisters in cartons of 10, 14, 20, 28, 30, 50, 56, 60, 90, 98 and
100 tablets.
White, HDPE bottle with a child-resistant polypropylene screw cap containing 60
tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements for disposal

7

MARKETING AUTHORISATION HOLDER
Amneal Pharma Europe Limited
70 Sir John Rogerson’s Quay
Dublin 2
Ireland

8

MARKETING AUTHORISATION NUMBER(S)
PL 42357/0215

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
17/01/2017

10

DATE OF REVISION OF THE TEXT
17/01/2017

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