Atomoxetine

Also known as: (R)-N-Methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine

Interactions

Active ingredient Atomoxetine interacts in the following cases:

Pressor agents, drugs that increase blood pressure

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

End-stage renal disease

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.

Moderate hepatic insufficiency, severe hepatic insufficiency

For patients with moderate hepatic insufficiency (Child-Pugh Class B), initial and target doses should be reduced to 50% of the usual dose. For patients with severe hepatic insufficiency (Child-Pugh Class C), initial dose and target doses should be reduced to 25% of usual dose.

Anti-hypertensive drugs

Atomoxetine should be used cautiously with anti-hypertensive drugs. Because of a possible increase in blood pressure, atomoxetine may decrease the effectiveness of anti-hypertensive drugs/drugs used to treat hypertension. Attention should be paid to monitoring of blood pressure and review of treatment of atomoxetine or anti-hypertensive drugs may be justified in the case of significant changes of blood pressure.

CYP2D6 inhibitors

In patients receiving these drugs, atomoxetine exposure may be 6-to 8-fold increased and Cssmax 3 to 4 times higher, because it is metabolised by the CYP2D6 pathway. Slower titration and final lower dosage of atomoxetine may be necessary in patients who are already taking CYP2D6 inhibitor drugs. If a CYP2D6 inhibitor is prescribed or discontinued after titration to the appropriate atomoxetine dose has occurred, the clinical response and tolerability should be re-evaluated for that patient to determine if dose adjustment is needed.

Caution is advised when combining atomoxetine with potent inhibitors of cytochrome P450 enzymes other than CYP2D6 in patients who are poor CYP2D6 metabolisers as the risk of clinically relevant increases in atomoxetine exposure in vivo is unknown.

Drugs that affect noradrenaline

Drugs that affect noradrenaline should be used cautiously when co-administered with atomoxetine because of the potential for additive or synergistic pharmacological effects. Examples include antidepressants, such as imipramine, venlafaxine, and mirtazapine, or the decongestants pseudoephedrine or phenylephrine.

Salbutamol

Atomoxetine should be administered with caution to patients treated with high dose nebulised or systemically administered salbutamol (or other beta2 agonists) because cardiovascular effects can be potentiated.

Contradictory findings regarding this interaction were found. Systemically administered salbutamol (600 μg i.v. over 2 hrs) in combination with atomoxetine (60 mg twice daily for 5 days) induced increases in heart rate and blood pressure. This effect was most marked after the initial coadministration of salbutamol and atomoxetine but returned towards baseline at the end of 8 hours. However, in a separate study the effects on blood pressure and heart rate of a standard inhaled dose of salbutamol (200 μg) were not increased by the short-term coadministration of atomoxetine (80 mg once daily for 5 days) in a study of healthy Asian adults who were extensive atomoxetine metabolisers. Similarly, heart rate after multiple inhalations of salbutamol (800 μg) did not differ in the presence or absence of atomoxetine.

Attention should be paid to monitoring heart rate and blood pressure, and dose adjustments may be justified for either atomoxetine or salbutamol (or other beta2 agonists) in the event of significant increases in heart rate and blood pressure during coadministration of these drugs.

Pre-existing structural cardiac abnormalities

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

Congenital or acquired long QT

Atomoxetine should be used with caution in patients with congenital or acquired long QT or a family history of QT prolongation.

Pregnancy

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 and/or lactation outcomes. Atomoxetine should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus.

Nursing mothers

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

Effects on ability to drive and use machines

Data on the effects on the ability to drive and use machines are limited. Strattera has a minor influence on the ability to drive and use machines. Atomoxetine has been associated with increased rates of fatigue, somnolence, and dizziness relative to placebo in paediatric and adult patients. Patients should be advised to use caution when driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected by atomoxetine.

Adverse reactions


Paediatric population

Summary of the safety profile

In paediatric placebo-controlled trials, headache, abdominal pain1 and decreased appetite are the adverse events most commonly associated with atomoxetine, and are reported by about 19%, 18% and 16% of patients, respectively, but seldom lead to drug discontinuation (discontinuation rates are 0.1% for headache, 0.2% for abdominal pain and 0.0% for decreased appetite). Abdominal pain and decreased appetite are usually transient.

Associated with decreased appetite, some patients experienced growth retardation early in therapy in terms of both weight and height gain. On average, after an initial decrease in weight and height gain, patients treated with atomoxetine recovered to mean weight and height as predicted by group baseline data over the long-term treatment.

Nausea, vomiting and somnolence2 can occur in about 10% to 11% of patients, particularly during the first month of therapy. However, these episodes were usually mild to moderate in severity and transient, and did not result in a significant number of discontinuations from therapy (discontinuation rates ≤0.5%).

In both paediatric and adult placebo‑controlled trials, patients taking atomoxetine experienced increases in heart rate, systolic and diastolic blood pressure.

Because of its effect on noradrenergic tone, orthostatic hypotension (0.2%) and syncope (0.8%) have been reported in patients taking atomoxetine. Atomoxetine should be used with caution in any condition that may predispose patients to hypotension.

The following table of undesirable effects is based on adverse event reporting and laboratory investigations from clinical trials and post-marketing spontaneous reports in children and adolescents:

Tabulated list of adverse reactions:

Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

Metabolism and nutrition disorders

Very common: Appetite decreased

Common: Anorexia (loss of appetite)

Psychiatric disorders

Common: Irritability, mood swings, insomnia3, agitation, anxiety, depression and depressed mood, tics

Uncommon: Suicide-related events, aggression, hostility, emotional lability Psychosis (including hallucinations)

Nervous system disorders

Very common: Headache, somnolence2

Common: Dizziness

Uncommon: Syncope, tremor, migraine, paraesthesia, hypoaesthesia, Seizure

Eye disorders

Common: Mydriasis

Uncommon: Vision blurred

Cardiac disorders

Uncommon: Palpitations, sinus tachycardia. QT interval prolongation

Vascular disorders

Rare: Raynaud’s phenomenon

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea

Gastro-intestinal disorders

Very common: Abdominal pain1, vomiting, nausea

Common: Constipation, dyspepsia

Hepatobiliary disorders

Uncommon: Blood bilirubin increased

Rare: Abnormal/increased liver function tests, jaundice, hepatitis, liver injury, acute hepatic failure

Skin and subcutaneous tissue disorders

Common: Dermatitis, pruritis, rash

Uncommon: Hyperhydrosis, 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: Blood pressure increased4, heart rate increased4

Common: Weight decreased

1 Also includes abdominal pain upper, stomach discomfort, abdominal discomfort and epigastric discomfort.
2 Also includes sedation
3 Includes initial, middle and terminal (early morning wakening) insomnia
4 Heart rate and blood pressure findings are based on measured vital signs.

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 (24.1% of PMs, 17.0% of EMs); insomnia combined (including insomnia, middle insomnia and initial insomnia, 14.9% of PMs, 9.7% of EMs); depression combined (including depression, major depression, depressive symptom, depressed mood and dysphoria, 6.5% of PMs and 4.1% of EMs), weight decreased (7.3% of PMs, 4.4% of EMs), constipation 6.8% of PMs, 4.3% of EMs); tremor (4.5% of PMs, 0.9% of EMs); sedation (3.9% of PMs, 2.1% of EMs); excoriation (3.9% of PMs, 1.7% of EMs); enuresis (3.0% of PMs, 1.2% of EMs); conjunctivitis (2.5% of PMs, 1.2% of EMs); syncope (2.5% of PMs, 0.7% of EMs); early morning awakening (2.3% of PMs, 0.8% of EMs); mydriasis (2.0% of PMs, 0.6% of EMs). The following event did not meet the above criteria but is noteworthy: generalised anxiety disorder (0.8% of PMs and 0.1% of EMs). In addition, in trials lasting up to 10 weeks, weight loss was more pronounced in PM patients (mean of 0.6 kg in EM and 1.1kg in PM).

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 common adverse events (≥5%) reported were appetite decreased (14.9%), insomnia (11.3%), headache (16.3%), dry mouth (18.4%) and nausea (26.7%). The majority of these events were mild or moderate in severity and the events most frequently reported as severe were nausea, insomnia, fatigue and headache. A complaint of urinary retention or urinary hesitancy in adults should be considered potentially related to atomoxetine.

The following table of undesirable effects is based on adverse event reporting and laboratory investigations from clinical trials and post-marketing spontaneous reports in adults.

Tabulated list of adverse reactions:

Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

Metabolism and nutrition disorders

Very common: Appetite decreased

Psychiatric disorders

Very common: Insomnia2

Common: Agitation, libido decreased, sleep disorder, depression and depressed mood, anxiety

Uncommon: Suicide-related events, aggression, hostility and emotional lability, restlessness, tics

Rare: Psychosis (including hallucinations)

Nervous system disorders

Very common: Headache

Common: Dizziness, dysgeusia, paraesthesia, somnolence (including sedation), tremor

Uncommon: Syncope, migraine, Hypoaesthesia

Rare: Seizure

Eye disorders

Uncommon: Vision blurred

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 pain1, constipation, dyspepsia, flatulence, vomiting

Hepato-biliary disorders

Rare: Abnormal/increased liver function tests, jaundice, hepatitis, liver injury, acute hepatic failure, blood bilirubin increased

Skin and subcutaneous tissue disorders

Common: Dermatitis, hyperhydrosis, rash

Uncommon: Allergic reactions4, pruritis, urticaria

Musculoskeletal and connective tissue disorders

Uncommon: Muscle spasms

Renal and urinary disorders

Common: Dysuria, pollakuria, urinary hesitation, urinary retention

Uncommon: Micturation urgency

Reproductive system and breast disorders

Common: Dysmenorrhoea, ejaculation disorder, erectile dysfunction, prostatitis, male genital pain

Uncommon: Ejaculation failure, menstruation irregular, orgasm abnormal

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: Blood pressure increased3, heart rate increased3

Common: Weight decreased

1 Also includes abdominal pain upper, stomach discomfort, abdominal discomfort and epigastric discomfort.
2 Also includes initial insomnia, middle insomnia and terminal (early morning wakening) insomnia.
3 Heart rate and blood pressure findings are based on measured vital signs.
4 Includes anaphylactic reactions and angioneurotic oedema.

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: vision blurred (3.9% of PMs, 1.3% of EMs), dry mouth (34.5% of PMs, 17.4% of EMs), constipation (11.3% of PMs, 6.7% of EMs), feeling jittery (4.9% of PMs, 1.9% of EMs), decreased appetite (23.2% of PMs, 14.7% of EMs), tremor (5.4% of PMs, 1.2% of EMs), insomnia (19.2% of PMs, 11.3% of EMs), sleep disorder (6.9% of PMs, 3.4% of EMs), middle insomnia (5.4% of PMs, 2.7% of EMs), terminal insomnia (3% of PMs, 0.9% of EMs), urinary retention (5.9% of PMs, 1.2% of EMs), erectile dysfunction (20.9% of PMs, 8.9% of EMs), ejaculation disorder (6.1% of PMs, 2.2% of EMs), hyperhidrosis (14.8% of PMs, 6.8% of EMs), peripheral coldness (3% of PMs, 0.5% of EMs).

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