Attentra Capsules

ATTENTRA is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children 6 years of age or older, adolescents and adults.

Treatment must be initiated by or under the supervision of a medical practitioner with appropriate knowledge and experience of childhood and/or adolescent behavioural disorders (for example, paediatrician or child/adolescent psychiatrist) (see section 4.4).

The recommended initial dose and subsequent dosage escalations of ATTENTRA should not be exceeded because of potential side effects (see section 4.8). ATTENTRA capsules are not intended to be opened. ATTENTRA is an ocular irritant. In the event of capsule content coming into 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.

Posology: ATTENTRA may be discontinued without tapering the dose.

Dosing of children and adolescents up to 70 kg body weight: ATTENTRA 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 patientu2019s weight and available dosage strengths of ATTENTRA). No additional benefit has been demonstrated for doses higher than 1,2 mg/kg/day.

Dosing of children and adolescents over 70 kg body weight and adults: ATTENTRA 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 for adults is 80 mg.

Long-term use: No fixed dose-response studies have been conducted in adults. The recommended daily dose of 80 mg reflects the optimal daily dose of 1,2 mg/kg/day demonstrated in children and adolescents. No controlled long-term studies have been conducted in adults. Open-label study data up to 97 weeks of treatment with atomoxetine are consistent with maintenance of efficacy in long-term treatment.

Missing a dose: If patients miss a dose, they should take it as soon as possible; however, they should not take more than the prescribed total daily amount of ATTENTRA in any 24-hour period.

Special populations: Renal and hepatic insufficiency: For those ADHD patients who have hepatic insufficiency or end-stage renal disease, cautious titration of ATTENTRA to the desired clinical response is recommended (see section 5.2). ATTENTRA clearance may be reduced in patients with hepatic insufficiency. ATTENTRA may exacerbate hypertension in patients with end-stage renal disease.

Elderly population: The use of ATTENTRA in patients over 65 years of age has not been systematically evaluated.

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

Method of administration: For oral use. ATTENTRA may be taken with or without food.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Monoamine oxidase inhibitors: ATTENTRA should not be used in combination with monoamine oxidase inhibitors (MAOIs), including linezolid.
• ATTENTRA should not be used within a minimum of 2 weeks after discontinuing therapy with MAOIs. Treatment with MAOIs should not be initiated within 2 weeks after discontinuing atomoxetine (see section 4.5).
• Narrow angle glaucoma: ATTENTRA should not be used in patients with narrow-angle glaucoma, as the use of atomoxetine is associated with an increased incidence of mydriasis.
• Severe cardiovascular or cerebrovascular disorders: ATTENTRA should not be used in patients with severe cardiovascular or cerebrovascular disorders (see section 4.4). 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.
• Pheochromocytoma: ATTENTRA should not be used in patients with pheochromocytoma or a history of pheochromocytoma (see section 4.4).
• ATTENTRA should not be used in patients with impairment of liver function.

Treatment must only be initiated by or under the supervision of a medical practitioner with appropriate knowledge and experience of childhood and adolescent behaviour disorders (e.g. paediatrician or child/adolescent psychiatrist).

Suicide-related behaviour: Suicide-related behaviour (suicide attempts and suicidal ideation) has been reported in patients treated with ATTENTRA. In clinical trials, suicide-related behaviours were less frequent, but more frequently observed among children and adolescents treated with ATTENTRA compared to those treated with placebo, where there were no events. In adult 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 ATTENTRA at usual doses. Although some serious structural cardiac abnormalities alone carry an increased risk of sudden death, ATTENTRA should only be used with caution in patients with known serious structural cardiac abnormalities and in consultation with a cardiac specialist.

Cardiovascular effects: ATTENTRA can affect heart rate and blood pressure. Most patients taking ATTENTRA experience a modest increase in heart rate (mean <10 bpm) and/or increase in blood pressure (mean <5 mm Hg) (see section 4.8). 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 ATTENTRA 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. ATTENTRA should not be used in patients with severe cardiovascular or cerebrovascular disorders (see section 4.3). ATTENTRA 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 ATTENTRA treatment should undergo a prompt specialist cardiac evaluation.

In addition, ATTENTRA 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, ATTENTRA 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 medicines that elevate blood pressure) should be assessed at every visit for neurological signs and symptoms after initiating treatment with ATTENTRA.

Hepatic effects: Less frequently, spontaneous reports of liver injury, manifested by elevated hepatic enzymes and bilirubin with jaundice, have been reported. Also, severe liver injury, including acute liver failure, have been reported. ATTENTRA should be discontinued in patients with jaundice or laboratory evidence of liver injury and should not be restarted. Signs and symptoms likely to indicate liver involvement include pruritus, dark urine, jaundice, right upper quadrant tenderness or unexplained u2018flu-likeu2019 symptoms. Laboratory testing to determine liver enzyme levels and bilirubin should be done upon the first sign or symptom of possible liver involvement. Due to the seemingly idiosyncratic nature of the liver injury, routine monitoring of liver function is unlikely to be helpful in minimising the risk of such reactions.

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 ATTENTRA, and discontinuation of treatment should be considered. The possibility that ATTENTRA 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 ATTENTRA compared to those treated with placebo. Emotional lability was more frequently observed in clinical trials among children treated with ATTENTRA 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 ATTENTRA 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: Allergic reactions, including anaphylactic reactions, rash, angioneurotic oedema and urticaria, have been reported in patients taking ATTENTRA.

Seizures: Seizures are a potential risk with ATTENTRA. ATTENTRA 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 (see section 4.5).

Growth and development: Growth and development should be monitored in children and adolescents during treatment with ATTENTRA. 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. Patients requiring long-term therapy should be carefully monitored.

New-onset or worsening of comorbid depression, anxiety and tics: There have been rare post-marketing reports of anxiety and depression or depressed mood and very rare reports of tics in patients taking ATTENTRA (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.

Serotonin syndrome: Serotonin syndrome has been reported following concomitant use of atomoxetine, as contained in ATTENTRA, with other serotonergic medicinal products e.g. serotonin-norepinephrine re-uptake inhibitors (SNRIs), selective serotonin re-uptake inhibitors (SSRIs), other SNRIs, triptans, opioids, and tricyclic and tetracyclic antidepressants. If concomitant use of ATTENTRA 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 ATTENTRA therapy should be considered depending on the severity of the symptoms.

Paediatric population under six years of age: ATTENTRA should not be used in patients less than six years of age as efficacy and safety have not been established in this age group. The efficacy of ATTENTRA beyond 18 months of treatment and safety of ATTENTRA beyond 2 years of treatment has not been systematically evaluated.

Geriatric use: The safety and efficacy of ATTENTRA in geriatric patients have not been established. Other therapeutic use: ATTENTRA is not indicated for the treatment of major depressive episodes and/or anxiety. ATTENTRA should not be used in patients with Raynaudu2019s phenomenon.

Effects on micturition: The rates of urinary retention and urinary hesitation may be increased. Urinary retention or urinary hesitancy should be considered potentially related to ATTENTRA.

Monoamine oxidase inhibitors (MAOIs): ATTENTRA should not be used with MAOIs (see section 4.3).

CYP2D6 inhibitors (SSRIs (e.g. fluoxetine, paroxetine), quinidine, terbinafine): In patients receiving these medicines, ATTENTRA 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 ATTENTRA may be necessary in patients who are already taking CYP2D6 inhibitor medicines. If a CYP2D6 inhibitor is prescribed or discontinued after titration to the appropriate ATTENTRA 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 ATTENTRA 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 (see section 4.8).

Salbutamol (or other beta-2 agonists): ATTENTRA should be administered with caution to patients treated with high dose nebulised or systemically administered salbutamol (or other beta-2 agonists) because cardiovascular effects can be potentiated. Attention should be paid to monitoring heart rate and blood pressure, and dose adjustments may be justified for either ATTENTRA or salbutamol (or other beta-2 agonists) in the event of significant increases in heart rate and blood pressure during co-administration of these medicines.

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

Medicines lowering seizure threshold: Seizures are a potential risk with ATTENTRA. Caution is advised with concomitant use of medicines 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-hypertensive medicines: ATTENTRA should be used cautiously with anti-hypertensive medicines. Because of a possible increase in blood pressure, atomoxetine may decrease the effectiveness of anti-hypertensive medicines/medicines used to treat hypertension. Attention should be paid to monitoring of blood pressure and review of treatment of ATTENTRA or anti-hypertensive medicines may be justified in the case of significant changes of blood pressure.

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

Medicines that affect noradrenaline: Medicines that affect noradrenaline should be used cautiously when co-administered with ATTENTRA 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.

Serotoninergic medicines: ATTENTRA should be used with caution in combination with serotonergic medicines, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake 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).

Medicines that affect gastric pH: Medicines that elevate gastric pH (magnesium hydroxide/aluminium hydroxide, omeprazole) had no effect on atomoxetine bioavailability.

Medicines highly bound to plasma protein: In vitro medicine-displacement studies were conducted with atomoxetine and other highly-bound medicines 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.

Methylphenidate: Co-administration of methylphenidate with ATTENTRA did not increase cardiovascular effects beyond those seen with methylphenidate administration alone.

Alcohol: Consumption of ethanol with ATTENTRA did not change the intoxicating effects of ethanol.

Pregnancy: Safety and efficacy have not been demonstrated in pregnancy. ATTENTRA should not be used during pregnancy.

Lactation: ATTENTRA and/or its metabolites were excreted in the milk of rats. It is not known if ATTENTRA is excreted in human milk. Women using ATTENTRA should not breastfeed their infants.

Data on the effects on the ability to drive and use machines are limited. ATTENTRA has a minor influence on the ability to drive and use machines. ATTENTRA 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 ATTENTRA (see section 4.8).

Paediatric population: Summary of the safety profile: In paediatric trials headache, abdominal pain and decreased appetite are the adverse events most commonly associated with atomoxetine, but seldom lead to medicine discontinuation. 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 over long-term treatment. Nausea, vomiting and somnolence can occur in 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. In both paediatric and adult 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 and syncope have been reported in patients taking atomoxetine. Atomoxetine should be used with caution in any condition that may predispose patients to hypotension.

TABLE 1: TABULATED SUMMARY OF ADVERSE REACTIONS IN CHILDREN AND ADOLESCENTS

SYSTEM ORGAN CLASS: FREQUENT: LESS FREQUENT: FREQUENCY UNKNOWN:

Metabolism and nutrition disorders: Decreased appetite, anorexia (loss of appetite)

Psychiatric disorders: Irritability, mood swings, insomnia, agitation*, anxiety, depression and depressed mood*, tics* Suicide-related events, aggression, hostility, emotional lability*, psychosis (including hallucinations)* Bruxism

Nervous system disorders: Headache, somnolence, dizziness Syncope, tremor, migraine, paraesthesia*, hypoaesthesia*, seizure**

Eye disorders: Mydriasis Vision blurred, conjunctivitis

Cardiac disorders: Palpitations, sinus tachycardia, QT interval prolongation**

Vascular disorders: Raynaudu2019s phenomenon

Respiratory, thoracic and mediastinal disorders: Dyspnoea*

Gastrointestinal disorders: Abdominal pain, 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 Hyperhydrosis, 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* Asthenia

Investigations: Blood pressure increased, heart rate increased, weight decreased

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

Also includes sedation

Includes initial, middle and terminal (early morning wakening) insomnia

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; insomnia combined (including insomnia, middle insomnia and initial insomnia); depression combined (including depression, major depression, depressive symptom, depressed mood and dysphoria); weight decreased; constipation; tremor; sedation; excoriation; enuresis; conjunctivitis; syncope; early morning awakening; mydriasis. The following event did not meet the above criteria but is noteworthy: generalised anxiety disorder. In addition, in trials lasting up to 10 weeks, weight loss was more pronounced in PM patients.

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 frequent adverse events reported were appetite decreased, insomnia, headache, dry mouth and nausea. 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.

TABLE 2: TABULATED LIST OF ADVERSE REACTIONS IN ADULTS

SYSTEM ORGAN CLASS: FREQUENT: LESS FREQUENT:

Metabolism and nutrition disorders: Decreased appetite

Psychiatric disorders: Insomnia, 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: Blurred vision

Cardiac disorders: Palpitations, tachycardia QT interval prolongation**

Vascular disorders: Flushing, hot flush Peripheral coldness, Raynaud's phenomenon

Respiratory, thoracic and mediastinal disorders: Dyspnoea*

Gastrointestinal disorders: Dry mouth, nausea, abdominal pain, 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, hyperhydrosis, rash Allergic reactions

Musculoskeletal and connective tissue disorders: Muscle spasms

Renal and urinary disorders: Dysuria, pollakiuria, 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*

Investigations: Blood pressure increased, heart rate increased, weight decreased

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

Also includes initial insomnia, middle insomnia and terminal (early morning wakening) insomnia

Heart rate and blood pressure findings are based on measured vital signs.

Includes anaphylactic reactions and angioneurotic oedema

* See section 4.4 ** See section 4.4 and section 4.5

Signs and symptoms: 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 medicine.

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.