Atomoxetine Hydrochloride

Registered South African indications:

• Attention Deficit/Hyperactivity Disorder (ADHD)

WARNING: SUICIDAL IDEATION IN CHILDREN AND ADOLESCENTS Atomoxetine hydrochloride increases the risk of suicidal ideation in short-term studies of children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). Those considering its use must weigh this risk against clinical need. Comorbid conditions with ADHD may also heighten the risk of suicidal ideation and behaviour. Patients starting therapy should be monitored closely for signs of suicidality, clinical worsening, or unusual behavioural changes. Families and caregivers should be advised to observe closely and maintain communication with the prescriber. Atomoxetine Hydrochloride is approved for treating ADHD in both paediatric and adult patients, but not for major depressive disorder.

Registered South African contraindications

• Hypersensitivity to atomoxetine or to any of the 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
• Severe cardiovascular disorders
  -  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, 15-20mmHg in blood pressure or 20 beats/ minute in heart rate)
• Pheochromocytoma or a history of pheochromocytoma
• Narrow-angle glaucoma
  - Atomoxetine hydrochloride was associated with an increased risk of mydriasis and therefore its use is not recommended in patients with narrow angle glaucoma

Contraindications registered in other jurisdictions

• 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
• Initiation of treatment with MAOI within 2 weeks after discontinuing atomoxetine hydrochloride
• Narrow-angle glaucoma
  - Atomoxetine hydrochloride was associated with an increased risk of mydriasis
• Severe cardiovascular or cerebrovascular disorders, such as
  - 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)
  - Cerebral aneurysm
  - Stroke
• Pheochromocytoma or a history of pheochromocytoma

Recommendations in South Africa & other jurisdictions

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment (South African recommendations)
• Moderate to severe hepatic impairment (Recommendations in other jurisdictions)
• Elderly

Suicidal behaviour, hostility

• Suicidal behaviour, suicidal ideation, hostility (including aggression, oppositional behaviour, and anger), and emotional lability were observed more frequently in clinical trials among patients treated with atomoxetine hydrochloride compared to those on placebo, though not statistically significant
• Patients starting treatment for ADHD should be closely monitored for the emergence or worsening of suicidal behaviour, hostility, or emotional lability
• Serious psychiatric adverse effects cannot be excluded; hence, vigilant monitoring is crucial
• Special consideration is needed for children with personal or family history of mood disorders, as they may have an increased risk of experiencing psychiatric adverse events

Sudden death and pre-existing cardiac abnormalities

• Sudden death has occurred in patients with structural cardiac abnormalities who were taking atomoxetine hydrochloride at standard doses
• While serious structural cardiac abnormalities alone may increase the risk of sudden death, use of atomoxetine hydrochloride in such patients should be approached with caution
• It is advised that atomoxetine hydrochloride only be prescribed to patients with significant cardiac abnormalities after consulting with a cardiac specialist

Cardiovascular effects

• Atomoxetine hydrochloride can significantly elevate heart rate and blood pressure, measurement of heart rate and blood pressure is recommended before starting treatment and periodically during treatment to monitor significant increases
• While most patients experience a modest increase in heart rate (mean <10bpm) and blood pressure (mean <5mmHg), about 5-10% of patients may experience clinically significant changes in heart rate (20 beats per minute or greater) or blood pressure (15 to 20 mmHg or greater)
• Use atomoxetine hydrochloride cautiously in patients with conditions like hypertension, tachycardia, cardiovascular or cerebrovascular disease, which could be worsened by increased blood pressure or heart rate
• Avoid use in patients with severe cardiovascular disorders where increased heart rate or blood pressure could be detrimental
• Also, use cautiously in patients with congenital or acquired long QT syndrome, or a family history of QT prolongation
• Due to reports of orthostatic hypotension, caution is advised in conditions predisposing to hypotension or where abrupt changes in blood pressure or heart rate may occur

Cerebrovascular effects

• Assess patients with risk factors for cerebrovascular conditions (e.g., history of cardiovascular disease, medications that elevate blood pressure) for neurological signs and symptoms at every visit after starting atomoxetine hydrochloride treatment

Hepatic effects

• Discontinue atomoxetine hydrochloride in patients exhibiting signs of jaundice or laboratory evidence of liver injury, and do not restart the treatment
• There have been spontaneous reports of liver injury characterised by elevated hepatic enzymes and bilirubin levels, sometimes associated with severe liver damage or acute liver failure
• Symptoms indicative of liver issues include pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained "flu-like" symptoms
• Conduct laboratory tests for liver enzyme levels and bilirubin at the first sign or symptom of potential liver involvement
• Routine monitoring of liver functions may not be effective in preventing idiosyncratic liver injuries

Psychotic or manic symptoms

• Atomoxetine hydrochloride can induce psychotic or manic symptoms, such as hallucinations, delusional thinking, mania, or agitation, in patients without prior history
• If such symptoms occur, consider the potential causal role of atomoxetine hydrochloride and think about discontinuing treatment
• Atomoxetine hydrochloride may also exacerbate pre-existing psychotic or manic symptoms

Possible allergic events

• Although uncommon, allergic reactions such as anaphylaxis, rash, angioedema, and urticaria have been reported in patients taking atomoxetine hydrochloride

Seizures

• There is a potential risk of seizures with atomoxetine hydrochloride
• Use caution when prescribing atomoxetine hydrochloride to patients with a history of seizures
• Consider discontinuing atomoxetine hydrochloride if a patient develops seizures or if there is an increase in seizure frequency without another identifiable cause

Paediatric use

• Atomoxetine hydrochloride's safety and efficacy have not been established for children under the age of 6
• The long-term efficacy (beyond 18 months) and safety (beyond 2 years) of atomoxetine hydrochloride in paediatric settings have not been systematically evaluated

Growth and development monitoring

• Continuous monitoring of growth and development is crucial for children and adolescents undergoing treatment with atomoxetine hydrochloride
• Consideration for dose adjustment or a pause in therapy may be necessary for those not showing satisfactory growth or weight gain
• While there is no evidence suggesting a negative impact of atomoxetine hydrochloride on cognition or sexual maturation, the long-term data available is limited

New-onset or worsening comorbid conditions

• Studies indicate that atomoxetine hydrochloride does not exacerbate tics in patients with ADHD and chronic motor tics or Tourette’s Disorder
• Adolescents with ADHD and comorbid major depressive disorder did not show worsening depression symptoms while treated with atomoxetine hydrochloride compared to those treated with placebo
• In studies involving both paediatric and adult patients with ADHD and comorbid anxiety disorders, atomoxetine-treated patients did not experience worsening of anxiety compared to placebo-treated patients
• Patients undergoing atomoxetine hydrochloride treatment for ADHD should be closely monitored for any new or worsening symptoms of anxiety, depression, or tics

Depression and other therapeutic use

• Atomoxetine hydrochloride is not effective for the treatment of depression and should not be used for this purpose (South African recommendations)
• Atomoxetine hydrochloride 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 (Recommendations in other jurisdictions)

Sorbitol content

• Each ml of atomoxetine hydrochloride contains 32.97mg of sorbitol
• Patients with hereditary fructose intolerance (HFI) should not use atomoxetine hydrochloride

Sodium content

• Atomoxetine hydrochloride contains 2.64mg of sodium per ml
• Taking the maximum dose of 100mg of atomoxetine hydrochloride is equivalent to 3.3% of the WHO recommended maximum daily sodium intake of 2g for an adult

Sodium benzoate

• This medicinal product contains 0.8mg of sodium benzoate per ml

Ability to drive and use machines

• Atomoxetine hydrochloride may cause somnolence and dizziness. Patients should exercise caution when driving or operating machinery
• It's important to ensure that atomoxetine hydrochloride does not adversely affect their ability to perform such tasks safely

Additional South African recommendations

Raynaud’s phenomenon

• Atomoxetine hydrochloride should not be used in patients with Raynaud’s phenomenon

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

South African registered indications and dosages

Attention Deficit/Hyperactivity Disorder (ADHD)

• Oral (sol): Initial: 40mg, as the total daily dose; Maintain initial dose for a min. of 7 days; Up-titrate based on clinical response and tolerability; Maintenance: 80mg, daily; Max: 80mg/24hrs

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The recommended initial dose and subsequent dosage escalations of atomoxetine hydrochloride should not be exceeded because of potential side effects

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

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Atomoxetine hydrochloride may be discontinued without tapering the dose

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Atomoxetine hydrochloride can be administered with or without food. It is not recommended to mix atomoxetine hydrochloride oral solution in food or water as it can prevent the patient receiving a full dose or could negatively affect the taste

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

South African registered indications and dosages

Attention-Deficit/Hyperactivity Disorder (ADHD)

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)

Younger than 6 years

• Not established for use

6 years and older

• ≤70kg: Oral (sol): Initial: 0.5mg/kg, as the total daily dose; Maintain initial dose for a min. of 7 days; Up-titrate based on clinical response and tolerability; Maintenance: Approx. 1.2mg/kg/day, depending on the patient’s weight and available dosage strengths; The oral solution should be dosed in accordance with the following table:

Weight range (kg)	Starting dose (ml/day)	Target dose (ml/day)
16-18	2	5
19	2	6
20-21	3	6
22-24	3	7
25-28	3	8
29-31	4	9
32-34	4	10
35	4	11
36-38	5	11
39-41	5	12
42-44	5	13
45-48	6	14
49-51	6	15
52-54	7	16
55-58	7	17
59	7	18
60-61	8	18
62-64	8	19
65-67	8	20
68-69	9	20
≥70	10	20

• >70kg: See adult dosage

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The recommended initial dose and subsequent dosage escalations of atomoxetine hydrochloride should not be exceeded because of potential side effects

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 No additional benefit has been demonstrated for doses higher than 1.2mg/kg/day. The safety of single doses over 1.8mg/kg/day and total daily doses above 1.8mg/kg have not been systematically evaluated. In some cases, it might be appropriate to continue treatment into adulthood

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The efficacy of atomoxetine hydrochloride beyond 18 months of treatment and safety of atomoxetine hydrochloride beyond 2 years of treatment has not been systematically evaluated

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Atomoxetine hydrochloride may be discontinued without tapering the dose

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Atomoxetine hydrochloride can be administered with or without food. It is not recommended to mix atomoxetine hydrochloride oral solution in food or water as it can prevent the patient receiving a full dose or could negatively affect the taste

Pregnancy

South African recommendations

• Caution
• Safety and efficacy have not been demonstrated in pregnancy

Recommendations in other jurisdictions

• Caution; not recommended
• Animal studies in general do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development
• For atomoxetine hydrochloride 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

Breastfeeding

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; not recommended
• Atomoxetine hydrochloride and/or its metabolites were excreted in the milk of rats
• It is not known if it is excreted in human milk. Women using atomoxetine hydrochloride should not breastfeed their infants

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• No information available

South African recommendations

• Caution; no dose adjustment recommended
  End-stage renal disease: For those ADHD patients who have end-stage renal disease, cautious titration of atomoxetine hydrochloride to the desired clinical response is recommended
  Atomoxetine hydrochloride may exacerbate hypertension in patients with end-stage renal disease

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended
  Atomoxetine hydrochloride can be administered to ADHD patients with end-stage renal disease or lesser degrees of renal insufficiency using the usual dosing regimen
  Atomoxetine hydrochloride may exacerbate hypertension in patients with end-stage renal disease
• CYP2D6 poor metabolisers: Caution; dose adjustment recommended
  About 7% of Caucasians are CYP2D6 poor metabolisers, lacking a functional CYP2D6 enzyme. These individuals experience significantly higher exposure to atomoxetine compared to those with a functional enzyme. Consequently, poor metabolizers have an increased 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

South African recommendations

• Caution; no dose adjustment recommended
  For those ADHD patients who have hepatic insufficiency, cautious titration of atomoxetine hydrochloride to the desired clinical response is recommended
  Atomoxetine hydrochloride clearance may be reduced in patients with hepatic insufficiency

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

South African recommendations

• Caution; no information available

Recommendations in other jurisdictions

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

Paediatrics

Metabolism and Nutrition Disorders

Very common

• Decreased appetite

Common

• Anorexia (loss of appetite)

Psychiatric Disorders

Common

• Irritability
• Mood swings
• Insomnia
  - Includes initial, middle and terminal (early morning wakening) insomnia
• Agitation
• Anxiety
• Depression
• Depressed mood
• Tics

Uncommon

• Suicide-related events
• Aggression
• Hostility
• Emotional lability
• Psychosis (including hallucinations)

Nervous System Disorders

Very common

• Headache
• Somnolence
  - Includes sedation

Common

• Dizziness

Uncommon

• Syncope
• Tremor
• Migraine
• Paraesthesia
• Hypoaesthesia
• Seizure
• Orthostatic hypotension

Eye Disorders

Common

• Mydriasis

Uncommon

• Blurred vision

Cardiac Disorders

Uncommon

• Palpitations
• Sinus tachycardia
• QT interval prolongation

Vascular Disorders

Rare

• Raynaud's phenomenon

Respiratory, Thoracic, and Mediastinal Disorders

Uncommon

• Dyspnoea

Gastrointestinal Disorders

Very common

• Abdominal pain
  - Upper abdominal pain
  - Stomach discomfort
  - Abdominal discomfort
  - Epigastric discomfort
• Vomiting
• Nausea

Common

• Constipation
• Dyspepsia

Hepatobiliary Disorders

Uncommon

• Increased blood bilirubin

Rare

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

Skin and Subcutaneous Tissue Disorders

Common

• Dermatitis
• Pruritus
• Rash

Uncommon

• Hyperhidrosis
• Allergic reactions

Renal and Urinary Disorders

Rare

• Urinary hesitation
• Urinary retention

Reproductive System and Breast Disorders

Rare

• Priapism
• Male genital pain

General Disorders and Administration Site Conditions

Common

• Fatigue
• Lethargy
• Chest pain

Uncommon

• Asthenia

Investigations

Very common

• Increased blood pressure
• Increased heart rate

Common

• Decreased weight

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CYP2D6 poor metabolisers (PM)

Metabolism and Nutrition Disorders

Very common

• Appetite decreased

Common

• Weight decreased

Psychiatric Disorders

Very common

• Insomnia combined (including insomnia, middle insomnia, and initial insomnia)

Common

• Depression combined (including depression, major depression, depressive symptom, depressed mood, and dysphoria)

Uncommon

• Generalised anxiety disorder

Gastrointestinal Disorders

Common

• Constipation

Nervous System Disorders

Common

• Tremor
• Sedation
• Syncope

Skin and Subcutaneous Tissue Disorders

Common

• Excoriation

Renal and Urinary Disorders

Common

• Enuresis

Eye Disorders

Common

• Conjunctivitis
• Mydriasis

Sleep Disorders

Common

• Early morning awakening

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Adults

Metabolism and Nutrition Disorders

Very common

• Decreased appetite

Psychiatric Disorders

Very common

• Insomnia
  - Initial insomnia, middle insomnia and terminal (early morning wakening) insomnia

Common

• Agitation
• Decreased libido
• Sleep disorder
• Depression and depressed mood
• Anxiety

Uncommon

• Suicide-related events
• Aggression
• Hostility and emotional lability
• Restlessness
• Tics

Rare

• Psychosis (including hallucinations)

Nervous System Disorders

Very common

• Headache

Common

• Dizziness
• Dysgeusia
• Paraesthesia
• Somnolence (including sedation)
• Tremor

Uncommon

• Syncope
• Migraine
• Hypoaesthesia

Rare

• Seizure

Eye Disorders

Uncommon

• Blurred vision

Cardiac Disorders

Common

• Palpitations
• Tachycardia

Uncommon

• QT interval prolongation

Vascular Disorders

Common

• Flushing
• Hot flush

Uncommon

• Peripheral coldness

Rare

• Raynaud’s phenomenon

Respiratory, Thoracic and Mediastinal Disorders

Uncommon

• Dyspnoea

Gastrointestinal Disorders

Very common

• Dry mouth
• Nausea

Common

• Abdominal pain
  - Upper abdominal pain
  - Stomach discomfort
  - Abdominal discomfort
  - Epigastric discomfort
• Constipation
• Dyspepsia
• Flatulence
• Vomiting

Hepatobiliary Disorders

Rare

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

Skin and Subcutaneous Tissue Disorders

Common

• Dermatitis
• Hyperhidrosis
• Rash

Uncommon

• Allergic reactions
  - Anaphylactic reactions
  - Angioneurotic oedema
• Pruritus
• Urticaria

Musculoskeletal and Connective Tissue Disorders

Uncommon

• Muscle spasms

Renal and Urinary Disorders

Common

• Dysuria
• Pollakuria
• Urinary hesitation
• Urinary retention

Uncommon

• Micturition urgency

Reproductive System and Breast Disorders

Common

• Dysmenorrhoea
• Ejaculation disorder
• Erectile dysfunction
• Prostatitis
• Male genital pain

Uncommon

• Ejaculation failure
• Menstruation irregular
• Abnormal orgasm

Rare

• Priapism

General Disorders and Administration Site Conditions

Common

• Asthenia
• Fatigue
• Lethargy
• Chills
• Feeling jittery
• Irritability
• Thirst

Uncommon

• Feeling cold
• Chest pain

Investigations

Very common

• Increased blood pressure
• Increased heart rate

Common

• Decreased weight

• Monoamine oxidase inhibitors
• Linezolid
• CYP2D6 inhibitors
• Beta-adrenergic receptor agonists
• Salbutamol (high dose nebulised or systemically)
• Other beta-2 agonists
• Selective serotonin reuptake inhibitors
• 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 

Specific cases may require

• Hepatic function (if signs and symptoms of liver dysfunction emerge during treatment or several weeks after discontinuation)
• Cardiac evaluation (medical history and family history of sudden death or ventricular arrhythmia or any patient who experiences chest pain during physical activity, unexplained fainting, or any signs of cardiac disease while undergoing treatment)
  - Electrocardiogram (ECG) (if findings suggest cardiac disease)
• Growth in children
  - Weight
  - Height
• Weight in adults

Additional observations

• Appetite in children
• Sleep changes
• Behavioural changes
  - Appearance or worsening of suicide-related behaviour, hostility or emotional lability
  - Suicidality (suicidal thinking and behaviour), clinical worsening, or unusual changes in behaviour
• Appearance or worsening of anxiety symptoms, depressed mood and depression or tics
• Prior to treatment, assess for risk factors of bipolar disorder such as personal or family history of bipolar disorder, mania, hypomania, and depression
•  Monitor for any signs or symptoms of mania or hypomania during the course of the treatment

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 drug in poor metabolisers at steady state.