Atomoxetine
Indications
| Indication | Approved Population | First Approval | Status |
|---|---|---|---|
| Attention-Deficit/Hyperactivity Disorder (ADHD) | Adults and pediatric patients ≥6 years | 2002 | FDA Approved |
Atomoxetine occupies a distinct position in ADHD pharmacotherapy as the first non-stimulant medication FDA-approved for ADHD (approved November 2002) — and the first new ADHD agent in decades that is not a controlled substance. It works by selective inhibition of the presynaptic norepinephrine transporter (NET), increasing synaptic norepinephrine and, to a lesser extent, dopamine in the prefrontal cortex (where dopamine reuptake is also predominantly NET-mediated). Atomoxetine produces no euphoria, has no abuse potential demonstrated in controlled studies, and is not a Schedule controlled substance — making it useful in patients with substance-use concerns, in households with diversion risk, or where stimulant side effects are problematic.
Clinically, atomoxetine is generally considered a second-line option in ADHD because efficacy is modestly lower than stimulants and full clinical effect typically takes 4–6 weeks. Per the Cortese et al. 2018 network meta-analysis and major guidelines (AAP 2019, NICE NG87), stimulants remain first-line in most patients. Atomoxetine is preferred over stimulants in specific scenarios: patients with active substance use disorder or family substance use concerns, severe stimulant-related adverse effects (tics, anxiety, severe insomnia, anorexia), patients with pre-existing significant tic disorder where the FDA label specifically notes atomoxetine does not worsen tics, and patients with comorbid anxiety where the FDA label specifically notes it does not worsen anxiety.
Pediatric <6 years: Safety and efficacy not established. Atomoxetine is not approved for use in children under 6 years.
Major depressive disorder: Atomoxetine is NOT approved for major depressive disorder. The boxed warning specifically notes this distinction.
Tourette’s syndrome and anxiety: The FDA label specifically notes that atomoxetine does NOT worsen tics in patients with ADHD and comorbid Tourette’s disorder, and does NOT worsen anxiety in patients with ADHD and comorbid anxiety disorders. This is a clinically meaningful advantage over stimulant therapy in these comorbid populations.
ADHD with comorbid substance use disorder: Frequently chosen off-label as a non-controlled option. Evidence quality moderate.
Adult ADHD with anxiety or stimulant intolerance: Used when stimulants exacerbate anxiety or are not tolerated. Evidence quality moderate.
Treatment-resistant depression (augmentation): Limited evidence; not recommended as standard practice given lack of MDD efficacy in pivotal trials.
Cognitive symptoms in autism spectrum disorder with ADHD: Some specialist use; modest evidence for ADHD-symptom improvement; close monitoring for irritability and aggression required.
Dosing
Atomoxetine is administered orally once or twice daily, with or without food. Dosing is weight-based in pediatric patients up to 70 kg and fixed-dose in patients over 70 kg and adults. Capsules should be swallowed whole — they are not intended to be opened, as the capsule contents are an ocular irritant. Atomoxetine can be discontinued without tapering (no withdrawal syndrome).
By Indication and Population
| Clinical Scenario | Starting Dose | Titration | Target Dose | Maximum | Notes |
|---|---|---|---|---|---|
| ADHD — children/adolescents up to 70 kg | 0.5 mg/kg/day | Increase after minimum 3 days; may divide BID (morning + late afternoon/early evening) or give as single morning dose | 1.2 mg/kg/day | 1.4 mg/kg/day or 100 mg, whichever is less | No additional benefit demonstrated above 1.2 mg/kg/day Full effect typically takes 4–6 weeks |
| ADHD — children/adolescents >70 kg and adults | 40 mg PO once daily | Increase after minimum 3 days; may divide BID or give as single morning dose; after 2–4 weeks may increase further if response inadequate | 80 mg/day | 100 mg/day | No data support increased effectiveness above 100 mg/day Single doses >120 mg or daily >150 mg not systematically evaluated |
| Moderate hepatic impairment (Child-Pugh B) | Reduce initial AND target dose to 50% of normal | 50% of normal max | 2-fold AUC increase in EMs with moderate HI | ||
| Severe hepatic impairment (Child-Pugh C) | Reduce initial AND target dose to 25% of normal | 25% of normal max | 4-fold AUC increase in EMs with severe HI | ||
| Strong CYP2D6 inhibitor (paroxetine, fluoxetine, quinidine, bupropion) — pediatric <70 kg | 0.5 mg/kg/day | Maintain initial dose for at least 4 weeks | 1.2 mg/kg/day only if symptoms not improved at 4 weeks AND initial dose well tolerated | Per CYP2D6 metaboliser status | CYP2D6 inhibition produces atomoxetine exposure similar to PM phenotype |
| Strong CYP2D6 inhibitor — >70 kg or adults | 40 mg/day | Maintain initial dose for at least 4 weeks | 80 mg/day only if symptoms not improved at 4 weeks AND initial dose well tolerated | 80 mg/day | Same caveats as pediatric |
| Known CYP2D6 poor metabolisers (~7% of Caucasian population) | Same starting doses as above; treat as if on strong CYP2D6 inhibitor | Slow titration; maintain initial dose for at least 4 weeks | Reduced target if not tolerated | 10× higher AUC, 5× higher Cmax than EMs at same dose | |
Special Populations
- Pediatric <6 years: Not approved; safety and efficacy not established.
- Geriatric (≥65 years): Clinical trials did not include sufficient numbers of patients ≥65 years to establish differential safety or efficacy. Cardiovascular comorbidity is more common; baseline ECG and BP/HR measurement is reasonable. Consider initiating at the lower end of the adult dosing range.
- Renal impairment: No dose adjustment required. End-stage renal disease patients have higher systemic exposure than healthy subjects, but no difference when corrected for mg/kg dose; the FDA label does not require renal-based dose reduction.
- Hepatic impairment: Significant adjustments required (see table). Atomoxetine is extensively metabolised hepatically, and impaired clearance can produce supratherapeutic exposure even at standard doses.
- CYP2D6 poor metabolisers: Approximately 7% of Caucasians are PMs. CYP2D6 phenotype testing is not routinely required, but poor metaboliser status may be inferred when adverse effects are disproportionate to dose. PMs have a markedly higher rate of insomnia, weight loss, sexual dysfunction (in adults), constipation, depressive symptoms, and cardiovascular effects compared to EMs.
- Pregnancy: Limited human data. Animal studies show decreased pup survival and decreased pup body weight at doses with maternal toxicity. Use only when potential benefit justifies potential risk to the foetus.
- Lactation: Limited data on excretion in human milk. Decision to breastfeed should consider individual risk-benefit, including the importance of treatment to the mother.
Unlike stimulants, which produce same-day clinical effects, atomoxetine’s therapeutic action emerges gradually over 4–6 weeks. This is a downstream pharmacodynamic effect of sustained noradrenergic stimulation rather than an acute pharmacokinetic phenomenon. Counsel patients explicitly: any judgment about efficacy before week 4–6 at target dose is premature. Stopping atomoxetine because “it isn’t working” at 2 weeks is one of the most common reasons for treatment failure. Encourage adherence and set realistic expectations at the time of initiation.
Before initiating atomoxetine, the FDA labelling requires: (1) careful cardiac history including family history of sudden cardiac death or ventricular arrhythmia, plus a physical examination — further evaluation (ECG, echocardiogram) if findings suggest cardiac disease; (2) screen for personal or family history of bipolar disorder, mania, or hypomania (added in the January 2022 label update — Section 2.4); (3) baseline blood pressure and heart rate; (4) baseline weight and height in children; (5) assessment of suicide risk in pediatric and adolescent patients with discussion of the boxed warning. Document each step in the medical record.
Pharmacology
Mechanism of Action
Atomoxetine is a selective inhibitor of the presynaptic norepinephrine transporter (NET). Its binding affinity for NET is markedly greater than for the dopamine transporter (DAT) or serotonin transporter (SERT), and it lacks meaningful affinity for monoamine receptors, alpha- and beta-adrenergic receptors, dopaminergic receptors, serotonergic receptors, or muscarinic receptors. This selectivity profile distinguishes it pharmacologically from both stimulants (which act primarily on DAT and as monoamine releasers) and most antidepressants.
Within the prefrontal cortex — a key region implicated in ADHD pathophysiology — dopamine reuptake is also predominantly NET-mediated (rather than DAT-mediated). Therefore, atomoxetine’s NET inhibition increases not only synaptic norepinephrine but also synaptic dopamine specifically in prefrontal cortex, while leaving subcortical dopaminergic circuits relatively unaffected. This regional selectivity is thought to underlie atomoxetine’s efficacy in ADHD without producing the euphorigenic and abuse-related effects characteristic of stimulants. The FDA label states that the precise mode of therapeutic action in ADHD is unknown.
Implications of CYP2D6 metabolism:
- Marked PK variability based on metaboliser phenotype: Atomoxetine is primarily metabolised by CYP2D6 to 4-hydroxyatomoxetine (which is then rapidly conjugated). Approximately 7% of Caucasians and lower percentages of other ethnicities are CYP2D6 poor metabolisers (PMs). PMs have approximately 10-fold higher AUC and 5-fold higher peak concentration compared to extensive metabolisers (EMs) at the same dose, translating to longer effective half-life (~22 h vs ~5 h) and higher rates of dose-related adverse effects.
- Phenotypic conversion via drug interaction: Strong CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine, bupropion, terbinafine, cinacalcet) effectively convert EMs to PM-equivalent exposure. Dose adjustments per FDA label apply.
- No abuse liability: Atomoxetine produces no euphoria and is not a controlled substance. Multiple human studies have shown no abuse potential, no rewarding effects, and no withdrawal syndrome on discontinuation.
- No food effect of clinical significance. Food slightly delays Tmax but does not significantly affect AUC. Atomoxetine may be taken with or without food.
- No tapering required on discontinuation.
Cardiovascular pharmacodynamics: atomoxetine produces small mean increases in heart rate (approximately 5 bpm in EMs, 9 bpm in PMs in pediatric trials) and blood pressure. Some patients show clinically important increases (≥20 bpm or ≥15 mmHg DBP / ≥20 mmHg SBP) — observed in roughly 5–10% of patients across pediatric and adult trials. The cardiovascular profile is qualitatively similar to but generally smaller in magnitude than stimulants.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapidly absorbed; oral bioavailability ~63% in EMs and ~94% in PMs; Tmax 1–2 hours; food slightly delays Tmax but does not affect AUC | Take with or without food; the difference in bioavailability between EMs and PMs reflects extensive first-pass CYP2D6 metabolism |
| Distribution | Volume of distribution ~0.85 L/kg; protein binding ~98% (primarily albumin) | High protein binding theoretically allows displacement interactions, but in practice no clinically significant interactions with other highly protein-bound drugs (warfarin, aspirin, diazepam, phenytoin) have been demonstrated |
| Metabolism | Primary: CYP2D6 → 4-hydroxyatomoxetine (active metabolite, rapidly conjugated to inactive 4-hydroxyatomoxetine-O-glucuronide); minor: CYP2C19 → N-desmethylatomoxetine; PMs use compensatory pathways | ~7% of Caucasians are CYP2D6 PMs with 10-fold higher AUC; concomitant use of strong CYP2D6 inhibitors produces PM-equivalent exposure; dose adjustment required |
| Elimination | Half-life ~5 hours in EMs; ~22 hours in PMs; ~80% urinary excretion (mostly as conjugated metabolites); ~17% fecal; less than 3% as unchanged atomoxetine | Despite short half-life in EMs, the once- or twice-daily dosing reflects pharmacodynamic duration of effect; renal impairment does not require dose adjustment after correction for mg/kg dose |
Onset of clinical effect: Atomoxetine’s full clinical effect on ADHD symptoms typically requires 4–6 weeks at target dose, in contrast to the same-day onset characteristic of stimulants. This time course reflects downstream pharmacodynamic adaptation rather than slow steady-state pharmacokinetics.
Side Effects
The atomoxetine adverse-event profile differs from stimulants in clinically meaningful ways. Pediatric trials are dominated by gastrointestinal effects, somnolence, and decreased appetite; adult trials show prominent dry mouth, nausea, insomnia, and sexual dysfunction. The most distinctive features are the boxed warning for suicidal ideation in pediatrics, rare but serious hepatotoxicity, and disproportionately higher rates of sexual dysfunction and other dose-related adverse effects in CYP2D6 poor metabolisers. All quantitative incidence data below are taken directly from the Strattera FDA prescribing information clinical trial tables (Tables 1–4; revised 1/2022).
| Adverse Effect | Population / Incidence | Clinical Note |
|---|---|---|
| Headache (children/adolescents) | 19% vs 15% placebo small absolute difference but most common pediatric AE | Often transient; assess for hydration, sleep, and stress factors; usually self-resolves |
| Abdominal pain (children/adolescents) | 18% vs 10% placebo | Most common GI symptom; take with food; usually transient over first few weeks |
| Decreased appetite (both populations) | 16% in children, 16% in adults vs 4%, 3% placebo respectively | Less severe than with stimulants but still notable; encourage front-loaded breakfast and calorie-dense evening intake |
| Nausea (adults) | 26% adults, 10% children vs 6%, 5% placebo | Major reason for adult discontinuation; take with food; usually decreases after first 2–3 weeks |
| Dry mouth (adults) | 20% adults vs 5% placebo; 35% in adult PMs vs 17% in EMs | Encourage hydration, sugar-free gum; prominent in PMs — useful clinical clue |
| Insomnia (adults) | 15% adults vs 8% placebo; 19% in adult PMs vs 11% in EMs | Generally less than stimulants; consider morning-only dosing; reduce dose if persistent |
| Vomiting (children/adolescents) | 11% vs 6% placebo | Take with food; usually transient over first few weeks |
| Somnolence (children/adolescents) | 11% vs 4% placebo | Distinctive feature compared to stimulants; consider evening dosing if affects daytime alertness |
| Fatigue (adults) | 10% adults, 8% children vs 6%, 3% placebo | Often transient; consider dose reduction if persistent |
| Adverse Effect | Population / Incidence | Clinical Note |
|---|---|---|
| Constipation (adults) | 8% adults vs 3% placebo; 11% PMs vs 7% EMs | Encourage fluids and fibre; can be persistent |
| Dizziness (adults) | 8% adults, 5% children vs 3%, 2% placebo | May reflect orthostasis; check BP changes; rise slowly from sitting/lying |
| Erectile dysfunction (adult males) | 8% adult males vs 1% placebo; 21% in PMs vs 9% in EMs | Significant cause of discontinuation; markedly higher in CYP2D6 PMs |
| Somnolence (adults) | 8% adults vs 5% placebo | Less common in adults than children; assess for excess sedation if higher dose |
| Abdominal pain (adults) | 7% adults vs 4% placebo | Take with food |
| Urinary hesitation (adults) | 6% adults vs 1% placebo; urinary retention 1.7% | Counsel about; assess for prostatic causes in older men |
| Irritability (children/adolescents) | 6% children, 5% adults vs 3%, 3% placebo | Often dose-related; consider whether it represents emergence of aggressive behaviour (now a labeled warning) |
| Dyspepsia (adults) | 4% adults vs 2% placebo | Take with food |
| Vomiting (adults) | 4% adults vs 2% placebo | Take with food; usually transient |
| Hyperhidrosis (adults) | 4% adults vs 1% placebo; 15% PMs vs 7% EMs | Sympathomimetic effect; usually tolerable |
| Ejaculation disorder (adult males) | 4% adult males vs 1% placebo; 6% PMs vs 2% EMs | Markedly higher in CYP2D6 PMs; counsel; consider dose reduction |
| Abnormal dreams (adults) | 4% adults vs 3% placebo | Usually tolerable; reduce dose if persistent and disruptive |
| Weight decreased | 3% children, 2% adults vs 0%, 1% placebo | Plot growth at every visit in children; less than with stimulants |
| Anorexia (children/adolescents) | 3% children vs 1% placebo | Distinguish from “decreased appetite”; manage with calorie-dense foods |
| Palpitations (adults) | 3% adults vs 1% placebo | Investigate if persistent; ECG if cardiac concern |
| Hot flush (adults) | 3% adults vs 0% placebo | Sympathomimetic effect |
| Chills (adults) | 3% adults vs 0% placebo | Generally tolerable |
| Libido decreased (adults) | 3% adults vs 1% placebo | Counsel; consider dose reduction |
| Sleep disorder (adults) | 3% adults vs 1% placebo; 7% PMs vs 3% EMs | Distinct from “insomnia”; investigate sleep architecture if persistent |
| Paraesthesia (adults) | 3% adults vs 0% placebo | Usually mild and transient |
| Dysmenorrhea (adult females) | 3% adult females vs 2% placebo | Counsel; may improve with continued therapy |
| Rash (children/adolescents) | 2% children vs 1% placebo | Usually mild; evaluate for serious cutaneous reactions if extensive |
| Feeling jittery (adults) | 2% adults vs 1% placebo | Often dose-related |
| Dysuria (adults) | 2% adults vs 0% placebo | Reflects bladder neck noradrenergic effects; assess for urinary retention |
| Thirst (adults) | 2% adults vs 1% placebo | Generally tolerable; ensure adequate hydration |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Suicidal ideation in pediatric patients (boxed warning) | 0.4% (5/1357) atomoxetine vs 0% (0/851) placebo in pooled pediatric trials All events in children ≤12 years; all in first month; 1 attempt, no completed suicides | First month of treatment, especially during initiation or dose change | Counsel families about boxed warning; daily observation by caregivers; rapid prescriber access; consider discontinuation if emergent suicidality, severe agitation, or behavioural change; adult analyses did NOT show increased risk |
| Severe liver injury (post-marketing) | Rare post-marketing reports including markedly elevated enzymes (>20× ULN), jaundice, and one case requiring liver transplant | Most cases within 120 days of initiation; some occur months later; lab abnormalities can worsen for weeks after discontinuation | DISCONTINUE and DO NOT restart in patients with jaundice or laboratory evidence of liver injury; check LFTs at first symptom (pruritus, dark urine, jaundice, RUQ tenderness, “flu-like” illness); routine LFT screening NOT required |
| Sudden death, stroke, MI | Rare post-marketing reports at therapeutic doses, primarily in patients with structural cardiac disease or other serious cardiac problems | Any time; risk concentrated in those with pre-existing cardiac disease | Avoid in known structural cardiac abnormality, cardiomyopathy, serious arrhythmia, coronary disease; investigate exertional chest pain, syncope, arrhythmia promptly |
| New psychotic or manic symptoms | Uncommon; FDA labelled warning (Section 5.5, added 1/2022) | Days to weeks after initiation or dose increase | Consider discontinuation; evaluate for underlying bipolar disorder; do not restart without specialist input |
| Mania induction in patients with bipolar disorder | Increased risk; FDA labelled warning (Section 5.6, added 1/2022) | Any time during treatment | Screen for personal/family history of bipolar disorder before initiation; if mania emerges, discontinue and refer to psychiatry |
| Aggressive behaviour or hostility | Reported; FDA labelled warning (Section 5.7, added 1/2022) | During initiation or dose changes | Monitor for emergence or worsening; consider causal role of atomoxetine; evaluate for dose reduction or discontinuation |
| Clinically important BP/HR increases | ~5–10% of patients have potentially clinically important changes DBP ≥15 mmHg, SBP ≥20 mmHg, or HR ≥20 bpm; higher in PMs | During initiation or dose increase | Measure BP/HR at baseline, dose changes, and periodically; consider dose reduction or alternative therapy if sustained |
| Allergic reactions (anaphylaxis, angioedema, urticaria, rash) | Uncommon | Minutes to days; can also emerge later | Permanent discontinuation; emergency care if airway involvement; document allergy |
| Priapism | Rare post-marketing reports in pediatric and adult males; some cases prolonged >4 hours | Any time; may follow dose changes | Counsel pediatric and adult males; emergency urology evaluation for any erection >4 hours; permanent damage possible without prompt treatment |
| Urinary retention | ~1.7% adults vs 0% placebo 6% in adult CYP2D6 PMs vs 1% in EMs | Days to weeks; persistent | Counsel; consider dose reduction or discontinuation; rare cause of treatment failure |
| Mydriasis / narrow-angle glaucoma exacerbation | Increased risk; contraindicated in narrow-angle glaucoma | Any time; capsule contents are an ocular irritant if opened | Avoid in narrow-angle glaucoma; counsel about not opening capsules; immediate eye flush if contact occurs |
| Seizures | 0.2% (12/5073) in pediatric trials; 0.1% in adults slightly higher in PMs (0.3%) vs EMs (0.2%) | Any time | Use cautiously in seizure disorder; discontinue if seizure occurs |
| Orthostatic hypotension and syncope | Orthostasis 1.8% pediatric short-term vs 0.5% placebo; syncope 0.8% in long-term pediatric population | Acute dose changes; PMs at higher risk | Measure BP supine and standing if symptoms; rise slowly; reduce dose if symptomatic |
Growth Effects (Pediatric, Long-Term)
Long-term growth data come from open-label studies compared to normative population data. Weight and height gain of pediatric patients lags behind predicted for the first 9–12 months, then rebounds. At 3 years of treatment, patients have gained on average 17.9 kg (0.5 kg more than predicted) and 19.4 cm (0.4 cm less than predicted). In short-term controlled trials (up to 9 weeks), atomoxetine-treated patients lost an average of 0.4 kg and gained 0.9 cm, vs 1.5 kg gain and 1.1 cm gain in placebo. Patients who were pre-pubertal at treatment initiation (girls ≤8 y, boys ≤9 y) showed greater growth deficits at 3 years (−2.1 kg, −1.2 cm vs predicted) than late-pubertal patients. CYP2D6 poor metabolisers showed greater 2-year growth deficits than EMs (−2.4 kg, −1.1 cm vs −0.2 kg, −0.4 cm).
If an adult on standard atomoxetine doses develops marked dry mouth (35% in PMs vs 17% in EMs), severe insomnia (19% vs 11%), erectile dysfunction (21% vs 9%), or hyperhidrosis (15% vs 7%), CYP2D6 poor metaboliser phenotype is a likely contributor. Two practical responses: (1) reduce dose by approximately 50% and reassess tolerability over 4 weeks; or (2) consider CYP2D6 genotype testing if available. Co-administration of strong CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion, quinidine) phenocopies PM status — always re-check the medication list.
Drug Interactions
Atomoxetine’s interaction profile is dominated by CYP2D6 metabolism. The current Strattera PI Section 7 covers nine interaction categories: MAOIs, CYP2D6 inhibitors, antihypertensive drugs and pressor agents, albuterol/beta2 agonists, atomoxetine’s effect on CYP enzymes, alcohol, methylphenidate, drugs highly bound to plasma protein, and drugs that affect gastric pH. Atomoxetine itself does NOT inhibit clinically important CYP enzymes at therapeutic doses, and concomitant alcohol does not change atomoxetine pharmacokinetics.
Atomoxetine and its 4-hydroxyatomoxetine metabolite, at therapeutic doses, do NOT cause clinically significant inhibition or induction of CYP1A2, CYP2D6, CYP2C9, CYP2C19, or CYP3A4 enzymes. This means atomoxetine is unlikely to cause clinically meaningful changes in the metabolism of co-administered drugs that are substrates of these enzymes. This is a clinically useful difference from many antidepressants (e.g., fluoxetine, paroxetine, bupropion, fluvoxamine), which are CYP inhibitors and complicate polypharmacy management.
Monitoring
Atomoxetine monitoring is structured around five pillars: psychiatric symptoms (especially suicidal ideation in pediatric patients during the first month), cardiovascular vital signs, hepatic safety (symptom-based, not routine LFTs), growth in children, and clinical response — recognising that response takes 4–6 weeks to fully emerge.
-
Suicidal ideation and behavioural changes (pediatric)
Weekly during first month, then at every visit; daily caregiver observation
Routine Per boxed warning. All pediatric ideation events in pivotal trials occurred in first month. Counsel families to watch for agitation, irritability, anxiety, panic attacks, insomnia, hostility, aggression, akathisia, hypomania/mania, and any unusual behavioural change. Provide rapid prescriber access (phone/portal) for caregivers to report concerns. -
Blood pressure and heart rate
Baseline, then at every dose change and every routine visit (≥3-monthly)
Routine Mean expected rise: HR 5 bpm (EMs) to 9 bpm (PMs) pediatric, 7.5–11 bpm adults; some patients larger increases. About 5–10% have clinically important changes. Adult tachycardia 1.5%; pediatric 0.3%. Sustained BP >130/80 in adults or >95th centile in children warrants dose reduction or alternative therapy. -
Liver injury surveillance
Symptom-driven; routine LFTs not required
Trigger-based Counsel patients/parents about symptoms: pruritus, dark urine, jaundice, right upper quadrant pain, unexplained “flu-like” illness. Check LFTs at any such symptom. If laboratory evidence of injury or jaundice — DISCONTINUE permanently and DO NOT restart. Most cases occur within 120 days of initiation. -
Height and weight (pediatric)
Every 3–6 months; plot on growth chart
Routine First 9–12 months: weight/height lag predicted curve; subsequently rebounds. Pre-pubertal patients show greater 3-year deficits. Plot on standardised growth chart; if not tracking expected curve, consider treatment interruption or dose reduction. -
Psychiatric symptom screen
Every visit
Routine Screen for new mania, psychosis, agitation, suicidal ideation (pediatric), aggressive behaviour or hostility (added 2022). Document family history of bipolar disorder at baseline. -
ADHD response (4–6 week assessment)
At 4 weeks and 6 weeks at target dose; then every visit
Routine Atomoxetine’s full clinical effect emerges over 4–6 weeks at target dose. Use validated ADHD rating scales (e.g., ADHD-RS, Conners) to track. Do NOT abandon treatment as ineffective before 6 weeks at target dose. Adjust dose only after adequate trial. -
Sexual function (adults)
At 6 weeks and every visit thereafter
Routine Erectile dysfunction (8% adults), ejaculation disorder (4%), libido decreased (3%), dysmenorrhea (3% females). Higher rates in CYP2D6 PMs (ED 21%, ejaculation disorder 6%). Routinely inquire — patients often will not volunteer. -
Urinary symptoms
Every visit
Routine Adult urinary hesitation 5.6%, urinary retention 1.7%; markedly higher in PMs (urinary retention 6%). Investigate any new urinary symptom; consider prostatic causes in older men; rare cause of treatment discontinuation. -
CYP2D6 inhibitor / inducer review
At each medication change
Trigger-based When adding paroxetine, fluoxetine, bupropion, quinidine, terbinafine, cinacalcet, or other strong CYP2D6 inhibitors — atomoxetine dose should be reduced and slowly titrated. Conversely, when these are stopped, atomoxetine may need re-titration upward. -
ECG / cardiology referral
Only when cardiac risk factors or symptoms identified
Trigger-based Routine baseline ECG is not mandated by FDA labelling but is reasonable when family history suggests inherited arrhythmia (long QT, HCM) or in symptomatic patients. Investigate exertional chest pain, syncope, or palpitations promptly. -
Treatment continuation review
Annually
Routine Periodically reassess ongoing need for atomoxetine. No tapering required to discontinue. Symptoms typically return within 1–2 weeks of discontinuation; this is expected and not a withdrawal syndrome.
For pediatric patients in the first month of atomoxetine therapy, the highest-yield monitoring intervention is structured weekly contact (in person, by phone, or by portal message) with a brief screen for new mood, behavioural, or suicidal symptoms — alongside daily caregiver observation. After the first month, the highest-yield review combines BP/HR, weight/height plot, ADHD response (using a validated scale at 4–6 weeks), and brief LFT-symptom screen.
Contraindications & Cautions
Absolute Contraindications
- Concomitant treatment with monoamine oxidase inhibitors (MAOIs), or use within 2 weeks of MAOI discontinuation in either direction — including linezolid and IV methylene blue. Risk of serious, sometimes fatal reactions including hyperthermia, autonomic instability, and features resembling neuroleptic malignant syndrome.
- Known hypersensitivity to atomoxetine or other components of Strattera — including prior anaphylaxis, angioedema, urticaria, or rash.
- Narrow-angle glaucoma — atomoxetine causes mydriasis and is not recommended.
- Pheochromocytoma or history of pheochromocytoma — serious reactions including elevated BP and tachyarrhythmia have been reported.
- Severe cardiovascular disorders that would deteriorate with clinically important increases in BP (e.g., 15–20 mmHg) or HR (e.g., 20 bpm) — includes severe coronary disease, severe valvular disease, severe arrhythmias, severe hypertension.
Relative Contraindications (Specialist Input Recommended)
- Pediatric depression or active suicidal ideation — given the boxed warning on suicidal ideation in pediatric patients, use only when ADHD treatment benefit clearly outweighs risk; co-management with mental health professional and intensive monitoring required.
- Bipolar disorder or strong family history — added in Jan 2022 label update (Section 5.6); screen all patients before initiation; if mania emerges, discontinue and refer to psychiatry.
- Pre-existing structural cardiac abnormalities, cardiomyopathy, serious arrhythmias, or other serious cardiac disease in children/adolescents — sudden death has been reported; cardiology assessment required before considering use.
- Adults with clinically significant cardiac abnormalities — sudden deaths, stroke, MI reported; consideration should be given to NOT treating these patients.
- Active hepatic disease or history of severe drug-induced liver injury — atomoxetine has caused rare but severe liver injury including transplant-requiring failure; avoid unless benefit clearly outweighs risk; if used, vigilance for symptoms is essential.
- Pre-existing significant hypertension or tachyarrhythmia — ensure stable control before initiation.
- Pediatric <6 years — not approved; safety and efficacy not established.
- Pregnancy — limited human data; animal toxicity at maternally toxic doses; use only when benefit justifies risk.
- Lactation — limited data; weigh individual benefits and risks.
- Moderate-to-severe hepatic impairment — dose reductions required (50% in Child-Pugh B, 25% in Child-Pugh C).
Use with Caution
- Known CYP2D6 poor metabolisers or patients on strong CYP2D6 inhibitors — start at lower dose and titrate slowly; monitor for dose-related adverse effects.
- History of seizure disorder or EEG abnormalities — atomoxetine may slightly lower seizure threshold; ensure good baseline seizure control before initiation; discontinue if seizure occurs.
- Concurrent use of antihypertensives or pressor agents — monitor BP closely.
- Concurrent beta2 agonists (especially systemic/high-dose albuterol) — potentiated cardiovascular effects.
- History of urinary retention, prostatic hyperplasia, or bladder outlet obstruction — atomoxetine can cause urinary hesitation and retention.
- Pediatric patients on long-term therapy — monitor growth quarterly; especially important for pre-pubertal patients.
- Older adults (≥65 years) — limited safety data; cardiovascular comorbidity is more common; baseline BP/HR and ECG reasonable.
- Patients with depression, anxiety, or suicidal ideation history — close monitoring throughout treatment; integrated mental health management.
- Patients with active or recent substance use disorder — atomoxetine is preferred over stimulants in these patients due to lack of abuse potential; however, comorbid substance use complicates ADHD management; specialist input recommended.
Strattera (atomoxetine) increased the risk of suicidal ideation in short-term studies in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). Anyone considering the use of Strattera in a child or adolescent must balance this risk with the clinical need.
Pooled analyses of short-term (6 to 18 weeks) placebo-controlled trials of Strattera in children and adolescents (12 trials involving over 2200 patients) revealed an average risk of suicidal ideation of 0.4% (5/1357) on Strattera vs 0% (0/851) on placebo. There was 1 suicide attempt; no completed suicides. All ideation events occurred in children ≤12 years old, and all occurred during the first month of treatment.
A similar analysis in adult patients treated with Strattera for either ADHD or major depressive disorder did NOT reveal an increased risk of suicidal ideation or behaviour.
Pre-treatment: Discuss the boxed warning with patients (if age-appropriate) and families. Document discussion. Screen for personal/family history of bipolar disorder, mania, or hypomania (Section 2.4, added 1/2022).
During treatment: All pediatric patients should be monitored closely for clinical worsening, suicidality, and unusual changes in behaviour, especially during the initial few months and at times of dose changes. Counsel families to observe daily for the emergence of agitation, irritability, anxiety, panic attacks, insomnia, hostility, aggression, akathisia, hypomania, or mania — these may be precursors to suicidality. Consider discontinuation if such symptoms emerge severely or abruptly.
Strattera is not approved for major depressive disorder.
Patient Counselling
Purpose of Therapy
Strattera (atomoxetine) is a non-stimulant prescription medicine used to treat attention-deficit/hyperactivity disorder (ADHD) in adults and children aged 6 and older. It is different from stimulant ADHD medicines like Ritalin, Concerta, Adderall, and Vyvanse — it is not a controlled substance and works in a different way. It can help improve attention, reduce impulsivity, and reduce hyperactivity. Strattera works best when combined with non-medication strategies — behavioural strategies, school or workplace accommodations, sleep hygiene, exercise, and (where appropriate) parent or family training. It is not a cure for ADHD; it manages symptoms while you are taking it.
How to Take
Strattera is usually taken once a day in the morning, or sometimes split into two doses (morning and late afternoon). It can be taken with or without food. Swallow the capsules whole — do not open them, chew them, or crush them. The contents of the capsule can irritate the eye if it gets in. If a capsule is accidentally opened and the contents touch the eye, flush the eye immediately with water and seek medical advice. Strattera does not need to be tapered when stopped.
Sources
- U.S. Food and Drug Administration. STRATTERA (atomoxetine) capsules — Prescribing Information. Eli Lilly and Company. Revised January 2022. Reference ID 4916119. accessdata.fda.gov Most recent FDA-approved label for Strattera; primary source for all quantitative adverse-event incidence data, drug interaction sections, dosing recommendations, weight loss data, growth data, CYP2D6 PM/EM data, and labelled warnings used in this monograph. Recent major changes (1/2022): Bipolar Screening (2.4), New Psychotic/Manic Symptoms (5.5), Bipolar Disorder Screening (5.6), Aggressive Behaviour or Hostility (5.7).
- U.S. Food and Drug Administration. FDA approves first non-stimulant drug for treatment of ADHD. FDA News Release, November 26, 2002. Press release accompanying the original 2002 FDA approval of atomoxetine — the first non-stimulant medication approved for ADHD.
- U.S. Food and Drug Administration. FDA Public Health Advisory: Suicidal Thinking in Children and Adolescents Being Treated with Strattera. September 29, 2005. Original FDA public health advisory leading to the boxed warning on suicidal ideation in pediatric patients.
- Michelson D, Faries D, Wernicke J, et al; Atomoxetine ADHD Study Group. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics. 2001;108(5):E83. doi: 10.1542/peds.108.5.e83 Pivotal pediatric phase 3 randomized dose-response trial supporting FDA approval; established the 1.2 mg/kg/day target dose.
- Michelson D, Adler L, Spencer T, et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry. 2003;53(2):112–120. doi: 10.1016/S0006-3223(02)01671-2 Pivotal adult phase 3 trials supporting FDA approval in adult ADHD.
- Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2018;5(9):727–738. doi: 10.1016/S2215-0366(18)30269-4 Network meta-analysis comparing ADHD medications across age groups; methylphenidate is favoured in children/adolescents while amphetamines are favoured in adults; atomoxetine is positioned as a useful second-line option.
- Cooper WO, Habel LA, Sox CM, et al. ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med. 2011;365(20):1896–1904. doi: 10.1056/NEJMoa1110212 Large cohort study (~1.2 million patients aged 2–24) showing no significant increase in serious cardiovascular events with ADHD medications including atomoxetine.
- Wolraich ML, Hagan JF Jr, Allan C, et al; Subcommittee on Children and Adolescents with Attention-Deficit/Hyperactive Disorder. Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics. 2019;144(4):e20192528. doi: 10.1542/peds.2019-2528 American Academy of Pediatrics guideline; recommends FDA-approved non-stimulants (atomoxetine, guanfacine ER, clonidine ER) as alternatives when stimulants are not tolerated, ineffective, or undesirable.
- National Institute for Health and Care Excellence (NICE). Attention deficit hyperactivity disorder: diagnosis and management. NICE guideline NG87. nice.org.uk/guidance/ng87 UK national guideline; positions atomoxetine as a non-stimulant option after methylphenidate or lisdexamfetamine, particularly when stimulants are contraindicated or not tolerated.
- Bymaster FP, Katner JS, Nelson DL, et al. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002;27(5):699–711. doi: 10.1016/S0893-133X(02)00346-9 Foundational mechanistic study demonstrating atomoxetine’s selective effect on prefrontal cortex norepinephrine and dopamine, mediated through NET inhibition.
- Sauer JM, Ring BJ, Witcher JW. Clinical pharmacokinetics of atomoxetine. Clin Pharmacokinet. 2005;44(6):571–590. doi: 10.2165/00003088-200544060-00002 Comprehensive review of atomoxetine pharmacokinetics, including detailed CYP2D6 phenotype data, drug-drug interactions, and pediatric/adult PK comparisons.
- Garnock-Jones KP, Keating GM. Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents. Paediatr Drugs. 2009;11(3):203–226. doi: 10.2165/00148581-200911030-00005 Comprehensive Adis review of atomoxetine in pediatric ADHD covering efficacy, tolerability, dosing, and clinical positioning.
- Bangs ME, Tauscher-Wisniewski S, Polzer J, et al. Meta-analysis of suicide-related behavior events in patients treated with atomoxetine. J Am Acad Child Adolesc Psychiatry. 2008;47(2):209–218. doi: 10.1097/chi.0b013e31815d88b2 Manufacturer’s pooled meta-analysis of suicide-related events that informed the FDA boxed warning; documented the 0.4% pediatric ideation rate vs 0% in placebo.
- Reed VA, Buitelaar JK, Anand E, et al. The safety of atomoxetine for the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a comprehensive review of over a decade of research. CNS Drugs. 2016;30(7):603–628. doi: 10.1007/s40263-016-0349-0 Comprehensive long-term safety review covering hepatic, cardiovascular, growth, suicidal ideation, and other safety signals from over a decade of post-marketing experience.
- Huybrechts KF, Bröms G, Christensen LB, et al. Association between methylphenidate and amphetamine use in pregnancy and risk of congenital malformations. JAMA Psychiatry. 2018;75(2):167–175. doi: 10.1001/jamapsychiatry.2017.3644 Large multinational cohort study evaluating birth defect risk with stimulant exposure during pregnancy; provides reference data for ADHD medication safety in pregnancy.