Atomoxetine

Drugbox
IUPAC_name = (3"R")-"N"-methyl-3-(2-methylphenoxy)-3-phenyl-propan-1-amine

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width = 150
CAS_number=83015-26-3
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
291.820 g/mol (hydrochloride)
smiles = CNCC [C@@H] (Oc1ccccc1C)c1ccccc1
bioavailability= 63 to 94%
protein_bound = 40%
metabolism = Hepatic, via CYP2D6
elimination_half-life= 5 hours
excretion =Renal (>80%) and fecal (<17%)
pregnancy_AU = B3
pregnancy_US = C
legal_UK = POM
legal_status = Unscheduled (U.S.)
routes_of_administration= Oral (Capsules: 10, 18, 25, 40, and 60 mg; in some countries 80 and 100 mg are also available)

Atomoxetine is a non-stimulant drug approved for the treatment of attention-deficit hyperactivity disorder (ADHD). It is sold in the form of the hydrochloride salt of atomoxetine. This chemical is manufactured, marketed and sold under the brand name Strattera by Eli Lilly and Company, the original patent filing company. Generics of atomoxetine are sold into all 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 within the United States due to patent license manufacturing restrictions chosen by the owner of the US patent Eli Lilly and Company.

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, is not scheduled as a controlled substance and has proven in clinical trials to offer 24 hour coverage of symptoms associated with ADHD in adults and children.

Although the drug can be "felt" right away, it does not start "working properly" for 3-4 weeks time. Users should expect to feel tired and groggy for a few weeks. Eventually, the system adapts to the drug and the benefits can be felt. Users are recommended to continue taking the drug for at least three weeks before deciding to discontinue its use.

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.

Though approved for ADHD, many doctors prescribe it off-label as an anti-psychotic in cases of certain disorders of thought and less serious mental problems, such as dyslexia, dyspraxia (clumsiness), and schizoaffective disorder. This is due to its help in 'calming down' and steadying of thought processes, improving symptoms associated with less serious types and degrees of schizophrenia. In this case, atomoxetine has great potential in the treatment of schizophrenia and the Predominantly Inattentive subtype of ADHD (once separately designated Attention-Deficit Disorder (ADD), now often referred to as the subtype ADD-PI). In many cases of the above-mentioned disorders of thought, it is said to work seamlessly better and with less negative side-effects than any of the available (approved) anti-psychotics.

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 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.

ide effects

The most common side effects in children, adolescents, and adults are upset stomach, sporadic nausea, and sudden vomiting. The medication's tendency to decrease appetite may contribute to this problem, as taking Strattera on an empty stomach is usually discouraged; it can also be a problem in itself, in the form of hunger pangs. Consumption of dairy products can cause further upset.

A significant minority of adult male patients taking Strattera suffer minor to severe sexual side effects, including erectile dysfunction, retrograde ejaculation, painful orgasm, and the decoupling of orgasm from ejaculation, wherein ejaculation takes place up to ten seconds before or after orgasm.

Occasionally after prolonged use some teenagers have experienced slow onset mild depression while using Strattera Fact|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.

Discontinuation adverse effects

The central nervous system (CNS) adapts to the presence of psychoactive drugs. Such adaptation commonly involves the readjustment of neuroreceptors to compensate for the acute pharmacological action of the medication. This adaptation theory also explains why withdrawal symptoms and signs can occur on the discontinuation of such medications as clearance of drug can occur at a rate faster than the brain can readjust to the absence of medication. Hence, pharmacodynamic and pharmacokinetic factors contribute to the risk of a withdrawal syndrome.

Psychiatric reactions

In September 2005, Strattera was determined to increase risk of suicidal thoughts among children and adolescents; 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. [http://www.foxnews.com/story/0,2933,170777,00.html] , [http://sfgate.com/cgi-bin/article.cgi?f=/n/a/2005/09/29/financial/f092936D43.DTL&hw=Strattera&sn=001&sc=1000] . The FDA has required that black box warnings be placed on all antidepressant medications warning that may result in increased risk of suicidal tendencies in children and adolescents; therefore, Strattera bears such a warning.

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 schizo-affective disorder. At that point, the positive gains in Strattera should be weighed against possible risks to the patient and the public.

In less than three years on the market 10,988 adverse "psychiatric reactions" have been reported to Eli Lilly for the ADHD drug Strattera, according to the British Medicines and Healthcare products Regulatory Agency (MHRA), January 2006.

A FOI Release by the UK Medicines and Healthcare products Regulatory Agency discloses that the administration of Strattera increases risks of suicidal ideation, serious hepatic reactions and seizures in children with ADHD.

:"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)."

:"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." [Quoted from [http://www.psychiater.nu/wp-content/uploads/2008/08/vrijgegeven-documenten-strattera-schandaal.pdf STRATTERA (atomoxetine) Risk Benefit Assessment, Preliminary Assessment Report of 9 December 2005 (FOI 06/056 Release by MHRA)] ]

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 produce strong stimulating effects like most other ADHD medications (which are usually dopamine reuptake inhibitors). Monkeys will not self-administer atomoxetine at the doses tested (Gasior et al, Neuropharm 30:758, 2005; Wee & Woolverton, Drug Alcohol Depend 75:271, 2004). 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 (Spealman, JPET 271:53, 1995; Sasaki et al., Psychopharm 120:303, 1995). No place preference studies have been conducted with atomoxetine.

Off-label uses

While depression is most commonly associated with the neurotransmitter serotonin, an imbalance of other neurotransmitters may also result in clinical depression. To that end, atomoxetine, which inhibits the reuptake of norepinephrine, was originally explored by Eli Lilly as a treatment for depression, but did not show a 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. [cite journal | first = Spencer TJ| last = Biederman J| date = March, 2006 | title = Atomoxetine and adult attention-deficit/hyperactivity disorder: the effects of comorbidity| url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16649828&query_hl=2&itool=pubmed_docsum] [cite journal | first = Pilhatsch MK| last = Adli M| date = March, 2006 | title = Augmentation with atomoxetine in treatment-resistant depression with psychotic features. A case report| url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16555170&query_hl=2&itool=pubmed_docsum | doi = 10.1055/s-2006-931547 | journal = Pharmacopsychiatry | volume = 39 | pages = 79] [cite journal | first = Carpenter LL| last = Price LH| date = Oct, 2005 | title = Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants| url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16259536&query_hl=2&itool=pubmed_docsum] [cite journal | first = Kratochvil CJ| last = Biederman, J| date = Sept, 2005 | title = Atomoxetine alone or combined with fluoxetine for treating ADHD with comorbid depressive or anxiety symptoms| url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16113620&query_hl=2&itool=pubmed_docsum]

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 mg/day. The authors concluded that atomoxetine is effective for short term treatment of binge eating disorder. [Citation
last=McElroy
first=Susan
year= 2007
title= Atomoxetine in the Treatment of Binge-Eating Disorder: A Randomized Placebo-Controlled Trial
journal=Journal of Clinical Psychiatry
volume= 68
number= 3
pages= 390–398
url = http://www.psychiatrist.com.prxy3.ursus.maine.edu/privatepdf/2007/v68n03/v68n0306.pdf
pmid = 17388708 ]

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. [Citation
last=Gadde
first=K.M.
year= 2007
date = July 2006
title= Atomoxetine for weight reduction in obese women: a preliminary randomised controlled trial
journal=International Journal of Obesity
volume= 30
number= 7
pages= 1138–1142
pmid = 16418753
doi= 10.1038/sj.ijo.0803223 ]

References

External links

* [http://www.rxlist.com/cgi/generic3/strattera.htm RxList.com - Strattera]
* [http://www.strattera.com/1_2_taking_strattera/1_2_5_2_available.jsp Strattera Available Dosages]
* [http://medlibrary.org/drugs/other/strattera.html Detailed Strattera Consumer Information: Uses, Precautions, Side Effects]
* [http://www.lillytrials.com/results/by_product/results_strattera.html All Lilly trials]
* [http://www.ehs.lilly.com/msds/msds_atomoxetine_hydrochloride_tablets_and_capsules.html MSDS for Atomoxetine HCl]
* [http://www.druglib.com/druginfo/strattera/abstracts/ Strattera Related Published Studies ]
* [http://online.wsj.com/article/0,,SB108249266648388235,00.html?mod=home%5Fpage%5Fone%5Fus "By learning from failures, Lilly keeps drug pipeline full", The Wall Street Journal, April 21, 2004]