Out of date information, search another

Tenprolide Xl 400mg Prolonged-Release Tablets

Out of date information, search another

Informations for option: Tenprolide Xl 400mg Prolonged-Release Tablets, show other option

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Tenprolide XL 400mg Prolonged-release Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Tenprolide XL 400 mg Prolonged-release tablet contains 400 mg quetiapine (as quetiapine fumarate).

Excipient: 59.7 mg lactose monohydrate per tablet.

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Prolonged-release tablet

Tenprolide XL 400 mg Prolonged-release tablets are white to off-white, capsule shaped with dimensions of 22.1 mm x 8.9 mm, biconvex, film coated, printed with ‘245’ on one side with black ink.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

- Tenprolide XL 400mg Prolonged-release Tablets is indicated for the treatment of schizophrenia, including:

-preventing relapse in stable schizophrenic patients who have been maintained on quetiapine.

- Tenprolide XL 400mg Prolonged-release Tablets is indicated for treatment of bipolar disorder:

-for the treatment of moderate to severe manic episodes in bipolar disorder

-for the treatment of major depressive episodes in bipolar disorder

-for the prevention of recurrence in patients with bipolar disorder, in patients whose manic or depressive episode has responded to quetiapine treatment.

- Tenprolide XL 400mg Prolonged-release Tablets is indicated for addon treatment of major depressive episodes in patients with Major Depressive Disorder (MDD) who have had sub-optimal response to antidepressant monotherapy (see section 5.1). Prior to initiating treatment, clinicians should consider the safety profile of Tenprolide XL 200mg Prolonged-release Tablets (see section 4.4).

4.2 Posology and method of administration

Posology

Different dosing schedules exist for each indication. It must therefore be ensured that patients receive clear information on the appropriate dosage for their condition.

Tenprolide XL 400mg Prolonged-release Tablets should be administered once daily.

Adults:

For the treatment of schizophrenia and moderate to severe manic episodes in bipolar disorder

Tenprolide XL Prolonged-release Tablets should be administrated at least one hour before a meal. The daily dose at the start of therapy is 300 mg on Day 1 and 600 mg on Day 2. The recommended daily dose is 600 mg, however if clinically justified the dose may be increased to 800 mg daily. The dose should be adjusted within the effective dose range of 400 mg to 800 mg per day, depending on the clinical response and tolerability of the patient. For maintenance therapy in schizophrenia no dosage adjustment is necessary.

For the treatment of depressive episodes in bipolar disorder Tenprolide XL Prolonged-release Tablets should be administered at bedtime. The daily dose for the first four days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). The recommended daily dose is 300 mg. In clinical trials, no additional benefit was seen in the 600 mg group compared to the 300 mg group (see section 5.1). Individual patients may benefit from a 600 mg dose. Doses greater than 300 mg should be initiated by physicians experienced in treating bipolar disorder. In individual patients, in the event of tolerance concerns, clinical trials have indicated that dose reduction to a minimum of 200 mg could be considered.

For preventing recurrence in bipolar disorder

For preventing recurrence of manic, mixed or depressive episodes in bipolar disorder, patients who have responded to quetiapine for acute treatment of bipolar disorder should continue on Tenprolide XL Prolonged-release Tablets at the same dose administered at bedtime. Tenprolide XL Prolonged-release Tablets dose can be adjusted depending on clinical response and tolerability of the individual patient within the dose range of 300 mg to 800 mg/day. It is important that the lowest effective dose is used for maintenance therapy.

For add-on treatment of major depressive episodes in MDD Tenprolide XL Prolonged-release Tablets 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) and at 50 mg/day in short-term monotherapy trials. There is an increased risk of adverse events at higher doses. Clinicians should therefore ensure that the lowest effective dose, starting with 50 mg/day, is used for treatment. The need to increase the dose from 150 to 300 mg/day should be based on individual patient evaluation.

Switching from quetiapine immediate-release tablets:

For more convenient dosing, patients who are currently being treated with divided doses of immediate release quetiapine tablets may be switched to quetiapine prolonged-release at the equivalent total daily dose taken once daily. Individual dosage adjustments may be necessary.

Elderly:

As with other antipsychotics and antidepressants, quetiapine should be used with caution in the elderly, especially during the initial dosing period. The rate of dose titration of quetiapine may need to be slower, and the daily therapeutic dose lower, than that used in younger patients, depending on the clinical response and tolerability of the individual patient. The mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly patients when compared to younger patients. Elderly patients should be started on 50 mg/day. The dose can be increased in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the individual patient.

In elderly patients with major depressive episodes in MDD, dosing should begin with 50 mg/day on Days 1-3, increasing to 100 mg/day on Day 4 and 150 mg/day on Day 8. The lowest effective dose, starting from 50 mg/day should be used. Based on individual patient evaluation, if dose increase to 300 mg/day is required this should not be prior to Day 22 of treatment.

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

Paediatricpopulation:Tenprolide XL 400mg Prolonged-release Tablets 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 quetiapine 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 metabolized by the liver. Therefore, Tenprolide XL Prolonged-release Tablets should be used with caution in patients with known hepatic impairment, especially during the initial dosing period. Patients with hepatic impairment should be started on 50 mg/day. The dose can be increased in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the individual patient.

Method of administration

The tablets 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.

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 section 4.5).

4.4 Special warnings and precautions for use

As quetiapine has several indications, the safety profile should be considered with respect to the individual patient’s diagnosis and the dose being administered.

As Tenprolide XL 400mg Prolonged-release Tablets 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).

Paediatric population

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), certain adverse events occurred at a higher frequency in children and adolescents compared to adults (increased appetite, elevations in serum prolactin, vomiting, rhinitis and syncope) or may have different implications for children and adolescents (extrapyramidal symptoms and 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, bipolar mania and bipolar depression (see section 4.8).

Suicide/suicidal thoughts or clinical worsening:

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery. In addition, physicians should consider the potential risk of suicide-related events after abrupt cessation of quetiapine treatment, due to the known risk factors for the disease being treated.

Other psychiatric conditions for which Tenprolide XL 400mg Prolonged-release Tablets is prescribed can also be associated with an increased risk of suicide related events. In addition, these conditions may be co-morbid with major depressive episodes. The same precautions observed when treating patients with major depressive episodes should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta analysis of placebo controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

In shorter-term placebo controlled clinical studies of patients with major depressive episodes in bipolar disorder an increased risk of suicide-related events was observed in young adult patients (younger than 25 years of age) who were treated with quetiapine as compared to those treated with placebo (3.0% vs. 0%, respectively). In clinical studies of patients with MDD the incidence of suicide-related events observed in young adult patients (younger than 25 years of age) was 2.1% (3/144) for quetiapine and 1.3% (1/75) for placebo.

Extrapyramidal symptoms:

In placebo controlled clinical trials of adult patients quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major depressive episodes in bipolar disorder and major depressive disorder (see sections 4.8 and 5.1).

The use of quetiapine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Tardive dyskinesia:

If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of quetiapine should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment (see section 4.8).

Somnolence and dizziness:

Quetiapine treatment has been associated with somnolence and related symptoms, such as sedation (see section 4.8). In clinical trials for treatment of patients with bipolar depression and major depressive disorder, onset was usually within the first 3 days of treatment and was predominantly of mild to moderate intensity. 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) 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:

Quetiapine 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).

Neuroleptic malignant syndrome:

Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including quetiapine (see section 4.8). Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event, quetiapine should be discontinued and appropriate medical treatment given.

Severe neutropenia and agranulocytosis:

Severe neutropenia (neutrophil count <0.5 X 10⁹/L) has been 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 experiencesome cases were fatal.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).

Neutropenia should be considered in patients presenting with infection or fever, particularly in the absence of obvious predisposing factor(s), and should be managed as clinically appropriate.

Interactions:

4.5 Interaction with other medicinal products and other forms of interaction

Given the primary central nervous system effects of quetiapine, Tenprolide XL 400mg Prolonged-release Tablets should be used with caution in combination with other centrally acting medicinal products and alcohol.

CYP3A4 inhibitors

Cytochrome P450 (CYP) 3A4 is the enzyme that is primarily responsible for the cytochrome P450 mediated metabolism of quetiapine. In an interaction study in healthy volunteers, concomitant administration of quetiapine (dosage of 25 mg) with ketoconazole, a CYP3A4 inhibitor, caused a 5- to 8-fold increase in the AUC of quetiapine. On the basis of this, concomitant use of quetiapine with CYP3A4 inhibitors is contraindicated. It is also not recommended to consume grapefruit juice while on quetiapine therapy.

Carbamazepine and phenytoin

In a multiple dose trial in patients to assess the pharmacokinetics of quetiapine given before and during treatment with carbamazepine (a known hepatic enzyme inducer), co-administration of carbamazepine significantly increased the clearance of quetiapine. This increase in clearance reduced systemic quetiapine exposure (as measured by AUC) to an average of 13% of the exposure during administration of quetiapine alone; although a greater effect was seen in some patients. As a consequence of this interaction, lower plasma concentrations can occur, which could affect the efficacy of quetiapine therapy. Co-administration of quetiapine and phenytoin (another microsomal enzyme inducer) caused a greatly increased clearance of quetiapine by approx. 450%. In patients receiving a hepatic enzyme inducer, initiation of quetiapine treatment should only occur if the physician considers that the benefits of quetiapine outweigh the risks of removing the hepatic enzyme inducer. It is important that any change in the inducer is gradual, and if required, replaced with a non-inducer (e.g. sodium valproate) (see section 4.4).

Imipramine and fluoxetine

The pharmacokinetics of quetiapine were not significantly altered by coadministration of the antidepressants imipramine (a known CYP 2D6 inhibitor) or fluoxetine (a known CYP 3A4 and CYP 2D6 inhibitor).

Risperidone, haloperidol and thioridazine

The pharmacokinetics of quetiapine were not significantly altered by coadministration of the antipsychotics risperidone or haloperidol. Concomitant use of quetiapine and thioridazine caused an increased clearance of quetiapine with approx. 70%.

Cimetidine

The pharmacokinetics of quetiapine were not altered following coadministration with cimetidine.

Lithium

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

In a 6-week, randomised, study of lithium and quetiapine prolonged release tablets versus placebo and quetiapine prolonged release tablets in adult patients with acute mania, a higher incidence of extrapyramidal related events (in particular tremor), somnolence, and weight gain were observed in the lithium add-on group compared to the placebo add-on group (see section 5.1).

Sodium valproate

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.

Cardiovascular medicinal products

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

Caution should be exercised when quetiapine is used concomitantly with medicinal products known to cause electrolyte imbalance or to increase QT-interval.

Methadone and tricyclic antidepressants

There have been reports of false positive results in enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine. Confirmation of questionable immunoassay screening results by an appropriate chromatographic technique is recommended.

4.6 Fertility, pregnancy and lactation

Pregnancy

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, 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

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.

4.7 Effects on ability to drive and use machines

Given its primary central nervous system effects, quetiapine may interfere with activities requiring mental alertness. Therefore, patients should be

advised not to drive or operate machinery, until individual susceptibility to this is known.

4.8 Undesirable effects

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

As with other antipsychotics, syncope, neuroleptic malignant syndrome, leucopenia, neutropenia and peripheral oedema, have been associated with quetiapine.

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 to <1/10)

Uncommon (>1/1,000 to <1/100)

Rare (>1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data).

Blood and lymphatic system disorders
Very common:	23 Decreased haemoglobin
Common:	Leucopenia ’ , decreased neutrophil count, eosinophils increased ²⁸
Uncommon:	Thrombocytopenia, anaemia, platelet count decreased ¹⁴
Rare:	27 Agranulocytosis
Not known:	Neutropenia ¹
Immune system disorders
Uncommon:	Hypersensitivity (including allergic skin reactions)
Very rare:	Anaphylactic reaction ⁶
Endocrine disorders
Common:	Hyperprolactinaemia ¹⁶, decreases in total T₄ ²⁵, decreases in free T₄ ²⁵, decreases in total T₃ ²⁵, increases in TSH ²⁵
Uncommon:	Decreases in free T₃ ²⁵, hypothyroidism ²²
Very rare:	Inappropriate antidiuretic hormone secretion
Metabolism and nutritional disorders
Very common:	Elevations in serum triglycerides levels ^{11, 31}, elevations in total cholesterol (predominantly LDL cholesterol)

	^12,31, decreases in HDL cholesterol ^{18, 31}, weight gain ^{9 31}
Common:	Increased appetite, blood glucose increased to 7 31 hyperglycaemic levels ’
Uncommon:	Hyponatraemia ²⁰, diabetes mellitus ^{1 5 6}
Rare:	30 Metabolic syndrome
Psychiatric disorders
Common:	Abnormal dreams and nightmares, suicidal ideation and 21 suicidal behaviour
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, 1 22 Extrapyramidal symptoms ’ ,
Common:	dysarthria
Uncommon:	Seizure ¹, restless legs syndrome, tardive dyskinesia ^{1 6}, 4, 17 syncope
Cardiac disorders
Common:	Tachycardia ⁴, palpitations ²⁴
Uncommon:	QT prolongation ^{1 13, 19}, Bradycardia³²
Eye Disorders
Common:	Vision blurred
Vascular disorders
Common:	4 17 Orthostatic hypotension ^,
Rare:	Venous thromboembolism ¹
Respiratory, thoracic and mediastinal disorder
Common:	dyspnoea ²⁴
Uncommon	Rhinitis
Gastrointestinal disorders
Very common:	Dry mouth
Common:	Constipation, dyspepsia, vomiting ²⁶
Uncommon:	Dysphagia ⁸
Rare:	Pancreatitis ¹, Intestinal obstruction/Ileus
Hepato-biliary disorders
Common	Elevations in serum alanine aminotransaminases (ALT)³, Elevations in gamma-GT levels ³
Uncommon	Elevations in serum aspartate aminotransaminases (AST) ³
Rare:	Jaundice ⁶, hepatitis
Skin and subcutaneous tissue disorders
Very rare:	Angioedema ⁶ , Stevens-Johnson syndrome ⁶
Not known:	Toxic epidermal necrolysis, erythema multiforme
Musculoskeletal and connective tissue disorders

Very rare:	Rhabdomyolysis
Renal and urinary disorder
Uncommon:	Urinary retention
Pregnancy, puerperium and perinatal conditions
Not known:	Drug withdrawal syndrome neonatal (see section 4.6)
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.

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

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

(5) 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 >126 mg/dL (>7.0 mmol/L) or a non-fasting blood glucose >200 mg/dL (>11.1 mmol/L) on at least one occasion

(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.

(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 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.

(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 prolonged-release quetiapine therapy or early after treatment discontinuation (see sections 4.4 and 5.1).

(22) See section 5.1.

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

(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 anytime post-baseline in all trials. Shifts in total T₄, free T₄, total T₃and free T₃ are defined as <0.8 x LLN (pmol/L) and shift in TSH is >5 mlU/L at any time.

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

(27) Shift in neutrophils from >=1.5x10⁹/L at baseline to <0.5x10⁹/L at any time during treatment.

(28) Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline in all trials. Shifts in eosinophils are defined as >1x10⁹ cells/L at any time.

(29) Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline in all trials. Shifts in WBCs are defined as <3X10⁹ 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).

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

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

Paediatric population

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 adolescents 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 to <1/10)

Uncommon (>1/1,000 to <1/100)

Rare (>1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data).

Endorcine disorder
Very common:	Elevations in prolactin ^{1 2}
Metabolism and nutritional disorders
Very common:	Increased appetite
Nervous system disorders
Common:	Syncope
Respiratory, thoracic and mediastinal disorders
Common:	Rhinitis
Vascular disorder
Very common:	2 Increases in blood pressure
Gastrointenstinal disorders
Very common	Vomitting
General disorders and administration site conditions
Common	3 Irritability

(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 the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard

4.9 Overdose

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

Overdose could lead to QT-prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium, and/or agitation, coma and death. Patients with pre-existing sever cardiovascular disease may be at the increased risk of the effects of overdose (see section 4.4, 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.

Based on published literature, patients with delirium and agitation and a clear anticholinergic syndrome may be treated with physostigmine, 1-2 mg (under continuous ECG monitoring). This is not recommended as standard treatment, because of potential negative effect of physostigmine on cardiac conductance. Physostigmine may be used if there are no ECG aberrations. Do not use physostigmine in case of dysrhythmias, any degree of heart block or QRS-widening.

Whilst the prevention of absorption in overdose has not been investigated, gastric lavage can be indicated in severe poisonings and if possible to perform within one hour of ingestion. The administration of activated charcoal should be considered.

In cases of quetiapine overdose, refractory hypotension should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. Epinephrine and dopamine should be avoided, since beta stimulation may worsen hypotension in the setting of quetiapine-induced alpha blockade.

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

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antipsychotics; Diazepines, oxazepines and thiazepines, ATC code: N05A H04

Mechanism of action

Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite, norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and norquetiapine exhibit affinity for brain serotonin (5HT₂) and dopamine D₁- and D₂- receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT₂ relative to D2- receptors, which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal undesirable effect (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 a₁receptors, with a lower affinity at adrenergic a₂- 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.

In pre-clinical tests predictive of EPS, quetiapine is unlike typical antipsychotics and has an atypical profile. Quetiapine does not produce dopamine D₂-receptor supersensitivity after chronic administration. Quetiapine produces only weak catalepsy at effective dopamine D2-receptor blocking doses. Quetiapine demonstrates selectivity for the limbic system by producing depolarisation blockade of the mesolimbic but not the nigrostriatal dopamine-containing neurones following chronic administration. Quetiapine exhibits minimal dystonic liability in haloperidol-sensitised or drug-naive Cebus monkeys after acute and chronic administration (see section 4.8).

Clinical efficacy Schizophrenia

The efficacy of prolonged-release quetiapine 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 immediate-release quetiapine-to-prolonged-release quetiapine 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. Prolonged-release quetiapine 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 randomization to any visit. In patients stabilised on immediate-release quetiapine 400 mg to 800 mg, efficacy was maintained when patients were switched to an equivalent daily dose of prolonged-release quetiapine given once daily.

In a long-term study in stable schizophrenic patients who had been maintained on prolonged-release quetiapine for 16 weeks, prolonged-release quetiapine was more effective than placebo in preventing relapse. The estimated risks of relapse after 6 months treatments was 14.3% for the prolonged-release quetiapine treatment group compared to 68.2% for placebo. The average dose was 669 mg. There were no additional safety findings associated with treatment with prolonged-release quetiapine 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 prolonged-release quetiapine.

Bipolar Disorder

In the treatment of moderate to severe manic episodes, quetiapine demonstrated superior efficacy to placebo in reduction of manic symptoms at 3 and 12 weeks, in two monotherapy trials. The efficacy of prolonged-release quetiapine was further demonstrated with significance versus placebo in an additional 3 week study. Prolonged-release quetiapine was dosed in the range of 400 to 800 mg/day and the mean dose was approximately 600 mg/day. Quetiapine data in combination with divalproex or lithium in acute moderate to severe manic episodes at 3 and 6 weeks is limited; however, combination therapy was well tolerated. The data showed an additive effect at week 3. A second study did not demonstrate an additive effect at week 6.

In a clinical trial, in patients with depressive episodes in bipolar I or bipolar II disorder, 300 mg/day prolonged-release quetiapine showed superior efficacy to placebo in reduction of MADRS total score.

In 4 additional clinical trials with quetiapine, with a duration of 8 weeks in patients with moderate to severe depressive episodes in bipolar I or bipolar II disorder, immediate-release quetiapine 300 mg and 600 mg was significantly superior to placebo treated patients for the relevant outcome measures: mean improvement on the MADRS and for response defined as at least a 50% improvement in MADRS total score from baseline. There was no difference in magnitude of effect between the patients who received 300 mg immediate-release quetiapine and those who received 600 mg dose.

In the continuation phase in two of these studies, it was demonstrated that long-term treatment, of patients who responded on immediate-release quetiapine 300 or 600 mg, was efficacious compared to placebo treatment with respect to depressive symptoms, but not with regard to manic symptoms.

In two recurrence prevention studies evaluating quetiapine in combination with mood stabilizers, in patients with manic, depressed or mixed mood episodes, the combination with quetiapine was superior to mood stabilizers monotherapy in increasing the time to recurrence of any mood event (manic, mixed or depressed). Quetiapine was administered twice-daily totalling 400 mg to 800 mg a day as combination therapy to lithium or valproate.

In a 6-week, randomised, study of lithium and quetiapine pro-longed release tablets versus placebo and quetiapine pro-longed release tablets in adult patients with acute mania, the difference in YMRS mean improvement between the lithium add-on group and the placebo add-on group was 2.8 points and the difference in % responders (defined as 50% improvement from baseline on the YMRS) was 11% (79% in the lithium add-on group vs. 68% in the placebo add-on group).

In one long-term study (up to 2 years treatment) evaluating recurrence prevention in patients with manic, depressed or mixed mood episodes quetiapine was superior to placebo in increasing the time to recurrence of any mood event (manic, mixed or depressed), in patients with bipolar I disorder. The number of patients with a mood event was 91 (22.5%) in the quetiapine group, 208 (51.5%) in the placebo group and 95 (26.1%) in the lithium treatment groups respectively. In patients who responded to quetiapine, when comparing continued treatment with quetiapine to switching to lithium, the results indicated that a switch to lithium treatment does not appear to be associated with an increased time to recurrence of a mood event.

Major depressive episodes in MDD

Two short-term (6 week) studies enrolled patients who had shown an inadequate response to at least one antidepressant. Prolonged-release quetiapine 150 mg and 300 mg/day, given as add-on treatment to ongoing antidepressant therapy (amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline or venlafaxine) demonstrated superiority over antidepressant therapy alone in reducing depressive symptoms as measured by improvement in MADRS total score (LS mean change vs. placebo of 2-3.3 points).

Long-term efficacy and safety in patients with MDD has not been evaluated as 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 prolonged-release quetiapine as monotherapy treatment, however prolonged-release quetiapine is only indicated for use as add-on thereapy:

In three out of four short term (up to 8 weeks) monotherapy studies, in patients with major depressive disorder, prolonged-release quetiapine 50 mg, 150 mg and 300 mg/day demonstrated superior efficacy to placebo in reducing depressive symptoms as measured by improvement in the Montgomery-Asberg 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 prolonged-release quetiapine treatment for at least 12 weeks were randomised to either prolonged-release quetiapine once daily or placebo for up to 52 weeks. The mean dose of prolonged-release quetiapine during the randomised phase was 177 mg/day. The incidence of relapse was 14.2% for prolonged-release quetiapine 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, prolonged-release quetiapine 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 prolonged-release quetiapine 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 prolonged-release quetiapine was 160 mg/day. Other than the incidence of extrapyramidal symptoms (see section 4.8 and 'Clinical Safety' below) the tolerability of prolonged-release quetiapine 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 prolonged-release quetiapine and 3.2% for placebo. In a short-term placebo-controlled monotherapy trial in elderly patients with major depressive disorder, the aggregated incidence of extrapyramidal symptoms was 9.0% for prolonged-release quetiapine and 2.3% for placebo. In both bipolar depression and MDD, the incidence of the individual adverse events (eg, akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity) did not exceed 4% in any treatment group.

In short term, fixed dose (50 mg/day to 800 mg/day), placebo-controlled studies (ranging from 3 to 8 weeks), the mean weight gain for quetiapine-treated patients ranged from 0.8 kg for the 50 mg daily dose to 1.4 kg for the 600 mg daily dose (with lower gain for the 800 mg daily dose), compared to 0.2 kg for the placebo treated patients. The percentage of quetiapine treated patients who gained >7% of body weight ranged from 5.3% for the 50 mg daily dose to 15.5% for the 400 mg daily dose (with lower gain for the 600 and 800 mg daily doses), compared to 3.7% for placebo treated patients.

A 6-week, randomised, study of lithium and quetiapine prolonged release tablets versus placebo and quetiapine prolonged release tablets in adult patients with acute mania indicated that the combination of quetiapine prolonged release tablets with lithium leads to more adverse events (63% versus 48% in quetiapine prolonged release tablets in combination with placebo). The safety results showed a higher incidence of extrapyramidal symptoms reported in 16.8% of patients in the lithium add-on group and 6.6% in the placebo add-on group, the majority of which consisted of tremor, reported in 15.6% of the patients in the lithium add-on group and 4.9% in the placebo add-on group. The incidence of somnolence was higher in the quetiapine prolonged release tablets with lithium add-on group (12.7%) compared to the quetiapine prolonged release tablets with the placebo add-on group (5.5%). In addition, a higher percentage of patients treated in the lithium add-on group (8.0%) had weight gain (>7%) at the end of treatment compared to patients in the placebo add-on group (4.7%).

Longer term relapse prevention trials had an open label period (ranging from 4 to 36 weeks) during which patients were treated with quetiapine, followed by a randomised withdrawal period during which patients were randomised to quetiapine or placebo. For patients who were randomised to quetiapine, the mean weight gain during the open label period was 2.56 kg, and by week 48 of the randomised period, the mean weight gain was 3.22 kg, compared to open label baseline. For patients who were randomised to placebo, the mean weight gain during the open label period was 2.39 kg, and by week 48 of the randomised period the mean weight gain was 0.89 kg, compared to open label baseline.

In placebo-controlled studies in elderly patients with dementia-related psychosis, the incidence of cerebrovascular adverse events per 100 patient years was not higher in quetiapine-treated patients than in placebo-treated patients.

In all short-term placebo-controlled monotherapy trials in patients with a baseline neutrophil count >1.5 X 109/L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 X 109/L, was 1.9% in patients treated with quetiapine compared to 1.5% in placebo-treated patients. The incidence of shifts to >0.5-<1.0 x 109/L was the same (0.2%) in patients treated with quetiapine as with placebo-treated patients. In all clinical trials (placebo-controlled, open-label, active comparator) in patients with a baseline neutrophil count >1.5 X 109/L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 x 109/L was 2.9% and to <0.5 X 109/L was 0.21% in patients treated with quetiapine .

Quetiapine treatment was associated with dose-related decreases in thyroid hormone levels..The incidences of shifts in TSH was 3.2 % for quetiapine versus 2.7 % for placebo. The incidence of reciprocal, potentially clinically significant shifts of both T3 or T4 and TSH in these trials were rare, and the observed changes in thyroid hormone levels were not associated with clinically symptomatic hypothyroidism. The reduction in total and free T4 was maximal within the first six weeks of quetiapine treatment, with no further reduction during long-term treatment. For about 2/3 of all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment.

Cataracts/lens opacities

In a clinical trial to evaluate the cataractogenic potential of quetiapine (200800 mg/day) versus risperidone (2-8 mg/day) in patients with schizophrenia or schizoaffective disorder, the percentage of patients with increased lens opacity grade was not higher in quetiapine (4%) compared with risperidone (10%), for patients with at least 21 months of exposure.

Paediatric population

Children and adolescents (10 to 17 years of age)

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 Seroquel XR 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 safety

A 26-week open-label extension to the acute trials (n= 380 patients), with quetiapine flexibly dosed at 400-800 mg/day, provided additional safety data. Increases in blood pressure were reported in children and adolescents and increased appetite, extrapyramidal symptoms and elevations in serum prolactin were reported with higher frequency in children and adolescents than in adult patients (see sections 4.4 and 4.8).

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

5.2 Pharmacokinetic properties

Absorption

Quetiapine is well absorbed following oral administration. Prolonged-release quetiapine achieves peak quetiapine and norquetiapine plasma concentrations at approximately 6 hours after administration (T_max). Steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of that observed for quetiapine.

The pharmacokinetics of quetiapine and norquetiapine are linear and dose-proportional for doses up to 800 mg administered once daily. When prolonged-release quetiapine administered once daily is compared to the same total daily dose of immediate-release quetiapine fumarate administered twice daily, the area under the plasma concentration-time curve (AUC) is equivalent, but the maximum plasma concentration (C_max) is 13% lower at steady state. When prolonged-release quetiapine is compared to immediate-release quetiapine, the norquetiapine metabolite AUC is 18% lower.

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 prolonged-release quetiapine C_max and AUC of approximately 50% and 20% respectively. It cannot be excluded that the effect of a high fat meal on the formulation may be larger. In comparison, a light meal had no significant effect on the C_max or AUC of quetiapine. It is recommended that prolonged-release quetiapine is taken once daily without food.

Distribution

Quetiapine is approximately 83% bound to plasma proteins.

Metabolism

Quetiapine is extensively metabolised by the liver, with parent compound accounting for less than 5% of unchanged drug-related material in the urine or faeces, following the administration of radiolabelled quetiapine.

In vitro investigations established that CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. Norquetiapine is primarily formed and eliminated via CYP3A4.

Quetiapine and several of its metabolites (including norquetiapine) were found to be weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities in vitro. In vitro CYP inhibition is observed only at concentrations approximately 5 to 50 fold higher than those observed at a dose range of 300 to 800 mg/day in humans. Based on these in vitro results, it is unlikely that co-administration of quetiapine with other drugs will result in clinically significant drug inhibition of cytochrome P450 mediated metabolism of the other drug. From animal studies it appears that quetiapine can induce cytochrome P450 enzymes. In a specific interaction study in psychotic patients, however, no increase in the cytochrome P450 activity was found after administration of quetiapine.

Elimination

The elimination half lives of quetiapine and norquetiapine are approximately 7 and 12 hours, respectively. Approximately 73% of a radiolabelled drug was excreted in the urine and 21% in the faeces with less than 5% of the total radioactivity representing unchanged drug-related material. The average molar dose fraction of free quetiapine and the active human plasma metabolite norquetiapine is <5% excreted in the urine.

Special populations

Gender

The pharmacokinetics of quetiapine does not differ between men and women. Elderly

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

Renal impairment

The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 ml/min/1.73 m²), but the individual clearance values are within the range for normal subjects.

Hepatic impairment

The mean quetiapine plasma clearance decreases with approximately 25% in persons with known hepatic impairment (stable alcohol-cirrhosis). As quetiapine is extensively metabolised by the liver, elevated plasma levels are expected in the population with hepatic impairment. Dose adjustments may be necessary in these patients (see section 4.2).

Paediatric population

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-normalized 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.

No information is available for prolonged-release quetiapine in children and adolescents

5.3 Preclinical safety data

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

In rats, pigment deposition in the thyroid gland has been observed; in cynomolgus monkeys thyroid follicular cell hypertrophy, a lowering in plasma T₃ levels, decreased haemoglobin concentration and a decrease of red and white blood cell count have been observed; and in dogs lens opacity and cataracts. (For cataracts/lens opacities see section 5.1).

In an embryofoetal toxicity study in rabbits the foetal incidence of carpal/tarsal flexure was increased. This effect occurred in the presence of overt maternal effects such as reduced body weight gain. These effects were apparent at maternal exposure levels about 4 times greater than those in humans at the maximal therapeutic dose. The relevance of this finding for humans is unknown.

In a fertility study in rats, marginal reduction in male fertility and pseudopregnancy, protracted periods of diestrus, increased precoital interval and reduced pregnancy rate were seen. These effects are related to elevated

prolactin levels and not directly relevant to humans because of species differences in hormonal control of reproduction.

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

Tablet core Lactose monohydrate Cellulose, microcrystalline Magnesium oxide, light Carrageenan lambda Povidone (K-30)

Magnesium stearate

Tablet coating Carrageenan lambda Titanium dioxide (E171)

Macrogol 400

Printing ink

Opacode S-1-17823 black ink: Shellac glaze, iron oxide black (E172), propylene glycol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Store below 25°C.

6.5 Nature and contents of container

Alu/PVC/PVdC blisters and OPA/Alu/PVC-Alu blisters.

6.6

10

Pack sizes: 10, 60 and 100 tablets. Not all pack sizes may be marketed.

Special precautions for disposal

No special requirements.

MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf.

Reykjavikurvegi 76-78 220 HafnarfjorSur Iceland

MARKETING AUTHORISATION NUMBER(S)

PL 30306/0347

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20/01/2012

DATE OF REVISION OF THE TEXT

15/09/2014

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

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