Adverse reactions : תופעות לוואי

4.8   Undesirable effects
Paediatric population:
Summary of the safety profile
In paediatric placebo-controlled trials, headache, abdominal pain1 and decreased appetite are the adverse events most commonly associated with atomoxetine, and are reported by about 19%, 18% and 16% of patients respectively, but seldom lead to drug discontinuation (discontinuation rates are 0.1% for headache, 0.2% for abdominal pain and 0.0% for decreased appetite). Abdominal pain and decreased appetite are usually transient.

Associated with decreased appetite, some patients experienced growth retardation early in therapy in terms of both weight and height gain. On average, after an initial decrease in weight and height gain, patients treated with atomoxetine recovered to mean weight and height as predicted by group baseline data over the long-term treatment.

Nausea, vomiting and somnolence2 can occur in about 10% to 11% of patients particularly during the first month of therapy. However, these episodes were usually mild to moderate in severity and transient, and did not result in a significant number of discontinuation from therapy (discontinuation rates ≤ 0.5%).

In both paediatric and adult placebo-controlled trials, patients taking atomoxetine experienced increases in heart rate, systolic and diastolic blood pressure (see section 4.4).

Because of its effect on noradrenergic tone, orthostatic hypotension (0.2%) and syncope (0.8%) have been reported in patients taking atomoxetine.
Atomoxetine should be used with caution in any condition that may predispose patients to hypotension.

The following table of undesirable effects is based on adverse event reporting and laboratory investigations from clinical trials and post marketing spontaneous reports in children and adolescents:

Tabulated list of adverse reactions
Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).
System            Very common           Common            Uncommon             Rare Organ Class                 ≥1/10           ≥1/100 to         ≥1/1,000 to     ≥1/10,000 to <1/10              <1/100         <1/1,000

Metabolism          Appetite            Anorexia (loss and                 decreased.          of appetite).
nutrition disorders
Psychiatric                             Irritability,     Suicide-related disorders                               mood swings,      events,
insomnia3,        aggression,
agitation *,      hostility,
anxiety,          emotional depression and    lability*,
depressed         Psychosis mood *, tics *.   (including hallucinations)*
.
Nervous             Headache,           Dizziness.        Syncope,
system              somnolence2.                          tremor,
disorders                                                 migraine,
paraesthesia*,
hypoaesthesia*,
Seizure**.

Eye                                     Mydriasis.        Vision blurred.
disorders
Cardiac                                                   Palpitations, disorders                                                 sinus tachycardia.
QT interval prolongation **.
Vascular                                                                     Raynaud’s disorders                                                                    phenomenon.
Respiratory,                                              Dyspnoea (See thoracic and                                              section 4.4) mediastinal disorders
Gastro intestinal   Abdominal pain1,    Constipation,
disorders           vomiting, nausea.   dyspepsia.


Hepatobiliary                                             Blood bilirubin    Abnormal/incre disorders                                                 increased*.        ased liver function tests,
jaundice,
hepatitis, liver injury, acute hepatic failure*.
Skin and                                      Dermatitis,        Hyperhidrosis, subcutaneous tissue                           pruritus, rash.    allergic disorders                                                        reactions.

Renal and urinary                                                                    Urinary hesitation, disorders                                                                            urinary retention.


Reproductive system                                                                  Priapism, male genital pain.
and breast disorders


General disorders and                         Fatigue,           Asthenia.
administration site                           lethargy.
conditions                                    Chest pain
(see section
4.4).



Investigations           Blood pressure       Weight increased4, heart    decreased.
rate increased4.

1Also includes abdominal pain upper, stomach discomfort, abdominal discomfort and epigastric discomfort.
2 Also includes sedation
3 Includes initial, middle and terminal (early morning wakening) insomnia 4 Heart rate and blood pressure findings are based on measured vital signs
*       See section 4.4
**      See section 4.4 and section 4.5

CYP2D6 poor metabolisers (PM)
The following adverse events occurred in at least 2% of CYP2D6 poor metaboliser (PM) patients and were statistically significantly more frequent in PM patients compared with CYP2D6 extensive metaboliser (EM) patients: appetite decreased (24.1% of PMs, 17.0% of EMs); insomnia combined (including insomnia, middle insomnia and initial insomnia, 14.9% of PMs, 9.7% of EMs); depression combined (including depression, major depression, depressive symptom, depressed mood and dysphoria, 6.5% of PMs and 4.1% of EMs), weight decreased (7.3% of PMs, 4.4% of EMs), constipation 6.8% of PMs, 4.3% of EMs); tremor (4.5% of PMs, 0.9% of EMs); sedation (3.9% of PMs, 2.1% of EMs); excoriation (3.9% of PMs, 1.7% of EMs); enuresis (3.0% of PMs, 1.2% of EMs); conjunctivitis (2.5% of PMs, 1.2% of EMs); syncope (2.5% of PMs, 0.7% of EMs); early morning awakening (2.3% of PMs, 0.8% of EMs); mydriasis (2.0% of PMs, 0.6% of EMs). The following event did not meet the above criteria but is noteworthy: generalised anxiety disorder (0.8% of PMs and 0.1% of EMs). In addition, in trials lasting up to 10 weeks, weight loss was more pronounced in PM patients (mean of 0.6 kg in EM and 1.1kg in PM).
Adults:
Summary of the safety profile
In adult ADHD clinical trials, the following system organ classes had the highest frequency of adverse events during treatment with atomoxetine: gastrointestinal, nervous system and psychiatric disorders. The most common adverse events (≥5%) reported were appetite decreased (14.9%), insomnia (11.3%) headache (16.3%), dry mouth (18.4%) and nausea (26.7%). The majority of these events were mild or moderate in severity and the events most frequently reported as severe were nausea, insomnia, fatigue and headache. A complaint of urinary retention or urinary hesitancy in adults should be considered potentially related to atomoxetine.

The following table of undesirable effects is based on adverse event reporting and laboratory investigations from clinical trials and post marketing spontaneous reports in adults.

Tabulated list of adverse reactions
Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).
System Organ        Very          Common           Uncommon                Rare Class         common      ≥1/100 to <1/10      ≥1/1,000 to         ≥1/10,000 to ≥1/10                             <1/100             <1/1,000

Metabolism         Appetite and nutrition      decreased.
disorders
Psychiatric        Insomnia2.   Agitation*,        Suicide-related   Psychosis disorders                       libido             events*,          (including decreased, sleep   aggression,       hallucinations) *.
disorder,          hostility and depression and     emotional depressed          lability*,
mood*, anxiety,    restlessness,
tics*.
Nervous system     Headache.    Dizziness,         Syncope,          Seizure**.
disorders                       dysgeusia,         migraine.
paraesthesia,      hypoaesthesia* somnolence
(including sedation),
tremor.
Eye Disorders                                      Vision blurred.
Cardiac                         Palpitations,      QT interval disorders                       tachycardia.       prolongation**
Vascular                        Flushing, hot      Peripheral        Raynaud’s disorders                       flush.             coldness.         phenomenon.
Respiratory,                                       Dyspnoea (see thoracic and                                       section 4.4).
mediastinal disorders
Gastrointestinal   Dry          Abdominal disorders          mouth,       pain1,
nausea.      constipation,
dyspepsia,
flatulence,
vomiting.
Hepatobiliary                                                        Abnormal/increased disorders                                                            liver function tests, jaundice, hepatitis,
liver injury, acute hepatic failure, blood bilirubin increased*.
Skin and                        Dermatitis,        Allergic subcutaneous                    hyperhydrosis,     reactions4,
tissue disorders                rash.              pruritis,
urticaria.
Musculoskeletal                                    Muscle and connective                                     spasms.
tissue disorders
Renal and                        Dysuria,             Micturation urinary                          pollakuria,          urgency.
disorders                        urinary hesitation,
urinary retention.
Reproductive                     Dysmenorrhoea,       Ejaculation       Priapism.
system and                       ejaculation          failure,
breast                           disorder,            menstruation disorders                        erectile             irregular,
dysfunction,         orgasm prostatitis, male    abnormal.
genital pain.
General                          Asthenia,            Feeling cold.
disorders and                    fatigue,             Chest pain (see administration                   lethargy, chills     section 4.4) site conditions                  feeling jittery,
irritability,
thirst.
Investigations     Blood         Weight pressure      decreased.
increased3,
heart rate increased3.

1Also includes abdominal pain upper, stomach discomfort, abdominal discomfort and epigastric discomfort.
2
Also includes initial insomnia, middle insomnia and terminal (early morning wakening) insomnia.
3
Heart rate and blood pressure findings are based on measured vital signs.
4 Includes anaphylactic reactions and angioneurotic oedema.
*       See section 4.4
**      See section 4.4 and section 4.5

CYP2D6 poor metabolisers (PM)
The following adverse events occurred in at least 2% of CYP2D6 poor metaboliser (PM) patients and were statistically significantly more frequent in PM patients compared with CYP2D6 extensive metaboliser (EM) patients: vision blurred (3.9% of PMs, 1.3% of EMs), dry mouth (34.5% of PMs, 17.4% of EMs), constipation (11.3% of PMs, 6.7% of EMs), feeling jittery (4.9% of PMs, 1.9% of EMs), decreased appetite (23.2% of PMs, 14.7% of EMs), tremor (5.4% of PMs, 1.2% of EMs), insomnia (19.2% of PMs, 11.3% of EMs), sleep disorder (6.9% of PMs, 3.4% of EMs), middle insomnia (5.4% of PMs, 2.7% of EMs), terminal insomnia (3% of PMs, 0.9% of EMs), urinary retention (5.9% of PMs, 1.2% of EMs), erectile dysfunction (20.9% of PMs, 8.9% of EMs), ejaculation disorder (6.1% of PMs, 2.2% of EMs), hyperhidrosis (14.8% of PMs, 6.8% of EMs), peripheral coldness (3% of PMs, 0.5% of EMs).
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.
http://forms.gov.il/globaldata/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il