Atomoxetine: Wikis

  
  

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Atomoxetine
Systematic (IUPAC) name
(3R)-N-methyl-3-(2-methylphenoxy)-3-phenyl-propan-1-amine; (R)-N-methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine
Identifiers
CAS number 83015-26-3
ATC code N06BA09
PubChem 54841
DrugBank APRD00614
ChemSpider 49516
Chemical data
Formula C17H21NO 
Mol. mass 255.355 g/mol
291.820 g/mol (hydrochloride)
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 63 to 94%
Protein binding 40%
Metabolism Hepatic, via CYP2D6
Half life 5 hours
Excretion Renal (>80%) and fecal (<17%)
Therapeutic considerations
Pregnancy cat. B3(AU) C(US)
Legal status POM (UK) -only (US)
Routes Oral (Capsules: 10, 18, 25, 40, and 60 mg; in some countries 80 and 100 mg are also available)
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. 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]

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,[2][3] 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.[4]

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.[2][3] 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.[5][6]

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.

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.

Side effects

The side effects include, dry mouth, insomnia, nausea, decreased appetite, constipation, dizziness, sweating, dysuria, sexual problems, weight changes, palpitations, increases in heart rate and blood pressure.[7]

Occasionally after prolonged use some teenagers have experienced slow onset mild depression while using Strattera[citation needed]

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.[8]

Such side effects can be particularly prevalent when a dosage which exceeds the dosage to weight ratio is administered to a patient. This increase in the medication to weight ratio may be cause by a change (loss or drop) in weight and must be watched carefully.

Discontinuation adverse effects

Strattera can be discontinued without being tapered.[9]

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. "There is no standard time for a product to retain black triangle status. However, an assessment is usually made following two years of post-marketing experience and the black triangle symbol is not removed until the safety of the drug is well established."[10]

"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)." 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.[11][12]

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."[13]

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."

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.[14]

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 (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

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.[15][16][17][18]

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.[19]

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.[20]

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.[5]

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.[21]

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. ^ 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. 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ a b Unni JC (July 2006). "Atomoxetine". Indian Pediatrics 43 (7): 603–6. PMID 16891679. http://www.indianpediatrics.net/july2006/603.pdf. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ "Strattera: Side Effects, Use for ADHD | Health and Life
  9. ^ "Stratetera prescribing information see section 2.3 on page 3". http://pi.lilly.com/us/strattera-pi.pdf. Retrieved 22 September 2009. 
  10. ^ http://www.mhra.gov.uk/Safetyinformation/Reportingsafetyproblems/Medicines/Reportingsuspectedadversedrugreactions/Healthcareprofessionalreporting/BlackTriangleScheme/index.htm
  11. ^ http://www.foxnews.com/story/0,2933,170777,00.html
  12. ^ http://sfgate.com/cgi-bin/article.cgi?f=/n/a/2005/09/29/financial/f092936D43.DTL&hw=Strattera&sn=001&sc=1000
  13. ^ Quoted from STRATTERA (atomoxetine) Risk Benefit Assessment, Preliminary Assessment Report of 9 December 2005 (FOI 06/056 Release by MHRA)
  14. ^ http://www.24-7pressrelease.com/press-release/strattera-10988-adverse-psychiatric-reactions-reported-in-less-than-three-years-16662.php
  15. ^ 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. PMID 16649828. http://article.psychiatrist.com/?ContentType=START&ID=10002486. 
  16. ^ 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. 
  17. ^ 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. PMID 16259536. http://article.psychiatrist.com/?ContentType=START&ID=10001475. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ 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. 
  21. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 118-120.

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