Adverse reactions : תופעות לוואי

4.8   Undesirable effects
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).

SOC                  Very              Common              Uncommon           Rare             Very Rare Not known Common
Blood and            Decreased         Leucopenia 1, 28,   Neutropenia1,      Agranulocytosi lymphatic            haemoglobin22     decreased                              s26 Thrombocytope system                                 neutrophil          nia, Anaemia, disorders                              count,              platelet count eosinophils         decreased13 increased27

Immune system                                              Hypersensitivity                    Anaphylactic disorders                                                 (including                            reaction5 allergic skin reactions)

Endocrine                             Hyperprolactina     Decreases in                          Inappropriat disorders                             emia15,             free T3 24,                           e decreases in        Hypothyroidism                        antidiuretic 21 total T4 24,                                              hormone decreases in                                              secretion free T4 24,
decreases in total T3 24,
increases in
TSH 24

Metabolism and   Elevations in        Increased           Hyponatraemia19, Metabolic nutritional      serum                appetite, blood     Diabetes         syndrome29 1,5 disorders        triglyceride         glucose             Mellitus levels 10,30         increased to        Exacerbation of
Elevations in        hyperglycaemic      pre-existing total cholesterol    levels 6, 30        diabetes
(predominantly
LDL cholesterol) 11,30
Decreases in
HDL cholesterol 17,30,
Weight gain 8,30
Psychiatric                           Abnormal                                Somnambulis disorders                             dreams and                              m and related  nightmares,                             reactions such as
Suicidal ideation                       sleep talking and                                     and sleep related
Suicidal                                eating disorder behaviour20
Nervous system   Dizziness 4, 16,     Dysarthria          Seizure 1,
disorders        somnolence 2,16,                         Restless legs headache,                                syndrome,
Extrapyramidal                           Tardive symptoms1, 21                            dyskinesia 1, 5,
Syncope 4,16
Confusional state
4                                                         cardiomyopathy Cardiac                               Tachycardia ,       QT and myocarditis disorders                             Palpitations23      prolongation 1,12, 18

Bradycardia32

Eye disorders                         Vision blurred
Vascular                          Orthostatic                             Venous                             Stroke33 disorders                         hypotension 4,16                        thromboembolis m
1
23
Respiratory,                      Dyspnoea              Rhinitis thoracic     and mediastinal disorder

Gastrointestinal     Dry mouth    Constipation,         Dysphagia7        Pancreatitis1, disorders                         dyspepsia,                              Intestinal vomiting25                              obstruction/Ileus

Hepato-biliary                    Elevations in         Elevations in     Jaundice5, disorders                         serum alanine         serum aspartate   Hepatitis aminotransferas       aminotransferas e (ALT)3,             e (AST) 3
Elevations in gamma-GT levels3

Skin and                                                                                      Angioedema5,   Toxic subcutaneous                                                                                  Stevens-       Epidermal tissue disorders                                                                              Johnson        Necrolysis syndrome5      Erythema
Multiforme,
Acute
Generalized
Exanthematous
Pustulosis
(AGEP),
Drug Rash with
Eosinophilia and Systemic
Symptoms


SOC                Very        Common              Uncommon         Rare                    Very Rare          Not Common                                                                                     known (DRESS)
Cutaneous vasculitis
Musculoskeletal                                                                             Rhabdomyoly and connective                                                                              sis tissue disorders
Renal and                                          Urinary urinary                                            retention disorders
Pregnancy,                                                                                                  Drug puerperium and                                                                                              withdrawal perinatal                                                                                                   syndrome conditions                                                                                                  neonatal31 Reproductive                                             Sexual              Priapism, system and                                               dysfunction         galactorrhoea, breast disorders                                                             breast swelling, menstrual disorder
General            Withdrawal (dis   Mild asthenia,                          Neuroleptic disorders and      continuation)     peripheral                              malignant administration     symptoms 1,9      oedema,                                 syndrome 1, site conditions                      irritability,                           hypothermia pyrexia
Investigations                                                               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 been taken from post-marketing data only.
6.   Fasting blood glucose ≥126 mg/dL (≥7.0 mmol/L) or a non-fasting blood glucose ≥200 mg/dL (≥11.1 mmol/L) 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 ≥200 mg/dL (≥2.258 mmol/L) (patients ≥18 years of age) or ≥150 mg/dL         (≥1.694 mmol/L) (patients <18 years of age) on at least one occasion.
11. Cholesterol ≥240 mg/dL (≥6.2064 mmol/L) (patients ≥18 years of age) or ≥200 mg/dL (≥5.172 mmol/L) (patients <18 years of age) 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).
12. See text below.
13. Platelets ≤100 x 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: 40 mg/dL (1.025 mmol/L) males; 50 mg/dL (1.282 mmol/L) females at any time.
18. Incidence of patients 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 patients 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 ≤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.
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 x 10 9L at baseline to <0.5 x 109/L at any time during treatment and based on patients with severe neutropenia (<0.5 x 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 any time post-baseline in all trials. Shifts in eosinophils are defined as >1 x 10 9 cells/L at any time.
28. Based on shifts from normal baseline to potentially clinically important value at any time post-baseline in all trials. Shifts in WBCs are defined as ≤3 x 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. 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. 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.

Paediatric population
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 adolescent 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).

SOC                                    Very Common                               Common Endocrine disorders                    Elevations in prolactin1
Metabolism and nutritional             Increased appetite disorders

Nervous system disorders               Extrapyramidal symptoms3, 4             Syncope 
Vascular disorders                     Increases in blood pressure2

Respiratory, thoracic and                                                      Rhinitis mediastinal disorders

Gastrointestinal disorders             Vomiting

General disorders and                                                          Irritability3 administration site conditions
1. Prolactin levels (patients < 18 years of age): >20 μg/L (>869.56 pmol/L) males; >26 μg/L (>1130.428 pmol/L) females at any time. Less than 1% of patients had an increase to a prolactin level >100 μg/L.
2. Based on shifts above clinically significant thresholds (adapted from the National
Institutes of Health criteria) or increases >20 mmHg 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 might be associated with different clinical implications in children and adolescents as compared to adults.
4. See section 5.1.


Reporting of suspected adverse events
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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il