View source for Atomoxetine

{{Drugbox|
|IUPAC_name = (3''R'')-''N''-methyl-3-(2-methylphenoxy)-3-phenylpropan-1-amine; (''R'')-''N''-methyl-3-phenyl-3-(''o''-tolyloxy)propan-1-amine
| image = Atomoxetine.svg
| image2= Atomoxetine3d.png
| width = 150
| InChI = 1/C17H21NO/c1-14-8-6-7-11-16(14)19-17(12-13-18-2)15-9-4-3-5-10-15/h3-11,17-18H,12-13H2,1-2H3/t17-/m1/s1
| InChIKey = VHGCDTVCOLNTBX-QGZVFWFLBV
| CAS_number=83015-26-3
| ChemSpiderID = 49516
| ATC_prefix=N06
| ATC_suffix=BA09
| ATC_supplemental=
| PubChem=54841
| DrugBank=APRD00614
| C=17 | H=21 | N=1 | O=1
| molecular_weight = 255.355 g/mol<br>291.820 g/mol (hydrochloride)
| smiles = O(c1ccccc1C)[C@@H](c2ccccc2)CCNC
| bioavailability= 63 to 94%
| protein_bound = 40%
| metabolism = [[Hepatic]], via [[CYP2D6]]
| elimination_half-life= 5 hours
| excretion =[[Kidney|Renal]] (>80%) and fecal (<17%)
| pregnancy_AU = B3
| pregnancy_US = C
| legal_UK = POM
| legal_US = Rx-only
| routes_of_administration= Oral (Capsules: 10, 18, 25, 40, and 60 mg; in some countries 80 and 100 mg are also available)
}}

[[Image:Strattera.jpg|thumb|right|250px|Eli Lilly's Strattera capsules.]]
'''Atomoxetine''' is a drug approved for the treatment of [[attention-deficit hyperactivity disorder]] (ADHD). It is sold in the form of the [[hydrochloride]] salt of atomoxetine, a [[norepinephrine reuptake inhibitor]]. This compound is manufactured, marketed and sold in the [[United States]] under the brand name '''Strattera''' by [[Eli Lilly and Company]], the original [[patent]] filing company, and current U.S. patent owner. [[generic drug|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.<ref name="orangeBook">{{cite web |url=http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021411&Product_No=002&table1=OB_Rx |title=Patent and Exclusivity Search Results |accessdate=26 April 2009 |work=Electronic Orange Book |publisher=US Food and Drug Administration}}</ref> 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.<ref>{{cite news |url=http://www.chicagotribune.com/business/sns-ap-us-eli-lilly-patent,0,7016147.story |title=Drugmaker Eli Lilly loses patent case over ADHD drug, lowers revenue outlook | work=Chicago Tribune}}</ref>

==Use==
Classified as a [[norepinephrine reuptake inhibitor|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,<ref name=Wee>{{cite journal |author=Wee S, Woolverton WL |title=Evaluation of the reinforcing effects of atomoxetine in monkeys: comparison to methylphenidate and desipramine |journal=Drug and Alcohol Dependence |volume=75 |issue=3 |pages=271–6 |year=2004 |month=September |pmid=15283948 |doi=10.1016/j.drugalcdep.2004.03.010}}</ref><ref name=Gasior>{{cite journal |author=Gasior M, Bergman J, Kallman MJ, Paronis CA |title=Evaluation of the reinforcing effects of monoamine reuptake inhibitors under a concurrent schedule of food and i.v. drug delivery in rhesus monkeys |journal=Neuropsychopharmacology |volume=30 |issue=4 |pages=758–64 |year=2005 |month=April |pmid=15526000 |doi=10.1038/sj.npp.1300593}}</ref> is not scheduled as a controlled substance and has shown in [[clinical trial]]s to offer 24-hour coverage of symptoms associated with ADHD in adults and children.<ref>{{cite journal |author=Velásquez-Tirado JD, Peña JA |title=Evidencia actual sobre la atomoxetina. Alternativa terapéutica para el trastorno por déficit de atención e hiperactividad |trans_title=Current evidence about atomoxetine. A therapeutic alternative for the treatment of attention deficit hyperactivity disorder |language=Spanish |journal=Revista de Neurología |volume=41 |issue=8 |pages=493–500 |year=2005 |pmid=16224736 |url=http://www.revneurol.com/LinkOut/formMedLine.asp?Refer=2004594&Revista=RevNeurol}}</ref>

Full 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. Atomoxetine has a low abuse potential.<ref name=Wee/><ref name=Gasior/> 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. 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, again to minimize side effects.<ref name="pmid16891679">{{cite journal |author=Unni JC |title=Atomoxetine |journal=Indian Pediatrics |volume=43 |issue=7 |pages=603–6 |year=2006 |month=July |pmid=16891679 |url=http://www.indianpediatrics.net/july2006/603.pdf}}</ref><ref>{{cite journal |author=Prasad S, Steer C |title=Switching from neurostimulant therapy to atomoxetine in children and adolescents with attention-deficit hyperactivity disorder : clinical approaches and review of current available evidence |journal=Paediatric Drugs |volume=10 |issue=1 |pages=39–47 |year=2008 |pmid=18162007 |doi=10.2165/00148581-200810010-00005}}</ref>

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&nbsp;–  and subsequently approved&nbsp;–  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.

==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&nbsp;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]], [[Indigo dye|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 well designed 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.<ref name="atomox">{{cite journal |author=Garnock-Jones KP, Keating GM |title=Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents |journal=Paediatric Drugs |volume=11 |issue=3 |pages=203–26 |year=2009 |pmid=19445548 |doi=10.2165/00148581-200911030-00005}}</ref>

==Side effects==
The side effects include, [[dry mouth]], [[tiredness]], [[nausea]], [[decreased appetite]], [[constipation]], [[dizziness]], [[sweating]], [[dysuria]], [[sexual problems]], increased obsessive behavior, weight changes, [[palpitations]], increases in [[heart rate]] and [[blood pressure]].<ref>{{cite journal |author=Simpson D, Plosker GL |title=Spotlight on atomoxetine in adults with attention-deficit hyperactivity disorder |journal=CNS Drugs |volume=18 |issue=6 |pages=397–401 |year=2004 |pmid=15089111 |doi=10.2165/00023210-200418060-00011}}</ref>

Occasionally after prolonged use some teenagers have experienced slow onset mild depression while using Strattera.{{Citation needed|date=October 2007}}

Two confirmed cases of liver injury have been reported by [[Eli Lilly and Company]] out of approximately two million prescriptions written. In both cases upon discontinuation of atomoxetine, patients' liver functions returned to normal.

Other side effects can include psychosis, mood disorders, depression, abnormal thought patterns, suicidal thoughts or tendencies, and self injury.<ref>{{cite web |author= |date=January 14, 2010 |title=Strattera: Side Effects, Use for ADHD |url=http://healthlifeandstuff.com/2010/01/strattera-use-side-effects/ |publisher=Health and Life}}{{MEDRS|date=August 2010}}</ref>

Such side effects can be particularly prevalent when a dosage which exceeds the dosage to weight ratio is administered to a patient.{{Citation needed|date=April 2010}} This increase in the medication to weight ratio may be caused by a change (loss or drop) in weight and must be watched carefully.{{Citation needed|date=April 2010}}

===Discontinuation adverse effects===
Strattera can be discontinued without being tapered.<ref>{{cite book |author= |chapter=2.3 General Dosing Information |page=3 |month=June |year=2009 |title=Strattera prescribing information |url=http://pi.lilly.com/us/strattera-pi.pdf |publisher=[[Eli Lilly and Company]]}}</ref>

===Psychiatric reactions===
Strattera is included on the [[Black triangle (pharmacovigilance)|Black Triangle List]] for drugs under intensive surveillance, maintained by the [[Medicines and Healthcare products Regulatory Agency|British Medicines and Healthcare products Regulatory Agency (MHRA)]]. It has had this listing since 2004.{{Citation needed|date=March 2010}} "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."<ref>{{cite web |title=How long is a drug under the Black Triangle Scheme (▼)? |url=http://www.mhra.gov.uk/Safetyinformation/Howwemonitorthesafetyofproducts/Medicines/BlackTriangleproducts/index.htm#7 |work=New drugs and vaccines under intensive surveillance |date=15 March 2010 |publisher=[[Medicines and Healthcare products Regulatory Agency]]}}</ref>

:"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)."{{Cite quote|date=March 2010}} 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.<ref>{{cite news |author=[[Reuters]] |date=September 29, 2005 |title=Lilly to Put Suicide Warning on Strattera Label |url=http://www.foxnews.com/story/0,2933,170777,00.html |publisher=[[Fox News Channel]]}}</ref><ref><nowiki>http://sfgate.com/cgi-bin/article.cgi?f=/n/a/2005/09/29/financial/f092936D43.DTL&hw=Strattera&sn=001&sc=1000</nowiki>{{Dead link|date=March 2010}}</ref>

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."<ref>{{cite book |author=[[Commission on Human Medicines]] ad hoc Expert Advisory Group on Strattera |month=January |year=2006 |chapter=1.0 The Issue |page=2 |title=Strattera (atomoxetine) – Risk:Benefit Assessment |url=http://www.mhra.gov.uk/home/groups/es-foi/documents/foidisclosure/con2024013.pdf |publisher=[[Medicines and Healthcare products Regulatory Agency]]}}</ref>

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 concluded "atomoxetine [to be] associated with treatment-emergent psychotic or manic symptoms in children and adolescents ''without a history of such disorders''."{{Cite quote|date=March 2010}}

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.<ref>{{cite press release |title=Strattera - 10,988 adverse 'psychiatric reactions' reported in less than three years |publisher=Larsson, Janne |date=August 1, 2006 |url=http://www.24-7pressrelease.com/press-release/strattera-10988-adverse-psychiatric-reactions-reported-in-less-than-three-years-16662.php |accessdate=2010-03-25}}{{MEDRS|date=August 2010}}</ref>

For off label use, it is important to monitor the potential increase of paranoia symptoms (since this is a side effect of Strattera) in patients with schizoaffective disorder. At that point, the positive gains in Strattera should be weighed against possible risks to the patient and the public.

==Potential for abuse==
To date, the potential for abuse of Strattera has not been exhaustively researched. 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.<ref name="Gasior"/><ref name="Wee"/> 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.<ref>{{cite journal |author=Spealman RD |title=Noradrenergic involvement in the discriminative stimulus effects of cocaine in squirrel monkeys |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=275 |issue=1 |pages=53–62 |year=1995 |month=October |pmid=7562595 |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7562595}}</ref><ref>{{cite journal |author=Sasaki JE, Tatham TA, Barrett JE |title=The discriminative stimulus effects of methamphetamine in pigeons |journal=Psychopharmacology |volume=120 |issue=3 |pages=303–10 |year=1995 |month=August |pmid=8524978 |doi=10.1007/BF02311178}}</ref> No place preference studies have been conducted with atomoxetine.{{Citation needed|reason=probably should be replaced with "as of [year], no place preference..."|date=March 2010}}

==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 secret]]s. 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.<ref>{{cite journal |author=Spencer TJ, Faraone SV, Michelson D, ''et al.'' |title=Atomoxetine and adult attention-deficit/hyperactivity disorder: the effects of comorbidity |journal=The Journal of Clinical Psychiatry |volume=67 |issue=3 |pages=415–20 |year=2006 |month=March |pmid=16649828 |doi=10.4088/JCP.v67n0312}}</ref><ref>{{cite journal |author=Pilhatsch MK, Burghardt R, Wandinger KP, Bauer M, Adli M |title=Augmentation with atomoxetine in treatment-resistant depression with psychotic features. A case report |journal=Pharmacopsychiatry |volume=39 |issue=2 |pages=79–80 |year=2006 |month=March |pmid=16555170 |doi=10.1055/s-2006-931547}}</ref><ref>{{cite journal |author=Carpenter LL, Milosavljevic N, Schecter JM, Tyrka AR, Price LH |title=Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants |journal=The Journal of Clinical Psychiatry |volume=66 |issue=10 |pages=1234–8 |year=2005 |month=October |pmid=16259536 |doi=10.4088/JCP.v66n1005}}</ref><ref>{{cite journal |author=Kratochvil CJ, Newcorn JH, Arnold LE, ''et al.'' |title=Atomoxetine alone or combined with fluoxetine for treating ADHD with comorbid depressive or anxiety symptoms |journal=Journal of the American Academy of Child and Adolescent Psychiatry |volume=44 |issue=9 |pages=915–24 |year=2005 |month=September |pmid=16113620 |doi=10.1097/01.chi.0000169012.81536.38}}</ref>

==Experimental uses==
A small (40 people), 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 results of the trial was that atomoxetine was "associated with a significantly greater rate of reduction in binge-eating episode frequency, weight, [and] body mass index." The average daily dose given was 106&nbsp;mg/day. The authors concluded that atomoxetine is effective for short term treatment of binge eating disorder.<ref>{{cite journal |author=McElroy SL, Guerdjikova A, Kotwal R, ''et al.'' |title=Atomoxetine in the treatment of binge-eating disorder: a randomized placebo-controlled trial |journal=The Journal of Clinical Psychiatry |volume=68 |issue=3 |pages=390–8 |year=2007 |month=March |pmid=17388708 |doi=10.4088/JCP.v68n0306}}</ref>

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&nbsp;mg/day with a gradual increase to 100&nbsp;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&nbsp;kg (3.7% of their body mass) vs a 0.1&nbsp;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.<ref>{{cite journal |author=Gadde KM, Yonish GM, Wagner HR, Foust MS, Allison DB |title=Atomoxetine for weight reduction in obese women: a preliminary randomised controlled trial |journal=International Journal of Obesity |volume=30 |issue=7 |pages=1138–42 |year=2006 |month=July |pmid=16418753 |doi=10.1038/sj.ijo.0803223}}</ref>

==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. Atomoxetine is highly protein bound so dialysis is unlikely to be of benefit.<ref name="pmid16891679" />

==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.<ref>{{cite book |first=Randall C. |last=Baselt |title=Disposition of Toxic Drugs and Chemicals in Man |edition=8th |publisher=Biomedical Publications |location=Foster City, CA |year=2008 |pages=118–20 |isbn=0-931890-08-X}}</ref>
==Synthesis==
[[File:Atomoxetine synthesis.png|600px]]

Foster, B. J.; Lavagnino, E. R.; European Patent, 1982, {{Cite patent|EP|0052492}}.

==References==
{{Reflist}}

==External links==
* [http://www.strattera.com Strattera by Eli Lilly and Company]
* [http://www.rxlist.com/cgi/generic3/strattera.htm RxList.com - Strattera]
* [http://medlibrary.org/drugs/other/strattera.html Detailed Strattera Consumer Information: Uses, Precautions, Side Effects]
* [http://www.clinicalstudyresults.org/search/?company_id=8&drug_name_id=79&r=1&submitted=1&page=1 All disclosed Lilly trials]
* [http://ehs.lilly.com/msds/msds_atomoxetine_hydrochloride_tablets_and_capsules.pdf MSDS for Atomoxetine HCl]
* [http://www.druglib.com/druginfo/strattera/abstracts/ Strattera Related Published Studies]

{{Stimulants}}
{{Antidepressants}}
{{Antihyperkinetics}}
{{Adrenergics}}

[[Category:Norepinephrine reuptake inhibitors]]
[[Category:Eli Lilly and Company]]
[[Category:Nootropics]]
[[Category:Phenol ethers]]
[[Category:Amines]]

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