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        Common                Uncommon                Rare          Very rare       Not Known Blood and     Decreased          Leucopenia1, 28,      Neutropenia1,           Agranulocyt lymphatic     haemoglobin22      decreased             Thrombocytopeni         osis 26 system                           neutrophil count,     a, Anaemia,
disorders                        eosinophils           platelet count increased27           decreased13
Immune                                                 Hypersensitivity                      Anaphylactic system                                                 (including allergic                   reaction5 disorders                                              skin reactions) Endocrine                        Hyperprolactinaemi    Decreases in free                     Inappropriate disorders                        a15, decreases in     T3 24,                                antidiuretic total T424,           Hypothyroidism21                      hormone decreases in free                                           secretion T4 24, decreases in total T3 24,
increases in TSH 24
Metabolism    Elevations in      Increased appetite,   Hyponatraemia 19,       Metabolic and           serum              blood glucose         Diabetes                syndrome29 nutritional   triglyceride       increased to          Mellitus 1,5 disorders     levels 10,30       hyperglycaemic        Exacerbation of Elevations in      levels 6, 30          pre-existing total                                    diabetes cholesterol
(predominantly
LDL cholesterol)
11,30

Decreases in
HDL cholesterol
17,30, Weight
 gain 8,30
Psychiatric                      Abnormal dreams                               Somnambu disorders                        and nightmares,                               lism and Suicidal ideation                             related and suicidal                                  reactions behaviour20                                   such as sleep talking and sleep related eating disorder
Nervous       Dizziness 4, 16,   Dysarthria            Seizure 1,
system        somnolence 2,1                           Restless legs disorders     6, headache,                             syndrome,
Extrapyramidal                           Tardive symptoms1, 21                            dyskinesia 1, 5,
Syncope 4,16
Confusional state
Cardiac                          Tachycardia 4,        QT                                                    cardiomyop disorders                        Palpitations23        prolongation 1,12, 18                                 athy and Bradycardia32                                         myocarditis
Eye                              Vision blurred
disorders
Vascular                  Orthostatic                               Venous                         Stroke33 disorders                 hypotension 4,16                          thromboem bolism1
Respiratory               Dyspnoea 23           Rhinitis
, thoracic and mediastinal disorder
Gastrointes   Dry mouth   Constipation,         Dysphagia7          Pancreatitis tinal                     dyspepsia,                                1, Intestinal  disorders                 vomiting25                                obstruction/ Ileus
Hepato-                   Elevations in serum   Elevations in       Jaundice5 biliary                   alanine               serum aspartate     Hepatitis disorders                 aminotransferase      aminotransferase
(ALT)3,               (AST) 3
Elevations in gamma-GT levels3
Skin and                                                                            Angioedema5,   Toxic subcutaneo                                                                          Stevens-       Epidermal us tissue                                                                           Johnson        Necrolysis, Erythema disorders                                                                           syndrome5 Multiforme,
Acute
Generalize d
Exanthema to us
Pustulosis
(AGEP),
Drug Rash with
Eosinophili a and
Systemic
Symptoms
(DRESS),
Cutaneous vasculitis
Musculoske                                                                          Rhabdomyolys letal and                                                                           is connective tissue disorders
Renal and                                       Urinary retention urinary disorders
Pregnancy,                                                                                         Drug puerperium                                                                                         withdrawal and                                                                                                syndrome perinatal                                                                                          neonatal31 conditions
Reproducti                                      Sexual              Priapism, ve system                                       dysfunction         galactorrho and breast                                                                  ea, breast disorders                                                                   swelling, menstrual disorder
General        Withdrawal        Mild asthenia,                             Neuroleptic disorders      (discontinuatio   peripheral oedema,                         malignant and            n)                irritability, pyrexia                      syndrome 1 administrati   symptoms 1,9                                                 , on site                                                                     hypothermi conditions                                                                  a Investigatio                                                                Elevations ns                                                                          in blood creatine phosphokin ase14

(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 post marketing data with the immediate release formulation of quetiapine.
(6)       Fasting blood glucose ≥126mg/dL(≥7.0 mmol/L) or a non fasting blood glucose ≥200mg/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 109/L 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 109 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 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).


SOC                                    Very Common                             Common Endocrine disorders                    Elevations in prolactin   1


Metabolism and nutritional             Increased appetite disorders
Nervous system disorders            Extrapyramidal symptoms 3, 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 >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 might be associated with different clinical implications in children and adolescents as compared to adults.
(4) See section 5.1

Reporting of suspected adverse reactions
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