|Systematic (IUPAC) name|
|Pregnancy cat.||B3 (AU) C (US)|
|Legal status||Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)|
|Bioavailability||63 to 94%|
|Metabolism||Hepatic, via CYP2D6|
|Excretion||Renal (80%) and faecal (17%)|
|Mol. mass||255.36 g/mol
291.81 g/mol (hydrochloride)
|(what is this?)|
Atomoxetine (brand name: Strattera) is a drug approved for the treatment of attention-deficit hyperactivity disorder (ADHD). It is a selective norepinephrine reuptake inhibitor (NRI), not to be confused with serotonin norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs), both of which are currently the most prescribed form of antidepressants.
- 1 Medical use
- 2 Adverse effects
- 3 Detection in biological fluids
- 4 Chemistry and composition
- 5 Pharmacology
- 6 Synthesis
- 7 History
- 8 Production and brand-names
- 9 References
- 10 External links
Attention deficit-hyperactivity disorder
Classified as a norepinephrine (noradrenaline) reuptake inhibitor, atomoxetine is approved for use in children, adolescents, and adults. However, its efficacy has not been studied in children under six years old. Its primary advantage over the standard stimulant treatments for ADHD is that it has no abuse potential.
The initial therapeutic effects of atomoxetine usually take 2-4 weeks to be become apparent. A further 2-4 weeks may be required for the full therapeutic effects to be seen. Its efficacy may be less than that of stimulant medications.
There has been some suggestion that atomoxetine might be a helpful adjunct in patients with major depression, especially in cases where ADHD occurs comorbidly to major depression. A randomised double-blind placebo-controlled trial found that atomoxetine was an efficacious treatment for paediatric nocturnal enuresis. Another randomised double-blind placebo-controlled trial found that atomoxetine was an efficacious treatment for binge eating disorder. A randomised double-blind placebo-controlled trial found that atomoxetine is an efficacious weight loss medication.
Very common (>10% incidence) adverse effects include:
- Nausea (26%)
- Xerostomia (dry mouth) (20%)
- Appetite loss (16%)
- Insomnia (15%)
- Fatigue (10%)
Common (1-10% incidence) adverse effects include:
- Constipation (8%)
- Dizziness (8%)
- Erectile dysfunction (8%)
- Somnolence (8%)
- Abdominal pain (7%)
- Urinary hesitation (6%)
- Tachycardia (high heart rate) (5-10%)
- Hypertension (high blood pressure) (5-10%)
- Irritability (5%)
- Abnormal Dreams (4%)
- Dyspepsia (4%)
- Ejaculation disorder (4%)
- Hyperhidrosis (4%)
- Vomiting (4%)
- Hot flashes (3%)
- Paraesthesia (3%)
- Menstrual disorder (3%)
- Weight loss (2%)
- Sinus headache
- Mood swings
Uncommon (0.1-1% incidence) adverse effects include:
Rare (0.01-0.1% incidence) adverse effects include:
- Raynaud's phenomenon
- Abnormal/increased liver function tests
- Liver injury
- Acute hepatic failure
- Urinary retention
- Male genital pain
The FDA of the US has issued a black box warning for suicidal behaviour/ideation. Similar warnings have been issued in Australia. Unlike stimulant medications atomoxetine does not have abuse liability or the potential to cause withdrawal effects on abrupt discontinuation.
- Hypersensitivity to atomoxetine or any of the excipients in the product
- Symptomatic cardiovascular disease including:
- -moderate to severe hypertension
- -atrial fibrillation
- -atrial flutter
- -ventricular tachycardia
- -ventricular fibrillation
- -or ventricular flutter
- -advanced arteriosclerosis
- Severe cardiovascular disorders
- Uncontrolled hyperthyroidism
- Concomitant treatment with monoamine oxidase inhibitors
- Narrow angle glaucoma
- Poor metabolisers (due to the metabolism of atomoxetine by CYP2D6)
Atomoxetine is a substrate for CYP2D6 and hence concurrent treatment with CYP2D6 inhibitors or inducers is not recommended as this can lead to significant elevations or reductions of plasma atomoxetine levels, respectively. Other possible drug interactions include with:
- Antihypertensive and pressor agents, due to the potential pressor effect of indirect sympathetics such as atomoxetine.
- Norepinephrine-acting agents such as α1 adrenoceptor agonists or norepinephrine reuptake inhibitors due to the potential for additive or synergistic pharmacologic effects.
- β-adrenoceptor agonists due to the potential for the effects of these drugs to be potentiated by atomoxetine.
- Tricyclic antidepressants as they may potentiate the cardiovascular effects of atomoxetine.
- Highly plasma protein-bound drugs due to the potential of atomoxetine to displace these drugs from plasma proteins and hence potentiate their adverse effects. Examples include diazepam, paroxetine and phenytoin.
- Gastrointestinal symptoms
- Abnormal behaviour
- Dry mouth
and less commonly:
- QTc interval prolongation
Recommended treatment of overdoses include activated charcoal treatment to prevent further absorption of the drug.
Detection in biological fluids
Atomoxetine may be quantitated in plasma, serum or whole blood in order to distinguish extensive versus poor metabolizers in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage.
Chemistry and composition
Atomoxetine is designated chemically as (−)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride, and has a molecular mass of 291.82. It has a solubility of 27.8 mg/mL in water. Atomoxetine is a white solid that exists as a granular powder inside the capsule, along with pre-gelatinized starch and dimethicone. The capsule shells contain gelatin, sodium lauryl sulfate, FD&C Blue No. 2, synthetic yellow iron oxide, titanium dioxide, red iron oxide, edible black ink, and trace amounts of other inactive ingredients.
Atomoxetine inhibits NET, SERT and DAT with respective Ki values of 5, 77 and 1451 nM. In microdialysis studies it increased NE and DA levels by 3 fold in the prefrontal cortices but did not alter DA levels in the striatum or nucleus accumbens. Atomoxetine also acts as an NMDA-receptor antagonist at clinically relevant doses. The role of NMDA-receptor antagonism in atomoxetine's therapeutic profile remains to be further elucidated, but recent literature has further implicated glutaminergic dysfunction as central in ADHD pathophysiology and etiology.
4-hydroxyatomoxetine, the principle metabolite of atomoxetine, exhibits affinity for μ-opioid receptors and κ-opioid receptors. Creighton et al. reported no activation of μ-opioid receptors and a partial agonist effect at κ-opioid receptors. The clinical significance of these effects are not known.
|Protein||Ki (nM) for atomoxetine||Ki (nM) for 4-hydroxyatomoxetine|
|Alpha adrenergic receptors||>1000||?|
|Beta adrenergic receptors||>1000||?|
|D1 & D2||>1000||?|
|M1 & M2||>1000||?|
|H1 & H2||>1000||?|
|δ1 opioid receptor||?||300|
|κ1 opioid receptor||?||95|
|μ opioid receptor||?||422|
Foster, B. J.; Lavagnino, E. R.; European Patent, 1982, EP 0052492 .
This compound is manufactured, marketed and sold in the United States under the brand name Strattera by Eli Lilly and Company as a hydrochloride salt (atomoxetine HCl), the original patent filing company, and current U.S. patent owner. There is currently no generic manufactured directly in the United States since it is under patent until 2017. On August 12, 2010, Lilly lost a lawsuit that challenged Lilly's patent on Strattera, increasing the likelihood of an earlier entry of a generic into the US market. On September 1, 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States. In a July 29, 2011 conference call, however, Sun Pharmaceutical's Chairman stated "Lilly won that litigation on appeal so I think [generic Strattera]’s deferred."
Production and brand-names
In India, Atomoxetine is found under different names like Tomoxetin, Attentrol, Axepta, Atokem and Attentin.
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- Strattera by Eli Lilly and Company
- RxList.com - Strattera
- Detailed Strattera Consumer Information: Uses, Precautions, Side Effects
- All disclosed Lilly trials
- MSDS for Atomoxetine HCl
- Strattera Related Published Studies