Atomoxetine Hydrochloride

Registered South African indications:

• Attention Deficit/Hyperactivity Disorder (ADHD)

Registered South African contraindications

• Hypersensitivity to the active ingredient or to any of its excipients
• Coadministration with monoamine oxidase inhibitors (MAOI) or within 2 weeks of discontinuing therapy with MAOI, (including linezolid)
• Initiation of treatment with MAOI within 2 weeks after discontinuing atomoxetine hydrochloride
• Narrow-angle glaucoma
• Severe cardiovascular or cerebrovascular disorders, including
  - Severe hypertension or heart rate changes that are clinically important
  - Heart failure, arterial occlusive disease, angina
  - Haemodynamically significant congenital heart disease, cardiomyopathies, myocardial infarction
  - Potentially life-threatening dysrhythmias and channelopathies, cerebral aneurysm, or stroke
• Pheochromocytoma or a history of pheochromocytoma
• Uncontrolled hypertension
• Impairment of liver function

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or to any of its excipients
• Narrow-angle glaucoma
• Severe cardiovascular disorders:
  - Severe hypertension
  - Heart failure
  - Arterial occlusive disease
  - Angina
  - Haemodynamically significant congenital heart disease
  - Cardiomyopathies 
  - Myocardial infarction
  - Potentially life-threatening arrhythmias
  - Channelopathies (disorders caused by the dysfunction of ion channels)
• Severe cerebrovascular disorders:
  - Cerebral aneurysm
  - Stroke
• Pheochromocytoma, or a history thereof
• Coadministration with monoamine oxidase inhibitors or within 14 days of their use

• Pregnancy
• Breastfeeding
• Renal impairment
• Moderate to severe hepatic impairment (Recommendations in other jurisdictions)
• Elderly
• Porphyria
• Suicide-related behaviour
• Known serious structural cardiac abnormalities
• History or presence of cardiac disease
• Conditions that may predispose patients to hypotension or conditions associated with abrupt heart rate or blood pressure changes
• Underlying medical conditions could be worsened by increases in blood pressure and heart rate:
  - Hypertension
  - Tachycardia
  - Cardiovascular or cerebrovascular disease
• Congenital or acquired long QT or a family history of QT prolongation
• Additional risk factors for cerebrovascular conditions:
  - History of cardiovascular disease
  - Coadministration with medicines that elevate blood pressure
• Pre-existing psychotic or manic symptoms
• Pre-existing aggressive behaviour, hostility or emotional lability
• History of seizures  
• Long-term therapy in children
• Treatment of major depressive episodes and/or anxiety
• CYP2D6 poor metabolisers (See additional prescribing points)
• Fructose intolerance (certain formulations)
• Capsules content coming in contact with the eye
• May affect ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: cap

South African registered indications and dosages

Attention Deficit/Hyperactivity Disorder (ADHD)

• Oral (cap): Initial: 40mg, dly, for a minimum of 7 days; Titrate up according to clinical response and tolerability; Maintenance: 80mg, dly; Max: 80mg/24hrs

No additional benefit has been demonstrated for doses higher than 80mg

Atomoxetine may be discontinued without tapering the 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 atomoxetine in any 24hr period

Atomoxetine hydrochloride 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 hydrochloride 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

Atomoxetine hydrochloride can be administered with or without food. The capsules should not be opened and the contents inside the capsules should not be removed and taken in any other way

Paed. forms avail. in SA and covered in this monograph: cap

South African registered indications and dosages

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)

Attention Deficit/Hyperactivity Disorder (ADHD)

Younger than 6 years

• Not established for use

Older than 6 years and ≤70kg

• Oral (cap): Initial: 0.5mg/kg, dly, for a minimum of 7 days; Titrate up according to clinical response and tolerability; Maintenance: Approx. 1.2mg/kg/day (depending on the patient's weight and available dosage strengths of atomoxetine); Max: 1.2mg/kg/24hrs

No additional benefit has been demonstrated for doses higher than 1.2mg/kg/day

Older than 6 years and >70kg

• See adult dosage

Atomoxetine may be discontinued without tapering the 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 atomoxetine in any 24hr period

Atomoxetine hydrochloride 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 hydrochloride 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

Atomoxetine hydrochloride can be administered with or without food. The capsules should not be opened and the contents inside the capsules should not be removed and taken in any other way

Pregnancy 

• Caution
• Animal studies in general do not indicate direct harmful effects with respect to pregnancy, embryonal/ foetal development, parturition or postnatal development
• 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 outcomes. Atomoxetine should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus

Breastfeeding

• Caution; not recommended
• Atomoxetine and/or its metabolites were excreted in the milk of rats. It is not known if atomoxetine is excreted in human milk. Such data are insufficient to indicate either an association or a lack of association between atomoxetine and adverse breastfeeding outcomes. Because of the lack of data, atomoxetine should be avoided during breastfeeding

Fertility 

• A study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioural and sexual development. Slight delays in the onset of vaginal patency (all doses) and preputial separation (≥10 mg/kg/day), and slight decreases in epididymal weight and sperm number (≥10 mg/kg/day) were seen; however, there were no effects on fertility or reproductive performance. The significance of these findings to humans is unknown

• Caution; no dose adjustment recommended

  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

South African recommendations

• Contraindicated
  Atomoxetine hydrochloride should not be used in patients with impairment of liver function

Recommendations in other jurisdictions

• Mild (Child-Pugh Class A):  No dose adjustment recommended
• Moderate (Child-Pugh Class B): Caution; dose adjustment recommended
  Initial and target doses should be reduced to 50% of the usual dose
• Severe (Child-Pugh Class C): Caution; dose adjustment recommended
  Initial dose and target doses should be reduced to 25% of the usual dose

• Caution; no information available
  The use of atomoxetine in patients over 65 years of age has not been systematically evaluated

Central Nervous system Disorders

• Headache
• Somnolence
• Dizziness
• Syncope
• Tremor
• Migraine
• Paraesthesia
• Hypoaesthesia
• Seizure
• Fatigue
• Irritability
• Mood swings
• Insomnia includes initial, middle and terminal (early morning wakening) insomnia)
• Agitation
• Anxiety
• Depression
  - Depressed mood
• Tics  
• Suicide-related events  
• Aggression
• Hostility
• Emotional lability
• Psychosis
  - Hallucinations

Cardiovascular Disorders

• Palpitations
• Sinus tachycardia
• QT prolongation
• Raynaud's phenomenon
• Increased blood pressure
• Increased heart rate

Respiratory Disorders

• Dyspnoea
• Chest pain

Gastrointestinal Disorders

• Abdominal pain
  - Upper abdominal pain
  - Stomach discomfort
  - Abdominal discomfort
  - Epigastric discomfort
• Nausea and vomiting
• Constipation
• Dyspepsia

Hepatobiliary Disorders 

• Increased bilirubin
• Abnormal/increased hepatic function tests  
• Jaundice
• Hepatitis
• Liver injury  
• Acute hepatic failure

Genitourinary Disorders

• Urinary hesitation
• Urinary retention
• Priapism
• Male genital pain

Endocrine and Metabolic Disorders

• Decreased appetite
• Anorexia (loss of appetite)
• Decreased weight

Skin and Subcutaneous Tissue Disorders 

• Dermatitis
• Pruritus
• Rash
• Hyperhydrosis
• Allergic reactions

Sensory Disorders

• Mydriasis
• Blurred vision

• Monoamine oxidase inhibitors
• CYP2D6 inhibitors
• Selective serotonin reuptake inhibitors
• Fluoxetine
• Paroxetine
• Quinidine
• Terbinafine
• Beta-2 agonists
• Salbutamol
• QT-prolonging agents
• Neuroleptics
• Class IA and III antiarrhythmics
• Moxifloxacin
• Erythromycin
• Methadone
• Mefloquine
• Tricyclic antidepressants
• Lithium
• Cisapride
• Agents that can cause electrolyte imbalance
• Thiazide diuretics
• Agents that lower the seizure threshold
• Phenothiazines 
• Butyrophenone
• Chloroquine
• Bupropion
• Tramadol
• Benzodiazepines
• Antihypertensive agents
• Pressor agents or medications that may increase blood pressure
• Agents that affect noradrenaline
• Imipramine
• Venlafaxine
• Mirtazapine
• Decongestants
• Pseudoephedrine
• Phenylephrine

• Blood pressure
• Heart rate
• Pulse

Specific cases may require

• Hepatic function
• Cardiac evaluation
• Growth in children
  - Weight
  - Height
• Weight in adults

Additional observations

• Appetite in children
• Sleep changes
• Behavioural changes
  - Appearance or worsening of aggressive behaviour, hostility or emotional lability
• Appearance or worsening of anxiety symptoms, depressed mood and depression or tics
• Signs of peripheral vasculopathy
• Neurological signs and symptoms
• Signs of misuse, abuse, or addiction

Information for the safe use of atomoxetine

• 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 the medicinal product 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
• 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
• 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
• 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 medicinal product 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

CYP2D6 poor metabolisers

• 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. For patients with a known poor metaboliser genotype, a lower starting dose and slower up titration of the dose may be considered

Worsening of suicide-related behaviour, psychotic and manic symptoms

• 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
• 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

Atomoxetine is a highly selective and potent inhibitor of the pre-synaptic noradrenaline transporter, its presumed mechanism of action, without directly affecting the serotonin or dopamine transporters. Atomoxetine has minimal affinity for other noradrenergic receptors or for other neurotransmitter transporters or receptors. Atomoxetine has two major oxidative metabolites: 4-hydroxyatomoxetine and N-desmethylatomoxetine. 4-hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the noradrenaline transporter but, unlike atomoxetine, this metabolite also exerts some inhibitory activity at the serotonin transporter. However, any effect on this transporter is likely to be minimal, as the majority of 4-hydroxyatomoxetine is further metabolised such that it circulates in plasma at much lower concentrations (1% of atomoxetine concentration in extensive metabolisers and 0.1% of atomoxetine concentration in poor metabolisers). N-desmethylatomoxetine has substantially less pharmacological activity compared with atomoxetine. It circulates in plasma at lower concentrations in extensive metabolisers and at comparable concentrations to the parent medicinal product in poor metabolisers at steady-state.

Capsule 10mg

• Atastrat 10 (Sandoz SA)
• Attencit 10mg (Pharma Dynamics)
• Attentra 10 (Teva Pharmaceuticals)
• Concitron 10mg (Austell Laboratories)
• Inir (Dr Reddy's Lab)
• Strattera (Eli Lilly) originator

Capsule 18mg

• Atastrat 18 (Sandoz SA)
• Attencit 18mg (Pharma Dynamics)
• Attentra 18 (Teva Pharmaceuticals)
• Concitron 18mg (Austell Laboratories)
• Inir (Dr Reddy's Lab)
• Strattera (Eli Lilly) originator

Capsule 25mg

• Atastrat 25 (Sandoz SA)
• Attencit 25mg (Pharma Dynamics)
• Attentra 25 (Teva Pharmaceuticals)
• Atteze 25 (Abex Pharmaceutica)
• Concitron 25mg (Austell Laboratories)
• Inir (Dr Reddy's Lab)
• Strattera (Eli Lilly) originator
• Stratex 25 (Unicorn Pharmaceuticals)

Capsule 40mg

• Atastrat 40 (Sandoz SA)
• Attencit 40mg (Pharma Dynamics)
• Attentra 40 (Teva Pharmaceuticals)
• Atteze 40 (Abex Pharmaceutica)
• Concitron 40mg (Austell Laboratories)
• Inir (Dr Reddy's Lab)
• Strattera (Eli Lilly) originator
• Stratex 40 (Unicorn Pharmaceuticals)

Capsule 60mg

• Atastrat 60 (Sandoz SA)
• Attencit 60mg (Pharma Dynamics)
• Attentra 60 (Teva Pharmaceuticals)
• Atteze 60 (Abex Pharmaceutica)
• Concitron 60mg (Austell Laboratories)
• Inir (Dr Reddy's Lab)
• Strattera (Eli Lilly) originator
• Stratex 60 (Unicorn Pharmaceuticals)

Capsule 80mg

• Atastrat 80 (Sandoz SA)
• Attencit 80mg (Pharma Dynamics)
• Attentra 80 (Teva Pharmaceuticals)
• Atteze 80 (Abex Pharmaceutica)
• Concitron 80mg (Austell Laboratories)
• Strattera (Eli Lilly) originator

Oral solution (per ml) 4 mg

• Atomoxetine (Eli Lilly) originator