Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Accord Healthcare Limited, Sage House, 319, Pinner Road, North Harrow, Middlesex, HA1 4HF, United Kingdom
Hypersensitivity to the active substance(s) or to any of the excipients listed in Section 6.1.
Concomitant administration of cytochrome P450 3A4 inhibitors, such as HIV-protease inhibitors, azole-antifungal agents, erythromycin, clarithromycin and nefazodone, is contraindicated. (see Section 4.5).
As Atrolak XL 50 mg has several indicationthe 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).
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).
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 adults 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.
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 also section 4.8).
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.
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).
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.
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.
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).
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.
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 (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 Quetiapine therapy. Such patients should have a WBC count and an absolute neutrophil count (ANC) performed promptly, especially in the absence of predisposing factors.
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.)
See also 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 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 utilized antipsychotic guidelines (see Sections 4.8 and 5.1).
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.
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.
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 have been reported in clinical trials and during the post-marketing experience, however, a causal relationship to quetiapine has not been established. Treatment with quetiapine should be reassessed in patients with suspected cardiomyopathy or myocarditis.
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) 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 as a combination of the following symptoms: extensive cutaneous rash or exfoliative dermatitis, fever, lymphadenopathy and possible eosinophilia. If signs and symptoms suggestive of these severe skin reactions appear, quetiapine should be withdrawn immediately and alternative treatment should be considered.
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).
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.
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 (see Section 4.8) has been reported with quetiapine. Quetiapine should be used with caution in patients at risk for aspiration pneumonia.
Constipation represents a risk factor for intestinal obstruction. Constipation and intestinal obstruction have been reported with quetiapine (see section 4.8 Undesirable effects). 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.
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 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.
Quetiapine data in combination with divalproex or lithium in acute moderate to severe manic episodes is limited; however, combination therapy was well tolerated (see Sections 4.8 and 5.1). The data showed an additive effect at week 3.
Atrolak XL 50 mg contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Atrolak XL contain less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
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.
Given the primary central nervous system effects of quetiapine, quetiapine should be used with caution in combination with other centrally acting medicinal products and alcohol.
Caution should be exercised treating patients receiving other medications having anti-cholinergic (muscarinic) effects (see Section 4.4).
Cytochrome P450 (CYP) 3A4 is the enzyme that is primarily responsible for the cytochrome P450 mediated metabolism of quetiapine. In an interaction study in healthy volunteers, concomitant administration of quetiapine (dosage of 25 mg) with ketoconazole, a CYP3A4 inhibitor, caused a 5- to 8-fold increase in the AUC of quetiapine. On the basis of this, concomitant use of quetiapine with CYP3A4 inhibitors is contraindicated. It is also not recommended to consume grapefruit juice while on quetiapine therapy.
In a multiple dose trial in patients to assess the pharmacokinetics of quetiapine given before and during treatment with carbamazepine (a known hepatic enzyme inducer), co-administration of carbamazepine significantly increased the clearance of quetiapine. This increase in clearance reduced systemic quetiapine exposure (as measured by AUC) to an average of 13% of the exposure during administration of quetiapine alone; although a greater effect was seen in some patients. As a consequence of this interaction, lower plasma concentrations can occur, which could affect the efficacy of quetiapine therapy. Co-administration of quetiapine and phenytoin (another microsomal enzyme inducer) caused a greatly increased clearance of quetiapine by approx. 450%. 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) (see Section 4.4).
The pharmacokinetics of quetiapine were not significantly altered by co-administration of the antidepressants imipramine (a known CYP 2D6 inhibitor) or fluoxetine (a known CYP 3A4 and CYP 2D6 inhibitor).
The pharmacokinetics of quetiapine were not significantly altered by co-administration of the antipsychotics risperidone or haloperidol. Concomitant use of quetiapine and thioridazine caused an increased clearance of quetiapine with approx. 70%.
The pharmacokinetics of quetiapine were not altered following co-administration with cimetidine.
The pharmacokinetics of lithium were not altered when co-administered with quetiapine.
In a 6-week, randomised, study of lithium and quetiapine prolonged-release tablets versus placebo and quetiapine prolonged-release tablets in adult patients with acute mania, a higher incidence of extrapyramidal related events (in particular tremor), somnolence, and weight gain were observed in the lithium add-on group compared to the placebo add-on group (see Section 5.1).
The pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically relevant extent when co-administered. A retrospective study of children and adolescents who received valproate, quetiapine, or both, found a higher incidence of leucopenia and neutropenia in the combination group versus the monotherapy groups.
Formal interaction studies with commonly used cardiovascular medicinal products have not been performed.
Caution should be exercised when quetiapine is used concomitantly with medicinal products known to cause electrolyte imbalance or to increase QT interval.
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.
The moderate amount of published data from exposed pregnancies (i.e. between 300-1000 pregnancy outcomes), including individual reports and some observational studies do not suggest an increased risk of malformations due to treatment. However, based on all available data, a definite conclusion cannot be drawn. Animal studies have shown reproductive toxicity (see section 5.3). Therefore, quetiapine should only be used during pregnancy if the benefits justify the potential risks.
Neonates exposed to antipsychotics (including quetiapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
Based on very limited data from published reports on quetiapine excretion into human breast milk, excretion of quetiapine at therapeutic doses appears to be inconsistent. Due to lack robust data, a decision must be made whether to discontinue breast-feeding or to discontinue Quetiapine prolonged release tablet therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
The effects of quetiapine on human fertility have not been assessed. Effects related to elevated prolactin levels were seen in rats, although these are not directly relevant to humans (see section 5.3 preclinical data).
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.
The most commonly reported Adverse Drug Reactions (ADRs) with quetiapine (≥10%) are somnolence, dizziness, headache, dry mouth, withdrawal (discontinuation) symptoms, elevations in serum triglyceride levels, elevations in total cholesterol (predominantly LDL cholesterol), decreases in HDL cholesterol, weight gain, decreased haemoglobin and extrapyramidal symptoms.
The incidences of ADRs associated with quetiapine therapy, are tabulated below (Table 1) according to the format recommended by the Council for International Organizations of Medical Sciences (CIOMS III Working Group 1995).
Table 1. ADRs associated with quetiapine therapy:
The frequencies of adverse events are ranked according to the following: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100, rare (≥1/10,000, <1/1000), very rare (<1/10,000), and not known (cannot be estimated from the available data).
Very Common: Decreased haemoglobin22
Common: Leucopenia1,28, decreased neutrophil count, eosinophils increased27
Uncommon: Neutropenia1, Thrombo-cytopenia, Anaemia, platelet count decreased13
Rare: Agranulo-cytosis26
Uncommon: Hypersensitivity (including allergic skin reactions)
Very Rare: Anaphylactic reaction5
Common: Hyper-prolactinaemia15, decreases in total T424, decreases in free T424, decreases in total T324, increases in TSH24
Uncommon: Decreases in free T324, Hypo-thyroidism21
Very Rare: Inappropriate antidiuretic hormone secretion
Very Common: Elevations in serum triglyceride levels10,30, Elevations in total cholesterol (predominantly LDL cholesterol)11,30, Decreases in HDL cholesterol17,30, Weight gain8,30
Common: Increased appetite, blood glucose increased to hyperglycaemic levels6,30
Uncommon: Hyponatraemia19, Diabetes Mellitus1,5, Exacerbation of pre-existing diabetes
Rare: Metabolic syndrome29
Common: Abnormal dreams and nightmares, Suicidal ideation and suicidal behaviour20
Rare: Somnambulism and related reactions such as sleep talking and sleep related eating disorder
Very Common: Dizziness4,16, Somnolence2,16, Headache, Extrapyramidal symptoms1,21
Common: Dysarthria
Uncommon: Seizure1, Restless legs syndrome, Tardive dyskinesia1,5, Syncope4,16
Common: Tachycardia4, Palpitations23
Uncommon: QT prolongation1,12,18, Bradycardia32
Not known: Cardiomyopathy, Myocarditis
Common: Vision blurred
Common: Orthostatic hypotension4,16
Rare: Venous thrombo-embolism1
Not known: Stroke34
Common: Dyspnoea23
Uncommon: Rhinitis
Very Common: Dry mouth
Common: Constipation, dyspepsia, vomiting25
Uncommon: Dysphagia7
Rare: Pancreatitis1, Intestinal obstruction/Ileus
Common: Elevations in serum alanine amino-transferase (ALT)3, Elevations in gamma-GT levels3
Uncommon: Elevations in serum aspartate amino-transferase (AST)3
Rare: Jaundice5, Hepatitis
Very Rare: Angioedema5, Stevens-Johnson syndrome5
Not known: Toxic Epidermal Necrolysis, Erythema Multiforme, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)33, Cutaneous vasculitis
Very Rare: Rhabdomyolysis
Uncommon: Urinary retention
Not known: Drug withdrawal syndrome neonatal31
Uncommon: Sexual dysfunction
Rare: Priapism, galactorrhoea, breast swelling, menstrual disorder
Very Common: Withdrawal (discontinuation) symptoms1,9
Common: Mild asthenia, peripheral oedema, irritability, pyrexia
Rare: Neuroleptic malignant syndrome1, hypothermia
Rare: Elevations in blood creatine phosphokinase14
1 See Section 4.4.
2 Somnolence may occur, usually during the first two weeks of treatment and generally resolves with the continued administration of quetiapine.
3 Asymptomatic elevations (shift from normal to >3 X ULN at any time) in serum transaminase (ALT, AST) or gamma-GT-levels have been observed in some patients administered quetiapine. These elevations were usually reversible on continued quetiapine treatment.
4 As with other antipsychotics with alpha1 adrenergic blocking activity, quetiapine may commonly induce orthostatic hypotension, associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period. (See Section 4.4).
5 Calculation of Frequency for these ADR’s have only been taken from postmarketing data with the immediate-release formulation of quetiapine.
6 Fasting blood glucose ≥7.0 mmol/L (≥126 mg/dL) or a non fasting blood glucose ≥11.1 mmol/L (≥200 mg/dL) on at least one occasion.
7 An increase in the rate of dysphagia with quetiapine vs. placebo was only observed in the clinical trials in bipolar depression.
8 Based on >7% increase in body weight from baseline. Occurs predominantly during the early weeks of treatment in adults.
9 The following withdrawal symptoms have been observed most frequently in acute placebo-controlled, monotherapy clinical trials, which evaluated discontinuation symptoms: insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and irritability. The incidence of these reactions had decreased significantly after 1 week post-discontinuation.
10 Triglycerides ≥2.258 mmol/L (≥200 mg/dL) (patients ≥18 years of age) or ≥1.694 mmol/L (≥150 mg/dL) (patients <18 years of age) on at least one occasion.
11 Cholesterol ≥6.2064 mmol/L (≥240 mg/dL) (patients ≥18 years of age) or ≥5.172 mmol/L (≥200 mg/dL) (patients <18 years of age) on at least one occasion. An increase in LDL cholesterol of ≥0.769 mmol/L (≥30 mg/dL) has been very commonly observed. Mean change among patients who had this increase was ≥1.07 mmol/L (41.7 mg/dL).
12 See text below.
13 Platelets ≤100 × 109/L on at least one occasion.
14 Based on clinical trial adverse event reports of blood creatine phosphokinase increase not associated with neuroleptic malignant syndrome.
15 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.
16 May lead to falls.
17 HDL cholesterol: ≤1.025 mmol/L (<40 mg/dL) males; ≤1.282 mmol/L (<50 mg/dL) females at any time.
18 Incidence of patient who have a QTc shift from <450 msec to ≥450 msec with a ≥30 msec increase. In placebo-controlled trials with quetiapine, the mean change and the incidence of patient who have a shift to a clinically significant level is similar between quetiapine and placebo
19 Shift from >132 mmol/L to ≤132 mmol/L on at least one occasion.
20 Cases of suicidal ideation and suicidal behaviours have been reported during quetiapine therapy or early after treatment discontinuation (see Sections 4.4 and 5.1).
21 See Section 5.1.
22 Decreased haemoglobin to 8.07 mmol/L (≤13 g/l) males, 7.45 mmol/L (≤12 g/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 hemoglobin at any time was 1.50 g/l.
23 These reports often occurred in the setting of tachycardia, dizziness, orthostatic hypotension and/or underlying cardiac/respiratory disease.
24 Based on shifts from normal baseline to potentially clinically important value at any time post-baseline in all trials. Shifts in total T4, free T4, total T3 and free T3 are defined as <0.8 x LLN (pmol/L) and shift in TSH is >5 mIU/L at any time.
25 Based upon the increased rate of vomiting in elderly patients (≥65 years of age).
26 Based on shift in neutrophils from ≥=1.5 × 109/L at baseline to <0.5 × 109/L at any time during treatment and based on patients with severe neutropenia (<0.5 × 109/L) and infection during all quetiapine clinical trials (see Section 4.4).
27 Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline in all trials. Shifts in eosinophils are defined as > 1 × 109 cells/L at any time.
28 Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline in all trials. Shifts in WBCs are defined as ≤3 × 109 cells/L at any time.
29 Based on adverse event reports of metabolic syndrome from all clinical trials with quetiapine.
30 In some patients, a worsening of more than one of the metabolic factors of weight, blood glucose and lipids was observed in clinical studies (See Section 4.4).
31 See Section 4.6.
32 May occur at or near initiation of treatment and be associated with hypotension and/or syncope. Frequency based on adverse event reports of bradycardia and related events in all clinical trials with quetiapine.
33 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
34 Based on one retrospective non-randomised epidemiological study.
Cases of QT prolongation, ventricular arrhythmia, sudden unexplained death, cardiac arrest and torsades de pointes have been reported with the use of neuroleptics and are considered class effects.
The same ADRs described above for adults should be considered for children and adolescents. The following table summarises ADRs that occur in a higher frequency category in children and adolescents patients (10-17 years of age) than in the adult population or ADRs that have not been identified in the adult population.
Table 2. ADRs in children and adolescents associated with quetiapine therapy that occur in a higher frequency than adults, or not identified in the adult population:
The frequencies of adverse events are ranked according to the following: Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000) and very rare (<1/10,000).
Very Common: Elevations in prolactin1
Very Common: Increased appetite
Very Common: Extrapyramidal symptoms3,4
Common: Syncope
Very Common: Increases in blood pressure2
Common: Rhinitis
Very Common: Vomiting
Common: Irritability3
1 Prolactin levels (patients <18 years of age): >20 ug/L (>869.56 pmol/L) males; >26 ug/L (>1130.428 pmol/L) females at any time. Less than 1% of patients had an increase to a prolactin level >100 ug/L.
2 Based on shifts above clinically significant thresholds (adapted from the National Institutes of Health criteria) or increases >20mmHg for systolic or >10 mmHg for diastolic blood pressure at any time in two acute (3-6 weeks) placebo-controlled trials in children and adolescents.
3 Note: The frequency is consistent to that observed in adults, but irritability might be associated with different clinical implications in children and adolescents as compared to adults.
4 See Section 5.1.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Not applicable.
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