editorial changes made throughout the document.

Section 4.8 - Drug rash with eosinophilia and systemic symptoms (DRESS) added as 'Not known' undesirable effect under SOC Skin and subcutaneous tissue disorders.

Section 4.8 - 'Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in association with quetiapine treatment.' added to section 4.8. 

Section 4.9 - 'In case of overdose with extended-release quetiapine there is a delayed peak sedation and peak pulse and prolonged recovery compared with IR Quetiapine overdose. In case of a quetiapine extended-release overdose gastric bezoar formation has been reported and appropriate diagnostic imaging is recommended to further guide patient management. Endoscopic pharmacobezoar removal has been performed successfully in some cases.' added in overdose section 4.9.

Section 10 - change to the date of revision to 4th October 2018.

Change to warnings or special precautions for use – Section 4.4 additional caution for people with a history of alcohol and drug abuse.

Change to date of revision – Section 9 Date of renewal to 23^rd November 2016 and Section 10 to 15^th September 2016

Change to improve clarity and readability – Sections 2, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.8, 4.9, 5.1, 5.2, 5.3, 6.1, minor editorial updates to bring in line with latest QRD template.

Section 4.4: addition of information on sleep apnoea syndrome

Section 4.4: addition of information on anti-cholingeric (muscarinic) effects

Section 4.5: addition of information on patients receiving other medications that have anti-cholinergic effects

Section 4.8: editorial change

Section 4.9: addition of anti-cholingeric effects as a symptom of overdose

Section 5.1: addition of text regarding quetiapine having low or no affinity for muscarinic receptors while norquetiapine does which may explain anti-cholingeric (muscarinic) effects

Section 5.1: Paediatric population: clinical safety: amendment of rates weight gain of baseline body weight vs placebo:  in the bipolar depression trial from 12.5% vs 6% to 13.7% vs 6.8%

Section 10: updated date of revision

Section 2 – editorial changes

Section 4.2 – editorial changes

Section 4.4 – editorial changes

Section 4.4 –removal of text that ‘data do not establish a causal relationship between quetiapine treatment and death in elderly patients with dementia.’

Section 4.8 – ADR table - ‘neutropenia’ side effect moved from ‘not known’ frequency to ‘uncommon’

Section 4.8 – ADR table – ‘exacerbation of pre-existing diabetes’ side effect from ‘very rare’ to ‘uncommon’

Section 4.8 – footnotes: editorial changes

Section 5.1 – editorial changes

Section 5.2 – editorial changes

Section 10 – updated date of revision

section 1 – editorial changes

section 2- editorial changes

section 3 –editorial changes

section 4.1 – editorial changes

section 4.2 – editorial changes

section 4.3 - editorial changes

section 4.4 - editorial changes, amendment of text for severe neutropenia and agranulocytosis,a ddition of text for cardiomyopathy and myocarditis. More information added to constipiation and intestinal obstruction section

section 4.5 – editorial changes

section 4.6 – amendment of text on pregnancy, breast-feeding and fertility

section 4.8 – amendment of ADR  table. Paediatric ADR table, editorial changes

section 4.8 – amendment of HPRA address (ADR statement)

section 4.9 - editorial changes

section 5.1 – amendment of mechanism of action text regarding norquetiapine

section 5.2 – editorial changes

section 5.3 – amendment in text re embrofoetal toxicity study

section 6.1 - editorial changes

section 10 – updated date of revision

- Section 4.1 & 4.2

Administrative changes: amended line spacing and addition of hard spaces.

- Section 4.4

Addition of irritability to the safety profile with a different implication for children and adolescents

Addition of agranulocytosis and management thereof

Addition of constipation and intestinal obstruction as a risk factor

Administrative changes to formatting and layout

 

- Section 4.8

Unknown updated to Not known

Addtional and unnecessary spaces removed

Addition of Intestinal obstruction/ Ileus and urinary retention to table and addition of neutropenia to table footnotes

Changed transaminases to aminotransferase

Addition of table 2 heading ADRs in children and adolescents higher than or not identified in adults

Moved elevations in prolactin to endocrine disorders

Moved increases in blood pressure to vascular disorders

Added extraprimidal symptoms as very common

Addition of adverse event reporting instructions

 

- Section 4.9

Addition of a heading for symptoms and simplification of symptoms

Removal of quantities of quetiapine resulting in a fatal outcome or survival following an overdose

Addition of published literature information for management of overdose

 

- Section 5.1 and 5.2

Administrative changes to improve text layout and readability

 

- Section 5.3

Addition of embryofoetal and fertility data

- Section 10
Updated date of revision

Section 4.4 – Paediatrics

Section 4.5 – Lithium PAC

Section 4.8 – Paediatrics and CSP

Section 5.1 - Lithium PAC and Paediatrics
Section 10 - updated date of revision

editorial changes
section 10 - updated date of revision

Section 4.4

 

Revised wording of Metabolic Risk warning, addition of Pancreatitis warning and minor editorial change to replace Seroquel with quetiapine.

Section 4.6

 

Revised wording concerning excretion into breast milk and addition of information relating to risks associated with exposure of neonates to antipsychotics.

 

Section 4.8

 

Adverse Events table revised based on approved Core Safety Profile.

 

Section 4.9

 

Minor editorial change to replace Seroquel with quetiapine.

 

Section 10

 

Date of revision updated to 26^th April 2012.

 

Section 3

 

Administrative correction to tablet appearance (for immediate release only).

 

Section 4.1

 

Administrative change to indications (for immediate release only).

 

Section 4.2

 

Clarification different dosing required for different indications.

 

Section 4.4

 

Clarification the safety profile should be considered in accordance with dose and indication.

Administrative changes to replace Seroquel with quetiapine.

Expanded suicide risk warning.

Moved text on Extrapyramidal symptoms and Tardive Dyskinesia.

Added dizziness to heading with somnolence and added clarification on the risk to elderly.

Added information on incidence of seizures.

 

Section 4.5

 

Information on interaction with valproate and quetiapine.

 

Section 4.8

 

Addition of new undesirable effects in line with current information.

Moved some text to clinical safety section 5.1.

 

Section 4.9

 

Addition of symptoms and management of overdose.

 

Section 5.1

 

Addition of text to clinical safety from 4.8.

 

Section 5.2

 

Addition of text to pharmacokinetic properties.

 

Section 10

 

Date of revision changed to 19^th December 2011

 

Section 4.5

Additional text at end of section:

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.

 

Section 4.8

Additional side effects:

Under Endocrine disorders

Very rare:              Inappropriate antidiuretic hormone secretion

 

Under Metabolism and nutritional disorders

Uncommon:          Hyponatraemia²⁰

 

Under Psychiatric disorders the footnote for ‘Suicidal Behaviour’ changes from 20 to 21

 

Under Nervous system orders

Common – the footnote for Extrapyramidal symptoms changes from 21 to 22

 

Under Musculoskeletal and connective tissue disorders

Very rare:          Rhabdomyolysis

 

Under Reproductive system and breast disorders

Uncommon:          Sexual dysfunction

 

Rare:                      breast swelling, menstrual disorder

 

Under Investigation

Very common      Decreased haemoglobin ²³

 

 

Under table there is additional footnotes:

(20) - Shift from >132 mmol/L to ≤132 mmol/L on at least one occasion.

 

 (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.

 

Section 5.1

Additional  information regarding Cataracts/lens opacities

Cataracts/lens opacities

In a clinical trial to evaluate the cataractogenic potential of Seroquel (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 Seroquel (4%) compared with risperidone (10%), for patients with at least 21 months of exposure.

 

Section 5.3

Reference to Cataracts/lens opacities in section 5.1

 

Section 10

Revision date of text: 24^th February 2011

Sections 1, 2 and 3

Addition of 150mg strength

 

Section 4.1

New indication text:

·         add-on treatment of major depressive episodes in patients with Major Depressive Disorder (MDD) who have had sub-optimal response to antidepressant monotherapy (see section 5.1). Prior to initiating treatment, clinicians should consider the safety profile of Seroquel XR (see section 4.4).

 

 

Section 4.2
New text first paragraph

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

 

New additional text regarding the MDD indication and use in the Elderly.

 

Section 4.4

New text first and second paragraph regarding MDD

 

New additional text under ‘Suicide’heading, Extrapyramidal Symptoms heading; Somnolence heading (which now includes dizziness);

 

New section heading and text ‘Weight’

 

Changed text under heading ‘Hyperglycaemia’

 

Section 4.8

Additional side effect under heading ‘psychiatric disorders’

Suicidal ideation and suicidal behaviour²⁰

 

side effect moved from ‘investigation’ heading to under heading ‘vascular disorders’

Rare: Venous thromboembolism¹

 

Two additional footnotes under table.

 

Section 5.2

New additional text regarding MDD

 

Section 6.5 and Section 8

Includes 150mg strength

 

Section 10

Date of revision of text: 21^st October 2010

Section 4.4

Additional text penultimate paragraph

 

Venous Thromboembolism (VTE)

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Seroquel XR and preventive measures undertaken.

 

Section 4.8

In the first table under the heading ‘Nervous system disorders’

Common:       addition of ‘Dysarthria’

Uncommon:   deletion of ‘Dysarthria’

 

In the first table under the heading ‘Investigations’

Rare:  addition of ‘Venous thromboembolism’

 

Section 10

New revision date of text: 19^th February 2010

Changes to include paediatric information

 

Section 4.2

Additional new text regarding children and adolescents

 

Children and Adolescents:

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

 

Section 4.4

Additional new text regarding children and adolescents

 

Children and adolescents (10 to 17 years of age)

Seroquel XR is not recommended for use in children and adolescents below 18 years of age, due to a lack of data to support use in this age group. Clinical trials with Seroquel 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 and extrapyramidal symptoms) and one was identified that has not been previously seen in adult studies (increases in blood pressure). Changes in thyroid function tests have also been observed in children and adolescents.

 

Furthermore, the long-term safety implications of treatment with Seroquel 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 Seroquel, quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia and bipolar mania (see section 4.8).

 

 

In the same section under the heading Extrapyramidal symptoms:

The text includes the words ‘adult patients’

In placebo controlled clinical trials of adult patients quetiapine……

 

Section 4.8

Additional text in the footnotes 11 and 12 to include information on patients less than 18 years of age.

 

Additionally, new text and frequencies table regarding Children and adolescents (10 to 17 years of age)

 

Section 5.1

New additional text regarding Children and adolescents (10 to 17 years of age)

 

Section 5.2

New additional text regarding Children and adolescents (10 to 17 years of age)

 

Section 10

Revision date of text: 29 January 2010

Section 4.4

Heading Tardive Dyskinesia –additional text:

The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment.

 

Heading Lipids – changed text to include information on HDL

Increases in triglycerides, LDL and total cholesterol, and decreases in HDL cholesterol have been observed in clinical trials with quetiapine (see section 4.8). Lipid changes should be managed as clinically appropriate.

 

Heading QT Prolongation – changed text

In clinical trials and use in accordance with the SPC, quetiapine was not associated with a persistent increase in absolute QT intervals. In post marketing, QT prolongation was reported with quetiapine at the therapeutic doses (see Section 4.8) and in overdose (see section 4.9). As with other antipsychotics, caution should be exercised when quetiapine is prescribed in patients with cardiovascular disease or family history of QT prolongation. Also caution should be exercised when quetiapine is prescribed either with medicines known to increase QT interval or with concomitant neuroleptics, especially in the elderly, in patents with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia (see section 4.5).

 

New Heading – Dysphagia

Dysphagia (see section 4.8 Undesirable effects) has been reported with quetiapine. Quetiapine should be used with caution in patients at risk for aspiration pneumonia.

 

Section 4.8

Changes to Table:

Heading of Nervous System Disorders in Table.

Change of frequency from Very Rare to Uncommon of Tardive Dyskinesia with an additional footnumber number 1.

 

Heading of Investigations

Very Common:  additional information: Decreases in HDL cholesterol  with footnote number 18

Uncommon QT prolongation with footnote numbers 1,13,19

 

Footnotes under table

(12) change of text

Cholesterol ≥240 mg/dL (³6.2064 mmol/L) 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).

 

(18) and (19) – Additional footnotes

 

Section 5.1

Heading Mechanism of Action:

end of 4th sentence, additional text:

compared to typical antipsychotics.

 

Heading Pharmacodynamic effects:

2^nd paragraph, 1^st line – change of text from the word ‘standard’ to ‘typical’

 

Section 10

Revision date of text: 27 November 2009

Section 4.1, 4.2, 4.4 and 5.1
New indication – Recurrence prevention

Section 10
New revision date of text: 21 October 2009

Section 4.5

Change of last sentence in paragraph 2 to:

'It is also not recommended to consume grapefruit juice while on quetiapine therapy.'

Section 4.8

Addition of common side effect:

'Endocrine disorders: Hyperprolactinaemia'

Addition of common side effect:

'Metabolism and nutritional disorders: Increased appetite'

Addition of rare side effect:

'Reproductive system and breast disorders: Galactorrhoea'

Addition of common side effect:

'General disorders and administration site conditions: Irritability'

Change of side effect from common to very common:

'Investigations: Weight gain'

New information added to point (9) under table:

'(9) Based on >7% increase in body weight from baseline. Occurs predominantly during the early weeks of treatment in adults.'

New points under table:

(16) Prolactin levels (patients >18 years of age): >20 μg/L (>869.56 pmol/L) males; >30 μg/L  (>1304.34 pmol/L) females at any time.
(17) May lead to falls.

Section 5.1

Deletion of paragraph under Clinical Efficacy:

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

Section 10

Change of date to:

'17th July 2009'

Section 1

Addition of strength:

150mg

 

Section 2

Addition of qualitative and quantitative composition for new strength:

Seroquel XR 150 mg contains 150 mg quetiapine (as quetiapine fumarate)

Excipient : 71 mg lactose (anhydrous)  per tablet

 

Section 3

Addition of pharmaceutical form for new strength :

Seroquel XR 150 mg tablets are white and engraved with XR 150 on one side

 

Section 4.4

Addition of paragraph:

 

Suicide/suicidal thoughts or clinical worsening:

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

 

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

 

Section 4.8

Addition of side-effects to table:

 

Blood and lymphatic system disorders

Uncommon: Thrombocytopenia

 

Psychiatric disorders

Common: Abnormal dreams and nightmares

 

Investigations

Uncommon: Platelet count decreased ¹⁴

Rare: Elevations in blood creatine phosphokinase ¹⁵

 

Addition of footnotes 14 & 15:

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.

Section 6.5

Addition of packs for new strength

 

Section 8

Addition of marketing authorisation number for new strength:

150 mg tablets:            PA 970/18/12

 

Section 9

Addition of date of authorisation for new strength:

150 mg: 30^th January 2009

 

Section 10:

 

Change of date:

11^th March 2009

 

Section 2:

 

Excipient information

 

Sections 4.1, 4.2, 4.4 & 5.1:

 

New indication: bipolar disorder

 

Section 4.4:

 

Information regarding lactose

 

Section 4.8:

 

Additional side-effects regarding bipolar disorder, and lipids and withdrawal

 

Section 10:

 

Change of date to 5th December 2008

Section 4.1

 

Seroquel XR is indicated for the treatment of moderate to severe manic episodes in the framework of bipolar disorder.

 

Paragraph 4- Addition of text:

 

Seroquel XR is not indicated for the prevention of recurrence of manic or depressive episodes.

 

Section 4.2

 

In placebo-controlled clinical trials for schizophrenia and bipolar mania, the incidence of extrapyramidal symptoms with quetiapine was no different from that of placebo across the recommended therapeutic dose range.

 

To include paragraph on Severe Neutropenia:

 

Severe neutropenia (neutrophil count <0.5 X 10⁹/L) has been uncommonly reported in quetiapine clinical trials. Most cases of severe neutropenia have occurred within a couple of months of starting therapy with quetiapine. There was no apparent dose relationship. During post-marketing experience, resolution of leucopenia and/or neutropenia has followed cessation of therapy with quetiapine. Possible risk factors for neutropenia include pre-existing low white cell count (WBC) and history of drug induced neutropenia.  Quetiapine should be discontinued in patients with a neutrophil count <1.0 X 10⁹/L. Patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 X 10⁹/L). (See section 5.1).

 

Paragraph 9 Hyperglycaemia - Deletion of text:

 

Hyperglycaemia or exacerbation of pre-existing diabetes has been reported  in very rare cases during treatment with quetiapine

 

To include paragraph on Lipids:

 

Increases in triglycerides and cholesterol have been observed in clinical trials with quetiapine (see section 4.8).  Lipid increases should be managed as clinically appropriate.

 

Paragraph 12 Withdrawal- Change of text:

 

Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and irritability have been described after abrupt cessation of quetiapine. Gradual withdrawal over a period of at least one to two weeks is advisable.

 

To include paragraph on Additional Information:

 

Quetiapine data in combination with divalproex or lithium in acute moderate to severe manic episodes is limited; however, combination therapy was well tolerated (see section 4.8 and 5.1). The data showed an additive effect at week 3. A second study did not demonstrate an additive effect at week 6

 

Section 4.8

Changes to table Adverse Events:

 

Metabolism and nutritional disorders-

Deletion of text under Very Rare: hyperglycaemia

 

Nervous system disorders-

Addition of text under Uncommon: Dysarthria

 

Addition of Eye Disorders-

Common: Vision blurred

 

Gastrointestinal disorders-

Addition of Uncommon- Dysphagia

 

General disorders and administration site conditions-

Addition of Very common: Withdrawal (discontinuation) symptoms

 

Investigations

Addition of Very common:

Elevations in serum triglyceride levels

Elevations in total cholesterol (predominantly LDL cholesterol)

 

Addition of text under Common-

blood glucose increased to hyperglycaemic levels

 

Deletion of text under Uncommon-

elevations in non-fasting serum triglyceride levels, elevations in total cholesterol (predominantly LDL cholesterol)

 

Changes to references of table

 

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 long-term studies of schizophrenia and bipolar disorder the aggregated incidence of treatment-emergent extrapyramidal symptoms was similar between quetiapine and placebo.

 

Section 5.1

 

Deletion of paragraph 3:

 

Lack of induction of EPS is considered a feature of atypical antipsychotics.

 

Addition of text after last paragraph:

 

In the treatment of moderate to severe manic episodes, Seroquel demonstrated superior efficacy to placebo in reduction of manic symptoms at 3 and 12 weeks, in two monotherapy trials. The efficacy of Seroquel XR was further demonstrated with significance versus placebo in an additional 3 week study. Seroquel XR was dosed in the range of 400 to 800 mg/day and the mean dose was approximately 600 mg/day. Seroquel 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 placebo-controlled monotherapy trials in patients with a baseline neutrophil count 1.5 X 10⁹/L, the incidence of at least one occurrence of neutrophil count <1.5 X 10⁹/L, was 1.72% in patients treated with quetiapine compared to 0.73% in placebo-treated patients. In all clinical trials (placebo-controlled, open-label, active comparator; patients with a baseline neutrophil count 1.5 X 10⁹/L), the incidence of at least one occurrence of neutrophil count <0.5 X 10⁹/L was 0.21% in patients treated with quetiapine and 0% in placebo treated patients and the incidence 0.5 - <1.0 X 10⁹/L was 0.75% in patients treated with quetiapine and 0.11% in placebo-treated patients.

 

Section 10

 

25^th November 2008