Quero XR Range 50/150/200/300/400mg FC tablets

QUERO XR is indicated for the treatment of:

• Schizophrenia
• prevention of relapse in stable schizophrenic patients who have been maintained on QUERO XR
• bipolar disorder including:
• treatment of manic episodes associated with bipolar disorder
• treatment of depressive episodes associated with bipolar disorder
• prevention of recurrence in the maintenance treatment of bipolar disorder (manic, mixed or depressive episodes), as monotherapy or in combination with mood stabilisers
• major depressive disorder
• preventing relapse in stable major depressive disorder patients who have been maintained on QUERO XR.

Posology

Quero XR should be administered once daily, with or without food. The tablets should be swallowed whole and not split, chewed or crushed.

Adults:

Treatment of schizophrenia: The daily dose at the start of therapy is 300 mg on Day 1, 600 mg on Day 2 and up to 800 mg after Day 2. The dose should be adjusted within the effective dose range of 400 - 800 mg per day, depending on the clinical response and tolerability of the patient. For maintenance therapy in schizophrenia, no dosage adjustment is necessary.

Treatment of manic episodes associated with bipolar disorder: The daily dose at the start of therapy is 300 mg on Day 1, 600 mg on Day 2 and up to 800 mg after Day 2. The dose should be adjusted within the effective dose range of 400 - 800 mg per day, depending on the clinical response and tolerability of the patient.

Treatment of depressive episodes associated with bipolar disorder: QUERO XR should be administered once daily in the evening. QUERO XR should be titrated as follows: 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). QUERO XR can be titrated to 400 mg on Day 5, and up to 600 mg by Day 8. Antidepressant efficacy was demonstrated with quetiapine at 300 mg and 600 mg, however no additional benefit was seen in the 600 mg group during short-term treatment.

Preventing recurrence in maintenance treatment of bipolar disorder: Patients who have responded to QUERO XR, in combination therapy to a mood stabiliser (lithium or valproate) for acute treatment of bipolar disorder, should continue on QUERO XR therapy at the same dose. The QUERO XR dose can be re-adjusted depending on clinical response and tolerability of the individual patient within the dose range of 400 - 800 mg/day.

Patients who have responded to QUERO XR for acute treatment of bipolar disorder should continue on QUERO XR therapy at the same dosing regimen. QUERO XR dose can be re-adjusted depending on clinical response and tolerability of the individual patient within the dose range of 300 - 800 mg/day.

For the treatment of major depressive disorder: QUERO XR should be administered once daily in the evening. Initial dosing should begin at 50 mg on Day 1 and 2, increased to 150 mg on Day 3 and 4. Further adjustments can be made upwards or downwards within the recommended dose range of 50 - 300 mg depending upon the clinical response and tolerability of the patient. For maintenance therapy in major depressive disorder the effective dose during initial treatment should be continued. The dose can be adjusted within the recommended dose range depending upon the clinical response and tolerability of the patient.

Switching from quetiapine immediate-release tablets: For more convenient dosing, patients who are currently being treated with divided doses of quetiapine immediate release dosage form may be switched to QUERO XR at the equivalent total daily dose taken once daily. Individual dosage adjustments may be necessary.

Special populations

Elderly: QUERO XR should be used with caution in the elderly, especially during the initial dosing period. The rate of dose titration of QUERO XR may need to be slower, and the daily therapeutic dose lower, than that used in younger patients. The mean plasma clearance of quetiapine was reduced by 30 - 50 % in elderly patients when compared to younger patients. Elderly patients should be started on 50 mg/day. The dose can be increased in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerance of the individual patient. In elderly patients with major depressive disorder, initial dosing should begin at 50 mg on Days 1 - 3, the dose can be increased to 100 mg on Day 4, 150 mg on Day 8 and then up to 300 mg depending on clinical response and tolerability.

Renal impairment: Dosage adjustment is not necessary in patients with renal impairment.

Hepatic impairment: Quetiapine is extensively metabolised by the liver, therefore, QUERO XR should be used with caution in patients with known hepatic impairment, especially during the initial dosing period. Patients with hepatic impairment should be started on 50 mg/day. The dose can be increased in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the individual patient.

Paediatric population: The safety and efficacy of QUERO XR have not been evaluated in children and adolescents.

Method of administration

QUERO XR is for oral use and should be administered once daily with or without food. The tablets should be swallowed whole and not split, chewed or crushed.

Missed dose

Doctors should advise patients who forget to take QUERO XR, to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to compensate for the missed dose.

Contraindications to be presented in bullet format where relevant

• Hypersensitivity to quetiapine or to any of the ingredients of QUERO XR (see 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)
• pregnancy and lactation (see section 4.6)
• safety and efficacy in children and adolescents have not been demonstrated
• advanced liver and renal dysfunction, as safety has not been demonstrated.

As QUERO 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 major depressive disorder (MDD) has not been evaluated as add-on therapy, however long-term efficacy and safety has been evaluated in adult patients as monotherapy.

Hyperglycaemia and diabetes mellitus: Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including quetiapine (as in QUERO XR). In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Weight should be monitored regularly. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia was resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect medicine.

Suicide/suicidal thoughts or clinical worsening: An increased risk of suicidal thoughts, self-harm and suicide (suicide-related events) are all associated with depression. Until significant remission occurs, this risk with continue. Patients should be closely monitored until an improvement occurs, since such an improvement may not happen during the first few weeks or more of therapy. The risk of suicide may increase in the early stages of treatment. In addition, medical practitioners should consider the potential risk of suicide-related events after abrupt cessation of QUERO XR treatment, due to the known risk factors for the disease being treated. An increased risk of suicide-related events can also be associated with other psychiatric disorders for which QUERO XR is prescribed, which may be co-morbid with major depressive disorder. When treating patients with other psychiatric disorders the same precautions should be observed. Patients who exhibit a significant degree of suicidal ideation before starting treatment with QUERO XR, and those with a history of suicide-related events, are at increased risk of suicidal thoughts or suicide attempts. These patients should be monitored closely during therapy. Close supervision of patients and in particular those at high risk, especially in early treatment and following dose changes, should be undertaken. 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 - 64 years without a history of self-harm during use of quetiapine with other antidepressants.

Severe neutropenia and agranulocytosis: Severe neutropenia (neutrophil count <0,5 x 10 9 /litre) without infection has been uncommonly reported in quetiapine clinical trials. There have been reports of agranulocytosis (severe neutropenia with infection) among patients treated with quetiapine, as contained in QUERO XR, during clinical trials, as well as post-marketing reports. Most cases of severe neutropenia have occurred within the first two 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. Neutropenia should be considered in patients presenting with infection, particularly in the absence of obvious predisposing factor(s), or in patients with unexplained fever, and should be managed as clinically appropriate. Quetiapine should be discontinued in patients with a neutrophil count <1,0 x 10 9 /litre. Patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1,5 x 10 9 /litre) (see section 5.1). 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 QUERO XR therapy. Such patients should have a WBC count and an absolute neutrophil count (ANC) performed promptly, especially in the absence of predisposing factors.

Lipids: Increases in triglycerides, LDL and total cholesterol, and decreases in HDL have been observed in clinical trials with quetiapine (see section 4.8). Lipid changes should be managed as clinically appropriate.

Metabolic risk: Given the observed risk for worsening of their metabolic profile, including changes in weight, blood glucose (see hyperglycaemia) and lipids, patientsu2019 metabolic parameters should be assessed at the time of treatment initiation and changes in these parameters should be regularly controlled during the course of treatment. Worsening in these parameters should be managed as clinically appropriate (see section 4.8).

Orthostatic hypotension: Quetiapine, as contained in QUERO XR, 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 medicine.

QUERO XR should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension. QUERO XR may induce orthostatic hypotension especially during the initial dose-titration period. Dose reduction or more gradual titration should be considered if orthostatic hypotension occurs, especially in patients with underlying cardiovascular disease.

Seizures: No data is available about the incidence of seizures in patients with a history of seizure disorder. Caution is recommended when treating patients with a history of seizures.

Tardive dyskinesia and extrapyramidal symptoms: Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic medicines, including quetiapine. There is a potential for QUERO XR to cause tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of QUERO XR should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment (see section 4.8). In placebo-controlled clinical trials for schizophrenia and bipolar mania, the incidence of extrapyramidal symptoms was no different from that of placebo across the recommended therapeutic dose range. This predicts that quetiapine has less potential than typical antipsychotic medicines to induce tardive dyskinesia in schizophrenia and bipolar mania patients. An increased incidence of extrapyramidal symptoms (EPS) are associated with quetiapine, as contained in QUERO XR, treatment in patients treated for major depressive episodes in bipolar disorder and major depressive disorder. The development of akathisia, characterised by distressing restlessness and the need to move often accompanied by the inability to sit down or standstill, has been associated with the use of quetiapine, as contained in QUERO XR. These symptoms usually occur during the first few weeks of therapy. It is not advised to increase the dose of QUERO XR in patients who experience these side-effects.

Neuroleptic malignant syndrome: Neuroleptic malignant syndrome has been associated with QUERO XR treatment. Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event, QUERO XR should be discontinued and appropriate medical treatment given.

Serotonin syndrome: Concomitant administration of QUERO XR and other serotonergic medicines, such as MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re- uptake inhibitors (SNRIs) or tricyclic antidepressants may result in serotonin syndrome, a potentially life-threatening condition (see section 4.5). If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms. If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

QT prolongation: Studies indicate quetiapine, as contained in QUERO XR, was not associated with a persistent increase in absolute QT intervals. However, QT prolongation has been 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 QUERO XR is prescribed in patients with cardiovascular disease or family history of QT prolongation. Also, caution should be exercised when QUERO XR 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).

Withdrawal: Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and irritability have been described after abrupt cessation of QUERO XR. Gradual withdrawal, over a period of at least one to two weeks, is advisable.

Somnolence and dizziness: QUERO XR treatment has been associated with somnolence and related symptoms, such as sedation (see section 4.8). Onset is usually within the first 3 days of treatment and predominantly of mild to moderate intensity. If patients with bipolar depression or MDD patients with major depressive episodes experience somnolence of severe intensity, they 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.

Sleep apnoea syndrome: Sleep apnoea syndrome has been reported in patients using QUERO XR. 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, QUERO XR should be used with caution.

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 QUERO XR is used at recommended doses, when used concomitantly with other medicines having anti-cholinergic effects, and in the setting of overdose. QUERO XR should be used with caution in patients receiving medicines having anti-cholinergic (muscarinic) effects. QUERO XR 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 and 4.9).

Dysphagia: Dysphagia and aspiration have been reported with QUERO XR. Although a causal relationship with aspiration pneumonia has not been established, QUERO XR should be used with caution in patients at risk for aspiration pneumonia.

Cardiomyopathy and myocarditis: Cardiomyopathy and myocarditis have been reported in clinical trials and during the post-marketing experience. Treatment with QUERO XR should be reassessed in patients with suspected cardiomyopathy or myocarditis.

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, QUERO XR should be withdrawn immediately and alternative treatment should be considered.

Constipation and intestinal obstruction: Constipation represents a risk factor for intestinal obstruction. Constipation and intestinal obstruction have been reported with QUERO XR. This includes fatal reports in patients who are at higher risk of intestinal obstruction, including those that are receiving multiple concomitant medicines 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 medicines. 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 QUERO XR and preventive measures undertaken.

Pancreatitis: Pancreatitis has been reported, 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, gallstones and alcohol consumption.

Misuse and abuse: Cases of misuse and abuse have been reported. Caution may be needed when prescribing QUERO XR to patients with a history of alcohol or drug abuse.

Hepatic effects: Concomitant use of QUERO XR with a strong hepatic enzyme inducer, such as carbamazepine or phenytoin, substantially decreases quetiapine plasma concentrations, which could affect the efficacy of QUERO XR therapy. In patients receiving a hepatic enzyme inducer, initiation of QUERO XR treatment should only occur if the doctor 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 QUERO XR, and should be monitored and managed as clinically appropriate.

Lactose anhydrous: QUERO XR 50, 150, 200, 300 and 400 mg contains 14,21 mg, 42,63 mg, 56,84 mg, 85,26 mg and 113,68 mg lactose anhydrous per tablet, respectively. Patients with the rare hereditary conditions of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take QUERO XR.

Additional information on special populations

Elderly patients with dementia-related psychosis: QUERO XR 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 antipsychotic medicines, 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. These data do not establish a causal relationship between quetiapine treatment and death in elderly patients with dementia.

Elderly patients with Parkinson's Disease (PD)/parkinsonism: A population-based retrospective study of quetiapine, (as contained in QUERO XR), 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 QUERO XR is prescribed to elderly patients with PD.

Paediatric population: QUERO 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 (see section 4.3). Studies have shown that in addition to the known safety profile identified in adults treated with quetiapine (see section 4.8), certain adverse events either:

• increased in frequency in children and adolescents when compared to adults (increased appetite, elevations in serum prolactin, vomiting, rhinitis and syncope)
• may have different implications for children and adolescents (extrapyramidal symptoms and irritability)
• have been reported in children and adolescents, but not identified in adults, such as increases in blood pressure and changes in thyroid function tests.

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).

Cytochrome P450 (CYP) 3A4 is the enzyme that is primarily responsible for the cytochrome P450 mediated metabolism of quetiapine, as contained in QUERO XR. 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 QUERO XR with CYP3A4 inhibitors is contraindicated (see section 4.3). QUERO XR should also be used with caution in combination with serotonergic medicines such as MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re- uptake inhibitors (SNRIs) or tricyclic antidepressants as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4). Concomitant use of QUERO XR with hepatic enzyme inducers such as carbamazepine may substantially decrease systemic exposure to quetiapine. Depending on clinical response, higher doses of QUERO XR may need to be considered if used concomitantly with a hepatic enzyme inducer. In patients receiving a hepatic enzyme inducer, initiation of QUERO XR therapy should only occur after careful consideration of 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).

Pregnancy

QUERO XR is contraindicated during pregnancy as safety has not been demonstrated (see section 4.3). Animal studies have shown reproductive toxicity (see section 5.3).

Breastfeeding

The degree to which quetiapine is excreted into human milk is unknown. Women who are breastfeeding should therefore be advised to avoid breastfeeding while taking QUERO XR (see section 4.3).

Fertility

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).

QUERO XR may cause somnolence, which may affect a patientu2019s judgement, their ability to think and their motor skills. Patients should therefore be cautioned about their ability to operate machinery and drive whilst taking QUERO XR.

Summary of the safety profile

The most commonly reported adverse reactions (ADRs) with QUERO XR are somnolence, dizziness, headache, dry mouth, withdrawal symptoms, asthenia, constipation, tachycardia, orthostatic hypotension and dyspepsia, elevations in serum triglyceride levels, elevations in total cholesterol (predominantly LDL cholesterol), decreases in HDL cholesterol, weight gain, decreased haemoglobin and extrapyramidal symptoms. Weight gain, syncope, neuroleptic malignant syndrome, leucopenia, neutropenia and peripheral oedema, have been associated with QUERO XR.

Tabulated list of adverse effects

System Organ Class

Frequency

Side effects

Blood and lymphatic system disorders

Frequent

Less frequent

Decreased haemoglobin, leucopenia, decreased neutrophil count, eosinophils increased

Agranulocytosis, anaemia, eosinophilia, thrombocytopenia, platelet count decreased, neutropenia, pancytopenia

Immune system disorders

Frequent

Frequency unknown

Hypersensitivity

Anaphylactic reaction*

Endocrine disorders

Frequent

Less frequent

Hyperprolactinaemia, decreases in total T 4 , decreases in free T 4 , decreases in total T 3 , increases in TSH

Decreases in free T 3 , hypothyroidism, inappropriate antidiuretic hormone secretion

Metabolism and nutrition disorders

Frequent

Less frequent

Increased appetite, blood glucose increased to hyperglycaemic levels, elevations in serum triglyceride levels and total cholesterol (predominantly LDL), decreases in HDL cholesterol

Hyponatraemia, hyperglycaemia, diabetes, exacerbation of pre-existing diabetes, metabolic syndrome

Psychiatric disorders

Frequent

Less frequent

Abnormal dreams and nightmares, mania, suicidal ideation and suicidal behaviour

Somnambulism and related reactions such as sleep related eating disorder and sleep talking

Nervous system disorders

Frequent

Less frequent

Dizziness, dysarthria, somnolence, syncope, extrapyramidal symptoms,

Restless leg syndrome, seizure, tardive dyskinesia, confusional state

Eye disorders

Frequent

Blurred vision

Cardiac disorders

Frequent

Less frequent

Frequency unknown

Palpitations, tachycardia

Bradycardia, QT prolongation

Cardiomyopathy, myocarditis

Vascular disorders

Frequent

Less frequent

Frequency unknown

Orthostatic hypotension

Venous thromboembolism

Stroke, hypertension

Respiratory, thoracic and mediastinal disorders

Frequent

Frequency unknown

Dyspnoea, rhinitis

Hyperventilation, respiratory alkalosis, acute respiratory failure

Gastrointestinal disorders

Frequent

Less frequent

Frequency unknown

Dry mouth, constipation, dyspepsia, vomiting

Dysphagia, pancreatitis, intestinal obstruction/Ileus

Abdominal pain

Hepatobiliary disorders

Frequent

Less frequent

Frequency unknown

Elevations in serum alanine aminotransferase (ALT), elevations in gamma-GT levels

Elevations in serum aspartate aminotransferase (AST)

Jaundice, hepatitis

Skin and subcutaneous tissue disorders

Less frequent

Frequency unknown

Angioedema, Stevens-Johnson syndrome

Toxic Epidermal Necrolysis, erythema multiforme, drug-rash with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), cutaneous vasculitis

Musculoskeletal, connective tissue and bone disorders

Less frequent

Rhabdomyolysis

Renal and urinary disorders

Frequent

Less frequent

Urinary tract infection

Urinary retention

Pregnancy, puerperium and perinatal conditions

Frequency unknown

Drug withdrawal syndrome neonatal

Reproductive system and breast disorders

Less frequent

Sexual dysfunction, priapism, galactorrhoea, breast swelling, menstrual disorder

General disorders and administrative site conditions

Frequent

Less frequent

Asthenia, peripheral oedema, withdrawal symptoms, headache, irritability, pyrexia

Neuroleptic malignant syndrome, hypothermia

Investigations

Frequent

Less frequent

Weight gain

Elevations in blood creatine phosphokinase, elevations in gamma-GT levels, elevations in non-fasting serum triglyceride levels, elevations in total cholesterol

*Post-marketing

a. Description of selected adverse reactions

Somnolence may occur upon initiation of treatment and resolve with continuous administration of therapy. The following side effects may occur in the early weeks of treatment: orthostatic hypotension associated with dizziness, tachycardia, syncope, increase in body weight from baseline, bradycardia associated with hypotension and/or syncope. The incidence of discontinuation symptoms include insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and irritability decreased significantly after 1-week post-discontinuation. An increase in LDL cholesterol of u226530 mg/dL (u22650,769 mmol/L) has been very commonly observed. Mean change among patients who had this increase was 41,7 mg/dL (u22651,07 mmol/L).

Asymptomatic elevations (shift from normal to u22653 x ULN at any time) in serum transaminase (ALT, AST) or gamma-GT levels have been observed in some patients administered quetiapine. These elevations are usually reversible on continued quetiapine treatment. An increase in the rate of dysphagia with quetiapine vs. placebo was only observed in the clinical trials in bipolar depression. 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. 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.

Signs and symptoms: Side-effects generally reported as a result of overdose with quetiapine, as contained in QUERO XR, include drowsiness, sedation, tachycardia, anti-cholinergic effects and hypotension. There have been very rare reports of quetiapine alone resulting in death or coma. Overdose could lead to QT-prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium and/or agitation, coma and death. Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose. (see section 4.4, Orthostatic hypotension).

Management of overdose: There is no specific antidote to quetiapine, as contained in QUERO XR. In cases of severe signs, the possibility of multiple medicine involvement should be considered, and intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system. Based on public literature, patients with delirium and agitation and a clear anti-cholinergic syndrome may be treated with physostigmine, 1 - 2 mg (under continuous ECG monitoring). This is not recommended as standard treatment, because of potential negative effect of physostigmine on cardiac conductance. Physostigmine may be used if there are no ECG aberrations. Do not use physostigmine in case of dysrhythmias, any degree of heart block or QRS-widening. Whilst the prevention of absorption in overdose has not been investigated, the administration of activated charcoal should be considered. In cases of quetiapine overdose refractory hypotension should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. Epinephrine and dopamine should be avoided, since beta stimulation may worsen hypotension in the setting of quetiapine-induced alpha blockade. Close medical supervision and monitoring should be continued until the patient recovers. In case of overdose with QUERO XR there is a delayed peak sedation and peak pulse and prolonged recovery. In case of a QUERO XR overdose gastric bezoar formation has been reported and appropriate diagnostic imaging is recommended to further guide patient management. Endoscopic pharmacobezoar removal has been performed successfully in some cases.