Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands
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 Special warnings and precautions for use – 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 pheochromocytoma or a history of pheochromocytoma (see section 4.4 Special warnings and precautions for use – Cardiovascular Effects).
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 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.
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 Contraindications – Severe Cardiovascular and Cerebrovascular Disorders). 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.
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.
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. STRATTERA should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted.
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 STRATTERA will cause the exacerbation of pre-existing psychotic or manic symptoms cannot be excluded.
Hostility (predominantly aggression, oppositional behaviour and anger) was more frequently observed in clinical trials among children, adolescents and adults treated with STRATTERA compared to those treated with placebo. Emotional lability was more frequently observed in clinical trials among children treated with STRATTERA compared to those treated with placebo. Patients should be closely monitored for the appearance or worsening of aggressive behaviour, hostility or emotional lability.
Although uncommon, allergic reactions, including anaphylactic reactions, rash, angioneurotic oedema, and urticaria, have been reported in patients taking atomoxetine.
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 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.
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.
Strattera should not be used in patients less than six years of age as efficacy and safety have not been established in this age group.
Strattera 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).
Atomoxetine should not be used with MAOIs (see section 4.3).
In patients receiving these drugs, atomoxetine exposure may be 6-to 8-fold increased and Cssmax 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 inhibitor drugs. 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.
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 drugs.
There is the potential for an increased risk of QT interval prolongation when atomoxetine is administered with other QT prolonging drugs (such as neuroleptics, class IA and III anti-arrhythmics, moxifloxacin, erythromycin, methadone, mefloquine, tricyclic antidepressants, lithium, or cisapride), drugs that cause electrolyte imbalance (such as thiazide diuretics), and drugs that inhibit CYP2D6.
Seizures are a potential risk with atomoxetine. Caution is advised with concomitant use of medicinal drugs 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.
Atomoxetine should be used cautiously with anti-hypertensive drugs. Because of a possible increase in blood pressure, atomoxetine may decrease the effectiveness of anti-hypertensive drugs/drugs used to treat hypertension. Attention should be paid to monitoring of blood pressure and review of treatment of atomoxetine or anti-hypertensive drugs may be justified in the case of significant changes of 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.
Drugs 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.
Drugs that elevate gastric pH (magnesium hydroxide/aluminium hydroxide, omeprazole) had no effect on atomoxetine bioavailability.
In vitro drug-displacement studies were conducted with atomoxetine and other highly-bound drugs 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.
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.
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.
Data on the effects on the ability to drive and use machines are limited. Strattera 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.
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 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).
Very common: Appetite decreased
Common: Anorexia (loss of appetite)
Common: Irritability, mood swings, insomnia3, agitation*, anxiety, depression and depressed mood*, tics*
Uncommon: Suicide-related events, aggression, hostility, emotional lability* Psychosis* (including hallucinations)
Very common: Headache, somnolence2
Common: Dizziness
Uncommon: Syncope, tremor, migraine, paraesthesia*, hypoaesthesia*, Seizure**
Common: Mydriasis
Uncommon: Vision blurred
Uncommon: Palpitations, sinus tachycardia. QT interval prolongation**
Rare: Raynaud’s phenomenon
Uncommon: Dyspnoea (see section 4.4)
Very common: Abdominal pain1, vomiting, nausea
Common: Constipation, dyspepsia
Uncommon: Blood bilirubin increased*
Rare: Abnormal/increased liver function tests, jaundice, hepatitis, liver injury, acute hepatic failure*
Common: Dermatitis, pruritis, rash
Uncommon: Hyperhydrosis, allergic reactions
Rare: Urinary hesitation, urinary retention
Rare: Priapism, male genital pain
Common: Fatigue, lethargy, chest pain (see section 4.4)
Uncommon: Asthenia
Very common: Blood pressure increased4, heart rate increased4
Common: 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 section 4.4 and section 4.5
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).
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).
Very common: Appetite decreased
Very common: Insomnia2
Common: Agitation*, libido decreased, sleep disorder, depression and depressed mood*, anxiety
Uncommon: Suicide-related events*, aggression, hostility and emotional lability*, restlessness, tics*
Rare: Psychosis* (including hallucinations)
Very common: Headache
Common: Dizziness, dysgeusia, paraesthesia, somnolence (including sedation), tremor
Uncommon: Syncope, migraine, Hypoaesthesia*
Rare: Seizure**
Uncommon: Vision blurred
Common: Palpitations, tachycardia
Uncommon: QT interval prolongation**
Common: Flushing, hot flush
Uncommon: Peripheral coldness
Rare: Raynaud’s phenomenon
Uncommon: Dyspnoea (see section 4.4)
Very common: Dry mouth, nausea
Common: Abdominal pain1, constipation, dyspepsia, flatulence, vomiting
Rare: Abnormal/increased liver function tests, jaundice, hepatitis, liver injury, acute hepatic failure, blood bilirubin increased*
Common: Dermatitis, hyperhydrosis, rash
Uncommon: Allergic reactions4, pruritis, urticaria
Uncommon: Muscle spasms
Common: Dysuria, pollakuria, urinary hesitation, urinary retention
Uncommon: Micturation urgency
Common: Dysmenorrhoea, ejaculation disorder, erectile dysfunction, prostatitis, male genital pain
Uncommon: Ejaculation failure, menstruation irregular, orgasm abnormal
Rare: Priapism
Common: Asthenia, fatigue, lethargy, chills, feeling jittery, irritability, thirst
Uncommon: Feeling cold, chest pain (see section 4.4)
Very common: Blood pressure increased3, heart rate increased3
Common: Weight decreased
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
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 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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.
Not applicable.
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