Atomoxetine

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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
AHFS/Drugs.commonograph
MedlinePlusa603013
Pregnancy cat.B3 (AU) C (US)
Legal statusPOM (UK) -only (US)
RoutesOral (Capsules: 10, 18, 25, 40, and 60 mg; in some countries 80 and 100 mg are also available)
Pharmacokinetic data
Bioavailability63 to 94%
Protein binding40%
MetabolismHepatic, via CYP2D6
Half-life5 hours
ExcretionRenal (>80%) and fecal (<17%)
Identifiers
CAS number83015-26-3 N
ATC codeN06BA09
PubChemCID 54841
DrugBankDB00289
ChemSpider49516 YesY
UNIIASW034S0B8 YesY
KEGGD07473 YesY
ChEBICHEBI:127342 YesY
ChEMBLCHEMBL641 YesY
Chemical data
FormulaC17H21NO 
Mol. mass255.36 g/mol
291.81 g/mol (hydrochloride)
 N (what is this?)  (verify)
 
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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
AHFS/Drugs.commonograph
MedlinePlusa603013
Pregnancy cat.B3 (AU) C (US)
Legal statusPOM (UK) -only (US)
RoutesOral (Capsules: 10, 18, 25, 40, and 60 mg; in some countries 80 and 100 mg are also available)
Pharmacokinetic data
Bioavailability63 to 94%
Protein binding40%
MetabolismHepatic, via CYP2D6
Half-life5 hours
ExcretionRenal (>80%) and fecal (<17%)
Identifiers
CAS number83015-26-3 N
ATC codeN06BA09
PubChemCID 54841
DrugBankDB00289
ChemSpider49516 YesY
UNIIASW034S0B8 YesY
KEGGD07473 YesY
ChEBICHEBI:127342 YesY
ChEMBLCHEMBL641 YesY
Chemical data
FormulaC17H21NO 
Mol. mass255.36 g/mol
291.81 g/mol (hydrochloride)
 N (what is this?)  (verify)
Eli Lilly's Strattera capsules.

Atomoxetine 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 selective serotonin and norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs), both of which are currently the most prescribed form of antidepressants. 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. Generics of atomoxetine are sold in all other countries; they are manufactured by Torrent Pharmaceuticals using the label Tomoxetin, Ranbaxy Laboratories (through its Division: Solus) using the label Attentin, Sun Pharmaceuticals (through its Division: Milmet Pharmaceuticals), and Intas Biopharmaceuticals. There is currently no generic manufactured directly in the United States since it is under patent until 2017.[1] 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.[2] On September 1, 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States.[3] 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."[4]

Contents

Use

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 advantage over stimulants for the treatment of ADHD is that it has less abuse potential than stimulants,[5][6] is not scheduled as a controlled substance, and has shown in clinical trials to offer 24-hour coverage of symptoms associated with ADHD in adults and children.[7]

Initial therapeutic effects of atomoxetine may take at least a week to be felt. Atomoxetine should be taken for 6–8 weeks before deciding whether it is effective or not. Many people respond to atomoxetine who don't respond to stimulants (for ADHD). Atomoxetine may be preferred over amphetamine-based stimulants in patients with psychiatric disorders, those who cannot tolerate stimulants, and those with a substance misuse recurring history. Stimulant drugs are not recommended for ADHD patients who suffer from nervous disorders like facial tics, spasms, etc. In such cases Atomoxetine is the better choice. Therapy is usually initiated by gradually increasing the dose to minimize typically minor side effects. As well, some individuals are sensitive to lower doses. If the individual is on stimulants, a gradual titration down of the stimulant dose may be prescribed to minimize side effects.[8][9]

Strattera was originally intended to be a new antidepressant drug; however, in clinical trials, no such benefits could be proven. Since norepinephrine is believed to play a role in ADHD, Strattera was tested – and subsequently approved – as an ADHD treatment.

Nomenclature

Atomoxetine was originally known as "tomoxetine". However, the U.S. Food and Drug Administration (FDA) requested the name be changed because, in their opinion, the similarity of "tomoxetine" to "tamoxifen" (a breast cancer drug) could lead to dispensing errors at pharmacies.

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 3 fold in the prefrontal cortices but did not alter DA levels in the striatum or nucleus accumbens.[10] Atomoxetine also acts as an NMDA-receptor antagonist at clinically relevant doses.[11] The role of NMDA-receptor antagonism in atomoxetine's therapeutic profile remains to be further elucidated, however recent literature has further implicated glutaminergic dysfunction as central in ADHD pathophysiology and etiology[citation needed]. Atomoxetine has little affinity for serotonergic, cholinergic, and adrenergic receptors.[12]

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.

Therapeutic efficacy

Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and adolescents, as observed in several placebo-controlled trials. A single morning dose was shown to be effective into the evening, and discontinuation of atomoxetine was not associated with symptom rebound.[13]

Side effects

The side effects include, dry mouth, tiredness, irritability, nausea, decreased appetite, constipation, dizziness, sweating, dysuria, sexual problems, decreased libido, urinary retention or hesitancy, increased obsessive behavior, weight changes, slowed growth in children, palpitations, increases in heart rate and blood pressure.[14][15][16]

Confirmed cases of severe liver damage have been reported by Eli Lilly and Company. A black box warning was issued by the FDA in 2004.[17][18][19]

Other side effects can include psychosis, mood swings, mood disorders, depression, abnormal thought patterns, suicidal thoughts or tendencies, and self injury.[20]

Discontinuation effects

Strattera can be discontinued without being tapered. Side effects are usually counter-reactions to usage effects: increased appetite and irregularity are common, as well as mood swings and blueness.[21]

Psychiatric reactions

Strattera is included on the Black Triangle List for drugs under intensive surveillance, maintained by the British Medicines and Healthcare Products Regulatory Agency (MHRA). It has had this listing since 2004.[citation needed] "The MHRA assesses the Black Triangle status of a product usually two years after marketing. However, there is no standard time for a product to retain Black Triangle status. The symbol is not removed until the safety of the drug is well established."[22]

"On 15 September 2005 the MHRA was informed by the Marketing Authorisation Holder for Strattera (Eli Lilly) of an analysis of double blind, randomised, placebo-controlled clinical trial data for atomoxetine which has identified a statistically significant increased risk of suicidal thoughts with atomoxetine compared to placebo in children with Attention Deficit/Hyperactivity Disorder (ADHD)."[23] One attempted suicide and five cases of suicidal thoughts were reported out of 1,357 young patients taking Strattera, while none was reported out of a control group of 851 taking placebos.[24][25]

In a further release by the MHRA of the Strattera (Atomoxetine) Risk Benefit Assessment, under the Freedom of Information act, on 9 December 2005, it was noted:

"Strattera (atomoxetine hydrochloride) is authorised through the Mutual Recognition Procedure with the UK as Reference Member State. On discussion with CMS (Germany, the Netherlands and Norway) and subsequently with the Pharmacovigilance Working Party, it was agreed that these new data warranted a full risk: benefit evaluation of atomoxetine in its licensed indications, particularly in light of previous concerns about its safety profile including serious hepatic reactions and seizures. In the interim warnings about the risk of suicidal behaviour with atomoxetine were added via an Urgent Safety Restriction (USR) procedure to allow timely communication of the risk to health professionals and patients."[26]

In the March 2009 issue of its Drug Safety Update, the MHRA declared that, after "continued case reports of possible nervous-system and psychiatric adverse effects prompted a review of data from all sources", it advised, "Atomoxetine is associated with treatment-emergent psychotic or manic symptoms in children and adolescents without a history of such disorders."[27]

On 1 August 2006, an article was published by Janne Larsson, in which he states an MHRA document was ordered made public by a court in Sweden. In it is revealed, according to Larsson, that Eli Lilly received 10,998 reports of adverse psychiatric reactions in a period of three years.[28]

Misuse potential

To date, atomoxetine's misuse potential has not been researched extensively. The two studies that have been performed suggest that atomoxetine has a low to moderate risk for abuse, since it has a long titration time (meaning that it may have no effect on the user unless they've been taking it regularly for days) and does not produce strong stimulating effects like most other ADHD medications. Monkeys will not self-administer atomoxetine at the doses tested.[5][6] However, rats, pigeons and monkeys trained to distinguish cocaine or methamphetamine from saline indicate that atomoxetine produces effects indistinguishable from low doses of cocaine or methamphetamine, but not at all like high doses of cocaine.[29][30]

Off-label uses

Atomoxetine, which inhibits the reuptake of norepinephrine, was originally explored by Eli Lilly as a treatment for depression, but did not show a favorable benefit-to-risk ratio in trials. Failed clinical trials are not submitted to drug regulatory agencies and are considered trade secrets. Subsequently, Lilly then chose to pursue an ADHD treatment route for atomoxetine. Many patients have seen a pronounced anti-depressive effect in conjunction with other antidepressants. More study is needed to understand the full pharmacodynamics.[31][32][33][34]

Experimental uses

In 2007, 40-participant, 10-week, double-blind clinical trial was reported in the Journal of Clinical Psychiatry on the effectiveness of atomoxetine for treating binge eating disorder. The average daily dose given was 106 mg/day. At the conclusion of the trial, it was reported that atomoxetine was "associated with a significantly greater rate of reduction in binge-eating episode frequency, weight, [and] body mass index." The authors concluded that atomoxetine is effective for short term treatment of binge eating disorder.[35]

A preliminary 12-week, randomized, double-blind, placebo-controlled trial was conducted at Duke University Medical Center which studied the effectiveness of atomoxetine on adult obese women. The study included 30 obese women with an average body mass index of 36.1. Fifteen women were given atomoxetine therapy starting at 25 mg/day with a gradual increase to 100 mg/day over 1 week. Fifteen women were given a placebo with identical dosing. By the end of the trial, the atomoxetine group lost an average of 3.6 kg (3.7% of their body mass) vs a 0.1 kg gain in the placebo group (0.2% gain). Three participants in the atomoxetine group and none in the placebo group lost greater than 5% of their mass.[36]

Overdose

Somnolence is the most common symptom of acute or chronic overdose. Other signs may include agitation, hyperactivity, abnormal behavior and gastrointestinal symptoms. Mydriasis causing blurred vision, tachycardia and dry mouth occasionally occurs as a result of overdose. Treatment of atomoxetine overdose may include gastric emptying and repeated doses of activated charcoal. However, lavage or "stomach pumping", is no longer an accepted procedure in emergency departments for overdose. Atomoxetine is highly protein bound so dialysis is unlikely to be of benefit.[8]

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.[37]

Synthesis

First step appears to be a Mannich reaction between acetophenone, paraformaldehyde and dimethylamine, although not formally written in the scheme. Atomoxetine synthesis.png

Foster, B. J.; Lavagnino, E. R.; European Patent, 1982, EP 0052492 .

References

  1. ^ "Patent and Exclusivity Search Results". Electronic Orange Book. US Food and Drug Administration. http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021411&Product_No=002&table1=OB_Rx. Retrieved 26 April 2009.
  2. ^ "Drugmaker Eli Lilly loses patent case over ADHD drug, lowers revenue outlook". Chicago Tribune. http://www.chicagotribune.com/business/sns-ap-us-eli-lilly-patent,0,7016147.story.
  3. ^ "Sun Pharma receives USFDA approval for generic Strattera capsules". http://www.ibtimes.com/articles/48022/20100901/sun-pharma-usfda-strattera-capsules-eli-lilly-atomoxetine-hydrochloride-attention-deficit-hyperactiv.htm#.
  4. ^ "Sun Pharma Q1 2011-12 Earnings Call Transcript 10.00 am, July 29, 2011". http://www.sunpharma.com/images/finance/FY12%20Q1%20Earnings%20Call%20Transcript.pdf.
  5. ^ a b Wee S, Woolverton WL (September 2004). "Evaluation of the reinforcing effects of atomoxetine in monkeys: comparison to methylphenidate and desipramine". Drug and Alcohol Dependence 75 (3): 271–6. doi:10.1016/j.drugalcdep.2004.03.010. PMID 15283948.
  6. ^ a b Gasior M, Bergman J, Kallman MJ, Paronis CA (April 2005). "Evaluation of the reinforcing effects of monoamine reuptake inhibitors under a concurrent schedule of food and i.v. drug delivery in rhesus monkeys". Neuropsychopharmacology 30 (4): 758–64. doi:10.1038/sj.npp.1300593. PMID 15526000.
  7. ^ Velásquez-Tirado JD, Peña JA (2005). "Evidencia actual sobre la atomoxetina. Alternativa terapéutica para el trastorno por déficit de atención e hiperactividad [Current evidence about atomoxetine. A therapeutic alternative for the treatment of attention deficit hyperactivity disorder]" (in Spanish). Revista de Neurología 41 (8): 493–500. PMID 16224736. http://www.revneurol.com/LinkOut/formMedLine.asp?Refer=2004594&Revista=RevNeurol.
  8. ^ a b Unni JC (July 2006). "Atomoxetine". Indian Pediatrics 43 (7): 603–6. PMID 16891679. http://www.indianpediatrics.net/july2006/603.pdf.
  9. ^ Prasad S, Steer C (2008). "Switching from neurostimulant therapy to atomoxetine in children and adolescents with attention-deficit hyperactivity disorder : clinical approaches and review of current available evidence". Paediatric Drugs 10 (1): 39–47. doi:10.2165/00148581-200810010-00005. PMID 18162007.
  10. ^ "Atomoxetine Increases Extracellular Levels of Norepinephrine and Dopamine in Prefrontal Cortex of Rat: A Potential Mechanism for Efficacy in Attention Deficit/Hyperactivity Disorder". http://academicdepartments.musc.edu/psychiatry/research/cns/upadhyayareferences/Bymaster_2002.pdf. Retrieved 9 July 2011.
  11. ^ "Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations". http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874851/?tool=pubmed.
  12. ^ "Atomoxetine: The First Nonstimulant for the Management of ADHD: Pharmacology". http://www.medscape.com/viewarticle/494611_2. Retrieved 9 July 2011.
  13. ^ Garnock-Jones KP, Keating GM (2009). "Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents". Paediatric Drugs 11 (3): 203–26. doi:10.2165/00148581-200911030-00005. PMID 19445548.
  14. ^ Simpson D, Plosker GL (2004). "Spotlight on atomoxetine in adults with attention-deficit hyperactivity disorder". CNS Drugs 18 (6): 397–401. doi:10.2165/00023210-200418060-00011. PMID 15089111.
  15. ^ http://www.healthcentral.com/druglibrary/408/strattera-side_effects_drug_interactions_2.html
  16. ^ "ADHD Drugs and Side Effects in Children". http://health.ltgovernors.com/mental-health/adhd-drugs-and-side-effects-in-children.html.
  17. ^ http://www.sciencedaily.com/releases/2004/12/041219133156.htm
  18. ^ http://www.rxlist.com/strattera-drug.htm
  19. ^ http://www.stratterasideeffects.com/
  20. ^ "Strattera: Side Effects, Use for ADHD". Health and Life. January 14, 2010. http://healthlifeandstuff.com/2010/01/strattera-use-side-effects/.[unreliable medical source?]
  21. ^ "2.3 General Dosing Information". Strattera prescribing information. Eli Lilly and Company. June 2009. p. 3. http://pi.lilly.com/us/strattera-pi.pdf.
  22. ^ "How long is a drug under the Black Triangle Scheme (▼)?". New drugs and vaccines under intensive surveillance. Medicines and Healthcare products Regulatory Agency. 15 March 2010. http://www.mhra.gov.uk/Safetyinformation/Howwemonitorthesafetyofproducts/Medicines/BlackTriangleproducts/index.htm#7.
  23. ^ "Strattera (atomoxetine) – Risk:Benefit Assessment". January 2006. http://www.mhra.gov.uk/home/groups/es-foi/documents/foidisclosure/con2024013.pdf
  24. ^ Reuters (September 29, 2005). "Lilly to Put Suicide Warning on Strattera Label". Fox News Channel. http://www.foxnews.com/story/0,2933,170777,00.html.
  25. ^ http://sfgate.com/cgi-bin/article.cgi?f=/n/a/2005/09/29/financial/f092936D43.DTL&hw=Strattera&sn=001&sc=1000[dead link]
  26. ^ Commission on Human Medicines ad hoc Expert Advisory Group on Strattera (January 2006). "1.0 The Issue". Strattera (atomoxetine) – Risk:Benefit Assessment. Medicines and Healthcare products Regulatory Agency. p. 2. http://www.mhra.gov.uk/home/groups/es-foi/documents/foidisclosure/con2024013.pdf.
  27. ^ "Atomoxetine: risk of psychotic or manic symptoms" (PDF). Drug safety update (Medicines and Healthcare products Regulatory Agency and Commission on Human Medicines) 8 (2): 4. March 2009. http://www.mhra.gov.uk/home/groups/pl-p/documents/publication/con041213.pdf. Retrieved February 1, 2011.
  28. ^ "Strattera - 10,988 adverse 'psychiatric reactions' reported in less than three years" (Press release). Larsson, Janne. August 1, 2006. http://www.24-7pressrelease.com/press-release/strattera-10988-adverse-psychiatric-reactions-reported-in-less-than-three-years-16662.php. Retrieved 2010-03-25.[unreliable medical source?]
  29. ^ Spealman RD (October 1995). "Noradrenergic involvement in the discriminative stimulus effects of cocaine in squirrel monkeys". The Journal of Pharmacology and Experimental Therapeutics 275 (1): 53–62. PMID 7562595. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7562595.
  30. ^ Sasaki JE, Tatham TA, Barrett JE (August 1995). "The discriminative stimulus effects of methamphetamine in pigeons". Psychopharmacology 120 (3): 303–10. doi:10.1007/BF02311178. PMID 8524978.
  31. ^ Spencer TJ, Faraone SV, Michelson D, et al. (March 2006). "Atomoxetine and adult attention-deficit/hyperactivity disorder: the effects of comorbidity". The Journal of Clinical Psychiatry 67 (3): 415–20. doi:10.4088/JCP.v67n0312. PMID 16649828.
  32. ^ Pilhatsch MK, Burghardt R, Wandinger KP, Bauer M, Adli M (March 2006). "Augmentation with atomoxetine in treatment-resistant depression with psychotic features. A case report". Pharmacopsychiatry 39 (2): 79–80. doi:10.1055/s-2006-931547. PMID 16555170.
  33. ^ Carpenter LL, Milosavljevic N, Schecter JM, Tyrka AR, Price LH (October 2005). "Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants". The Journal of Clinical Psychiatry 66 (10): 1234–8. doi:10.4088/JCP.v66n1005. PMID 16259536.
  34. ^ Kratochvil CJ, Newcorn JH, Arnold LE, et al. (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. doi:10.1097/01.chi.0000169012.81536.38. PMID 16113620.
  35. ^ McElroy SL, Guerdjikova A, Kotwal R, et al. (March 2007). "Atomoxetine in the treatment of binge-eating disorder: a randomized placebo-controlled trial". The Journal of Clinical Psychiatry 68 (3): 390–8. doi:10.4088/JCP.v68n0306. PMID 17388708.
  36. ^ Gadde KM, Yonish GM, Wagner HR, Foust MS, Allison DB (July 2006). "Atomoxetine for weight reduction in obese women: a preliminary randomised controlled trial". International Journal of Obesity 30 (7): 1138–42. doi:10.1038/sj.ijo.0803223. PMID 16418753.
  37. ^ Baselt, Randall C. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 118–20. ISBN 0-931890-08-X.

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