Geroquel 25mg, 100mg & 200mg Film-coated Tablets

  • Name:

    Geroquel 25mg, 100mg & 200mg Film-coated Tablets

  • Company:
    info
  • Active Ingredients:

    Quetiapine fumarate

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 29/08/19

files-icon(Click to Download)
Summary of Product Characteristics last updated on medicines.ie: 29/8/2019

Click on this link to Download PDF directly

Gerard Laboratories

Gerard Laboratories

Company Products

Medicine NameActive Ingredients
Medicine Name Abacavir/Lamivudine Mylan 600 mg/300 mg film-coated tablets Active Ingredients Abacavir hydrochloride, Lamivudine
Medicine Name Agerdex 1mg Film Coated Tablets Active Ingredients Anastrozole
Medicine Name Agomelatine Mylan 25 mg film-coated tablets Active Ingredients Agomelatine
Medicine Name Amisulpride 50mg & 200mg Tablets Active Ingredients Amisulpride
Medicine Name Amlodipine Mylan 5mg & 10mg Tablets Active Ingredients Amlodipine besilate
Medicine Name Amlodipine/Valsartan Mylan 5mg/80mg, 5mg/160mg, 10mg/160mg film-coated tablets Active Ingredients Amlodipine besilate, Valsartan
Medicine Name Areloger 7.5mg & 15mg Tablets Active Ingredients Meloxicam
Medicine Name Aripil 5mg & 10mg Film-coated Tablets Active Ingredients Donepezil Hydrochloride
Medicine Name Atazanavir Mylan 300 mg hard capsules Active Ingredients Atazanavir sulfate
Medicine Name Atenetic 50/12.5mg & 100/25mg Film - coated Tablets Active Ingredients Atenolol, Chlortalidone
Medicine Name Atorvastatin Mylan 10 mg, 20 mg, 40 mg & 80 mg film-coated tablets Active Ingredients Atorvastatin calcium trihydrate
Medicine Name Atovaquone/Proguanil Hydrochloride 250 mg/100 mg film-coated tablets Active Ingredients Atovaquone, Proguanil Hydrochloride
Medicine Name Azromax 250mg Film-coated tablets Active Ingredients Azithromycin monohydrate
Medicine Name Baclopar Tablets 10 mg Active Ingredients Baclofen
Medicine Name Bisoprolol Mylan Active Ingredients Bisoprolol Fumarate
Medicine Name Brabio 20mg/ml solution for injection, pre-filled syringe Active Ingredients Glatiramer Acetate
Medicine Name Brabio 40mg/ml solution for injection, pre-filled syringe Active Ingredients Glatiramer Acetate
Medicine Name Cifloxager 250 mg Film-coated Tablets Active Ingredients Ciprofloxacin hydrochloride
Medicine Name Cifloxager 500 mg Film-coated Tablets Active Ingredients Ciprofloxacin hydrochloride
Medicine Name Ciprager 10mg & 20mg Film Coated Tablets Active Ingredients citalopram hydrobromide
Medicine Name Ciprager 40mg Film Coated Tablets Active Ingredients citalopram hydrobromide
Medicine Name Ciprofloxacin Mylan 2mg/1ml solution for infusion Active Ingredients Ciprofloxacin
Medicine Name Clopidogrel Mylan 75 mg film-coated tablets Active Ingredients clopidogrel hydrochloride
Medicine Name Darunavir Mylan 800 mg film-coated tablets Active Ingredients darunavir ethanolate
Medicine Name Depreger 50mg & 100mg Film-Coated Tablets Active Ingredients sertraline hydrochloride
1 - 0 of 117 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 29 August 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 29 August 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 18 September 2018 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - what the product looks like and pack contents

Updated on 17 September 2018 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 12 September 2018 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - what the product looks like and pack contents

Updated on 12 September 2018 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 2 August 2018 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 4 - possible side effects
  • Change to section 6 - what the product contains
  • Change to section 6 - what the product looks like and pack contents

Updated on 2 August 2018 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.5 - Nature and contents of container

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 2 September 2016 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.4 Special warnings and precautions for use

Misuse and abuse
Cases of misuse and abuse have been reported. Caution may be needed when prescribing quetiapine to
patients with a history of alcohol or drug abuse.

 

Updated on 2 September 2016 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 31 August 2016 PIL

Reasons for updating

  • New PIL for new product

Updated on 31 August 2016 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to date of revision

Updated on 4 July 2016 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.4 Special warnings and precautions for use

Sleep apnoea syndrome
Sleep apnoea syndrome has been reported in patients using quetiapine. In patients receiving concomitant central nervous system depressants and who have a history of or are at risk of sleep apnoea, such as those who are overweight/obese or are male, quetiapine should be used with caution.

Anti-cholinergic (muscarinic) effects
Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes. This contributes to ADRs reflecting anti-cholinergic effects when quetiapine is used at recommended doses, when used concomitantly with other medications having anti-cholinergic effects, and in the setting of overdose. Quetiapine should be used with caution in patients receiving medications having anticholinergic (muscarinic) effects. Quetiapine should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, intestinal obstruction or related conditions, increased intraocular pressure or narrow angle glaucoma. (See sections 4.5, 4.8, 5.1, and 4.9.)

Elderly patients with dementia-related psychosis

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

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

In a meta-analysis of atypical antipsychotics, it has been reported that elderly patients with dementia-related psychosis are at an increased risk of death compared to placebo. However in two 10-week placebo-controlled quetiapine studies in the same patient population (n=710; mean age: 83 years; range: 56-99 years) the incidence of mortality in quetiapine-treated patients was 5.5% versus 3.2% in the placebo group. The patients in these trials died from a variety of causes that were consistent with expectations for this population. These data do not establish a causal relationship between quetiapine treatment and death in elderly patients with dementia.

4.5 Interaction with other medicinal products and other forms of interaction

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

Caution should be exercised treating patients receiving other medications having anti­cholinergic (muscarinic) effects (see section 4.4).

4.8 Undesirable effects

SOC

 

Very Common

 

Common

 

Uncommon

 

Rare

 

Very Rare

 

Not known

 

Blood and

lymphatic

system

disorders

 

 

Decreased

haemoglobin22

 

 

Leucopenia

 

1, 28,

 

Decreased neutrophil

count, eosinophils

increased27

 

 

Neutropenia1

Thrombocytopenia,

Anaemia, platelet

count decreased13

 

 

Agranulocytosis26

 

 

Neutropenia

 

 

1

Immune system

disorders

 

 

Hypersensitivity

(including allergic

skin reactions)

 

 

Anaphylactic

reaction5

 

 

Endocrine

disorders

 

 

Hyperprolactinaemia15,

decreases in total T424,

decreases in free T424,

decreases in total T324,

increases in TSH24

 

 

Decreases in free

T324,

Hypothyroidism21

 

 

Inappropriate

antidiuretic

hormone secretion

 

 

Metabolism and

nutritional

disorders

 

 

Elevations in

serum triglyceride

levels

 

10,30

 

Elevations in total

cholesterol

(predominantly

LDL

cholesterol)

 

11,30

 

Decreases in HDL

cholesterol

 

17,30

 

Weight gain

 

8,30

Increased appetite,

blood glucose increased

to hyperglycaemic

levels

 

6,30

Hyponatraemia19,

Diabetes Mellitus

 

1,5 Exacerbation of pre-existing diabetes

Metabolic

syndrome29

 

 

Exacerbation of

pre-existing

diabetes

 

 

 

Psychiatric

disorders

 

 

Abnormal dreams and

nightmares, Suicidal

ideation and suicidal

behaviour20

 

 

Somnambulism

and related

reactions such as

sleep talking and

sleep related

eating disorder

 

 

Nervous system

disorders

 

 

Dizziness

 

4, 16,

 

somnolence

 

2,16,

 

headache,

Extrapyramidal

symptoms

 

1, 21

Dysarthria

 

 

Seizure

 

1, Restless legs

 

syndrome, Tardive

dyskinesia

 

1, 5,

 

Syncope

 

4,16

Cardiac

disorders

 

 

Tachycardia4,

Palpitations23

 

 

QT prolongation

 

1,

4.9 Overdose

Symptoms
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 and anti-cholinergic effects.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Mechanism of action

Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite, norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and norquetiapine exhibit affinity for brain serotonin (5HT2) and dopamine D1- and D2- receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT2 relative to D2- receptors, which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal side effect (EPS) liability of quetiapine compared to typical antipsychotics. Quetiapine and norquetiapine have no
appreciable affinity at benzodiazepine receptors but high affinity at histaminergic and adrenergic alpha1 receptors, moderate affinity at adrenergic alpha2 receptors and moderate to high affinity at several muscarinic receptors. Quetiapine also has low or no affinity for muscarinic receptors, while norquetiapine has moderate to high affinity at several muscarinic receptors, which may explain anticholinergic (muscarinic effects). Inhibition of NET and partial agonist action at
5HT1A sites by norquetiapine may contribute to quetiapine’s therapeutic efficacy as an antidepressant.

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 13.7% vs. 6.8% in the bipolar depression trial. The rates of suicide related events in the active arm vs. placebo were 1.4% vs. 1.3% in the schizophrenia trial, 1.0% vs. 0% in the bipolar mania trial, and 1.1% vs. 0% in the bipolar depression trial. During an extended post-treatment follow-up phase of the bipolar depression trial, there were two additional suicide related events in two patients; one of these patients was on quetiapine at the time of the event.

Updated on 29 June 2016 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to further information section
  • Change to date of revision
  • Change to dosage and administration

Updated on 2 July 2015 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.1 - List of excipients
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Extensive updates in line with Article 30 referral.

Updated on 18 May 2015 PIL

Reasons for updating

  • Change to, or new use for medicine
  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to drug interactions
  • Change to information about drinking alcohol
  • Change to date of revision
  • Change to dosage and administration

Updated on 22 September 2014 PIL

Reasons for updating

  • Change to date of revision
  • Addition of manufacturer

Updated on 27 June 2014 PIL

Reasons for updating

  • Change to further information section
  • Change to date of revision
  • Introduction of new pack/pack size

Updated on 10 June 2014 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 6.5:
PVC/PVdC Aluminium Blisters
1, 3, 6, 7, 10, 14, 20, 28, 30, 50, 56, 60, 84, 90, 98, 100 tablets per pack.
25 mg tablets: perforated unit dose blister of 6x1 tablets per pack
25 mg, 100 mg, 200 mg, 300 mg tablets: perforated unit dose blister of 60 x 1 tablets per pack


Updated on 10 March 2014 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to instructions about missed dose
  • Change to storage instructions
  • Change to side-effects
  • Change to drug interactions
  • Change to information about pregnancy or lactation
  • Change to date of revision

Updated on 6 March 2014 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.1:
Treatment of schizophrenia.

Treatment of bipolar disorder including:
- moderate to severe manic episodes in 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.


Treatment of major depressive episodes in bipolar disorder.

Prevention of recurrence in patients with bipolar disorder, in patients whose manic or depressive episode has responded to quetiapine treatment.

Section 4.2:

For the treatment of moderate to severe manic episodes associated with bipolar disorder
Geroquel should be administered twice a day. As monotherapy or as adjunct therapy to mood stabilisers, tThe 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).


For the treatment of depressive episodes in bipolar disorder:, Geroquel tablets 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, Nno 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, studies 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 preventingon of recurrence of manic, mixed or 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.

Children and Adolescents Paediatric population

Section 4.4:
Children and adolescents (10 to 17 years of age) Paediatric population


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. This is more common in elderly patients and in younger patients. and therefore dDose reduction or more gradual titration should be considered if this occurs. A slower titration regimen could be considered in patients with underlying cardiovascular disease.

Hepatic effects
If jaundice develops, quetiapine should be discontinued.

Section 4.5:
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.

Section 4.8:
Blood and lymphatic system disorders
Very common Decreased haemoglobin23
Common: Leucopenia 1,279, Decreased neutrophil count, Eosinophils increased28
Uncommon: Thrombocytopenia, Anaemia, Platelet count decreased14
Rare: Agranulocytosis297



Metabolism and nutrition disorders
Very common: Elevations in serum triglyceride level11,31
Elevations in total cholesterol (predominantly LDL cholesterol)12,31
Decrease in HDL cholesterol18,31 , Weight gain 9,13
Common: Increased appetite , blood glucose increased to hyperglycaemic levels7, 131


Cardiac disorders
Common:
Uncommon: Tachycardia 4, Palpitations24
QT prolongation 1,13,19
Bradycardia33

Pregnancy, puerperium and perinatal conditions
Not known: Drug withdrawal syndrome neonatal
32 (see section 4.6)


26. Based upon the increased rate of vomiting in elderly patients (≥65 years of age).
27. Shift in neutrophils from >=1.5 x 10^9/L at baseline to <0.5 x 10^9/L at any time during treatment.
27. Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline in all trials. Shifts in WBCs are defined as ≤ 3X109cells/L at any time.
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 >1x 109 cells/L at any time.
29. Shift in neutrophils from >=1.5 x 10^9/L at baseline to <0.5 x 10^9/L at any time during treatment.Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline in all trials. Shifts in WBCs are defined as ≤ 3X109cells/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. See section 4.6
31. 33. May occur at or near initiation of treatment and be associated with hypotension and/or syncope. Frequency based on adverse reports of bradycardia and related events in all clinical trials with quetiapine.


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

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). 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 (e.g., akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity) were generally low and did not exceed 4% in any treatment group. In long-term studies of schizophrenia and bipolar disorder the aggregated incidence of treatment-emergent extrapyramidal symptoms was similar between quetiapine and 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 TBG were unchanged and in general, reciprocal increases in TSH were not observed, with no indication that quetiapine causes clinically relevant hypothyroidism.

Children and adolescents (10 to 17 years of age)
Paediatric population

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

IMB Pharmacovigilance,
Earlsfort Terrace,
IRL - Dublin 2,
Tel: +353 1 6764971;
Fax: +353 1 6762517.
Website: www.imb.ie;
e-mail: imbpharmacovigilance@imb.ie

Sectio 4.9:

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.

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.

Additionally, the following events have been reported in the setting of monotherapy overdose with quetiapine: QT-prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium, and/or agitation.

Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose (see Section 4.4:
Cardiovascular).

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

Section 5.1:


Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite, N-desalkyl norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and N-desalkyl 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 dopamine D2- receptors, which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal side effect (EPS) liability of quetiapine compared to typical antipsychotics. Additionally, N-desalkyl nor quetiapine has high affinity for the norepinephrine transporter (NET). Quetiapine and N-desalkyl nor quetiapine also have high affinity at histaminergic and adrenergic a1 receptors, with a lower affinity at adrenergic α2 and serotonin 5HT1A receptors. Quetiapine has no appreciable affinity at cholinergic muscarinic or benzodiazepine receptors.

Pharmacodynamic Effect

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 standard 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 results of these tests predict that quetiapine should have minimal EPS liability, and it has been hypothesised that agents with a lower EPS liability may also have a lower liability to produce tardive dyskinesia (see Section 4.8).
The extent to which the N-desalkyl norquetiapine metabolite contributes to the pharmacological activity of Quetiapine in humans is not known.


Clinical Efficacy
Schizophrenia
In 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 using variable doses of quetiapine, there were identified no differences between the quetiapine and placebo treatment groups in the incidence of EPS or concomitant use of anticholinergics. A placebo-controlled trial evaluating fixed doses of quetiapine across the range of 75 to 750 mg/day showed no evidence of an increase in EPS or the use of concomitant anticholinergics. The long-term efficacy of quetiapine IR in prevention of schizophrenic relapses has not been verified in blinded clinical trials. In open label trials, in patients with schizophrenia, quetiapine was effective in maintaining the clinical improvement during continuation therapy in patients who showed an initial treatment response, suggesting some long-term efficacy.

Bipolar Disorder
In four placebo-controlled clinical trials, evaluating doses of quetiapine up to 800 mg/day for the treatment of moderate to severe manic episodesbipolar mania, two each in monotherapy and as combination adjunct therapy to lithium or divalproexvalproate semisodium, there were no differences between the quetiapine and placebo treatment groups in the incidence of EPS or concomitant use of anticholinergics. Lack of induction of EPS is considered a feature of atypical antipsychotics.

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 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.

Unlike many other antipsychotics, quetiapine does not produce sustained elevations in prolactin, which is considered a feature of atypical antipsychotics. In a multiple fixed-dose clinical trial, in patients with schizophrenia, there were no differences in prolactin levels at study completion, for quetiapine across the recommended dose range, and placebo.

In the treatment of moderate to severe manic episodes, quetiapine demonstrated superior efficacy to placebo in reduction of manic symptoms at 3 and 12 weeks, in two monotherapy trials. There are no data from long-term studies to demonstrate quetiapine’s effectiveness in preventing subsequent manic or depressive episodes. Quetiapine data in combination with divalproex or lithium in moderate to severe manic episodes at 3 and 6 weeks is limited; however, combination therapy was well tolerated. The data showed an additive effect at week 3. A second study did not demonstrate an additive effect at week 6. There are no combination data available beyond week 6. The mean last week median dose of quetiapine in responders was approximately 600 mg/day and approximately 85% of the responders were in the dose range of 400 to 800 mg/day.

In 4 clinical trials with a duration of 8 weeks in patients with moderate to severe depressive episodes in bipolar I or bipolar II disorder, with or without rapid cycling courses, 51% of quetiapine treated patients had 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 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.from baseline. There was no difference in magnitude of effect between the patients who received 300 mg quetiapine and those who received 600 mg dose.

In the continuation treatment, the anti-depressant effect was maintained for patients on quetiapine (mean duration of treatment 30 weeks). Quetiapine reduced the risk of 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.phase in two of these studies, it was demonstrated that long-term treatment, of patients who responded on quetiapine 300 or 600 mg, was efficacious compared to placebo treatment with respect to depressive symptoms, but not with regard to manic symptoms.

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.Quetiapine was administered twice-daily totalling 400 mg to 800 mg a day as combination therapy to lithium or valproate.

Clinical safety
In short-term, placebo-controlled clinical trials in schizophrenia and bipolar mania the aggregated incidence of extrapyramidal symptoms was similar to placebo (schizophrenia: 7.8% for quetiapine and 8.0% for placebo; bipolar mania: 11.2% for quetiapine and 11.4% for placebo). Higher rates of extrapyramidal symptoms were seen in quetiapine treated patients compared to those treated with placebo in short-term, placebo-controlled clinical trials in MDD and bipolar depression. In short-term, placebo-controlled bipolar depression trials the aggregated incidence of extrapyramidal symptoms was 8.9% for quetiapine compared to 3.8% for placebo. In short-term, placebo-controlled monotherapy clinical trials in major depressive disorder the aggregated incidence of extrapyramidal symptoms was 5.4% for Quetiapine Prolonged-Release Tablets and 3.2% for placebo. In a short-term placebo-controlled monotherapy trial in elderly patients with major depressive disorder, the aggregated incidence of extrapyramidal symptoms was 9.0% for Quetiapine Prolonged-Release Tablets 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 long-term studies of schizophrenia and bipolar disorder the aggregated incidence of treatment-emergent extrapyramidal symptoms was similar between quetiapine and placebo.

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

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

In placebo-controlled studies in elderly patients with dementia-related psychosis, the incidence of cerebrovascular adverse events per 100 patient years was not higher in quetiapine-treated patients than in placebo-treated patients.
Clinical trials have demonstrated that quetiapine is effective when given twice a day, although quetiapine has a pharmacokinetic half-life of approximately 7 hours. This is further supported by the data from a positron emission tomography (PET) study, which identified that for quetiapine, 5HT2- and D2-receptor occupancy are maintained for up to 12 hours. The safety and efficacy of doses greater than 800 mg/day have not been evaluated.

The long-term efficacy of quetiapine in prevention of schizophrenic relapses has not been verified in blinded clinical trials. In open label trials, in patients with schizophrenia, quetiapine was effective in maintaining the clinical improvement during continuation therapy in patients who showed an initial treatment response, suggesting some long-term efficacy.

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 neutrophil count <1.5 x 109/L, was 1. 792% in patients treated with quetiapine compared to 0.731.3% in placebo-treated patients. The incidence of shifts to >0.5 - <1.0 X 109/L was the same (0.2%) in patients treated with quetiapine as with placebo-treated patients.In all clinical trials (placebo-controlled, open-label, active comparator; 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.

In fixed dose short-term placebo-controlled clinical trials, quetiapine treatment was associated with dose-related decreases in thyroid hormone levels. In short-term placebo-controlled clinical trials, the incidence of potentially clinically significant shifts in thyroid hormone levels were: total T4: 3.4% for quetiapine versus 0.6% for placebo; free T4: 0.7% for quetiapine versus 0.1% for placebo; total T3: 0.54% for quetiapine versus 0.0% for placebo and free T3: 0.2% for quetiapine versus 0.0% for placebo. The incidence of shifts in TSH was 3.2% for quetiapine versus 2.7% for placebo. In short-term placebo-controlled monotherapy trials, the incidence of reciprocal, potentially clinically significant shifts in T3 and TSH was 0.0% for both quetiapine and placebo and 0.1% for quetiapine versus 0.0% for placebo for shifts in T4 and TSH. These changes in thyroid hormone levels are generally not associated with clinically symptomatic hypothyroidism. The reduction in total and free T4 was maximal within the first six weeks of quetiapine treatment, with no further reduction during long-term treatment. In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment. In eight patients, where TBG was measured, levels of TBG were unchanged.

Cataracts/lens opacities
In a clinical trial to evaluate the cataractogenic potential of quetiapine (200-800 mg/day) versus risperidone (2-8 mg) in patients with schizophrenia or schizoaffective disorder, the percentage of patients with increased lens opacity grade was not higher in quetiapine (4%) compared with risperidone (10%), for patients with at least 21 months of exposure.

Children and adolescents (10 to 17 years of age) Paediatric population
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 quetiapine 400 mg/day and –6.56 for Quetiapine quetiapine 600 mg/day. Responder rates (YMRS improvement ≥50%) were 64% for Quetiapine 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 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.

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

A 26-week open-label extension to the acute trials (n= 380 patients), with Quetiapine 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).

Section 5.2:
Biotransformation
Steady-state peak molar concentrations of the active metabolite N-desalkyl nor-quetiapine are 35% of that observed for quetiapine.

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 safety and efficacy of doses greater than 800 mg/day have not been evaluated.


Metabolism
Quetiapine is extensively metabolised by the liver, with parent compound accounting for less than 5%
of unchanged medicinal productdrug-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.

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

Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces.
In a multiple-dose trial in healthy volunteers to assess the pharmacokinetics of quetiapine given before and during treatment with ketoconazole, co–administration of ketoconazole resulted in an increase in mean Cmax 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 tmax was unchanged

Quetiapine and several of its metabolites (including N-desalkyl nor-quetiapine) 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 coadministration of quetiapine with other medicinal products will result in clinically significant
medicinal product inhibition of cytochrome P450 mediated metabolism of the other medicinal productdrug.
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 N-desalkyl nor-quetiapine are approximately 7 and 12 hours, respectively.
The average molar dose fraction of free quetiapine and the active human plasma metabolite N-desalkylnor-
quetiapine is <5% excreted in the urine.

Linearity/non-linearity
The pharmacokinetics of quetiapine and N-desalkyl nor-quetiapine are linear across the approved dosing
range.

Section 5.3:
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: iIn 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).

Updated on 22 April 2013 PIL

Reasons for updating

  • Change of trade or active ingredient name
  • Change to date of revision
  • Correction of spelling/typing errors

Updated on 17 April 2013 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 2:

Excipient with known effect:



Section 4.2:
 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.

Geroquel tablets can be administered with or without food.

Method of administration
Geroquel tablets can be administered with or without food.

Section 4.5:

Paediatric population
Interaction studies have only been performed in adults.

Section 5.1:
Formatting changes

Section 5.2:
Absorption
Quetiapine is well absorbed and extensively metabolised following oral administration. The bioavailability of quetiapine is not significantly affected by administration with food.

Distribution
Quetiapine is approximately 83% bound to plasma proteins.

Biotransformation
Steady-state peak molar concentrations of the active metabolite N-desalkyl quetiapine are 35% of that observed for quetiapine.

Metabolism
Quetiapine is extensively metabolised by the liver, with parent compound accounting for less than 5%
of unchanged medicinal product-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. N-desalkyl quetiapine is
primarily formed and eliminated via CYP3A4.

Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces.

Quetiapine and several of its metabolites (including N-desalkyl quetiapine) 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 coadministration of quetiapine with other medicinal products will result in clinically significant
medicinal product inhibition of cytochrome P450 mediated metabolism of the other medicinal product.
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 N-desalkyl quetiapine are approximately 7 and 12 hours, respectively.
The average molar dose fraction of free quetiapine and the active human plasma metabolite N-desalkyl
quetiapine is <5% excreted in the urine.

Linearity/non-linearity
The pharmacokinetics of quetiapine and N-desalkyl quetiapine are linear across the approved dosing
range.

Special populations

Gender
The kinetics of Quetiapine do not differ between men and women.

Elderly patients
The pharmacokinetics of quetiapine and N-desalkyl quetiapine 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.
Renal impairment
The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 ml/min/1.73m2), but the individual clearance values are within the range for normal subjects. The average molar dose fraction of free quetiapine and the active human plasma metabolite N-desalkyl quetiapine is <5% excreted in the urine.

Quetiapine is extensively metabolised by the liver, with parent compound accounting for less than 5% of unchanged medicinal product-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.
Hepatic impairment
The mean quetiapine plasma clearance decreases with approx. 25% in persons with known hepatic impairment (stable alcohol cirrhosis). As quetiapine is extensively metabolised by the liver, elevated plasma levels are expected in the population with hepatic impairment. Dose adjustments may be necessary in these patients (see Section 4.2).

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

Quetiapine and several of its metabolites (including N-desalkyl quetiapine) 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 medicinal products will result in clinically significant medicinal product inhibition of cytochrome P450 mediated metabolism of the other medicinal product. 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
Children and adolescents (10 to 17 years of age)
Pharmacokinetic data were sampled in 9 children aged 10-12 years old and 12 adolescents, who were on steady-state treatment with 400 mg quetiapine twice daily. At steady-state, the dose-normalised plasma levels of the parent compound, quetiapine, in children and adolescents (10-17 years of age) were in general similar to adults, though Cmax in children was at the higher end of the range observed in adults. The AUC and Cmax for the active metabolite, norquetiapine, were higher, approximately 62% and 49% in children (10-12 years), respectively and 28% and 14% in adolescents (13-17 years), respectively, compared to adults.

Section 5.3:
Formatting

Updated on 11 June 2012 SmPC

Reasons for updating

  • New SPC for medicines.ie

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

None provided

Updated on 19 April 2012 PIL

Reasons for updating

  • New PIL for medicines.ie