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 effective 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 Quetiapine immediate-release tablets:

For more convenient dosing, patients who are currently being treated with divided doses of immediate-release Quetiapine tablets (Quetiapine IR) may be switched to Quetiapine 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 placebo-controlled 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.

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.

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).

(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.

(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.

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 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 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 Undesirable effects)

Clinical efficacy:

Schizophrenia

The efficacy of Quetiapine 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 active-controlled Quetiapine IR-to- Quetiapine 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 Quetiapine IR 400 mg to 800 mg, efficacy was maintained when patients were switched to an equivalent daily dose of Quetiapine XR given once daily.

In a long-term study in stable schizophrenic patients who had been maintained on 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 Montgomery-Åsberg Depression Rating Scale (MADRS) total score (LS mean change vs. placebo of 2-4 points).

In a monotherapy relapse prevention study, patients with depressive episodes stabilised on open-label 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, open-label, active comparator) in patients with a baseline neutrophil count ≥1.5 X 10⁹/L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 X 10⁹/L was 2.9% and to <0.5 X 10⁹/L was 0.21% in patients treated with quetiapine.

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.

Quetiapine XR achieves peak plasma concentrations at approximately 6 hours after administration (T_max). Quetiapine XR displays dose-proportional pharmacokinetics for doses of up to 800 mg administered once daily. The maximum plasma concentration (C_max) and the area under the plasma concentration-time curve (AUC) for Quetiapine XR administered once daily are comparable to those achieved for the same total daily dose of immediate-release quetiapine fumarate (Quetiapine 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 C_max 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 twice daily. At steady-state, the dose-normalised plasma levels of the parent compound, quetiapine, in children and adolescents (10-17 years of age) were in general similar to adults, though C_max in children was at the higher end of the range observed in adults.

The AUC and C_max 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 Silicone Dioxide

Opadry

Ferric Oxide Yellow

Simethicone Emulsion

Not applicable.