Stradent 10 Mg/18 Mg/25 Mg/40 Mg/60 Mg Capsules

STRADENT 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).

Posology

The recommended initial dose and subsequent dosage escalations of STRADENT should not be exceeded because of potential side effects (See Section 4.8). STRADENT are not intended to be opened. STRADENT 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.

Dosing of children and adolescents up to 70 kg body weight: STRADENT 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 STRADENT ). 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: STRADENT 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.

Special populations

Patients with renal impairment: For those ADHD patients who have end-stage renal disease, cautious titration of STRADENT to the desired clinical response is recommended. STRADENT may exacerbate hypertension in patients with end-stage renal disease.

Patients with hepatic impairment: For those ADHD patients who have hepatic insufficiency, cautious titration of STRADENT to the desired clinical response is recommended. STRADENT clearance may be reduced in patients with hepatic insufficiency.

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. Study data from patients on treatment with atomoxetine are consistent with maintenance of efficacy in long-term treatment.

Elderly patients: The safety and efficacy of STRADENT in elderly patients have not been established.

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

Method of administration

For oral administration STRADENT may be taken with or without food.

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 STRADENT in any 24-hour period.

Discontinuing STRADENT : STRADENT may be discontinued without tapering the dose.

STRADENT should not be used in patients with hypersensitivity to atomoxetine or to any of its excipients.

STRADENT should not be used in patients with uncontrolled hypertension or impairment of liver function.

Monoamine oxidase inhibitors: STRADENT should not be used in combination with monoamine oxidase inhibitors (MAOIs), including linezolid.

STRADENT 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 STRADENT.

Severe Cardiovascular Disorders: STRADENT should not be used in patients with severe cardiovascular disorders whose condition would be expected to deteriorate if they experienced increases in blood pressure or in heart rate that could be clinically important (for example 15 to 20 mm Hg in blood pressure or 20 beats per minute in heart rate) (see Section 4.4 u2013 Cardiovascular Effects).

Phaeochromocytoma: STRADENT should not be used in patients with phaeochromocytoma or a history of phaeochromocytoma (see Section 4.4 u2013 Cardiovascular Effects).

Narrow angle glaucoma: In clinical studies, the use of atomoxetine was associated with an increased risk of mydriasis and therefore its use is not recommended in patients with narrow angle glaucoma.

WARNING: SUICIDAL IDEATION IN CHILDREN AND ADOLESCENTS STRADENT (atomoxetine) increased the risk of suicidal ideation in short-term studies in children or adolescents with Attention-Deficit/Hyperactivity Disorder (AHDH). Anyone considering the use of STRADENT in a child or adolescent must balance this risk with the clinical need. Co-morbidities occurring with ADHD may be associated with an increase in the risk of suicidal ideation and/or behaviour. Patients who are started on therapy should be monitored closely for suicidality (suicidal thinking and behaviour), clinical worsening, or unusual changes in behaviour. Families and caregivers should be advised of the need for close observation and communication with the prescriber. STRADENT is approved for ADHD in paediatric and adult patients. STRADENT is not approved for major depressive disorder.

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).

Possible allergic events: Allergic reactions including anaphylactic reactions, rash, angio-oedema and urticarial have been reported in patients taking atomoxetine as in STRADENT.

Suicidal behaviour, hostility: Suicidal behaviour, suicidal ideation, hostility (predominantly aggression, oppositional behaviour and anger) and emotional lability were more frequently observed in clinical trials among patients treated with atomoxetine as in STRADENT compared to those treated with placebo but the differences were not statistically significant. Patients beginning treatment for ADHD should be carefully monitored for the appearance or worsening of suicide-related behaviour, hostility and emotional lability. The possibility of serious psychiatric adverse effects cannot be excluded. There is evidence that the risk of psychiatric adverse events is increased in children with a personal history of mood disorders, or who have a family history of mood disorders.

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

Cardiovascular effects: STRADENT can affect heart rate and blood pressure. Most patients taking STRADENT experience a modest increase in heart rate (mean <10 bpm) and/or increase in blood pressure (mean < 5 mm Hg) (see section 4.8).

However, combined data from controlled and uncontrolled ADHD clinical trials show that approximately 5-10 % of children and 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 u2013 26 % of children and adolescents, and 27 u2013 32 % of adults experiencing such changes in blood pressure and heart rate during STRADENT 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 STRADENT 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.

STRADENT should not be used in patients with severe cardiovascular or cerebrovascular disorders (see section 4.3 Contraindications u2013 Severe Cardiovascular and Cerebrovascular Disorders). STRADENT 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, STRADENT 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 STRADENT.

Hepatic effects: 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. STRADENT 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 flu-like 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 reaction.

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 STRADENT at usual doses. If such symptoms occur, consideration should be given to a possible causal role of STRADENT , and discontinuation of treatment should be considered. The possibility that STRADENT 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 a in STRADENT compared to those treated with placebo. Emotional lability was more frequently observed in clinical trials among children treated with atomoxetine a in STRADENT compared to those treated with placebo. Patients should be closely monitored for the appearance or worsening of aggressive behaviour, hostility or emotional lability.

Seizures: Seizures are a potential risk with STRADENT . STRADENT should be introduced with caution in patients with a history of seizure. Discontinuation of STRADENT 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 de velopment: Growth and development should be monitored in children and adolescents during treatment with STRADENT . Patients requiring long u2011 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 STRADENT 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 post-marketing 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 STRADENT should be monitored for the appearance or worsening of anxiety symptoms, depressed mood and depression or tics.

Paediatric population under six years of age: STRADENT 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 STRADENT beyond 18 months of treatment and safety of STRADENT beyond 2 years of treatment has not been systematically evaluated.

Elderly use : The safety and efficacy of STRADENT in elderly patients have not been established.

Other therapeutic use: STRADENT 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).

Effects on micturition: In adult ADHD controlled trials, the rates of urinary retention and urinary hesitation were increased among the STRADENT subjects compared with placebo subjects. A complaint of urinary retention or urinary hesitancy should be considered potentially related to STRADENT.

Effects of Other Medicines on Atomoxetine

MAOIs : STRADENT should not be used with MAOIs (see section 4.3).

CYP2D6 inhibitors {SSRIs (e.g., fluoxetine, paroxetine), quinidine, terbinafine}: In patients receiving these medicines, STRADENT 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 STRADENT 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 STRADENT 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 STRADENT 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 STRADENT exposure in vivo is unknown.

Midazolam: Co-administration of STRADENT (60 mg twice daily for 12 days) with midazolam, a model compound for CYP3A4 metabolised medicines (single dose of 5 mg), resulted in 15 % increase in AUC of midazolam. No dose adjustment is recommended for medicines metabolised by CYP3A.

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

Salbutamol (or other beta 2 agonists): STRADENT 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. Contradictory findings regarding this interaction were found. Systemically administered salbutamol (600 u03bcg i.v. over 2 hrs) in combination with STRADENT (60 mg twice daily for 5 days) induced increases in heart rate and blood pressure. This effect was most marked after the initial co-administration of salbutamol and STRADENT 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 u03bcg) were not increased by the short-term co- administration of STRADENT (80 mg once daily for 5 days) in a study of healthy Asian adults who were extensive STRADENT metabolisers. Similarly, heart rate after multiple inhalations of salbutamol (800 u03bcg) did not differ in the presence or absence of STRADENT.

Attention should be paid to monitoring heart rate and blood pressure, and dose adjustments may be justified for either STRADENT 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.

There is the potential for an increased risk of QT interval prolongation when STRADENT 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.

Seizures are a potential risk with STRADENT . 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: STRADENT should be used cautiously with anti-hypertensive medicines. Because of a possible increase in blood pressure, STRADENT may decrease the effectiveness of anti-hypertensive medicines used to treat hypertension. Attention should be paid to monitoring of blood pressure and review of treatment of STRADENT or anti-hypertensive medicines may be justified in the case of significant changes of blood pressure.

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

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

Medicines highly bound to plasma prote in: In vitro medicines-displacement studies were conducted with STRADENT and other highly- bound medicines at therapeutic concentrations. Warfarin, acetylsalicylic acid, phenytoin, or diazepam did not affect the binding of STRADENT to human albumin. Simila rly, STRADENT did not affect the binding of these compounds to human albumin.

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

Pregnancy Safety and efficacy have not been demonstrated in pregnancy.

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

Data on the effects on the ability to drive and use machines is limited. STRADENT has an influence on the ability to drive and use machines. STRADENT 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 STRADENT.

Paediatric population

a. Summary of the safety profile 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:

b. Tabulated list of adverse reactions System Organ Class Frequency Event Metabolism and nutrition disorders Frequent Appetite decreased Anorexia (loss of appetite) Psychiatric disorders Frequent Irritability, mood swings, insomnia 3 , agitation *, anxiety, depression and depressed mood *, tics Less frequent Suicide-related events, aggression, hostility, emotional lability * Psychosis (including hallucinations) * Nervous system disorders Frequent Headache, somnolence 2 Dizziness Less frequent Syncope, tremor, migraine, paraesthesia *, hypoaesthesia *, Seizure ** Eye disorders Frequent Mydriasis Less frequent Vision blurred Cardiac disorders Less frequent Palpitations, sinus tachycardia. QT interval prolongation ** Vascular disorders Less frequent Raynaudu2019s phenomenon Respiratory, thoracic and mediastinal disorders Less frequent Dyspnoea (see section 4.4 Gastro-intestinal disorders Frequent Abdominal pain1, vomiting, nausea Constipation, dyspepsia

Symptoms During post-marketing, there have been reports of non-fatal acute and chronic overdoses of STRADENT 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 STRADENT , seizures have been reported and very rarely QT prolongation. There have also been reports of fatal, acute overdoses involving a mixed ingestion of STRADENT and at least one other medicine.

Treatment 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 STRADENT is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose.