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Atomoxetine

Atomoxetine
Systematic (IUPAC) name
(3R)-N-methyl-3-(2-methylphenoxy)-3-phenylpropan-1-amine; (R)-N-methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine
Clinical data
Trade names Strattera
AHFS/Drugs.com
MedlinePlus
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 63 to 94%[1][2][3]
Protein binding 98%[1][2][3]
Metabolism Hepatic, via CYP2D6[1][2][3]
Biological half-life 5.2 hours[1][2][3]
Excretion Renal (80%) and faecal (17%)[1][2][3]
Identifiers
CAS Registry Number  N
ATC code N06
PubChem CID:
IUPHAR/BPS
DrugBank  Y
ChemSpider  Y
UNII  Y
KEGG  Y
ChEBI  Y
ChEMBL  Y
Chemical data
Formula C17H21NO
Molecular mass 255.36 g/mol
291.81 g/mol (hydrochloride)
 N   

Atomoxetine (brand name: Strattera) is a norepinephrine reuptake inhibitor approved for the treatment of attention deficit hyperactivity disorder (ADHD).[4]

Contents

  • Medical use 1
    • Attention deficit hyperactivity disorder 1.1
    • Investigational uses 1.2
  • Adverse effects 2
    • Contraindications 2.1
    • Interactions 2.2
    • Overdose 2.3
  • Detection in biological fluids 3
  • Chemistry and composition 4
  • Pharmacology 5
  • History 6
  • Brand names 7
  • References 8
  • External links 9

Medical use

Attention deficit hyperactivity disorder

Classified as a norepinephrine (noradrenaline) reuptake inhibitor, atomoxetine is approved for use in children, adolescents, and adults.[4] However, its efficacy has not been studied in children under six years old.[2] Its primary advantage over the standard stimulant treatments for ADHD is that it has little known abuse potential.[2]

The initial therapeutic effects of atomoxetine usually take 2–4 weeks to become apparent.[1] A further 2–4 weeks may be required for the full therapeutic effects to be seen.[5] Its efficacy may be less than that of stimulant medications.[6]

Unlike α2 adrenoceptor agonists such as guanfacine and clonidine, atomoxetine's use can be abruptly stopped without significant withdrawal effects being seen.[2]

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.[7][8][9] Several randomised double-blind placebo-controlled trials found that atomoxetine was an efficacious treatment for various disorders like pediatric bedwetting,[10] binge eating disorder,[11] and is an efficacious weight loss medication.[12]

Adverse effects

Incidence of adverse effects:[2][3][13][14]

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:

  • 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%)
  • Depression
  • Sinus headache
  • Dermatitis
  • Mood swings

Uncommon (0.1-1% incidence) adverse effects include:

Rare (0.01-0.1% incidence) adverse effects including

The FDA of the US has issued a black box warning for suicidal behaviour/ideation.[3] Similar warnings have been issued in Australia.[2][16] Unlike stimulant medications, atomoxetine does not have abuse liability or the potential to cause withdrawal effects on abrupt discontinuation.[2]

Contraindications

Contraindications include:[2]

  • 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
-ventricular flutter
-advanced arteriosclerosis

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.[17] Other possible drug interactions include:[2]

Overdose

Atomoxetine is relatively non-toxic in overdose. Single-drug overdoses involving over 1500 mg of atomoxetine have not resulted in death.[2] The most common symptoms of overdose include:[2]

  • Gastrointestinal symptoms
  • Somnolence
  • Dizziness
  • Tremor
  • Abnormal behaviour
  • Hyperactivity
  • Agitation
  • Dry mouth
  • Tachycardia
  • Hypertension
  • Mydriasis

Less common symptoms:[2]

The recommended treatment for atomoxetine overdose includes use of activated charcoal to prevent further absorption of the drug.[2]

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.[18]

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.[4] It has a solubility of 27.8 mg/ml in water.[4] Atomoxetine is a white solid that exists as a granular powder inside the capsule, along with pregelatinized starch and dimethicone.[4] 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.[4]

Pharmacology

Atomoxetine inhibits NET, SERT, and DAT with respective Ki values of 5, 77, and 1451 nM.[19]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.[20] Atomoxetine's selective increase in NE and DA are due to a lack of high concentrations of DAT in the prefrontal cortex, and the nucleus accumbens's relative paucity of NE neurons.[21] Atomoxetine also acts as an NMDA receptor antagonist at clinically relevant doses.[22] 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.[23][24]

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.[25] 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.[26]

Binding profile[19][20][25][27]
Protein Ki (nM) for atomoxetine Ki (nM) for 4-hydroxyatomoxetine
SERT 77 ?
NET 5 ?
DAT 1451 ?
5-HT receptors >1000 ?
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
σ1 receptor >1000 ?

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.[28] 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.[29] On 1 September 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States.[30] 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."[31]

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 generic made by Sun Pharmaceuticals.

References

  1. ^ a b c d e f "atomoxetine (Rx) – Strattera". Medscape Reference. WebMD. Retrieved 10 November 2013. 
  2. ^ a b c d e f g h i j k l m n o p q "STRATTERA® (atomoxetine hydrochloride)". TGA eBusiness Services. Eli Lilly Australia Pty. Limited. 21 August 2013. Retrieved 10 November 2013. 
  3. ^ a b c d e f g "ATOMOXETINE HYDROCHLORIDE capsule [Mylan Pharmaceuticals Inc.]". DailyMed. Mylan Pharmaceuticals Inc. October 2011. Retrieved 10 November 2013. 
  4. ^ a b c d e f (atomoxetine hydrochloride) CAPSULES for Oral Use. Full Prescribing Information"®"STRATTERA (PDF).  
  5. ^ Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell.  
  6. ^ Kooij, JJS (2013). Adult ADHD Diagnostic Assessment and Treatment (PDF). Springer London.  
  7. ^ Spencer TJ, Faraone SV, Michelson D, Adler, LA; Reimherr, FW; Glatt, SJ; Biederman, J (March 2006). "Atomoxetine and adult attention-deficit/hyperactivity disorder: the effects of comorbidity". The Journal of Clinical Psychiatry 67 (3): 415–20.  
  8. ^ Carpenter LL, Milosavljevic N, Schecter JM, Tyrka AR, Price LH (October 2005). "Augmentation with open-label atomoxetine for partial or non-response to antidepressants". The Journal of Clinical Psychiatry 66 (10): 1234–8.  
  9. ^ Kratochvil CJ, Newcorn JH, Arnold LE, Duesenberg, D; Emslie, GJ; Quintana, H; Sarkis, EH; Wagner, KD; Gao, H; Michelson, D; Biederman, J (September 2005). "Atomoxetine alone or combined with fluoxetine for treating ADHD with comorbid depressive or anxiety symptoms". Journal of the American Academy of Child and Adolescent Psychiatry 44 (9): 915–24.  
  10. ^ Sumner, CR; Schuh, KJ; Sutton, VK; Lipetz, R; Kelsey, DK (December 2006). "Placebo-controlled study of the effects of atomoxetine on bladder control in children with nocturnal enuresis". Journal of Child and Adolescent Psycho-pharmacology 16 (6): 699–711.  
  11. ^ McElroy, SL; Guerdjikova, A; Kotwal, R; Welge, JA; Nelson, EB; Lake, KA; Keck, PE Jr; Hudson, JI (March 2007). "Atomoxetine in the treatment of binge-eating disorder: a randomized placebo-controlled trial". The Journal of Clinical Psychiatry 68 (3): 390–8.  
  12. ^ Gadde, KM; Yonish, GM; Wagner, HR; Foust, MS; Allison, DB (July 2006). "Atomoxetine for weight reduction in obese women: a preliminary randomized controlled trial". International Journal of Obesity 30 (7): 1138–42.  
  13. ^ "Strattera 10mg, 18mg, 25mg, 40mg, 60mg, 80mg or 100mg hard capsules". electronic Medicines Compendium. 28 May 2013. Retrieved 10 November 2013. 
  14. ^ "Strattera Product Insert". Retrieved 8 December 2013. 
  15. ^ "STRATTERA Medication Guide" (PDF).  
  16. ^ "Atomoxetine and suicidality in children and adolescents". Australian Prescriber 36 (5). October 2013. p. 166. Retrieved 10 November 2013. 
  17. ^ Horn, John R.; Hansten, Philip D. (2008). "Get to Know an Enzyme: CYP2D6". Pharmacy Times. Retrieved 19 February 2015. 
  18. ^ Baselt, Randall C. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 118–20.  
  19. ^ a b Roth, BL; Driscol, J (12 January 2011). Database"i"PDSP K. Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 10 November 2013. 
  20. ^ a b Bymaster, FP; Katner, JS; Nelson, DL; Hemrick-Luecke, SK; Threlkeld, PG; Heiligenstein, JH; Morin, SM; Gehlert, DR; Perry, KW (November 2002). "Atomoxetine Increases Extracellular Levels of Norepinephrine and Dopamine in Prefrontal Cortex of Rat: A Potential Mechanism for Efficacy in Attention Deficit/Hyperactivity Disorder" (PDF). Neuropsychopharmacology 27 (5): 699–711.  
  21. ^ Stahl, Stephen M. (17 March 2008). "17". Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications (3rd ed.). New York: Cambridge University Press. p. 891.  
  22. ^ Ludolph, AG; Udvardi, PT; Schaz, U; Henes, C; Adolph, O; Weigt, HU; Fegert, JM; Boeckers, TM; Föhr, KJ (May 2010). "Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations" (PDF). British Journal of Pharmacology 160 (2): 283–291.  
  23. ^ Lesch, KP; Merker, S; Reif, A; Novak, M (June 2013). "Dances with black widow spiders: dysregulation of glutamate signalling enters centre stage in ADHD". European Neuropsychopharmacology 23 (6): 479–491.  
  24. ^ "New gene study of ADHD points to defects in brain signaling pathways". Children's Hospital of Philadelphia. 4 December 2011. 
  25. ^ a b Creighton, CJ; Ramabadran, K; Ciccone, PE; Liu, J; Orsini, MJ; Reitz, AB (2 August 2004). "Synthesis and biological evaluation of the major metabolite of atomoxetine: elucidation of a partial kappa-opioid agonist effect.". Bioorganic & Medicinal Chemistry Letters 14 (15): 4083–5.  
  26. ^ Kobayashi, T; Washiyama, K; Ikeda, K (Jun 2010). "Inhibition of G-protein-activated inwardly rectifying K+ channels by the selective norepinephrine reuptake inhibitors atomoxetine and reboxetine.". Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 35 (7): 1560–9.  
  27. ^ Bymaster, FP; Katner, JS; Nelson, DL; Hemrick-Luecke, SK; Threlkeld, PG; Heiligenstein, JH; Morin, SM; Gehlert, DR; Perry, KW (November 2002). "Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder". Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 27 (5): 699–711.  
  28. ^ "Patent and Exclusivity Search Results". Electronic Orange Book. US Food and Drug Administration. Retrieved 26 April 2009. 
  29. ^ "Drugmaker Eli Lilly loses patent case over ADHD drug, lowers revenue outlook". Chicago Tribune. 
  30. ^ "Sun Pharma receives USFDA approval for generic Strattera capsules". International Business Times. 
  31. ^ "Sun Pharma Q1 2011-12 Earnings Call Transcript 10.00 am, July 29, 2011" (PDF). 

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
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