Atomoxetine (brand name: Strattera) is a norepinephrine reuptake inhibitor approved for the treatment of attention deficit hyperactivity disorder (ADHD).
Medical use
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 little known abuse potential.
The initial therapeutic effects of atomoxetine usually take 2â€"4 weeks to be become apparent. A further 2â€"4 weeks may be required for the full therapeutic effects to be seen. Its efficacy may be less than that of stimulant medications.
Unlike α2 adrenoceptor agonists such as guanfacine and clonidine, atomoxetine's use can be abruptly stopped without significant withdrawal effects being seen.
Investigational uses
There has been some suggestion that atomoxetine might be a helpful adjunct in people with major depression, especially in cases where ADHD occurs comorbidly to major depression. Several randomised double-blind placebo-controlled trials found that atomoxetine was an efficacious treatment for various disorders like paediatric bedwetting, binge eating disorder, and is an efficacious weight loss medication.
Adverse effects
Incidence of adverse effects:
Very common (>10% incidence) adverse effects include:
- Nausea (26%)
- Dry mouth (20%)
- Appetite loss (16%)
- Insomnia (15%)
- Fatigue (10%)
- Headache
- Cough
Common (1-10% incidence) adverse effects include:
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
- Jaundice
- Hepatitis
- Liver injury
- Acute liver failure
- Urinary retention
- Priapism
- 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.
Contraindications
Contraindications include:
Interactions
Atomoxetine is a substrate for CYP2D6 and hence concurrent treatment with CYP2D6 inhibitors such as bupropion (Wellbutrin) or fluoxetine (Prozac) is not recommended, as this can lead to significant elevations of plasma atomoxetine levels. CYP2D6 is not very susceptible to enzyme induction. Other possible drug interactions include:
Overdose
Atomoxetine is relatively non-toxic in overdose. Single-drug overdoses involving over 1500Â mg of atomoxetine have not resulted in death. The most common symptoms of overdose include:
Less common symptoms:
- Seizures
- QTc interval prolongation
The recommended treatment for atomoxetine overdose includes use of activated charcoal 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 (âˆ')-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 pregelatinized starch and dimethicone. The capsule shells contain gelatin, sodium lauryl sulfate, FD&C Blue No. 2, yellow iron oxide, titanium dioxide, red iron oxide, edible black ink, and trace amounts of other inactive ingredients.
Pharmacology
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 three-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 relatively weak affinity for μ-opioid receptors and κ-opioid receptors. Creighton et al. reported antagonism of μ-opioid receptors and a partial agonist effect at κ-opioid receptors. The clinical significance of these effects are not known.
Atomoxetine has been found to inhibit both brain and cardiac G protein-coupled inwardly-rectifying potassium channels, a characteristic it shares with the related drug reboxetine.
Synthesis
The first step of the synthesis of atomoxetine appears to be a Mannich reaction between acetophenone, paraformaldehyde and dimethylamine, although that step is not formally written in the scheme cited below.
Foster, B. J.; Lavagnino, E. R.; European Patent, 1982, EP 0052492Â .
History
This compound is manufactured, marketed, and sold in the United States as the hydrochloride salt (atomoxetine HCl) under the brand name Strattera by Eli Lilly and Company, the original patent-filing company and current U.S. patent owner. Strattera was approved by the FDA in 2006 for the treatment of ADHD. No generic is manufactured directly in the United States since it is under patent until 2017. On 12 August 2010, Lilly lost a lawsuit that challenged its patent on Strattera, increasing the likelihood of an earlier entry of a generic into the US market. On 1 September 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States. In a 29 July 2011 conference call, however, Sun Pharmaceutical's Chairman stated "Lilly won that litigation on appeal so I think [generic Strattera]’s deferred."
Brand names
In India, atomoxetine is sold under brand names including Tomoxetin, Attentrol, Axepta, Atokem, and Attentin. In Romania atomoxetine is sold under the brand name Strattera and as a money saving generic made by Sun Pharmaceuticals.
See also
- Doxylamine
- Orphenadrine
- Fluoxetine
- Reboxetine
References
External links
- 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