When a pharmaceutical company changes an SPC or PIL, 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.
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 19th December 2011
New sub heading ‘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).
Additional text under the sub heading ‘Cardiovascular’:
A slower titration regimen could be considered in patients with underlying cardiovascular disease.
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.
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: 24th February 2011
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.
Change of text in penultimate paragraph of section.
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
Revision date of text: 24th February 2011
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.
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’
Changes to include paediatric information
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.
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……
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)
New additional text regarding Children and adolescents (10 to 17 years of age)
Includes description of shape and engraving
Includes information regarding recurrence prevention.
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.
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 8th September 2009
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).
Addition of side-effects to table:
Blood and lymphatic system disorders
Uncommon: Thrombocytopenia
Investigations
Uncommon: Platelet count decreased 14
Rare: Elevations in blood creatine phosphokinase 15
Addition of footnotes 14 & 15:
Section 10:
Change of date:
Section 2:
Exipient information
Sections 4.1, 4.2, 4.4 & 5.1:
New indication: bipolar disorder
Section 4.4:
Information regarding lactose
Section 4.4 - 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).
Hyperglycaemia
deletion of the words ¡®in very rare cases¡¯
Section 4.8 - Change to Table ¨C Investigators section
Addition of the 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 10 ¨C New revision date of text
14 February 2008
Severe NeutropeniaSevere 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).
Change of text: blood glucose increased to hyperglycaemic levels 7
Section 4.5 - Additional section text:
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)”
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).
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.
New revision date of text: 19 September 2007
Additional new text in the QT Prolongation Paragraph, sentence 3 now includes:
…when quetiapine is prescribed in patients with cardiovascular disease or family history of QT prolongation. Also caution should be exercised when quetiapine is prescribed with medicines known to increase QTc interval, and concomitant neuroleptics, especially….
Additional new last paragraph:
Caution should be exercised when quetiapine is used concomitantly with drugs known to cause electrolyte imbalance or to increase QTc interval.
Additional new paragraph after the table references:
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.
Section 4.8: change in text in table
Current text:
Very Rare: Neutropenia 3
New text:
Unknown: Neutropenia 3
Additionally in the table at the end
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 6.1 – Table of excipients - Change of text.
Lactose Monohydrate: Ferric Oxide, Red (E172) (25 mg tablets)