4.1. Therapeutic indications

Atomoxetine is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children aged 6 years and older, in adolescents and in adults as part of a comprehensive treatment programme. Treatment must be initiated by a specialist in the treatment of ADHD, such as a paediatrician, child/adolescent psychiatrist, or psychiatrist. Diagnosis should be made according to current DSM criteria or the guidelines in ICD.

In adults, the presence of symptoms of ADHD that were pre-existing in childhood should be confirmed. Third-party corroboration is desirable and atomoxetine should not be initiated when the verification of childhood ADHD symptoms is uncertain. Diagnosis cannot be made solely on the presence of one or more symptoms of ADHD. Based on clinical judgment, patients should have ADHD of at least moderate severity as indicated by at least moderate functional impairment in 2 or more settings (for example, social, academic, and/or occupational functioning), affecting several aspects of an individual's life.

Additional information for the safe use of this product: A comprehensive treatment programme typically includes psychological, educational and social measures and is aimed at stabilising patients with a behavioural syndrome characterised by symptoms which may include chronic history of short attention span, distractibility, emotional lability, impulsivity, moderate to severe hyperactivity, minor neurological signs and abnormal EEG. Learning may or may not be impaired.

Pharmacological treatment is not indicated in all patients with this syndrome and the decision to use atomoxetine must be based on a very thorough assessment of the severity of the patient's symptoms and impairment in relation to the patient's age and the persistence of symptoms.

4.2. Posology and method of administration

Posology

Atomoxetine can be administered as a single daily dose in the morning. Patients who do not achieve a satisfactory clinical response (tolerability [e.g., nausea or somnolence] or efficacy) when taking atomoxetine as a single daily dose might benefit from taking it as twice daily evenly divided doses in the morning and late afternoon or early evening.

Paediatric population

Dosing of paediatric population up to 70 kg body weight

Atomoxetine should be initiated at a total daily dose of approximately 0.5 mg/kg. The initial dose should be maintained for a minimum of 7 days prior to upward dose titration according to clinical response and tolerability. The recommended maintenance dose is approximately 1.2 mg/kg/day (depending on the patient's weight and available dosage strengths of atomoxetine). No additional benefit has been demonstrated for doses higher than 1.2 mg/kg/day. The safety of single doses over 1.8 mg/kg/day and total daily doses above 1.8 mg/kg have not been systematically evaluated. In some cases it might be appropriate to continue treatment into adulthood.

Dosing of paediatric population over 70 kg body weight

Atomoxetine should be initiated at a total daily dose of 40 mg. The initial dose should be maintained for a minimum of 7 days prior to upward dose titration according to clinical response and tolerability. The recommended maintenance dose is 80 mg. No additional benefit has been demonstrated for doses higher than 80 mg. The maximum recommended total daily dose is 100 mg. The safety of single doses over 120 mg and total daily doses above 150 mg have not been systematically evaluated.

Adults

Atomoxetine should be initiated at a total daily dose of 40 mg. The initial dose should be maintained for a minimum of 7 days prior to upward dose titration according to clinical response and tolerability. The recommended maintenance daily dose is 80 mg to 100 mg. The maximum recommended total daily dose is 100 mg. The safety of single doses over 120 mg and total daily doses above 150 mg have not been systematically evaluated.

Additional information for the safe used of this product

Pre-treatment screening

Prior to prescribing it is necessary to take an appropriate medical history and conduct a baseline evaluation of a patient's cardiovascular status, including blood pressure and heart rate (see sections 4.3 and 4.4).

Ongoing monitoring

Cardiovascular status should be regularly monitored with blood pressure and pulse recorded after each adjustment of dose and then at least every 6 months. For paediatric patients the use of a centile chart is recommended. For adults, current reference guidelines for hypertension should be followed (see section 4.4).

Withdrawal of Treatment

In the study programme no distinct withdrawal symptoms have been described. In cases of significant adverse effects, atomoxetine may be stopped abruptly; otherwise the dose may be tapered off over a suitable time period.

Treatment with atomoxetine need not be indefinite. Re-evaluation of the need for continued therapy beyond 1 year should be performed, particularly when the patient has reached a stable and satisfactory response.

Special Populations

Hepatic insufficiency

For patients with moderate hepatic insufficiency (Child-Pugh Class B), initial and target doses should be reduced to 50% of the usual dose. For patients with severe hepatic insufficiency (Child-Pugh Class C), initial dose and target doses should be reduced to 25% of usual dose (see section 5.2).

Renal insufficiency

Subjects with end-stage renal disease had higher systemic exposure to atomoxetine than healthy subjects (about a 65% increase), but there was no difference when exposure was corrected for mg/kg dose. Atomoxetine can therefore be administered to ADHD patients with end-stage renal disease or lesser degrees of renal insufficiency using the usual dosing regimen. Atomoxetine may exacerbate hypertension in patients with end-stage renal disease (see section 5.2).

Approximately 7% of Caucasians have a genotype corresponding to a non-functional CYP2D6 enzyme (called CYP2D6 poor metabolisers). Patients with this genotype have a several-fold higher exposure to atomoxetine when compared to patients with a functional enzyme. Poor metabolisers are therefore at higher risk of adverse events (see sections 4.8 and 5.2). For patients with a known poor metaboliser genotype, a lower starting dose and slower up titration of the dose may be considered.

Elderly population

The use of atomoxetine in patients over 65 years of age has not been systematically evaluated.

Paediatric population under six years of age

The safety and efficacy of atomoxetine in children under 6 years of age have not been established. Therefore, atomoxetine should not be used in children under 6 years of age (see section 4.4).

Method of administration

For oral use. Atomoxetine can be administered with or without food. For patients unable to swallow hard capsules, oral liquid formulations containing atomoxetine should be checked for availability.

The capsules should not be opened and the contents should not be removed and taken in any other way.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Atomoxetine should not be used in combination with monoamine oxidase inhibitors (MAOI). Atomoxetine should not be used within a minimum of 2 weeks after discontinuing therapy with MAOI. Treatment with MAOI should not be initiated within 2 weeks after discontinuing atomoxetine.

Atomoxetine should not be used in patients with narrow-angle glaucoma, as in clinical trials the use of atomoxetine was associated with an increased incidence of mydriasis.

Atomoxetine should not be used in patients with severe cardiovascular or cerebrovascular disorders (see section 4.4 - Cardiovascular effects). Severe cardiovascular disorders may include severe hypertension, heart failure, arterial occlusive disease, angina, haemodynamically significant congenital heart disease, cardiomyopathies, myocardial infarction, potentially life-threatening arrhythmias and channelopathies (disorders caused by the dysfunction of ion channels). Severe cerebrovascular disorders may include cerebral aneurysm or stroke.

Atomoxetine should not be used in patients with phaeochromocytoma or a history of phaeochromocytoma (see section 4.4 - Cardiovascular effects).

4.4. Special warnings and precautions for use

Suicide-related behaviour

Suicide-related behaviour (suicide attempts and suicidal ideation) has been reported in patients treated with atomoxetine. In double-blind clinical trials, suicide-related behaviours were uncommon, but more frequently observed among children and adolescents treated with atomoxetine compared to those treated with placebo, where there were no events. In adult double-blind clinical trials there was no difference in the frequency of suicide-related behaviour between atomoxetine and placebo. Patients who are being treated for ADHD should be carefully monitored for the appearance or worsening of suicide-related behaviour.

Sudden death and pre-existing cardiac abnormalities

Sudden death has been reported in patients with structural cardiac abnormalities who were taking atomoxetine at usual doses. Although some serious structural cardiac abnormalities alone carry an increased risk of sudden death, atomoxetine should only be used with caution in patients with known serious structural cardiac abnormalities and in consultation with a cardiac specialist.

Serotonin syndrome

Serotonin syndrome has been reported following concomitant use of atomoxetine with other serotonergic medicinal products (e.g. serotonin-norepinephrine reuptake inhibitors [SNRIs], selective serotonin reuptake inhibitors [SSRIs], other SNRIs, triptans, opioids, and tricyclic and tetracyclic antidepressants). If concomitant use of atomoxetine with a serotonergic medicinal product is warranted, prompt recognition of the symptoms of serotonin syndrome is important. These symptoms may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms. If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

Cardiovascular effects

Atomoxetine can affect heart rate and blood pressure. Most patients taking atomoxetine experience a modest increase in heart rate (mean <10 bpm) and/or increase in blood pressure (mean <5 mmHg) (see section 4.8).

However, combined data from controlled and uncontrolled ADHD clinical trials show that approximately 8-12% of children and adolescents, and 6-10% of adults experience more pronounced changes in heart rate (20 beats per minute or greater) and blood pressure (15-20 mmHg or greater). Analysis of these clinical trial data showed that approximately 15-26% of children and adolescents, and 27-32% of adults experiencing such changes in blood pressure and heart rate during atomoxetine treatment had sustained or progressive increases. Long-term sustained changes in blood pressure may potentially contribute to clinical consequences such as myocardial hypertrophy.

As a result of these findings, patients who are being considered for treatment with atomoxetine should have a careful history and physical exam to assess for the presence of cardiac disease, and should receive further specialist cardiac evaluation if initial findings suggest such history or disease.

It is recommended that heart rate and blood pressure be measured and recorded before treatment is started and, during treatment, after each adjustment of dose and then at least every 6 months to detect possible clinically important increases. For paediatric patients the use of a centile chart is recommended. For adults, current reference guidelines for hypertension should be followed.

Atomoxetine should not be used in patients with severe cardiovascular or cerebrovascular disorders (see section 4.3). Atomoxetine should be used with caution in patients whose underlying medical conditions could be worsened by increases in blood pressure and heart rate, such as patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease.

Patients who develop symptoms such as palpitations, exertional chest pain, unexplained syncope, dyspnoea or other symptoms suggestive of cardiac disease during atomoxetine treatment should undergo a prompt specialist cardiac evaluation.

In addition, atomoxetine should be used with caution in patients with congenital or acquired long QT or a family history of QT prolongation (see sections 4.5 and 4.8).

As orthostatic hypotension has also been reported, atomoxetine should be used with caution in any condition that may predispose patients to hypotension or conditions associated with abrupt heart rate or blood pressure changes.

Cerebrovascular effects

Patients with additional risk factors for cerebrovascular conditions (such as a history of cardiovascular disease, concomitant medications that elevate blood pressure) should be assessed at every visit for neurological signs and symptoms after initiating treatment with atomoxetine.

Hepatic effects

Very rarely, spontaneous reports of liver injury, manifested by elevated hepatic enzymes and bilirubin with jaundice, have been reported. Also very rarely, severe liver injury, including acute liver failure, have been reported. Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted.

Psychotic or manic symptoms

Treatment-emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, mania or agitation in patients without a prior history of psychotic illness or mania can be caused by atomoxetine at usual doses. If such symptoms occur, consideration should be given to a possible causal role of atomoxetine, and discontinuation of treatment should be considered. The possibility that atomoxetine will cause the exacerbation of pre-existing psychotic or manic symptoms cannot be excluded.

Aggressive behaviour, hostility or emotional lability

Hostility (predominantly aggression, oppositional behaviour and anger) was more frequently observed in clinical trials among children, adolescents and adults treated with atomoxetine compared to those treated with placebo. Emotional lability was more frequently observed in clinical trials among children treated with atomoxetine compared to those treated with placebo. Patients should be closely monitored for the appearance or worsening of aggressive behaviour, hostility or emotional lability.

Severe cases have been reported concerning paediatric patients, including reports of physical assault, or threatening behaviour and thoughts of harming others. Families and caregivers of paediatric patients treated with atomoxetine should be counselled to alert a healthcare professional immediately if significant changes in mood or patterns of behaviour are noted, particularly after starting treatment or changing the dose. Physicians should evaluate the need for dose adjustment or treatment discontinuation in patients experiencing behavioural changes.

Possible allergic events

Although uncommon, allergic reactions, including anaphylactic reactions, rash, angioedema, and urticaria, have been reported in patients taking atomoxetine.

Seizures

Seizures are a potential risk with atomoxetine. Atomoxetine should be introduced with caution in patients with a history of seizure. Discontinuation of atomoxetine should be considered in any patient developing a seizure or if there is an increase in seizure frequency where no other cause is identified.

Growth and development

Growth and development should be monitored in children and adolescents during treatment with atomoxetine. Patients requiring long-term therapy should be monitored and consideration should be given to dose reduction or interrupting therapy in children and adolescents who are not growing or gaining weight satisfactorily.

Clinical data do not suggest a deleterious effect of atomoxetine on cognition or sexual maturation; however, the amount of available long-term data is limited. Therefore, patients requiring long-term therapy should be carefully monitored.

New-onset or worsening of Comorbid Depression. Anxiety and Tics

In a controlled study of paediatric patients with ADHD and comorbid chronic motor tics or Tourette's Disorder, atomoxetine-treated patients did not experience worsening of tics compared to placebo-treated patients. In a controlled study of adolescent patients with ADHD and comorbid Major Depressive Disorder, atomoxetine-treated patients did not experience worsening of depression compared to placebo-treated patients. In two controlled studies (one in paediatric patients and one in adult patients) of patients with ADHD and comorbid anxiety disorders, atomoxetine-treated patients did not experience worsening of anxiety compared to placebo-treated patients.

There have been rare postmarketing reports of anxiety and depression or depressed mood and very rare reports of tics in patients taking atomoxetine (see section 4.8).

Patients who are being treated for ADHD with atomoxetine should be monitored for the appearance or worsening of anxiety symptoms, depressed mood and depression or tics.

Paediatric population under six years of age

Atomoxetine should not be used in patients less than six years of age as efficacy and safety have not been established in this age group.

Other therapeutic use

Atomoxetine is not indicated for the treatment of major depressive episodes and/or anxiety as the results of clinical trials in adults in these conditions, where ADHD is not present, did not show an effect compared to placebo (see section 5.1).

Ocular irritant

The capsules are not intended to be opened. Atomoxetine is an ocular irritant. In the event of the capsules content coming in contact with the eye, the affected eye should be flushed immediately with water, and medical advice obtained. Hands and any potentially contaminated surfaces should be washed as soon as possible.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on atomoxetine

MAOIs

Atomoxetine should not be used with MAOls (see section 4.3).

CYP2D6 inhibitors (SSRIs (e.g., fluoxetine, paroxetine), quinidine, terbinafine)

In patients receiving these medicinal products, atomoxetine exposure may be 6- to 8-fold increased and CSS max 3 to 4 times higher, because it is metabolised by the CYP2D6 pathway. Slower titration and final lower dosage of atomoxetine may be necessary in patients who are already taking CYP2D6 inhibitors. If a CYP2D6 inhibitor is prescribed or discontinued after titration to the appropriate atomoxetine dose has occurred, the clinical response and tolerability should be re-evaluated for that patient to determine if dose adjustment is needed.

Caution is advised when combining atomoxetine with potent inhibitors of cytochrome P450 enzymes other than CYP2D6 in patients who are poor CYP2D6 metabolisers as the risk of clinically relevant increases in atomoxetine exposure in vivo is unknown.

Serotoninergic medications

Atomoxetine should be used with caution in combination with serotonergic medicinal products, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), opioids as tramadol, and tetracyclic or tricyclic antidepressants as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4).

Salbutamol (or other beta2 agonists)

Atomoxetine should be administered with caution to patients treated with high dose nebulised or systemically administered salbutamol (or other beta2 agonists) because cardiovascular effects can be potentiated.

Contradictory findings regarding this interaction were found. Systemically administered salbutamol (600 μg i.v. over 2 hrs) in combination with atomoxetine (60 mg twice daily for 5 days) induced increases in heart rate and blood pressure. This effect was most marked after the initial coadministration of salbutamol and atomoxetine but returned towards baseline at the end of 8 hours. However, in a separate study the effects on blood pressure and heart rate of a standard inhaled dose of salbutamol (200 μg) were not increased by the short-term coadministration of atomoxetine (80 mg once daily for 5 days) in a study of healthy Asian adults who were extensive atomoxetine metabolisers. Similarly, heart rate after multiple inhalations of salbutamol (800 μg) did not differ in the presence or absence of atomoxetine.

Attention should be paid to monitoring heart rate and blood pressure, and dose adjustments may be justified for either atomoxetine or salbutamol (or other beta2 agonists) in the event of significant increases in heart rate and blood pressure during coadministration of these medicinal products.

There is the potential for an increased risk of QT interval prolongation when atomoxetine is administered with other QT-prolonging medicinal products (such as neuroleptics, class IA and III anti-arrhythmics, moxifloxacin, erythromycin, methadone, mefloquine, tricyclic antidepressants, lithium, or cisapride), substances that cause electrolyte imbalance (such as thiazide diuretics), and those that inhibit CYP2D6.

Seizures are a potential risk with atomoxetine. Caution is advised with concomitant use of medicinal products which are known to lower the seizure threshold (such as tricyclic antidepressants or SSRIs, neuroleptics, phenothiazines or butyrophenone, mefloquine, chloroquine, bupropion or tramadol) (see section 4.4). In addition, caution is advised when stopping concomitant treatment with benzodiazepines due to potential withdrawal seizures.

Anti-hypertensives

Atomoxetine should be used cautiously with anti-hypertensives. Because of a possible increase in blood pressure, atomoxetine may decrease the effectiveness of anti-hypertensives/ medicinal products used to treat hypertension. Attention should be paid to monitoring of blood pressure and review of treatment of atomoxetine or anti-hypertensives may be justified in the case of significant changes of blood pressure.

Pressor agents or medicinal products that increase blood pressure

Because of possible increase in effects on blood pressure, atomoxetine should be used cautiously with pressor agents or medications that may increase blood pressure (such as salbutamol). Attention should be paid to monitoring of blood pressure, and review of treatment for either atomoxetine or pressor agents may be justified in the case of significant change in blood pressure.

Medicinal products that affect noradrenaline

Medicinal products that affect noradrenaline should be used cautiously when co-administered with atomoxetine because of the potential for additive or synergistic pharmacological effects. Examples include antidepressants, such as imipramine, venlafaxine, and mirtazapine, or the decongestants pseudoephedrine or phenylephrine.

Medicinal products that affect gastric pH

Medicinal products that elevate gastric pH (magnesium hydroxide/aluminium hydroxide, omeprazole) had no effect on atomoxetine bioavailability.

Medicinal products highly bound to plasma protein

In vitro drug-displacement studies were conducted with atomoxetine and other highly-bound medicinal products at therapeutic concentrations. Warfarin, acetylsalicylic acid, phenytoin, or diazepam did not affect the binding of atomoxetine to human albumin. Similarly, atomoxetine did not affect the binding of these compounds to human albumin.

4.6. Fertility, pregnancy and lactation

Pregnancy

Animal studies in general do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). For atomoxetine clinical data on exposed pregnancies are limited. Such data are insufficient to indicate either an association or a lack of association between atomoxetine and adverse pregnancy and/or lactation outcomes. Atomoxetine should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus.

Breast-feeding

Atomoxetine and/or its metabolites were excreted in the milk of rats. It is not known if atomoxetine is excreted in human milk. Because of the lack of data, atomoxetine should be avoided during breast-feeding.

4.7. Effects on ability to drive and use machines

Data on the effects on the ability to drive and use machines are limited. Atomoxetine has a minor influence on the ability to drive and use machines. Atomoxetine has been associated with increased rates of fatigue, somnolence, and dizziness relative to placebo in paediatric and adult patients. Patients should be advised to use caution when driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected by atomoxetine.

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 discontinuation of treatment (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 discontinuations 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), not known (cannot be estimated from the available data).

System Organ Class

Very common

Common

Uncommon

Rare

Not known

Metabolism and nutrition disorders

Appetite decreased

Anorexia (loss of appetite)

Psychiatric disorders

Irritability, mood swings, insomnia3, agitation*, anxiety, depression and depressed mood*, tics*

Suicide-related events, aggression, hostility, emotional lability*, psychosis (including hallucinations)*

Bruxism

Nervous system disorders

Headache, somnolence2

Dizziness

Syncope, tremor, migraine, paraesthesia*, hypoaesthesia*, seizure**

Eye disorders

Mydriasis

Vision blurred

Cardiac disorders

Palpitations, sinus tachycardia, QT interval prolongation**

Vascular disorders

Raynaud's phenomenon

Respiratory, thoracic and mediastinal disorders

Dyspnoea (see section 4.4)

Gastrointestinal disorders

Abdominal pain1, vomiting, nausea

Constipation, dyspepsia

Hepatobiliary disorders

Blood bilirubin increased*

Abnormal/increased liver function tests, jaundice, hepatitis, liver injury, acute hepatic failure*

Skin and subcutaneous tissue disorders

Dermatitis, pruritus, rash

Hyperhidrosis, allergic reactions

Renal and urinary disorders

Urinary hesitation, urinary retention

Reproductive system and breast disorders

Priapism, male genital pain

General disorders and administration site conditions

Fatigue, lethargy, chest pain (see section 4.4)

Asthenia

Investigations

Blood pressure increased4, heart rate increased4

Weight decreased

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 sections 4.4 and 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 Class

Very common

Common

Uncommon

Rare

Metabolism and nutrition disorders

Appetite decreased

Psychiatric disorders

Insomnia2

Agitation*, libido decreased, sleep disorder, depression and depressed mood*, anxiety

Suicide-related events*, aggression, hostility and emotional lability*, restlessness, tics*

Psychosis (including hallucinations)*

Nervous system disorders

Headache

Dizziness, dysgeusia, paraesthesia, somnolence (including sedation), tremor

Syncope, migraine, hypoaesthesia*

Seizure**

Eye disorders

Vision blurred

Cardiac disorders

Palpitations, tachycardia

QT interval prolongation**

Vascular disorders

Flushing, hot flush

Peripheral coldness

Raynaud's phenomenon

Respiratory, thoracic and mediastinal disorders

Dyspnoea (see section 4.4)

Gastrointestinal disorders

Dry mouth, nausea

Abdominal pain1, constipation, dyspepsia, flatulence, vomiting

Hepatobiliary disorders

Abnormal/increased liver function tests, jaundice, hepatitis, liver injury, acute hepatic failure, blood bilirubin increased*

Skin and subcutaneous tissue disorders

Dermatitis, hyperhidrosis, rash

Allergic reactions4, pruritus, urticaria

Musculoskeletal and connective tissue disorders

Muscle spasms

Renal and urinary disorders

Dysuria, pollakuria, urinary hesitation, urinary retention

Micturition urgency

Reproductive system and breast disorders

Dysmenorrhoea, ejaculation disorder, erectile dysfunction, prostatitis, male genital pain

Ejaculation failure, menstruation irregular, orgasm abnormal

Priapism

General disorders and administration site conditions

Asthenia, fatigue, lethargy, chills, feeling jittery, irritability, thirst

Feeling cold, chest pain (see section 4.4)

Investigations

Blood pressure increased3, heart rate increased3

Weight decreased

1. Also includes abdominal pain upper, stomach discomfort, abdominal discomfort and epigastric discomfort.

2. 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 angioedema

* See section 4.4

** See sections 4.4 and 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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Signs and symptoms

During postmarketing, there have been reports of non-fatal acute and chronic overdoses of atomoxetine alone. The most commonly reported symptoms accompanying acute and chronic overdoses were gastrointestinal symptoms, somnolence, dizziness, tremor and abnormal behaviour. Hyperactivity and agitation have also been reported. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, blood pressure increased, mydriasis, dry mouth) were also observed and reports of pruritus and rash have been received. Most events were mild to moderate. In some cases of overdose involving atomoxetine, seizures have been reported and very rarely QT prolongation and serotonin syndrome have been reported. There have also been reports of fatal, acute overdoses involving a mixed ingestion of atomoxetine and at least one other medicinal product.

There is limited clinical trial experience with atomoxetine overdose.

Management

An airway should be established. Activated charcoal may be useful in limiting absorption if the patient presents within 1 hour of ingestion. Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive measures. The patient should be observed for a minimum of 6 hours. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose.