Section 4.8- editiorial changes to the ADR table 1.

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

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, 9 - Change to improve clarity and readability (in line with QRD template)

Section 4.4 – Addition of potential for misuse and abuse particularly by patients with a history of drug or alcohol abuse.

Section 9 – Addition of the Renewal Date

Section 10 – Date of last update

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 4.3 – 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 4.9 – editorial changes

Section 5.1 – 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 4.4 – editorial changes, addition of text for severe neutropenia and agranulocytosis, 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 6.5 – amendment of pack in table

section 10 – updated date of revision

- Section 4.9 Addition of the following words which were accidently rejected instead of accepted during the approval management of CNS 14 0003.

- 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 4.4

New sub heading ‘weight’

Weight

Weight gain has been reported in patients who have been treated with quetiapine, and should be

monitored and managed as clinically appropriate as in accordance with utilised antipsychotic guidelines (See Sections 4.8 and 5.1).

 

Section 4.4

Change of text under sub heading ‘Hyperglycaemia’

 

Section 4.4

Additional text under the sub heading ‘Cardiovascular’:

A slower titration regimen could be considered in patients with underlying cardiovascular disease.

 

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

Common:               Increased appetite

Uncommon:          Hyponatraemia²⁰

 

Under Vascular disorders

Rare:                      Venous thromboembolism 1

(this has been moved from the table under ‘Investigations’)

 

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 ²¹

 

Under table there is additional footnotes:

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

 

(21) 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 4.9

Change of text in penultimate paragraph of section.

 

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

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 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

Children and Adolescents:

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

 

 

Section 4.4

Additional new text regarding children and adolescents

Children and adolescents (10 to 17 years of age)

Seroquel 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 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 on growth and maturation have not been studied beyond 26 weeks. Long-term implications for cognitive and behavioural development are not known.

 

In placebo-controlled clinical trials with children and adolescent patients, quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia and bipolar mania (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 3

Includes description of shape and engraving

 

Section 4.1

Includes information regarding recurrence prevention.

 

Section 4.2

Change of text under the heading “For the treatment of depressive episodes in bipolar disorder”

And new text under the heading “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 therapy at the same dose. The dose may be adjusted depending on clinical response and tolerability of the individual patient, within the range of 300 to 800 mg/day administered twice daily. It is important that the lowest effective dose is used for maintenance therapy.

 

Section 5.1

New additional text:

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.

 

Section 6.1

Text of Core and Coating is now listed and table format removed.

 

Section 9

Renewal date from 8^th September 2009

 

Section 10

Revision date of text: 22nd December 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 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 10:

 

Change of date:

11^th March 2009

Section 2:

 

Exipient information

 

Sections 4.1, 4.2, 4.4 & 5.1:

 

New indication: bipolar disorder

 

Section 4.4:

 

Information regarding lactose

 

Section 10:

 

Change of date to 5th December 2008

Severe Neutropenia
Severe neutropenia (neutrophil count <0.5 X 10⁹/L) has been uncommonly reported in Seroquel clinical trials. Most cases of severe neutropenia have occurred within a couple of months of starting therapy with Seroquel.   There was no apparent dose  relationship. During post-marketing experience, resolution of leucopenia and/or neutropenia has followed cessation of therapy with Seroquel. 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).

Section 4.8 - Change to Table ¨C Investigators section

Change of text: blood glucose increased to hyperglycaemic levels ⁷

and to the References after the table ¨C reference 7

 

Section 5.1 -  additional paragraph to end of section.

In placebo-controlled monotherapy trials in patients with a baseline neutrophil count ¡Ý 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 Seroquel compared to 0.73% in placebo-treated patients.  In all clinical trials (placebo-controlled, open-label, active comparator; patients with a baseline neutrophil count ¡Ý1.5 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 Seroquel and 0% in placebo treated patients and the incidence ¡Ý0.5 - <1.0 X 10⁹/L was 0.75% in patients treated with Seroquel and 0.11% in placebo-treated patients.

Section 4.8 ¨C New revision date of text

14 February 2008

Section 4.5 - Additional section text:

Severe Neutropenia
Severe neutropenia (neutrophil count <0.5 X 10⁹/L) has been uncommonly reported in Seroquel clinical trials. Most cases of severe neutropenia have occurred within a couple of months of starting therapy with Seroquel.   There was no apparent dose  relationship. During post-marketing experience, resolution of leucopenia and/or neutropenia has followed cessation of therapy with Seroquel. 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).

Section 4.8 - Change to Table ¨C Investigators section

Change of text: blood glucose increased to hyperglycaemic levels ⁷

and to the References after the table ¨C reference 7

 

Section 5.1 -  additional paragraph to end of section.

In placebo-controlled monotherapy trials in patients with a baseline neutrophil count ¡Ý 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 Seroquel compared to 0.73% in placebo-treated patients.  In all clinical trials (placebo-controlled, open-label, active comparator; patients with a baseline neutrophil count ¡Ý1.5 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 Seroquel and 0% in placebo treated patients and the incidence ¡Ý0.5 - <1.0 X 10⁹/L was 0.75% in patients treated with Seroquel and 0.11% in placebo-treated patients.

Section 4.8 - New revision date of text

14 February 2008

Section 4.8

In the frequency of adverse events table:

Under the heading of Immune system disorders, additionally:

Very rare:    Anaphylactic reaction ⁷

 

Under the heading of Nervous system disorders, additionally text:

Uncommon:   Seizure ¹, restless leg syndrome

 

Under the heading Investigations, addition of text for Uncommon

“(predominantly LDL cholesterol)”

 

Section 4.9

First Paragraph:

Deletion of some text and new additional 2 sentences:

 

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 seroquel alone. However, survival has also been reported following acute overdoses of up to 30 grams.

 

New third paragraph:

Patients with pre-existing severe cardiovascular disease may be at increased risk of the effects of overdose. (See section 4,4 Special warnings and precautions for use: Cardiovascular).

 

Section 5.1

Additional text under the heading Mechanism of Action.

 

And new final paragraph under the heading Pharmacodynamic Effects:

The extent to which the N-desalkyl quetiapine metabolite contributes to the pharmacological activity of Seroquel in humans is not known.

 

Section 10

New revision date of text: 19 September 2007

Section 4.4  Additional new text under the sub heading “QT prolongation” after the first existing paragraph

 

Section 4.8: change in text in table

 

Current text:

Blood and lymphatic system disorders

Very Rare:  Neutropenia ³

New text:

Blood and lymphatic system disorders

Unknown:   Neutropenia ³

 

Additionally in the table at the end

 

Current text:

Investigations

Common:  Weight gain, elevations in serum transaminases (ALT, AST) ⁴,

New text:

Investigations

Common:   Weight gain, elevations in serum transaminases (ALT, AST) ⁴,  

                  decreased neutrophil count ⁸

 

 

In the references under the table.

 Reference (3) Deletion of text “or agranulocytosis”

 

Additional text - new reference -  number (8)

 

 

Section 5.1:  Change of text under section Mechanism of Action”

 

Section 5.1:  Additional new text

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.

Section 5.2:  Change of text

 

Section 6.1 – Table of excipients - Change of text.

Lactose Monohydrate:            Ferric Oxide, Red (E172) (25 mg tablets)

 

Section 10:  Change to Revision Date to 21 September 2006