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
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
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: 24th February 2011
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.
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
Addition of 150mg strength
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: 21st October 2010
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.
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’
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.
New additional text regarding MDD
Section 6.5 and Section 8
Includes 150mg strength
Date of revision of text: 21st October 2010
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.
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
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……
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)
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.
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
Heading Mechanism of Action:
end of 4th sentence, additional text:
compared to typical antipsychotics.
Heading Pharmacodynamic effects:
2nd paragraph, 1st line – change of text from the word ‘standard’ to ‘typical’
Addition of strength:
150mg
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
Addition of pharmaceutical form for new strength :
Seroquel XR 150 mg tablets are white and engraved with XR 150 on one side
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:
Addition of packs for new strength
Addition of marketing authorisation number for new strength:
150 mg tablets: PA 970/18/12
Addition of date of authorisation for new strength:
150 mg: 30th January 2009
Section 10:
Change of date:
11th 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
Change of date to 5th December 2008
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.
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
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
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.
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.
25th November 2008