Sequit is indicated for:
 Treatment of Schizophrenia.
 Treatment of bipolar disorder:
 For the treatment of moderate to severe manic episodes in bipolar disorder
 For the treatment of major depressive episodes in bipolar disorder
 For the prevention of recurrence of manic or depressed episodes in patients with bipolar
disorder who previously responded to Quetiapine treatment.

Different dosing schedules exist for each indication. It must therefore be ensured that patients
receive clear information on the appropriate dosage for their condition.
Sequit can be administered with or without food.
Adults:
For the treatment of schizophrenia
For the treatment of schizophrenia, Quetiapine should be administered twice a day. The total
daily dose for the first four days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3)
and 300 mg (Day 4) From Day 4 onwards, the dose should be titrated to the usual effective dose
of 300 to 450 mg/day. Depending on the clinical response and tolerability of the individual
patient, the dose may be adjusted within the range 150 to 750 mg/day.
For the treatment of moderate to severe manic episodes in bipolar disorder
For the treatment of manic episodes associated with bipolar disorder, Quetiapine should be
administered twice a day. The total daily dose for the first four days of therapy is 100 mg (Day
1), 200 mg (Day 2), 300 mg (Day 3) and 400 mg (Day 4). Further dosage adjustments up to 800
mg/day by Day 6 should be in increments of no greater than 200 mg/day.
The dose may be adjusted depending on clinical response and tolerability of the individual
patient, within the range of 200 to 800 mg/day. The usual effective dose is in the range of 400 to
800 mg/day.

For the treatment of major depressive episodes in bipolar disorder
Quetiapine should be administered once daily at bedtime. The total daily dose for the first four
days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). The
recommended daily dose is 300 mg. In clinical trials, no additional benefit was seen in the 600
mg group compared to the 300 mg group (see Section 5.1). Individual patients may benefit from
a 600 mg dose. Doses greater than 300 mg should be initiated by physicians experienced in
treating bipolar disorder. In individual patients, in the event of tolerance concerns, clinical trials
have indicated that dose reduction to a minimum of 200 mg could be considered.
For preventing recurrence in bipolar disorder
For preventing recurrence of manic, mixed or depressive episodes in bipolar disorder, patients
who have responded to Quetiapine for acute treatment of bipolar disorder should continue
therapy at the same dose. The dose may be adjusted depending on clinical response and
tolerability of the individual patient, within the range of 300 to 800 mg/day administered twice
daily. It is important that the lowest effective dose is used for maintenance therapy.
Elderly:
As with other antipsychotics, Quetiapine should be used with caution in the elderly, especially
during the initial dosing period. The rate of dose titration may need to be slower, and the daily
therapeutic dose lower, than that used in younger patients, depending on the clinical response
and tolerability of the individual patient. The mean plasma clearance of Quetiapine was reduced
by 30 - 50% in elderly subjects when compared to younger patients.
Efficacy and safety has not been evaluated in patients over 65 years with depressive episodes in
the framework of bipolar disorder.
Paediatric Population:
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 known hepatic impairment should be started with 25 mg/day. The dosage should be
increased daily with increments of 25 - 50 mg/day until an effective dosage, depending on the
clinical response and tolerability of the individual patient.

As Quetiapine has several indications, the safety profile should be considered with respect to the
individual patient's diagnosis and the dose being administered.
Paediatric population:
Quetiapine is not recommended for use in children and adolescents below 18 years of age, due to
a lack of data to support use in this age group. Clinical trials with Quetiapine have shown that in
addition to the known safety profile identified in adults (see Section 4.8), certain adverse events
occurred at a higher frequency in children and adolescents compared to adults (increased
appetite, elevations in serum prolactin, vomiting, rhinitis and syncope), or may have different
implications for children and adolescents (extrapyramidal symptoms and irritability) and one was
identified that has not been previously seen in adult studies (increases in blood pressure).
Changes in thyroid function tests have also been observed in children and adolescents.

Furthermore, the long-term safety implications of treatment with Quetiapine on growth and
maturation have not been studied beyond 26 weeks. Long-term implications for cognitive and
behavioural development are not known.
In placebo-controlled clinical trials with children and adolescent patients, Quetiapine was
associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo
in patients treated for schizophrenia, bipolar mania and bipolar depression (see Section 4.8).
Suicide/suicidal thoughts or clinical worsening:
Depression in bipolar disorder is associated with an increased risk of suicidal thoughts, self-harm
and suicide (suicide-related events). This risk persists until significant remission occurs. As
improvement may not occur during the first few weeks or more of treatment, patients should be
closely monitored until such improvement occurs. It is general clinical experience that the risk of
suicide may increase in the early stages of recovery.
In addition, physicians should consider the potential risk of suicide-related events after abrupt
cessation of Quetiapine treatment, due to the known risk factors for the disease being treated.
Other psychiatric conditions for which Quetiapine is prescribed can also be associated with an
increased risk of suicide related events. In addition, these conditions may be co-morbid with
major depressive episodes. The same precautions observed when treating patients with major
depressive episodes should therefore be observed when treating patients with other psychiatric
disorders.
Patients with a history of suicide related events, or those exhibiting a significant degree of
suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal
thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta
analysis of placebo controlled clinical trials of antidepressant drugs in adult patients with
psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants
compared to placebo in patients less than 25 years old.
Close supervision of patients and in particular those at high risk should accompany drug therapy
especially in early treatment and following dose changes. Patients (and caregivers of patients)
should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these
symptoms present.
In shorter-term placebo controlled clinical studies of patients with major depressive episodes in
bipolar disorder an increased risk of suicide-related events was observed in young adult patients
(younger than 25 years of age) who were treated with quetiapine as compared to those treated
with placebo (3.0% vs. 0%, respectively).
Metabolic Risk:
Given the observed risk for worsening of their metabolic profile, including changes in weight,
blood glucose (see hyperglycaemia) and lipids, which was seen in clinical studies, patients'
metabolic parameters should be assessed at the time of treatment initiation and changes in these
parameters should be regularly controlled for during the course of treatment. Worsening in these
parameters should be managed as clinically appropriate (see also Section 4.8).
Extrapyramidal symptoms:
In placebo controlled clinical trials of adult patients Quetiapine was associated with an increased
incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major
depressive episodes in bipolar disorder (see Sections 4.8 and 5.1).
The use of Quetiapine has been associated with the development of akathisia, characterised by a
subjectively unpleasant or distressing restlessness and need to move often accompanied by an
inability to sit or stand still. This is most likely to occur within the first few weeks of treatment.
In patients who develop these symptoms, increasing the dose may be detrimental.
Tardive Dyskinesia:
If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of
Quetiapine should be considered. The symptoms of tardive dyskinesia can worsen or even arise
after discontinuation of treatment (see Section 4.8).
Somnolence and dizziness:
Quetiapine treatment has been associated with somnolence and related symptoms, such as
sedation (see Section 4.8). In clinical trials for treatment of patients with bipolar depression,
onset was usually within the first 3 days of treatment and was predominantly of mild to moderate intensity. Patients experiencing somnolence of severe intensity may require more frequent
contact for a minimum of 2 weeks from onset of somnolence, or until symptoms improve and
treatment discontinuation may need to be considered.
Orthostatic hypotension:
Quetiapine treatment has been associated with orthostatic hypotension and related dizziness (see
Section 4.8) which, like somnolence has onset usually during the initial dose-titration period.
This could increase the occurrence of accidental injury (fall), especially in the elderly population.
Therefore, patients should be advised to exercise caution until they are familiar with the potential
effects of the medication.
Quetiapine should be used with caution in patients with known cardiovascular disease,
cerebrovascular disease, or other conditions predisposing to hypotension. Dose reduction or
more gradual titration should be considered if orthostatic hypotension occurs, especially in
patients with underlying cardiovascular disease.
Sleep apnoea syndrome
Sleep apnoea syndrome has been reported in patients using Quetiapine. In patients receiving
concomitant central nervous system depressants and who have a history of or are at risk for sleep
apnoea, such as those who are overweight/obese or are male, Quetiapine should be used with
caution.
Seizures:
In controlled clinical trials there was no difference in the incidence of seizures in patients treated
with quetiapine or placebo. No data is available about the incidence of seizures in patients with a
history of seizure disorder. As with other antipsychotics, caution is recommended when treating
patients with a history of seizures (see Section 4.8).
Neuroleptic Malignant Syndrome:
Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including
Quetiapine (see Section 4.8). Clinical manifestations include hyperthermia, altered mental status,
muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event,
Quetiapine should be discontinued and appropriate medical treatment given.

Severe Neutropenia and agranulocytosis:
Severe neutropenia (neutrophil count <0.5 X 109/L) has been reported in quetiapine clinical
trials. Most cases of severe neutropenia have occurred within a couple of months of starting
therapy with Quetiapine. There was no apparent dose relationship. During post-marketing
experience, some cases were fatal. Possible risk factors for neutropenia include pre-existing low
white blood cell count (WBC) and history of drug induced neutropenia. However, some cases
occurred in patients without pre-existing risk factors. Quetiapine should be discontinued in
patients with a neutrophil count <1.0 X 109/L. Patients should be observed for signs and
symptoms of infection and neutrophil counts followed (until they exceed 1.5 X 109/L) (see
Section 5.1).
Neutropenia should be considered in patients presenting with infection or fever, particularly in
the absence of obvious predisposing factor(s), and should be managed as clinically appropriate.
Patients should be advised to immediately report the appearance of signs/symptoms consistent
with agranulocytosis or infection (e.g., fever, weakness, lethargy, or sore throat) at any time
during 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 anti-cholinergic 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 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 postmarketing
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:
Quetiapine tablets contain lactose. Patients with rare hereditary problems of galactose
intolerance, the lapp lactase deficiency, or glucose-galactose malabsorption should not take this
medicine.

Given the primary central nervous system effects of quetiapine, quetiapine should be used with
caution in combination with other centrally acting medicinal products and alcohol.
Caution should be exercised treating patients receiving other medications having anti-cholinergic
(muscarinic) effects (see Section 4.4).
Cytochrome P450 (CYP) 3A4 is the enzyme that is primarily responsible for the cytochrome
P450 mediated metabolism of quetiapine. In an interaction study in healthy volunteers,
concomitant administration of quetiapine (dosage of 25 mg) with ketoconazole, a CYP3A4
inhibitor, caused a 5- to 8-fold increase in the AUC of quetiapine. On the basis of this,
concomitant use of quetiapine with CYP3A4 inhibitors is contraindicated. It is also not
recommended to consume grapefruit juice while on quetiapine therapy.
In a multiple dose trial in patients to assess the pharmacokinetics of quetiapine given before and
during treatment with carbamazepine (a known hepatic enzyme inducer), co-administration of
carbamazepine significantly increased the clearance of quetiapine. This increase in clearance
reduced systemic quetiapine exposure (as measured by AUC) to an average of 13% of the
exposure during administration of quetiapine alone; although a greater effect was seen in some
patients. As a consequence of this interaction, lower plasma concentrations can occur, which
could affect the efficacy of quetiapine therapy. Co-administration of quetiapine and phenytoin
(another microsomal enzyme inducer) caused a greatly increased clearance of quetiapine by
approx. 450%. In patients receiving a hepatic enzyme inducer, initiation of quetiapine treatment
should only occur if the physician considers that the benefits of quetiapine outweigh the risks of
removing the hepatic enzyme inducer. It is important that any change in the inducer is gradual,
and if required, replaced with a non-inducer (e.g. sodium valproate) (see Section 4.4).
The pharmacokinetics of quetiapine were not significantly altered by co-administration 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 co-administration 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 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 add-on group (see Section 5.1).
The pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically
relevant extent when co-administered. A retrospective study of children and adolescents who
received valproate, quetiapine, or both, found a higher incidence of leucopenia and neutropenia
in the combination group versus the monotherapy groups.
Formal interaction studies with commonly used cardiovascular medicinal products have not been
performed.
Caution should be exercised when quetiapine is used concomitantly with medicinal products
known to cause electrolyte imbalance or to increase QT interval.
There have been reports of false positive results in enzyme immunoassays for methadone and
tricyclic antidepressants in patients who have taken quetiapine. Confirmation of questionable
immunoassay screening results by an appropriate chromatographic technique is recommended.

Pregnancy
Pregnancy Category C:
The teratogenic potential of Quetiapine was studied in Wistar rats and Dutch Belted rabbits
dosed during the period of organogenesis. No evidence of a teratogenic effect was detected in
rats at doses of 25 to 200 mg/kg or 0.3 to 2.4 times the maximum human dose on an mg/m2 basis
or in rabbits at 25 to 100 mg/kg or 0.6 to 2.4 times the maximum human dose on a mg/m2 basis.
There was, however, evidence of embryo/fetal toxicity. Delays in skeletal ossification were
detected in rat fetuses at doses of 50 and 200 mg/kg (0.6 and 2.4 times the maximum human dose
on a mg/m2 basis) and in rabbits at 50 and 100 mg/kg (1.2 and 2.4 times the maximum human
dose on a mg/m2 basis). Fetal body weight was reduced in rat fetuses at 200 mg/kg and rabbit
fetuses at 100 mg/kg (2.4 times the maximum human dose on a mg/m2 basis for both species).There was an increased incidence of a minor soft tissue anomaly (carpal/tarsal flexure) in rabbit
fetuses at a dose of 100 mg/kg (2.4 times the maximum human dose on a mg/m2 basis).
Evidence of maternal toxicity (i.e., decreases in body weight gain and/or death) was observed at
the high dose in the rat study and at all doses in the rabbit study. In a peri/postnatal reproductive
study in rats, no drug-related effects were observed at doses of 1, 10, and 20 mg/kg or 0.01, 0.12,
and 0.24 times the maximum human dose on a mg/m2 basis. However, in a preliminary
peri/postnatal study, there were increases in fetal and pup death, and decreases in mean litter
weight at 150 mg/kg, or 3.0 times the maximum human dose on a mg/m2 basis.
There are no adequate and well-controlled studies in pregnant women and quetiapine should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
First trimester
The moderate amount of published data from exposed pregnancies (i.e. between 300-1000
pregnancy outcomes), including individual reports and some observational studies do not suggest
an increased risk of malformations due to treatment. However, based on all available data, a
definite conclusion cannot be drawn. Animal studies have shown reproductive toxicity (see
Section 5.3). Therefore, quetiapine should only be used during pregnancy if the benefits justify
the potential risks.
Third trimester
Neonates exposed to antipsychotics (including quetiapine) during the third trimester of
pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms
that may vary in severity and duration following delivery. There have been reports of agitation,
hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder.
Consequently, newborns should be monitored carefully.

Breast-feeding
Based on very limited data from published reports on quetiapine excretion into human breast
milk, excretion of quetiapine at therapeutic doses appears to be inconsistent. Due to lack of
robust data, a decision must be made whether to discontinue breast-feeding or to discontinue
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).

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

The most commonly reported Adverse Drug Reactions (ADRs) with quetiapine (≥10%) are somnolence, dizziness, headache, dry mouth, withdrawal (discontinuation) symptoms, elevations in serum triglyceride levels, elevations in total cholesterol (predominantly LDL cholesterol), decreases in HDL cholesterol, weight gain, decreased haemoglobin and extrapyramidal symptoms.

The incidences of ADRs associated with quetiapine therapy, are tabulated below (Table 1) according to the format recommended by the Council for International Organizations of Medical Sciences (CIOMS III Working Group; 1995).

Table 1 ADRs associated with quetiapine therapy

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

1. See section 4.4.

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

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

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

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

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

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

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

9. The following withdrawal symptoms have been observed most frequently in acute placebo-controlled, monotherapy clinical trials, which evaluated discontinuation symptoms: insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and irritability. The incidence of these reactions had decreased significantly after 1 week post-discontinuation.

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

11. Cholesterol ≥240 mg/dL (≥6.2064 mmol/L) (patients ≥18 years of age) or ≥200 mg/dL (≥5.172 mmol/L) (patients <18 years of age) on at least one occasion. An increase in LDL cholesterol of ≥30 mg/dL (≥0.769 mmol/L) has been very commonly observed. Mean change among patients who had this increase was 41.7 mg/dL (≥1.07 mmol/L).

12. See text below.

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

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

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

16. May lead to falls.

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

18. Incidence of patients who have a QTc shift from <450 msec to ≥450 msec with a ≥30 msec increase. In placebo-controlled trials with quetiapine the mean change and the incidence of patients who have a shift to a clinically significant level is similar between quetiapine and placebo.

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

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

21. See section 5.1.

22. Decreased haemoglobin to ≤13 g/dL (8.07 mmol/L) males, ≤12 g/dL (7.45 mmol/L) females on at least one occasion occurred in 11% of quetiapine patients in all trials including open label extensions. For these patients, the mean maximum decrease in haemoglobin at any time was –1.50 g/dL.

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

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

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

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

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

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

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

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

31. See section 4.6

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

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

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

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

Paediatric population

The same ADRs described above for adults should be considered for children and adolescents. The following table summarises ADRs that occur in a higher frequency category in children and adolescent patients (10-17 years of age) than in the adult population or ADRs that have not been identified in the adult population.

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

The frequencies of adverse events are ranked according to the following: Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000) and very rare (<1/10,000).

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

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

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

4. See section 5.1.

Reporting of suspected adverse reactions
To report any side effect(s):
Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662.
Call NPC at +966-11-2038222,
Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc
Other GCC States:
Please contact the relevant competent authority.

Symptoms
In general, reported signs and symptoms were those resulting from an exaggeration of the active
substance's known pharmacological effects, ie, 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 anti-cholinergic
syndrome may be treated with physostigmine, 1-2 mg (under continuous ECG monitoring). This
is not recommended as standard treatment, because of potential negative effect of physostigmine
on cardiac conductance. Physostigmine may be used if there are no ECG aberrations. Do not use
physostigmine in case of dysrhythmias, any degree of heart block or QRS-widening. Whilst the prevention of absorption in overdose has not been investigated, gastric lavage can be
indicated in severe poisonings and if possible to perform within one hour of ingestion. The
administration of activated charcoal should be considered.
In cases of quetiapine overdose, refractory hypotension should be treated with appropriate
measures such as intravenous fluids and/or sympathomimetic agents. Epinephrine and dopamine
should be avoided, since beta stimulation may worsen hypotension in the setting of quetiapineinduced
alpha blockade.
Close medical supervision and monitoring should be continued until the patient recovers.

Pharmacotherapeutic group: Antipsychotics
ATC code: N05A H04
Mechanism of action:
Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma
metabolite, norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine
and norquetiapine exhibit affinity for brain serotonin (5HT2) and dopamine D1- and D2-
receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT2
relative to D2- receptors, which is believed to contribute to the clinical antipsychotic properties
and low extrapyramidal side effect (EPS) liability of 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 or no affinity for muscarinic receptors,
while norquetiapine has moderate to high affinity at several muscarinic receptors, which may
explain anti-cholinergic (muscarinic) effects. Inhibition of NET and partial agonist action at
5HT1A sites by norquetiapine may contribute to Quetiapine's therapeutic efficacy as an
antidepressant.

Pharmacodynamic effects:
Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also
blocks the action of dopamine agonists, measured either behaviourally or electrophysiologically,
and elevates dopamine metabolite concentrations, a neurochemical index of D2-receptor
blockade.
In pre-clinical tests predictive of EPS, quetiapine is unlike typical antipsychotics and has an
atypical profile. Quetiapine does not produce dopamine D2 receptor supersensitivity after chronic
administration. Quetiapine produces only weak catalepsy at effective dopamine D2 receptor
blocking doses. Quetiapine demonstrates selectivity for the limbic system by producing
depolarisation blockade of the mesolimbic but not the nigrostriatal dopamine-containing
neurones following chronic administration. Quetiapine exhibits minimal dystonic liability in
haloperidol-sensitised or drug-naive Cebus monkeys after acute and chronic administration (see
Section 4.8.)
Clinical efficacy:
Schizophrenia
In three placebo-controlled clinical trials, in patients with schizophrenia, using variable doses of
quetiapine, there were no differences between the Quetiapine and placebo treatment groups in
the incidence of EPS or concomitant use of anti-cholinergics. A placebo-controlled trial
evaluating fixed doses of quetiapine across the range of 75 to 750 mg/day showed no evidence of
an increase in EPS or the use of concomitant anti-cholinergics. The long-term efficacy of
Quetiapine IR in prevention of schizophrenic relapses has not been verified in blinded clinical
trials. In open label trials, in patients with schizophrenia, quetiapine was effective in maintaining
the clinical improvement during continuation therapy in patients who showed an initial treatment
response, suggesting some long-term efficacy.
Bipolar Disorder
In four placebo-controlled clinical trials, evaluating doses of Quetiapine up to 800 mg/day for the
treatment of moderate to severe manic episodes, two each in monotherapy and as combination
therapy to lithium or divalproex, , there were no differences between the Quetiapine and placebo
treatment groups in the incidence of EPS or concomitant use of anti-cholinergics.

In the treatment of moderate to severe manic episodes, Quetiapine demonstrated superior
efficacy to placebo in reduction of manic symptoms at 3 and 12 weeks, in two monotherapy
trials. There are no data from long-term studies to demonstrate Quetiapine's effectiveness in
preventing subsequent manic or depressive episodes. Quetiapine data in combination with
divalproex or lithium in acute moderate to severe manic episodes at 3 and 6 weeks is limited;
however, combination therapy was well tolerated. The data showed an additive effect at week 3.
A second study did not demonstrate an additive effect at week 6.
The mean last week median dose of Quetiapine in responders was approximately 600 mg/day
and approximately 85% of the responders were in the dose range of 400 to 800 mg/day.
In 4 clinical trials with a duration of 8 weeks in patients with moderate to severe depressive
episodes in bipolar I or bipolar II disorder, Quetiapine IR 300 mg and 600 mg was significantly
superior to placebo treated patients for the relevant outcome measures: mean improvement on
the MADRS and for response defined as at least a 50% improvement in MADRS total score
from baseline. There was no difference in magnitude of effect between the patients who received
300 mg Quetiapine IR and those who received 600 mg dose.
In the continuation phase in two of these studies, it was demonstrated that long-term treatment,
of patients who responded on Quetiapine IR 300 or 600 mg, was efficacious compared to
placebo treatment with respect to depressive symptoms, but not with regard to manic symptoms.
In two recurrence prevention studies evaluating Quetiapine in combination with mood
stabilizers, in patients with manic, depressed or mixed mood episodes, the combination with
Quetiapine was superior to mood stabilizers monotherapy in increasing the time to recurrence of
any mood event (manic, mixed or depressed). Quetiapine was administered twice-daily totalling
400 mg to 800 mg a day as combination therapy to lithium or valproate.
In a 6-week, randomised, study of lithium and QUETIAPINE versus placebo and QUETIAPINE
in adult patients with acute mania, the difference in YMRS mean improvement between the
lithium add-on group and the placebo add-on group was 2.8 points and the difference in %
responders (defined as 50% improvement from baseline on the YMRS) was 11% (79% in the
lithium add-on group vs. 68% in the placebo add-on group).

In one long-term study (up to 2 years treatment) evaluating recurrence prevention in patients
with manic, depressed or mixed mood episodes quetiapine was superior to placebo in increasing
the time to recurrence of any mood event (manic, mixed or depressed), in patients with bipolar I
disorder. The number of patients with a mood event was 91 (22.5%) in the quetiapine group, 208
(51.5%) in the placebo group and 95 (26.1%) in the lithium treatment groups respectively. In
patients who responded to quetiapine, when comparing continued treatment with quetiapine to
switching to lithium, the results indicated that a switch to lithium treatment does not appear to be
associated with an increased time to recurrence of a mood event.
Clinical trials have demonstrated that Quetiapine is effective in schizophrenia and mania when
given twice a day, although quetiapine has a pharmacokinetic half-life of approximately 7 hours.
This is further supported by the data from a positron emission tomography (PET) study, which
identified that for quetiapine, 5HT2- and D2-receptor occupancy are maintained for up to 12
hours. The safety and efficacy of doses greater than 800 mg/day have not been evaluated.
Clinical safety
In short-term, placebo-controlled clinical trials in schizophrenia and bipolar mania the
aggregated incidence of extrapyramidal symptoms was similar to placebo (schizophrenia: 7.8%
for quetiapine and 8.0% for placebo; bipolar mania: 11.2% for quetiapine and 11.4% for
placebo). Higher rates of extrapyramidal symptoms were seen in quetiapine treated patients
compared to those treated with placebo in 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 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 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, openlabel,
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 (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 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 13.7% vs. 6.8% in the bipolar depression trial. The rates of suicide related events in the active arm vs. placebo were 1.4% vs. 1.3% in the schizophrenia trial, 1.0%
vs. 0% in the bipolar mania trial, and 1.1% vs. 0% in the bipolar depression trial. During an
extended post treatment follow-up phase of the bipolar depression trial, there were two additional
suicide related events in two patients; one of these patients was on quetiapine at the time of the
event.
Long-term safety
A 26-week open-label extension to the acute trials (n=380 patients), with 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.

Absorption
Quetiapine is well absorbed and extensively metabolised following oral administration. The
bioavailability of quetiapine is not significantly affected by administration with food. Steadystate
peak molar concentrations of the active metabolite norquetiapine are 35% of that observed
for quetiapine.
The pharmacokinetics of quetiapine and norquetiapine are linear across the approved dosing
range.
Distribution
Quetiapine is approximately 83% bound to plasma proteins.
Biotransformation
Quetiapine is extensively metabolised by the liver, with parent compound accounting for less
than 5% of unchanged drug-related material in the urine or faeces, following the administration
of radiolabelled quetiapine. In vitro investigations established that CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. Norquetiapine is
primarily formed and eliminated via CYP3A4.
Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces.
Quetiapine and several of its metabolites (including norquetiapine) were found to be weak
inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities in vitro. In vitro
CYP inhibition is observed only at concentrations approximately 5 to 50 fold higher than those
observed at a dose range of 300 to 800 mg/day in humans. Based on these in vitro results, it is
unlikely that co-administration of quetiapine with other drugs will result in clinically significant
drug inhibition of cytochrome P450 mediated metabolism of the other drug. From animal studies
it appears that quetiapine can induce cytochrome P450 enzymes. In a specific interaction study in
psychotic patients, however, no increase in the cytochrome P450 activity was found after
administration of quetiapine.
Elimination
The elimination half lives of quetiapine and norquetiapine are approximately 7 and 12 hours,
respectively. The average molar dose fraction of free quetiapine and the active human plasma
metabolite norquetiapine is <5% excreted in the urine.
Special populations
Gender
The kinetics of quetiapine do not differ between men and women.
Elderly
The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than that seen
in adults aged 18 to 65 years.
Renal Impairment
The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with
severe renal impairment (creatinine clearance less than 30 ml/min/1.73m2), but the individual
clearance values are within the range for normal subjects.
Hepatic Impairment
The mean quetiapine plasma clearance decreases with approx. 25% in persons with known
hepatic impairment (stable alcohol cirrhosis). As quetiapine is extensively metabolised by the liver, elevated plasma levels are expected in the population with hepatic impairment. Dose
adjustments may be necessary in these patients (see Section 4.2).
Paediatric population
Pharmacokinetic data were sampled in 9 children aged 10-12 years old and 12 adolescents, who
were on steady-state treatment with 400 mg quetiapine twice daily. At steady-state, the dosenormalised
plasma levels of the parent compound, quetiapine, in children and adolescents (10-17
years of age) were in general similar to adults, though Cmax in children was at the higher end of
the range observed in adults. The AUC and Cmax for the active metabolite, norquetiapine, were
higher, approximately 62% and 49% in children (10-12 years), respectively and 28% and 14% in
adolescents (13-17 years), respectively, compared to adults.

There was no evidence of genotoxicity in a series of in vitro and in vivo genotoxicity studies. In
laboratory animals at a clinically relevant exposure level the following deviations were seen,
which as yet have not been confirmed in long-term clinical research:
In rats, pigment deposition in the thyroid gland has been observed; in cynomolgus monkeys
thyroid follicular cell hypertrophy, a lowering in plasma T3 levels, decreased haemoglobin
concentration and a decrease of red and white blood cell count have been observed; and in dogs
lens opacity and cataracts. (For cataracts/lens opacities, see Section 5.1).
In an embryofetal toxicity study in rabbits the foetal incidence of carpal/tarsal flexure was
increased. This effect occurred in the presence of overt maternal effects such as reduced body
weight gain. These effects were apparent at maternal exposure levels similar or slightly above
those in humans at the maximal therapeutic dose. The relevance of this finding for humans is
unknown.
In a fertility study in rats, marginal reduction in male fertility and pseudopregnancy, protracted
periods of diestrus, increased precoital interval and reduced pregnancy rate were seen. These
effects are related to elevated prolactin levels and not directly relevant to humans because of
species differences in hormonal control of reproduction

Core:
 Lactose Monohydrate
 Microcrystalline Cellulose PH 101
 Dibasic Calcium Phosphate Dihydrate
 Sodium Starch Glycollate
 Povidone K 90
 Microcrystalline Cellulose PH 102
 Colloidal Silicone Dioxide (Aerosil 200)
 Magnesium Stearate
 Purified Water
Coating:
 Opadry White 03B28796 (which consist of (which consists of Hypromellose, Titanium
dioxide, Polyethylene Glycol).

Not applicable.

Do not store above 30°C.

Sequit (Quetiapine) 25/100/200/300 mg Film Coated is packed in Aluminium foil and Opaque
PVC /PVDC, blister pack of 3x10’s.

No special requirements.