Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Pediatric population:
Summary of the safety profile
In pediatric 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 pediatric 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 Organ     Very common           Common              Uncommon                   Rare Class           ≥1/10           ≥1/100 to <1/10     ≥1/1,000 to <1/100         ≥1/10,000 to <1/1,000
Metabolism      Appetite            Anorexia (loss of and nutrition   decreased.          appetite).
disorders
Psychiatric                         Irritability, mood   Suicide-related disorders                           swings,              events, aggression, insomnia3,           hostility,
agitation *,         emotional lability*,
anxiety,             Psychosis depression and       (including depressed mood       hallucinations)*.
*, tics *.
Nervous         Headache,           Dizziness.           Syncope, tremor, system          somnolence2.                             migraine,
disorders                                                paraesthesia*, hypoaesthesia*,
Seizure**.

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

Hepatobiliary                                            Blood bilirubin        Abnormal/increased disorders                                                increased*.            liver function tests, jaundice, hepatitis,
liver injury, acute hepatic failure*.
Skin and                            Dermatitis,          Hyperhidrosis, subcutaneous                        pruritus, rash.      allergic reactions.
tissue disorders
Renal and                                                                       Urinary hesitation, urinary                                                                         urinary retention.
disorders
Reproductive                                                                    Priapism, male system and                                                                      genital pain.
breast disorders



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

Investigations    Blood pressure     Weight increased4,        decreased.
heart rate increased4.
1
Also 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 1.1 kg 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      Common               Uncommon                  Rare Class             ≥1/10      ≥1/100 to <1/10         ≥1/1,000 to            ≥1/10,000 to <1/100                <1/1,000
Metabolism and     Appetite nutrition          decreased.
disorders
Psychiatric        Insomnia2.     Agitation*, libido   Suicide-related        Psychosis disorders                         decreased, sleep     events*,               (including disorder,            aggression,            hallucinations) *.
depression and       hostility and depressed            emotional mood*, anxiety,      lability*,
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 mouth,     Abdominal pain1,
disorders          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 spasms.
and connective tissue disorders
Renal and                         Dysuria,             Micturation urinary                           pollakuria,          urgency.
disorders                         urinary hesitation,
urinary retention.



    Reproductive                           Dysmenorrhoea,          Ejaculation         Priapism.
system and                             ejaculation             failure, breast disorders                       disorder, erectile      menstruation dysfunction,            irregular, orgasm prostatitis, male       abnormal.
genital pain.
General                                Asthenia, fatigue,      Feeling cold.
disorders and                          lethargy, chills        Chest pain (see administration                         feeling jittery,        section 4.4) site conditions                        irritability, thirst.
Investigations     Blood pressure      Weight increased3,         decreased.
Heart rate increased3.
1
Also 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 authorization 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