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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Quetiapine 25mg Film-coated Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 25mg quetiapine (as fumarate).

Excipients with known effect:

Each tablet contains 5.175 mg lactose monohydrate For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet

Light orange, 5.5 mm, round, biconvex, engraved with Q on one side

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Quetiapine is indicated for the treatment of:

Schizophrenia.

Bipolar disorder including: - manic episodes associated with bipolar disorder - major depressive episodes in bipolar disorder - preventing recurrence in bipolar disorder in patients whose manic, mixed or depressive episode has responded to quetiapine treatment.

4.2 Posology and method of administration

Method of administration

Quetiapine Film-coated Tablets can be administered with or without food. Posology

Adults

For the treatment of schizophrenia: Quetiapine should be administered twice a day. The total daily dose for the first 4 days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4).

From Day 4 onwards, the dose should be titrated to the usual effective dose range of 300 to 450 mg/day. Depending on the clinical response and tolerability of the individual patient, the dose may be adjusted within the range 150 to 750 mg/day.

For the treatment of manic episodes associated with bipolar disorder: Quetiapine should be administered twice a day. As monotherapy or as adjunct to mood stabilisers, the total daily dose for the first four days of therapy is 100 mg (Day 1), 200 mg (Day 2), 300 mg (Day 3) and 400 mg (Day 4). Further dosage adjustments up to 800 mg per day by Day 6 should be in increments of no greater than 200 mg per day.

The dose may be adjusted depending on clinical response and tolerability of the individual patient, within the range of 200 to 800 mg per day. The usual effective dose is in the range of 400 to 800 mg per day.

For the treatment of depressive episodes in bipolar disorder: Quetiapine should be administered once daily at bedtime. The total daily dose for the first four days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). The recommended daily dose is 300 mg. In clinical trials, no additional benefit was seen in the 600 mg group compared to the 300 mg group. 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 and mixed episodes in bipolar disorder, patients who have responded to quetiapine for acute treatment of bipolar disorder should continue therapy at the same dose. The dose may then be adjusted depending on clinical response and tolerability of the individual patient, within the range of 300 to 800 mg/day administered twice daily. It is important that the lowest effective dose is used for maintenance therapy.

Elderly

As with other antipsychotics, Quetiapine Film-coated Tablets should be used with caution in the elderly, especially during the initial dosing period. Elderly patients should be started on Quetiapine Film-coated tablets 25 mg/day. The dose should be increased daily in increments of 25 to 50 mg, to an effective dose, which is likely to be lower than that in younger patients.

Efficacy and safety have not been evaluated in patients over 65 years with depressive episodes in the framework of bipolar disorder.

Children and Adolescents

Quetiapine is not recommended for use in children and adolescents below 18 years of age, due to a lack of data to support use in this age group. The available evidence from placebo-controlled clinical trials is presented in sections 4.4, 4.8, 5.1 and 5.2.

Renal impairment

Dose adjustment is not necessary in patients with renal impairment.

Hepatic impairment

Quetiapine is extensively metabolised by the liver. Therefore, quetiapine should be used with caution in patients with known hepatic impairment, especially during the initial dose titration period. Patients with known hepatic impairment should be started with 25 mg/day. The dosage should be increased daily with increments of 25 - 50 mg/day until an effective dosage, depending on the clinical response and tolerability of the individual patient.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Concomitant administration of cytochrome P450 3A4 inhibitors such as 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).

4.4 Special warnings and precautions for use Children and adolescents (10 to 17 years of age)

Quetiapine Film-coated tablets are 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, vomiting, rhinitis and syncope) or may have different implications for children and adolescents (extrapyrimidal 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 on growth and maturation have not been studied beyond 26 weeks. Long-term implications for cognitive and behavioural development are not known.

In placebo-controlled clinical trials with children and adolescent patients, quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia and bipolar mania, and bipolar depression (see section 4.8 Undesirable effects).

Suicide/suicidal thoughts or clinical worsening

Depression in bipolar disorder is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

In clinical studies of patients with major depressive episodes in bipolar disorder an increased risk of suicide-related events was observed in young adult patients less than 25 years of age who were treated with quetiapine as compared to those treated with placebo (3.0% vs. 0%, respectively).

Somnolence

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, onset was usually within the first 3 days of treatment and was predominantly of mild to moderate intensity. Bipolar depression patients experiencing somnolence of severe intensity may require more frequent contact for a minimum of 2 weeks from onset of somnolence, or until symptoms improve and treatment discontinuation may need to be considered.

Cardiovascular disease

Quetiapine Film-coated Tablets 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; this is more common in elderly patients than in younger patients.

Dose reduction or more gradual titration should be considered if this occurs.

Seizures

In controlled clinical trials there was no difference in the incidence of seizures in patients treated with Quetiapine or placebo. As with other antipsychotics, caution is recommended when treating patients with a history of seizures (see section 4.8 Undesirable effects).

Extrapyramidal symptons

In placebo controlled clinical trials of adult patients quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major depressive episodes in bipolar disorder (see Section 4.8 Undesirable effects )

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 Quetiapine Film-coated Tablets should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment (see section 4.8 Undesirable effects).

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including Quetiapine Film-coated Tablets (see Section 4.8 Undesirable effects). Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event, Quetiapine Film-coated Tablets 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 was 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 Interactions 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 quetiapine treatment should only occur if the physician

considers that the benefits of quetiapine outweigh the risks of removing the hepatic enzyme inducer. It is important that any change in the inducer treatment is gradual, and if required, replaced with a non-inducer (e.g. sodium valproate).

Hyperglycaemia

Hyperglycaemia or exacerbation of pre-existing diabetes has been reported during treatment with quetiapine. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus (see also section 4.8 Undesirable effects).

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.

QT prolongation

In clinical trials and use in accordance with the SPC, quetiapine was not associated with a persistent increase in absolute QT interval. However, with overdose (see section 4.9) QT prolongation was observed. 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 with medicines known to increase QTc interval, and 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).

Acute withdrawal reactions

Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhoea, vomiting, dizziness and irritability have been described after abrupt cessation of quetiapine. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. 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

Quetiapine is not approved for the treatment of patients with dementia-related psychosis.

An approximately 3-fold increased risk of cerebrovascular adverse events have been seen in randomized placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Quetiapine should be used with caution in patients with an increased risk of stroke.

In a meta-analysis of atypical antipsychotic drugs, 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% compared to 3.2% in the placebo group. The patients in these trials died of a variety of causes that were consistent with expectations for this population. These data do not show causal relationship between quetiapine treatment and death in elderly patients with dementia.

Hepatic effects

If jaundice develops, Quetiapine film-coated tablets should be discontinued. Concomitant illness

Dysphagia (see Section 4.8 Undesirable effects) and aspiration have been reported with Quetiapine. Although a causal relationship with aspiration pneumonia has not been established, Quetiapine should be used with caution in patients at risk for aspiration pneumonia.

Venous thromboembolism

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.

Lactose

Quetiapine Film-coated 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 (valproate semisodium) 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.

4.5 Interaction with other medicinal products and other forms of interaction

Given the primary central nervous system effects of quetiapine, it should be used with caution in combination with other centrally acting drugs and alcohol.

Cytochrome P450 (CYP) 3A4 is the primary enzyme responsible for 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 and a CYP3A4 inhibitor is contraindicated. It is also not recommended to take quetiapine together with grapefruit juice.

Quetiapine did not induce the hepatic enzyme systems involved in the metabolism of antipyrine. However, 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 (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 can influence the effect of quetiapine therapy. Co-administration of quetiapine and phenytoin (microsomal enzyme inducer) caused a greatly increased clearance of quetiapine by approximately 450%. In patients receiving a hepatic enzyme inducer, initiation of quetiapine therapy should only occur if the physician considers that the benefits of quetiapine outweigh the risks of removing the hepatic enzyme inducer. It is important that any change in the inducer treatment is gradual, and if required, replaced with a non-inducer (e.g. sodium valproate) (see also section 4.4 Special warnings and special precautions for use).

The pharmacokinetics of quetiapine were not significantly altered following co-administration with the antidepressants imipramine (a known CYP 2D6 inhibitor) or fluoxetine (a known CYP 3A4 and CYP 2D6 inhibitor).

The pharmacokinetics of quetiapine were not significantly altered following co-administration with the antipsychotics risperidone or haloperidol. However co-administration of quetiapine and thioridazine caused increases in the clearance of quetiapine of about 70%.

The pharmacokinetics of quetiapine were not altered following coadministration with cimetidine, a known P450 enzyme inhibitor.

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

The pharmacokinetics of valproic acid and quetiapine were not altered to a clinically relevant extent when co-administered as valproate semisodium (also known as divalproex sodium (USAN)) and Quetiapine film-coated tablets (quetiapine fumarate). Valproate semisodium is a stable coordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship.

Caution should be exercised when quetiapine is used concomitantly with drugs known to cause electrolyte imbalance or to increase QTc interval.

4.6 Fertility, Pregnancy and lactation Pregnancy

The safety and efficacy of quetiapine during human pregnancy have not yet been established. Up to now there are no indications for harmfulness in animal tests, possible effects on the foetal eye have not been examined though. Therefore, Quetiapine should only be used during pregnancy if the benefits justify the potential risks. Following pregnancies in which Quetiapine was used, neonatal withdrawal symptoms were observed.

Neonates exposed to antipsychotics (including Quetiapine Film-coated Tablets) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.

Breastfeeding

The degree to which quetiapine is excreted into human milk is unknown. Women who are breast feeding should therefore be advised to avoid breast feeding while taking Quetiapine Film-coated Tablets.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

The most commonly reported Adverse Drug Reactions (ADRs) with Quetiapine Film-coated Tablets are somnolence, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension, and dyspepsia.

As with other antipsychotics, weight gain, syncope, neuroleptic malignant syndrome, leucopenia, neutropenia and peripheral edema, have been associated with Quetiapine Film-coated Tablets.

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

Common:    Leucopenia ¹

Uncommon:    Eosinophilia, Thrombocytopenia

Unknown:    Neutropenia ¹

Immune system disorders

Uncommon:    Hypersensitivity

Very rare:    Anaphylactic reaction ⁶

Endocrine disorders

Common:    Hyperprolactinaemia¹⁶

Metabolism and nutritional disorders Common:    Increased appetite

Very rare:    Diabetes Mellitus ^{1 5 6}

Psychiatric disorders

Common:    Abnormal dreams and nightmares

Nervous system disorders

4 17    2 17

Very Common:    Dizziness , somnolence    , headache

Common:    Syncope ^{4 17} , Extrapyramidal symptoms ^{1 13} , Dysarthria

Uncommon:    Seizure ¹ , Restless leg syndrome, Tardive dyskinesia ¹

Cardiac disorders

Common:    Tachycardia ⁴

Eye disorders Common:

Vascular disorders

4 17

Common:    Orthostatic hypotension ’

Respiratory, thoracic and mediastinal disorders

Common:    Rhinitis

Gastrointestinal disorders

Very Common:    Dry mouth

Common:    Constipation, dyspepsia

Uncommon:    Dysphagia ⁸

Hepato-biliary disorders

Rare:    Jaundice ⁶

Very rare:    Hepatitis ⁶

Skin and subcutaneous tissue disorders

Very rare:    Angioedema ⁶ , Stevens-Johnson    syndrome ⁶

Reproductive system and breast disorders Rare:    Priapism, galactorrhoea

General disorders and administration site conditions Very Common:    Withdrawal (discontinuation) symptoms ^{1 10}

Common:    Mild asthenia, peripheral oedema, irritability

Rare:    Neuroleptic malignant syndrome    ¹

Pregnancy, puerperium and perinatal conditions

Elevations in blood creatine phosphokinase ¹⁵ , Venous thromboembolism ¹

(1)    See section 4.4 Special Warnings and Special 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 in serum transaminase (ALT, AST) or gamma-GT levels have been observed in some patients administered Quetiapine.

(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 special precautions for use).

(5)    Exacerbation of pre-existing diabetes has been reported in very rare cases.

(6)    Calculation of frequency for these ADRs have been taken from post-marketing data only.

(7)    Fasting blood glucose ^7.0 mmol/L or a non fasting blood glucose ^ 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. ^{3 1 2}

(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 pg/L (>869.56 pmol/L) males;>30 pg/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.

Cases of QT prolongation, ventricular arrhythmia, sudden unexplained death, cardiac arrest and torsades de pointes have been reported with the use of neuroleptics and are considered class effects (see Section 4.4 Special warnings and special precautions for use).

In short-term, placebo-controlled clinical trials in bipolar depression the aggregated incidence of extrapyramidal symptoms was 8.9% for Quetiapine compared to 3.8% for placebo, though the incidence of the individual adverse events were generally low and did not exceed 4% in any treatment group. 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).

Quetiapine treatment was associated with small dose-related decreases in thyroid hormone levels, particularly total T4 and free T4. The reduction in total and free T 4 was maximal within the first two to four 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. Smaller decreases in total T₃ and reverse T₃ were seen only at higher doses. Levels of Thyroxine-binding Globulin (TBG) were unchanged and in general, reciprocal increases in Thyroid stimulating hormone (TSH) were not observed, with no indication that quetiapine causes clinically relevant hypothyroidism.

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

1 2

Very common:    Elevations in    prolactin    ,    increases in blood pressure

Nervous system disorders

Common:    Syncope

General disorders and administration    site    conditions

Common:    Irritability³

Respiratory, thoracic and mediastinal disorders Common:    Rhinitis

Gastrointestinal disorders Very common:    Vomiting

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

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

Yellow Card Scheme,

Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

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 quetiapine 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 or QT-prolongation.

In general, reported signs and symptoms were those resulting from an exaggeration of the known pharmacological effects of the active substance, i.e. drowsiness and sedation, tachycardia and hypotension.

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 special precautions for use: Cardiovascular).

Management

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.

Close medical supervision and monitoring should be continued until the patient recovers.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: Antipsychotics Therapeutic classification: N05AH04 Mechanism of action

Quetiapine is an atypical antipsychotic agent. Quetiapine and the active metabolite, norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and norquetiapine exhibit an 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 antipsychotic properties and low extrapyramidal symptoms (EPS) liability of quetiapine 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 a₁ receptors, with a lower affinity for adrenergic a₂-receptors and serotonin 5HT₁A receptors.

Quetiapine has no appreciable affinity at cholinergic 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.

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 A10 mesolimbic but not the A9 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.

The extent to which the norquetiapine metabolite contributes to the pharmacological activity of Quetiapine in humans is not known.

Clinical efficacy and safety

The results of three placebo-controlled clinical trials in patients with schizophrenia, including one that used a dose range of Quetiapine of 75 to 750 mg/day, identified no difference between Quetiapine and placebo in the incidence of EPS or use of concomitant anticholinergics.

In four controlled trials, evaluating doses of Quetiapine up to 800 mg for the treatment of bipolar mania, two each in monotherapy and as adjunct therapy to lithium or valproate semisodium, there were no differences between the Quetiapine and placebo treatment groups in the incidence of EPS or concomitant use of anticholinergics.

In clinical trials, Quetiapine has been shown to be effective in the treatment of both positive and negative symptoms of schizophrenia. In one trial against chlorpromazine, and two against haloperidol, Quetiapine showed similar short-term efficacy.

In clinical trials, Quetiapine has been shown to be effective as monotherapy or as adjunct therapy in reducing manic symptoms in patients with bipolar mania. The mean last week median dose of Quetiapine in responders, was approximately 600 mg and approximately 85% of the responders were in the dose range of 400 to 800 mg per day.

In 4 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 Quetiapine than with placebo. In continuation treatment the anti-depressant effect was maintained for patients on Quetiapine (mean duration of treatment 30 weeks). Quetiapine reduced the risk of a recurrent mood (manic and depressed) event by 49 %. Quetiapine 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.

In placebo-controlled monotherapy trials in patients with a baseline neutrophil count £ 1.5 X 10⁹/L, the incidence of at least one occurrence of neutrophil count <1.5 X 10⁹/L, was 1.72% in patients treated with Quetiapine compared to 0.73% in placebo-treated patients. In all clinical trials (placebo-controlled, open-label, active comparator; patients with a baseline neutrophil count ^ 1.5 X 10⁹/L), the incidence of at least one occurrence of neutrophil count <0.5 X 10⁹/L was 0.21% in patients treated with Quetiapine and 0% in placebo treated patients and the incidence ^ 0,5 - <1.0 X 10⁹/L was 0.75% in patients treated with Quetiapine and 0.11% in placebo-treated patients.

Children and adolescents (10 to 17 years of age)

Clinical efficacy

The efficacy and safety of Quetiapine was studied in a 3-week placebo controlled study for the treatment of mania (n= 284 patients from the US, aged 10-17). About 45% of the patient population had an additional diagnosis of ADHD. In addition, a 6-week placebo controlled study for the treatment of schizophrenia (n = 222 patients, aged 13-17) was performed. In both studies, patients with known lack of response to Quetiapine were excluded. Treatment with Quetiapine was initiated at 50 mg/day and on day 2 increased to 100 mg/day; subsequently the dose was titrated to a target dose (mania 400-600 mg/day; schizophrenia 400-800 mg/day) using increments of 100 mg/day given two or three times daily.

In the mania study, the difference in LS mean change from baseline in YMRS total score (active minus placebo) was -5.21 for Quetiapine 400 mg/day and -6.56 for Quetiapine 600 mg/day. Responder rates (YMRS improvement £50%) were 64% for Quetiapine 400 mg/day, 58% for 600 mg/day and 37% in the placebo arm.

In the schizophrenia study, the difference in LS mean change from baseline in PANSS total score (active minus placebo) was -8.16 for Quetiapine 400 mg/day and -9.29 for Quetiapine 800 mg/day. Neither low dose (400 mg/day) nor high dose regimen (800 mg/day) quetiapine was superior to placebo with respect to the percentage of patients achieving response, defined as £30% reduction from baseline in PANSS total score. Both in mania and schizophrenia higher doses resulted in numerically lower response rates.

In a third short-term placebo-controlled monotherapy trial with quetiapine in children and adolescent patients (10-17 years of age) with bipolar depression, efficacy was not demonstrated. No data are available on maintenance of effect or recurrence prevention in this age group.

Clinical safety

In the short-term pediatric trials with quetiapine described above, the rates of EPS in the active arm vs. placebo were 12.9% vs. 5.3% in the schizophrenia trial, 3.6% vs.1.1% in the bipolar mania trial, and 1.1% vs. 0% in the bipolar depression trial. The rates of weight gain >7% of baseline body weight in the active arm vs. placebo were 17% vs. 2.5% in the schizophrenia and bipolar mania trials, and 12.5% vs. 6% in the bipolar depression trial. The rates of suicide related events in the active arm vs. placebo were 1.4% vs. 1.3% in the schizophrenia trial, 1.0% vs. 0% in the bipolar mania trial, and 1.1% vs. 0% in the bipolar depression trial. During an extended posttreatment follow-up phase of the bipolar depression trial, there were two additional suicide related events in two patients; one of these patients was on quetiapine at the time of the event.

Long-term safetyA 26-week open-label extension to the acute trials (n= 380 patients), with quetiapine flexibly dosed at 400-800 mg/day, provided additional safety data. Increases in blood pressure were reported in children and adolescents and increased appetite, extrapyramidal symptoms and elevations in serum prolactin were reported with higher frequency in children and adolescents than in adult patients (see Section 4.4 Special warnings and special precautions for use and Section 4.8 Undesirable effects).

With respect to weight gain, when adjusting for normal growth over the longer term,an increase of at least 0.5 standard deviation from baseline in Body Mass Index (BMI) was used as a measure of a clinically significant change; 18.3% of patients who were treated with quetiapine for at least 26 weeks met this criterion.

5.2 Pharmacokinetic properties

Quetiapine is well absorbed and extensively metabolised following oral administration. The bioavailability of quetiapine is not significantly affected by administration with food. 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 elimination half-lives of quetiapine and norquetiapine are approximately 7 and 12 hours, respectively.

Clinical trials have demonstrated that Quetiapine is effective when given twice a day. This is further supported by data from a positron emission tomography (PET) study which identified that 5HT₂ and D₂ receptor occupancy are maintained for up to 12 hours after dosing with quetiapine.

The pharmacokinetics of quetiapine and norquetiapine are linear across the approved dosing range. The kinetics of quetiapine do not differ between men and women.

The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than that seen in adults aged 18 to 65 years.

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, 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 alcoholcirrhosis). As quetiapine is extensively metabolised by the liver, elevated plasma levels are expected in the population with hepatic impairment. Dose adjustments may be necessary in these patients (see section 4.2 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.

In a multiple-dose trial in healthy volunteers to assess the pharmacokinetics of quetiapine given before and during treatment with ketoconazole, coadministration of ketoconazole resulted in an increase in mean C_max and AUC of quetiapine of 235% and 522%, respectively, with a corresponding decrease in mean oral clearance of 84%. The mean half-life of quetiapine increased from 2.6 to 6.8 hours, but the mean t_max was unchanged.

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.

Paediatric population (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 Cmax 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.

5.3 Preclinical safety data

There was no evidence of genotoxicity in a series of in vitro and in vivo genotoxicity studies. In laboratory animals at a clinically relevant exposure level the following deviations were seen, which as yet have not been confirmed in long-term clinical research:

In rats, pigment deposition in the thyroid gland has been observed; in cynomolgus monkeys thyroid follicular cell hypertrophy, a lowering in plasma T3 levels, decreased haemoglobin concentration and a decrease of red and white blood cell count have been observed; and in dogs lens opacity and cataracts.

Taking these findings into consideration, the benefits of the treatment with quetiapine need to be balanced against the safety risks for the patient.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients Core

Microcrystalline cellulose Povidone K29-32

Calcium hydrogen phosphate dihydrate Sodium starch glycolate (Type A) Lactose monohydrate Magnesium stearate

Film-coat

Opadry II Pink 33G34594 containing:

Hypromellose 6cP

Titanium dioxide

Lactose monohydrate

Macrogol 3350

Triacetin

Iron oxide yellow (E172)

Iron oxide red (E172)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

Blisters (PVC/PVDC/Al and PVC/Al) Pack sizes: 6, 10, 20, 30, 50, 60, 90, 100 tablets*

Plastic (polyethylene) tablet containers Pack sizes: 6, 10, 20, 30, 50, 60, 90, 100 tablets*

* Not all pack sizes may be marketed

6.6 Special precautions for disposal

No special requirements for disposal

7 MARKETING AUTHORISATION HOLDER

Aptil Pharma Limited

9th Floor, CP House

97-107 Uxbridge Road, Ealing

1

   See text below.

2

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

3

   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).