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 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 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 1
Endocrine disorders                Elevations in prolactin
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