Rezal XR is indicated for: - Treatment of schizophrenia including: o preventing relapse in stable schizophrenic patients who have been maintained on Rezal XR (see section 5.1 Pharmacodynamic properties). - Treatment of bipolar disorder including: o manic episodes associated with bipolar disorder o major depressive episodes in bipolar disorder o preventing recurrence in bipolar disorder in patients whose manic, mixed or depressive episode has responded to quetiapine treatment. - Add-on treatment of major depressive episodes in patients with Major Depressive Disorder (MDD) who have had sub-optimal response to antidepressant monotherapy (see section 5.1 Pharmacodynamic properties). Prior to initiating treatment, clinicians should consider the safety profile of Rezal XR (see section 4.4 Special warnings and precautions for use).

Different dosing schedules exist for each indication. It must therefore be ensured that patients

receive clear information on the appropriate dosage for their condition.

Rezal XR should be administered once daily, without food (at least one hour before a meal).

The tablets should be swallowed whole and not split, chewed or crushed.

Adults:

For the treatment of schizophrenia

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. Enhanced efficacy at doses higher than 600 mg has not 

been demonstrated, although individual patients may benefit from a dose up to 800 mg daily.

Doses greater than 600 mg should be initiated by a specialist. 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 manic episodes associated with bipolar disorder

The daily dose at the start of therapy is 300 mg on Day 1, 600 mg on Day 2 and up to 800 mg

after Day 2. 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 the treatment of depressive episodes associated with bipolar disorder

Rezal XR 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. Individual patients may benefit from a 600 mg dose.

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. When treating depressive episodes in

bipolar disorder, treatment should be initiated by physicians experienced in treating bipolar

disorder.

For preventing recurrence in bipolar disorder

For prevention of recurrence of manic, depressive or mixed episodes in bipolar disorder,

patients who have responded to Rezal XR for acute treatment of bipolar disorder should

continue on Rezal XR at the same dose administered at bedtime. The dose may 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 effect ive dose is used for maintenance

therapy.

For add-on treatment of major depressive episodes in MDD:

Rezal XR should be administered prior to bedtime. The daily dose at the start of therapy is 50

mg on Day 1 and 2, and 150 mg on Day 3 and 4. Antidepressant effect was seen at 150 and

300 mg/day in short-term trials as add-on therapy (with amitriptyline, bupropion, citalopram,

duloxetine, escitalopram, fluoxetine, paroxetine, sertraline and venlafaxine - see section 5.1

Pharmacodynamic properties) 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 Rezal immediate-release tablets:

For more convenient dosing, patients who are currently being treated with divided doses of

immediate-release Rezal tablets (Rezal IR, tradename Seroquel) may be switched to Rezal XR

at the equivalent total daily dose taken once daily.

To ensure the maintenance of clinical response, a period of dose titration may be required.

Elderly:

As with other antipsychotics and antidepressants, Rezal XR should be used with caution in the

elderly, especially during the initial dosing period. The rate of dose titration of Rezal XR 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 have not been evaluated in patients over 65 years with depressive episodes

in the framework of bipolar disorder.

Children and Adolescents:

Rezal XR 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 placebocontrolled

clinical trials with Rezal 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, Rezal XR 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 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.

Hypersensitivity to the active substance or to any of the excipients of this product. Concomitant administration of cytochrome P450 3A4 inhibitors, such as HIV-protease inhibitors, azole-antifungal agents, erythromycin, clarithromycin and nefazodone, is contraindicated. (See also section 4.5 Interaction with other medicinal products and other forms of interaction).

As Rezal XR is indicated for the treatment of schizophrenia, bipolar disorder and add-on

treatment of major depressive episodes in patients with MDD, the safety profile should be

considered with respect to the individual patient's diagnosis and the dose being administered.

Long-term efficacy and safety in patients with MDD has not been evaluated as add-on therapy,

however long-term efficacy and safety has been evaluated in adult patients as monotherapy

(see section 5.1 Pharmacodynamic properties).

Children and adolescents (10 to 17 years of age)

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 Undesirable

effects), certain adverse events occurred at a higher frequency in children and adolescents

compared to adults (increased appetite, elevations in serum prolactin and extrapyramidal

symptoms) 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 treated with

quetiapine, quetiapine was associated with an increased incidence of extrapyramidal symptoms

(EPS) compared to placebo in patients treated for schizophrenia and bipolar mania (see section

4.8 Undesirable effects).

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 Rezal XR 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. 

Given the primary central nervous system effects of quetiapine, Rezal XR should be used with caution in combination with other centrally acting drugs and alcohol. Cytochrome P450 CYP3A4 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 Rezal XR 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 Rezal XR treatment should only occur if the physician considers that the benefits of Rezal XR 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 Special warnings and precautions for use). The pharmacokinetics of quetiapine were not significantly altered by co-administration of the antidepressants imipramine (a known CYP2D6 inhibitor) or fluoxetine (a known CYP3A4 and CYP2D6 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 of approx. 70%. The pharmacokinetics of quetiapine were not altered following co-administration with cimetidine. The pharmacokinetics of lithium were not altered when co-administered with quetiapine. The pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically relevant extent when co-administered. A retrospective study of children and adolescents who received valproate, quetiapine, or both, found a higher incidence of leucopenia and neutropenia in the combination group versus the monotherapy groups. Formal interaction studies with commonly used cardiovascular drugs have not been performed. Caution should be exercised when quetiapine is used concomitantly with drugs known to cause electrolyte imbalance or to increase QTc 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. 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. 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 section 4.8 Undesirable effects and section 5.1 Pharmacodynamic properties). 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: Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic drugs including quetiapine. If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of Rezal XR should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment (see section 4.8 Undesirable effects). Somnolence and dizziness: Quetiapine treatment has been associated with somnolence and related symptoms, such as sedation (see section 4.8 Undesirable effects). 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. Bipolar depression patients and patients with major depressive episodes in MDD 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. Quetiapine treatment has been associated with orthostatic hypotension and related dizziness (see section 4.8 Undesirable effects) 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. Cardiovascular: Rezal XR should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension. Quetiapine may induce orthostatic hypotension especially during the initial dose-titration period and therefore dose reduction or more gradual titration should be considered if this occurs. A slower titration regimen could be considered in patients with underlying cardiovascular disease. Seizures: In controlled clinical trials there was no difference in the incidence of seizures in patients treated with quetiapine or placebo. No data is available about the incidence of seizures in patients with a history of seizure disorder. As with other antipsychotics, caution is recommended when treating patients with a history of seizures (see section 4.8 Undesirable effects). Neuroleptic Malignant Syndrome: Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including quetiapine (see section 4.8 Undesirable effects). Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatinine phosphokinase. In such an event, Rezal XR should be discontinued and appropriate medical treatment given. Severe neutropenia: Severe neutropenia (neutrophil count <0.5 X 109/L) has been uncommonly reported in quetiapine clinical trials. Most cases of severe neutropenia have occurred within a couple of months of starting therapy with quetiapine. There is no apparent dose relationship. During post-marketing experience, resolution of leucopenia and/or neutropenia has followed cessation of therapy with quetiapine. Possible risk factors for neutropenia include pre-existing low white cell count (WBC) and history of drug induced neutropenia. 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 Pharmacodynamic properties). Interactions: See also section 4.5 Interaction with other medicinal products and other forms of interaction. 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 Rezal XR treatment should only occur if the physician considers that the benefits of Rezal XR 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 Undesirable effects and 5.1 Pharmacodynamic properties). 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 Undesirable effects). In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with any antipsychotic agent including quetiapine, should be observed for signs and symptoms of hyperglycaemia, (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control. Weight should be monitored regularly. Lipids: Increases in triglycerides, LDL and total cholesterol, and decreases in HDL cholesterol have been observed in clinical trials with quetiapine (see section 4.8 Undesirable effects). Lipid changes should be managed as clinically appropriate. Metabolic Risk: Given the observed changes in weight, blood glucose (see hyperglycaemia) and lipids seen in clinical studies, patients (including those with normal baseline values) may experience worsening of their metabolic risk profile, which should be managed as clinically appropriate (see also section 4.8 Undesirable effects). 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 Undesirable effects) and in overdose (see Section 4.9 Overdose). 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 Interaction with other medicinal products and other forms of interaction). Withdrawal: Acute withdrawal symptoms such as nausea, vomiting, insomnia, headache, diarrhoea, dizziness and irritability have been described after abrupt cessation of high doses of quetiapine. Gradual withdrawal over a period of at least one to two weeks is advisable (see section 4.8 Undesirable effects). Elderly patients with dementia-related psychosis: Rezal XR 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. Rezal XR should be used with caution in patients with risk factors for stroke. In a meta-analysis of atypical antipsychotics, it has been reported that elderly patients with dementia-related psychosis are at an increased risk of death compared to placebo. However in two 10-week placebo controlled quetiapine studies in the same patient population (n=710; mean age: 83 years; range: 56-99 years) the incidence of mortality in quetiapine treated patients was 5.5% versus 3.2% in the placebo group. The patients in these trials died from a variety of causes that were consistent with expectations for this population. These data do not establish a causal relationship between quetiapine treatment and death in elderly patients with dementia. Hepatic effects: If jaundice develops, Rezal XR should be discontinued. Concomitant Illness: Dysphagia (see section 4.8 Undesirable effects) and aspiration have been reported with Rezal XR. Although a causal relationship with aspiration pneumonia has not been established, Rezal XR should be used with caution in patients at risk for aspiration pneumonia. 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 Lipids), gallstones and alcohol consumption. Lactose: Rezal XR tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine. 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 Undesirable effects and 5.1 Pharmacodynamic properties). The data showed an additive effect at week 3. A second study did not demonstrate an additive effect at week 6. There are no combination data available beyond week 6.

Given the primary central nervous system effects of quetiapine, Rezal XR should be used with

caution in combination with other centrally acting drugs and alcohol.

Cytochrome P450 CYP3A4 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 pharmacokinet ics of quetiapine given before

and during treatment with carbamazepine (a known hepatic enzyme inducer), coadministration

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 Rezal XR therapy. Coadministration

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 Rezal XR treatment should only occur if the physician considers

that the benefits of Rezal XR 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 noninducer

(e.g. sodium valproate) (see section 4.4 Special warnings and precautions for use).

The pharmacokinetics of quetiapine were not significantly altered by co-administration of the

antidepressants imipramine (a known CYP2D6 inhibitor) or fluoxetine (a known CYP3A4 and

CYP2D6 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 of approx. 70%.

The pharmacokinetics of quetiapine were not altered following co-administration with

cimetidine.

The pharmacokinetics of lithium were not altered when co-administered with quetiapine.

The pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically

relevant extent when co-administered. A retrospective study of children and adolescents who

received valproate, quetiapine, or both, found a higher incidence of leucopenia and neutropenia

in the combination group versus the monotherapy groups.

Formal interaction studies with commonly used cardiovascular drugs have not been performed.

Caution should be exercised when quetiapine is used concomitantly with drugs known to cause

electrolyte imbalance or to increase QTc 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 Category C :

Risk Summary

There are no adequate and well-controlled studies of quetiapine use in pregnant women. In

limited published literature, there were no major malformations associated with quetiapine

exposure during pregnancy. In animal studies, embryo-fetal toxicity occurred. Quetiapine

should be used during pregnancy only if the potential benefit justifies the potential risk to the

fetus.

Human Data

There are limited published data on the use of quetiapine for treatment of schizophrenia and

other psychiatric disorders during pregnancy. In a prospective observational study, 21 women

exposed to quetiapine and other psychoactive medications during pregnancy delivered infants

with no major malformations. Among 42 other infants born to pregnant women who used

quetiapine during pregnancy, there were no major malformations reported (one study of 36

women, 6 case reports). Due to the limited number of exposed pregnancies, these

postmarketing data do not reliably estimate the frequency or absence of adverse outcomes.

Neonates exposed to antipsychotic drugs (including quetiapine), during the third trimester of

pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory

distress and feeding disorder in these neonates. These complications have varied in severity;

while in some cases symptoms have been self-limited, in other cases neonates have required

intensive care unit support and prolonged hospitalization.

Animal Data

When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no

teratogenic effect at doses up to 2.4 times the maximum recommended human dose (MRHD)

for schizophrenia of 800 mg/day based on mg/m2 body surface area. However, there was

evidence of embryo-fetal toxicity, which included delays in skeletal ossification occurring at 

approximately 1 and 2 times the MRHD of 800 mg/day in both rats and rabbits, and an

increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses at

approximately 2 times the MRHD. In addition, fetal weights were decreased in both

species.Maternal toxicity (observed as decreased body weights and/or death) occurred at 2

times the MRHD in rats and approximately 1-2 times the MRHD (all doses tested) in rabbits.

In a peri/postnatal reproductive study in rats, no drug-related effects were observed when

pregnant dams were treated with quetiapine at doses 0.01, 0.12, and 0.24 times the MRHD of

800 mg/day based on mg/m2 body surface area. However, in a preliminary peri/postnatal

study, there were increases in fetal and pup death, and decreases in mean litter weight at 3

times the MRHD.

Lacation

There have been published reports of quetiapine excretion into human breast milk, however the

degree of excretion was not consistent. Women who are breast-feeding should therefore be

advised to avoid breast-feeding while taking quetiapine.

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 are somnolence, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension and dyspepsia. The incidences of ADRs associated with quetiapine therapy, are tabulated below according to the format recommended by the Council for International Organizations of Medical Sciences (CIOMS III Working Group 1995). 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). Blood and lymphatic system disorders Very Common: Decreased haemoglobin23 Common: Leucopenia 1, 29, decreased neutrophil count, eosinophils increased 28 Uncommon: Thrombocytopenia, Anaemia, Platelet count decreased14 Rare: Agranulocytosis27 Unknown: Neutropenia 1 Immune system disorders Uncommon: Hypersensitivity (including allergic skin reactions) Very rare: Anaphylactic reaction 6 Endocrine disorders Common: Hyperprolactinaemia16, decreases in Total T425, decreases in Free T425, decreases in Total T325, increases in TSH25 Uncommon: Decrease in free T325, Hypothyroidism22 Very rare: Inappropriate antidiuretic hormone secretion Metabolism and nutritional disorders Very Common: Elevations in serum triglyceride levels11, 31, Elevations in total cholesterol (predominantly LDL cholesterol)12, 31, Decreases in HDL cholesterol18, 31, Weight gain9,31 Common: Increased appetite, Blood glucose increased to hyperglycaemic levels7, 31 Uncommon: Hyponatraemia 20, Diabetes Mellitus 1, 5, 6 Rare: Metabolic syndrome30 Psychiatric disorders Common: Abnormal dreams and nightmares, Suicidal ideation and suicidal behaviour 21 Rare: Somnambulism and related reactions such as sleep talking and sleep related eating disorder Nervous system disorders Very Common: Dizziness 4, 17, somnolence 2, 17, headache Common: Extrapyramidal symptoms 1,22, Dysarthria Uncommon: Seizure 1, restless leg syndrome, Tardive dyskinesia 1, 6, syncope 4, 17 Cardiac disorders Common: Tachycardia 4, Palpitations 24 Uncommon: QT prolongation1, 13, 19, bradycardia33 Eye disorders Common: Vision blurred Vascular disorders Common: Orthostatic hypotension 4, 17 Rare: Venous thromboembolism 1 Respiratory, thoracic and mediastinal disorder Common: Dyspnea 24 Uncommon: Rhinitis Gastrointestinal disorders Very Common: Dry mouth Common: Constipation, dyspepsia, vomiting 26 Uncommon: Dysphagia 1, 8 Rare: Pancreatitis1 Hepato-biliary disorders Common: Elevations in serum transaminases (ALT, AST)3, Elevations in gamma-GT levels3 Rare: Jaundice 6, Hepatitis Skin and subcutaneous tissue disorders Very rare: Angioedema 6, Stevens-Johnson syndrome 6 Unknown: Toxic Epidermal Necrolysis, Erythema Multiforme Musculoskeletal and connective tissue disorders Very rare: Rhabdomyolysis Pregnancy, puerperium and perinatal conditions Unknown: Drug withdrawal syndrome neonatal 32 Reproductive system and breast disorders Uncommon: Sexual dysfunction Rare: Priapism, Galactorrhoea, breast swelling, menstrual disorder General disorders and administration site conditions Very common Withdrawal (discontinuation) symptoms 1, 10 Common: Mild asthenia, peripheral oedema, irritability, pyrexia Rare: Neuroleptic malignant syndrome 1, hypothermia Investigations Rare: Elevations in blood creatine phosphokinase 15 (1) See section 4.4 Special warnings and precautions for use. (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 Special warnings and precautions for use). (5) Exacerbation of pre-existing diabetes has been reported in very rare cases. (6) Calculation of Frequency for these ADR's have only been taken from postmarketing data with the immediate-release formulation of quetiapine. (7) Fasting blood glucose ≥126mg/dL (≥ 7.0 mmol/L) or a non fasting blood glucose ≥200mg/dL (≥ 11.1 mmol/L) on at least one occasion. (8) An increase in the rate of dysphagia with quetiapine vs. placebo was only observed in the clinical trials in bipolar depression. (9) Based on >7% increase in body weight from baseline. Occurs predominantly during the early weeks of treatment in adults. (10) 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. (11) 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. (12) 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). (13) See text below. (14) Platelets ≤100 x 109/L on at least one occasion. (15) Based on clinical trial adverse event reports of blood creatine phosphokinase increase not associated with neuroleptic malignant syndrome. (16) 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. (17) May lead to falls. (18) HDL cholesterol: <40 mg/dL (1.025 mmol/L) males; <50 mg/dL (1.282 mmol/L) females at any time. (19) 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.   (20) Shift from >132 mmol/L to <132 mmol/L on at least one occasion. (21) Cases of suicidal ideation and suicidal behaviours have been reported during quetiapine therapy or early after treatment discontinuation (see sections 4.4 Special warnings and precautions for use and 5.1 Pharmacodynamic properties). (22) See section 5.1 (Pharmacodynamic properties). (23) Decreased haemoglobin to ≤13 g/dL (8.07mmol/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. (24) These reports often occurred in the setting of tachycardia, dizziness, orthostatic hypotension and/or underlying cardiac/respiratory disease. (25) 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. (26) Based upon the increased rate of vomiting in elderly patients (≥65 years of age). (27) Shift in neutrophils from ≥1.5 x 109/L at baseline to <0.5 x 109/L at any time during treatment. (28) 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. (29) 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. (30) Based on adverse event reports of metabolic syndrome from all clinical trials with quetiapine. (31) 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 Special Warnings and Precautions for Use) (32) See section 4.6 (Fertility, pregnancy and lactation). (33) 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 very rarely with the use of neuroleptics and are considered class effects. Children and adolescents (10 to 17 years of age) 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. 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). Metabolism and nutritional disorders Very common: Increased appetite Investigations   Very common: Elevations in prolactin 1, increases in blood pressure 2 Nervous system disorders   Very common: Extrapyramidal symptoms 3 General disorders and administration site conditions Common: Irritability 4 (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 Institute of Health criteria) or increases >20mmHg 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) See section 5.1 Pharmacodynamic properties. (4) Note: The frequency is consistent to that observed in adults, but irritability might be associated with different clinical implications in children and adolescents as compared to adults. To report any side effects Saudi Arabia National Pharmacovigilance & 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. to top of the page

Please contact the relevant competent authority. to top of the page

In general, reported signs and symptoms were those resulting from an exaggeration of the

drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and

hypotension.

Fatal outcome has been reported in clinical trials following an acute overdose at 13.6 grams,

and in post-marketing on doses as low as 6 grams of Rezal alone. However, survival has also

been reported following acute overdoses of up to 30 grams. In post marketing experience, there

have been very rare reports of overdose of quetiapine alone resulting in death or coma.

Additionally, the following events have been reported in the setting of monotherapy overdose

with Rezal XR: QT-prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory

depression, urinary retention, confusion, delirium and/or agitation.

Patients with pre-existing severe cardiovascular disease may be at an increased risk of the

effects of overdose. (See section 4.4 Special warnings and precautions for use:

Cardiovascular).

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. Whilst the prevention of

absorption in overdose has not been investigated, gastric lavage can be indicated in severe

poisonings and if possible to perform within one hour of ingestion. The administration of

activated charcoal should be considered. In cases of quetiapine overdose refractory hypotension should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should be avoided, since beta stimulation may worsen hypotension in the setting of quetiapine-induced alpha blockade). Close medical supervision and monitoring should be continued until the patient recovers.

Pharmacotherapeutic group: Antipsychotics

ATC code: N05AH04

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 Rezal compared to typical

antipsychotics. Additionally, norquetiapine has high affinity for the norepinephrine transporter

(NET). Quetiapine and norquetiapine also have high affinity at histaminergic and adrenergic

α1-receptors, with a lower affinity at adrenergic α2 and serotonin 5HT1A receptors. Quetiapine

has no appreciable affinity at muscarinic or benzodiazepine receptors.

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. The extent to which the norquetiapine metabolite contributes to

the pharmacological activity of Rezal in humans is not known.

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 dopaminecontaining

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 Undesirable effects)

Clinical efficacy:

Schizophrenia

The efficacy of Rezal XR 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 activecontrolled

Rezal IR-to-Rezal XR switching study in clinically stable outpatients with

schizophrenia.

The primary outcome variable in the placebo-controlled trial was change from baseline to final

assessment in the PANSS total score. Rezal XR 400 mg/day, 600 mg/day and 800 mg/day

were associated with statistically significant improvements in psychotic symptoms compared

to placebo. The effect size of the 600 mg and 800 mg doses was greater than that of the 400 mg

dose.

In the 6-week active-controlled switching study the primary outcome variable was the

proportion of patients who showed lack of efficacy, 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 Rezal IR 400 mg to 800 mg, efficacy was maintained when

patients were switched to an equivalent daily dose of Rezal XR given once daily.

In a long-term study in stable schizophrenic patients who had been maintained on Rezal XR

for 16 weeks, Rezal XR was more effective than placebo in preventing relapse. The estimated

risks of relapse after 6 months treatments was 14.3% for the Rezal XR treatment group

compared to 68.2% for placebo. The average dose was 669 mg. There were no additional

safety findings associated with treatment with Rezal XR for up to 9 months (median 7 months).

In particular, reports of adverse events related to EPS and weight gain did not increase with

longer-term treatment with Rezal XR.

Bipolar Disorder

In the treatment of moderate to severe manic episodes, quetiapine demonstrated superior

efficacy to placebo in reduction of manic symptoms at 3 and 12 weeks, in two monotherapy

trials. 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 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. There are no combination

data available beyond 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 a clinical trial, in patients with depressive episodes in bipolar I or bipolar II disorder, 300

mg/day Rezal XR showed superior efficacy to placebo in reduction of MADRS total score.

The antidepressant effect of Rezal XR was significant at Day 8 (week 1) and was maintained

through the end of the trial (week 8).

In 4 additional clinical trials in patients with depressive episodes in bipolar I or bipolar II

disorder, with and without rapid cycling courses, 51% of quetiapine treated patients had at least

a 50% improvement in MADRS total score at week 8 compared to 37% of the placebo treated

patients. The anti-depressant effect was significant at Day 8 (week 1). There were fewer

episodes of treatment-emergent mania with Rezal than with placebo. In continuation treatment

the anti-depressant effect was maintained for patients on Rezal (mean duration of treatment 30

weeks). Rezal reduced the risk of a recurrent mood (manic and depressed) event by 49%. Rezal

was superior to placebo in treating the anxiety symptoms associated with bipolar depression as

assessed by mean change from baseline to week 8 in HAM-A total score.

In one long-term study (up to 2 years treatment, mean quetiapine exposure 191 days)

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.

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). The risk of a recurrent event was reduced by

70%. Quetiapine was administered twice-daily totalling 400 mg to 800 mg a day as

combination therapy to lithium or valproate.

Major depressive episodes in MDD

Two short-term (6 week) studies enrolled patients who had shown an inadequate response to at

least one antidepressant. Rezal XR 150 mg and 300 mg/day, given as add-on treatment to

ongoing antidepressant therapy (amitriptyline, bupropion, citalopram, duloxetine, escitalopram,

fluoxetine, paroxetine, sertraline or venlafaxine) demonstrated superiority over antidepressant

therapy alone in reducing depressive symptoms as measured by improvement in MADRS total

score (LS mean change vs. placebo of 2-3.3 points).

Long-term efficacy and safety in patients with MDD has not been evaluated as add-on therapy,

however long-term efficacy and safety has been evaluated in adult patients as monotherapy

(see below).

The following studies were conducted with Rezal XR as monotherapy treatment, however

Rezal XR is only indicated for use as add-on therapy:

In three out of four short term (up to 8 weeks) monotherapy studies, in patients with major

depressive disorder, Rezal XR 50 mg, 150 mg and 300 mg/day demonstrated superior efficacy

to placebo in reducing depressive symptoms as measured by improvement in the MontgomeryÅsberg

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 Rezal XR treatment for at least 12 weeks were randomised to either Rezal XR once

daily or placebo for up to 52 weeks. The mean dose of Rezal XR during the randomised phase

was 177 mg/day. The incidence of relapse was 14.2% for Rezal XR treated patients and 34.4%

for placebo-treated patients.

In a short-term (9 week) study non-demented elderly patients (aged 66 to 89 years) with major

depressive disorder, Rezal XR dosed flexibly in the range of 50 mg to 300 mg/day

demonstrated superior efficacy to placebo in reducing depressive symptoms as measured by

improvement in MADRS total score (LS mean change vs placebo -7.54). In this study patients

randomised to Rezal XR received 50 mg/day on Days 1-3, the dose could be increased to 100

mg/day on Day 4, 150 mg/day on Day 8 and up to 300 mg/day depending on clinical response

and tolerability. The mean dose of Rezal XR was 160 mg/day. Other than the incidence of

extrapyramidal symptoms (see section 4.8 Undesirable effects and 'Clinical Safety' below) the

tolerability of Rezal XR 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 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 Rezal XR and

3.2% for placebo. In a short-term placebo-controlled monotherapy trial in elderly patients with

major depressive disorder, the aggregated incidence of extrapyramidal symptoms was 9.0% for

Rezal XR and 2.3% for placebo. In both bipolar depression and MDD, the incidence of the

individual adverse events was generally low and 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.

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 1.3% 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.

In fixed dose short-term placebo-controlled clinical trials, quetiapine treatment was associated

with dose-related decreases in thyroid hormone levels. In short-term placebo-controlled

clinical trials, the incidence of potentially clinically significant shifts in thyroid hormone levels

were: total T4: 3.4% for quetiapine versus 0.6% for placebo; free T4: 0.7% for quetiapine

versus 0.1% for placebo; total T3: 0.54% for quetiapine versus 0.0% for placebo and free T3:

0.2% for quetiapine versus 0.0% for placebo. The incidence of shifts in TSH was 3.2% for

quetiapine versus 2.7% for placebo. In short-term placebo-controlled monotherapy trials, the

incidence of reciprocal, potentially clinically significant shifts in T3 and TSH was 0.0% for

both quetiapine and placebo and 0.1% for quetiapine versus 0.0% for placebo for shifts in

T4 and TSH. These changes in thyroid hormone levels are generally 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. In nearly 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. In eight patients,

where TBG was measured, levels of TBG were unchanged.

Cataracts/lens opacities

In a clinical trial to evaluate the cataractogenic potential of Rezal (200-800 mg/day) versus

risperidone (2-8 mg) in patients with schizophrenia or schizoaffective disorder, the percentage

of patients with increased lens opacity grade was not higher in Rezal (4%) compared with

risperidone (10%), for patients with at least 21 months of exposure.

Children and adolescents (10 to 17 years of age)

The efficacy and safety of Rezal 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 Rezal were excluded. Treatment with Rezal

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 Rezal 400 mg/day and –6.56 for Rezal 600 mg/day.

Responder rates (YMRS improvement ≥50%) were 64% for Rezal 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 Rezal 400 mg/day and –9.29 for Rezal 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.

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

A 26-week open-label extension to the acute trials (n= 380 patients), with Rezal 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 section 4.4 Special warnings and precautions for use and section 4.8 Undesirable

effects).

Extrapyramidal Symptoms

In a short-term placebo-controlled monotherapy trial with Rezal in adolescent patients (13-17

years of age) with schizophrenia, the aggregated incidence of extrapyramidal symptoms was

12.9% for quetiapine and 5.3% for placebo, though the incidence of the individual adverse

events (e.g. akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor

hyperactivity, muscle rigidity, dyskinesia) did not exceed 4.1% in any treatment group. In a

short-term placebo-controlled monotherapy trial with Rezal in children and adolescent patients

(10-17 years of age) with bipolar mania, the aggregated incidence of extrapyramidal symptoms

was 3.6% for quetiapine and 1.1% for placebo. In a long-term open label study with Rezal of

schizophrenia and bipolar mania, the aggregated incidence of treatment-emergent EPS was

10%.

Weight Gain

In short-term clinical trials with Rezal in paediatric patients (10-17 years of age), 17% of

quetiapine treated patients and 2.5% of placebo treated patients gained ≥7% of their body

weight. When adjusting for normal growth over 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.

Suicide/Suicidal thoughts or Clinical worsening

In short-term placebo-controlled clinical trials with Rezal in paediatric patients with

schizophrenia, the incidence of suicide related events was 1.4% (2/147) for quetiapine and

1.3% (1/75) for placebo in patients <18 years of age. In short-term placebo-controlled trials

with Rezal in paediatric patients with bipolar mania, the incidence of suicide related events

was 1.0% (2/193) for quetiapine and 0% (0/90) for placebo in patients <18 years of age.

Quetiapine is well absorbed and extensively metabolised following oral administration.

Quetiapine is approximately 83% bound to plasma proteins. Steady-state peak molar

concentrations of the active metabolite norquetiapine are 35% of that observed for quetiapine.

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

range. The kinetics of quetiapine does not differ between men and women.

Rezal XR achieves peak plasma concentrations at approximately 6 hours after administration

(Tmax). Rezal XR displays dose-proportional pharmacokinetics for doses of up to 800 mg

administered once daily. The maximum plasma concentration (Cmax) and the area under the

plasma concentration-time curve (AUC) for Rezal XR administered once daily are comparable

to those achieved for the same total daily dose of immediate-release quetiapine fumarate

(Rezal IR) administered twice daily. The elimination half lives of quetiapine and norquetiapine

are approximately 7 and 12 hours, respectively.

The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than that

seen in adults aged 18 to 65 years.

There are no clinically relevant differences in the observed apparent oral clearance (CL/F) and

exposure of quetiapine between subjects with schizophrenia and bipolar disorder.

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. The average molar dose fraction of

free quetiapine and the active human plasma metabolite norquetiapine is <5% excreted in the

urine.

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. Approximately 73% of the radioactivity is excreted in the urine

and 21% in the faeces. The mean quetiapine plasma clearance decreases by 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 Posology

and method of administration).

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.

In a study examining the effects of food on the bioavailability of quetiapine, a high-fat meal

was found to produce statistically significant increases in the Rezal XR Cmax and AUC of

44% to 52% and 20% to 22%, respectively, for the 50 mg and 300 mg tablets. Rezal XR

should be taken at least one hour before a meal.

Children and adolescents (10 to 17 years of age)

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 (Seroquel) twice daily. At steadystate,

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 Rezal XR in children and adolescents.

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 Pharmacodynamic

properties).

Taking these findings into consideration, the benefits of the treatment with quetiapine need to

be balanced against the safety risks for the patient.

Lactose Microcrystalline Cellulose. Hypromellose Sodium Citrate Magnesium Stearate Colloidal Silicon Dioxide Opadry Ferric Oxide Yellow Ferric Oxide Red Simethicone Emulsion

Not applicable.

2 years.

Store below 30˚C.

Three Aluminum-PVC/PVDC blisters of 10 tablets each, packed in a printed carton with        folded leaflet.

No special requirements.