Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

As Seroquel XR has several indications the safety profile should be considered with respect to the individual patient's diagnosis and the dose being administered.
Long-term efficacy and safety in patients with MDD has not been evaluated as add-on therapy, however long-term efficacy and safety has been evaluated in adult patients as monotherapy (see section 5.1).

Paediatric population:
Quetiapine 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 quetiapine 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 vomiting, rhinitis and syncope) or may have different implications for children and adolescents (extrapyramidal symptoms and irritability) 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 quetiapine 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, bipolar mania and bipolar depression (see section 4.8).

Suicide/suicidal thoughts or clinical worsening
Depression 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 addition, physicians should consider the potential risk of suicide-related events after abrupt cessation of quetiapine treatment, due to the known risk factors for the disease being treated.
Other psychiatric conditions for which quetiapine is prescribed can also be associated with an increased risk of suicide related events. In addition, these conditions may be co-morbid with major depressive episodes. The same precautions observed when treating patients with major depressive episodes should therefore be observed when treating patients with other psychiatric disorders.
Patients with a history of suicide related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts and should receive careful monitoring during treatment. A meta-analysis of placebo controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.
Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

In shorter-term placebo controlled clinical studies of patients with major depressive episodes in bipolar disorder an increased risk of suicide-related events was observed in young adult patients younger than 25 years of age who were treated with quetiapine as compared to those treated with placebo (3.0% vs. 0%, respectively). In clinical studies of patients with MDD the incidence of suicide-related events observed in young adult patients (younger than 25 years of age) was 2.1% (3/144) for quetiapine and 1.3% (1/75) for placebo. A population-based retrospective study of quetiapine for the treatment of patients with major depressive disorder showed an increased risk of self-harm and suicide in patients aged 25 to 64 years without a history of self-harm during use of quetiapine with other antidepressants.

Metabolic risk
Given the observed risk for worsening of their metabolic profile, including changes in weight, blood glucose (see hyperglycaemia) and lipids, which was seen in clinical studies, patient's metabolic parameters should be assessed at the time of treatment initiation and changes in these parameters should be regularly controlled for during the course of treatment. Worsening in these parameters should be managed as clinically appropriate (see Section 4.8).

Extrapyramidal symptoms
In placebo controlled clinical trials of adult patients quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major depressive episodes in bipolar disorder and major depressive disorder. (see sections 4.8 and 5.1).
The use of quetiapine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Tardive Dyskinesia:
If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of quetiapine should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment (see Section 4.8)

Somnolence and dizziness:
Quetiapine treatment has been associated with somnolence and related symptoms, such as sedation (see Section 4.8). In clinical trials for treatment of patients with bipolar depression and major depressive disorder, onset was usually within the first 3 days of treatment and was predominantly of mild to moderate intensity. Patients experiencing somnolence of severe intensity may require more frequent contact for a minimum of 2 weeks from onset of somnolence, or until symptoms improve and treatment discontinuation may need to be considered.

Orthostatic Hypotension:
Quetiapine treatment has been associated with orthostatic hypotension and related dizziness (see section 4.8) which, like somnolence has onset usually during the initial dose-titration period. This could increase the occurrence of accidental injury (fall), especially in the elderly population.
Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication.
Quetiapine should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension. Dose reduction or more gradual titration should be considered if orthostatic hypotension occurs, especially in patients with underlying cardiovascular disease.

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 for sleep apnoea, such as those who are overweight/obese or are male, quetiapine should be used with caution.

Seizures
In controlled clinical trials there was no difference in the incidence of seizures in patients treated with quetiapine or placebo. No data is available about the incidence of seizures in patients with a history of seizure disorder. As with other antipsychotics, caution is recommended when treating patients with a history of seizures (see Section 4.8).

Neuroleptic Malignant Syndrome:
Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including quetiapine (see section 4.8). Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event, quetiapine should be discontinued and appropriate medical treatment given.

Severe Neutropenia and agranulocytosis:
Severe neutropenia (neutrophil count <0.5 X 109/L) has been 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, some cases were fatal. Possible risk factors for neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced neutropenia. However, some cases occurred in patients without pre-existing risk factors. 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).
Neutropenia should be considered in patients presenting with infection or fever, particularly in the absence of obvious predisposing factor(s) and should be managed as clinically appropriate.
Patients should be advised to immediately report the appearance of signs/symptoms consistent with agranulocytosis or infection (e.g., fever, weakness, lethargy, or sore throat) at any time during Seroquel therapy. Such patients should have a WBC count and an absolute neutrophil count (ANC) performed promptly, especially in the absence of predisposing factors.

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 anti-cholinergic (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.) 
Interactions:
See section 4.5.
Concomitant use of quetiapine with a strong hepatic enzyme inducer such as carbamazepine or phenytoin substantially decreases quetiapine plasma concentrations, which could affect the efficacy of quetiapine therapy. In patients receiving a hepatic enzyme inducer, initiation of quetiapine treatment should only occur if the physician considers that the benefits of quetiapine outweigh the risks of removing the hepatic enzyme inducer. It is important that any change in the inducer is gradual, and if required, replaced with a non-inducer (e.g. sodium valproate).

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).

Hyperglycaemia:
Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been reported rarely, including some fatal cases (see section 4.8). In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with any antipsychotic agent including quetiapine, should be observed for signs and symptoms of hyperglycaemia, (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control. Weight should be monitored regularly.

Lipids:
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.

QT Prolongation:
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 patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia (see section 4.5).

Cardiomyopathy and Myocarditis:
Cardiomyopathy and myocarditis have been reported in clinical trials and during the post-marketing experience, (see section 4.8). In patients with suspected cardiomyopathy or myocarditis discontinuation of quetiapine should be considered.

Severe Cutaneous Adverse Reactions
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Acute Generalized Exanthematous Pustulosis (AGEP), Erythema Multiforme (EM) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) which can be life threatening or fatal have been reported very rarely with quetiapine treatment.
SCARs commonly present with one or more of the following symptoms: extensive cutaneous rash which may be pruritic or associated with pustules exfoliative dermatitis, fever, lymphadenopathy and possible eosinophilia or neutrophilia. Most of these reactions occurred within 4 weeks after initiation of quetiapine therapy, some DRESS reactions occurred within 6 weeks after initiation of quetiapine therapy. If signs and symptoms suggestive of these severe skin reactions appear, quetiapine should be withdrawn immediately and alternative treatment should be considered.

Withdrawal
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. (see section 4.8)

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. 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.

Elderly patients with Parkinson's disease (PD)/parkinsonism
A population-based retrospective study of quetiapine for the treatment of patients with MDD, showed an increased risk of death during use of quetiapine in patients aged >65 years. This association was not present when patients with PD were removed from the analysis. Caution should be exercised if quetiapine is prescribed to elderly patients with PD.

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

Constipation and intestinal obstruction
Constipation represents a risk factor for intestinal obstruction. Constipation and intestinal obstruction have been reported with quetiapine (see section 4.8). This includes fatal reports in patients who are at higher risk of intestinal obstruction, including those that are receiving multiple concomitant medications that decrease intestinal motility and/or may not report symptoms of constipation. Patients with intestinal obstruction/ileus should be managed with close monitoring and urgent care.

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 quetiapine and preventive measures undertaken.

Pancreatitis
Pancreatitis has been reported in clinical trials and during post marketing experience.
Among post marketing reports, while not all cases were confounded by risk factors, many patients had factors which are known to be associated with pancreatitis such as increased triglycerides (see Section 4.4), gallstones, and alcohol consumption.

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.

Lactose
Seroquel XR tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Sodium
Seroquel XL 50 mg, 150 mg and 200 mg prolonged-release tablets contain less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
Seroquel XL 300 mg prolonged-release tablets and Seroquel XL 400 mg prolonged-release tablets contain 27 mg sodium per tablet, equivalent to 1.35% of the WHO recommended daily intake of 2 g sodium for an adult.


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.


Effects on Driving

4.7     Effects on ability to drive and use machines
Given its primary central nervous system effects, quetiapine may interfere with activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery, until individual susceptibility to this is known.