Atomoxetine

Atomoxetine

            Atomoxetine hydrochloride, approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) by the US Food and Drug Administration (USFDA) in November 2002, was the first nonstimulant pharmacological treatment for ADHD.¹  ADHD is observed in 3-7% of school age children and is characterized by impulsivity and a decreased control of attention compared to peers without the disorder.²  The pathophysiology of ADHD likely involves dysfunction of dopaminergic and noradrenergic pathways, as dopamine (DA) plays a critical role in attentional and psychomotor behaviors and the noradrenergic system is involved in processes that prime the prefrontal cortex (PFC) for sensory stimuli.^2,3  Typically, ADHD is treated by stimulant drugs, such as methylphenidate, which are classified as Schedule II controlled substances due to their high potential for abuse.¹  Additionally, approximately 30% of patients do not respond to stimulants and many others may be unable to tolerate the adverse effects associated with chronic psychostimulant use.¹  Lastly, stimulant medication use for ADHD may exacerbate comorbid conditions, including anxiety, tics, and disordered sleep, leading to a greater likelihood of treatment noncompliance in these patients.⁴  Thus, an alternative drug that operates distinctly from psychostimulants was of great interest to pharmaceutical scientists as an increasing number of individuals sought pharmacotherapy for their ADHD symptoms in the 1980s and 90s.⁵

            Atomoxetine is a synthetic norepinephrine reuptake inhibitor that selectively binds to the presynaptic norepinephrine transporters while minimally interacting with other monoamine transporters and receptors.⁶  An important exception demonstrated in most mechanistic studies of atomoxetine is that increases in extracellular norepinephrine are accompanied by increases in extracellular dopamine, though the drug may not directly interact with dopamine transporters.³  Norepinephrine is secreted into the locus ceruleus of the brain and then released to the PFC, and low concentrations of norepinephrine in the PFC are associated with many symptoms of ADHD.¹ In both animal and human models, atomoxetine increases free levels of norepinephrine and subsequently increases dopamine in the cortex, improving cognitive functions that depend on the integrity of the PFC.⁵  Atomoxetine contains a 3-aryloxypropylamine scaffold that contributes to its high binding affinity for the presynaptic norepinephrine transporters.⁷  Thus, through both local and systemic administration, atomoxetine increases the amount of extracellular norepinephrine and dopamine without much effect on other neurotransmitter transporters and neuronal receptors.³  Studies have demonstrated that atomoxetine and immediate-release methylphenidate are equally efficacious in their treatment of ADHD, though the extended-release form of methylphenidate is more effective than atomoxetine.^2,8  In situations where ADHD symptoms are not improved by a stimulant, a patient cannot tolerate psychostimulant therapy, a patient has comorbid conditions that worsen with stimulant use, or where there are concerns about the long term effects of taking a controlled substance, atomoxetine is an effective treatment alternative to traditional stimulants.²

            Atomoxetine was originally synthesized and studied by Eli Lilly and Company under the name tomoxetine for the treatment of depression in the 1980s, but the Phase II clinical trials were terminated in 1990 because the company already had a more promising drug for the treatment of depression in fluoxetine.¹  Throughout the early 1990s, the drug was studied in various animal models, including models of cataplexy and incontinence.¹  In 1998, studies demonstrated that tomoxetine had potential for treating ADHD, and the drug’s name was changed to atomoxetine to avoid confusion with tamoxifen, which is used to treat and prevent breast cancer.¹  Eli Lilly patented atomoxetine hydrochloride under the brand name Strattera on November 26, 2002, for ADHD treatment in children, adolescents, and adults.⁹  Before the FDA approved Strattera for the US market, Eli Lilly shares were trading for $64, and after the announcement of approval, the share values increased to $65.40.¹⁰  In 2009, Strattera generated approximately three percent of Eli Lilly’s revenue, spurring the company to pursue a patent lawsuit in hopes that it would delay the launch of generic atomoxetine.¹¹  In mid-August 2010, Eli Lilly lost the lawsuit.¹¹  Eli Lilly’s patent for Strattera expired in May 2017.⁹

            At the end of 2004, the USFDA updated the label on Strattera with warnings about potentially serious liver side effects.¹²  Leading up to this change, Eli Lilly discouraged doctors from prescribing Strattera to patients with jaundice or other signs of liver damage, after noticing links between Strattera use and severe liver injury.¹²  On September 28, 2005, Eli Lily began adding a black-box warning to Strattera.¹²  A black-box warning is the strictest warning included on labels of FDA-approved drugs that pose serious risks for consumers.¹³  This black-box warning for Strattera stated that the drug can increase suicidal ideation in children and adolescents.¹²  During several clinical trials assessing suicidal risk for patients on Strattera, five out of 1,357 youths saw an increase in suicidal thoughts, whereas none of the children in the placebo group experienced such thoughts.¹²  Additionally, clinical trials did not indicate an increased risk of suicidal ideation in adults on Strattera.¹²  In early 2006, the USFDA risk-management committee began monitoring reports of cardiovascular complications in patients using various ADHD medications, including Strattera.¹²  Currently, suicidal ideation, liver damage, and cardiovascular health problems are the three major potential side effects described with Strattera use.¹⁴

            In 2010, Sun Pharmaceutical Industries Ltd. (Sun Pharma), based in Mumbai, India, received USFDA approval for a new drug application (NDA) to market a generic version of atomoxetine hydrochloride tablets.¹⁵  Additionally, the company was also given 180 days of marketing exclusivity for the drug.¹⁵  The generic tablets were considered to be equivalent to Strattera capsules, and were formulated to have six different strengths: 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, and 100 mg.¹⁵  However, later that year it was found that Sun Pharma had several violations in Current Good Manufacturing Practice regulations at their New Jersey facility.¹⁵  These violations included inadequately recording procedures to ensure proper drug identity and quality, improper investigation of failed drug batches, inadequate quality control, inadequate inspection of labels and packaging, and improper protocol for reprocessing failed batches.¹⁶  Prior to this letter, the New Jersey facility of Sun Pharma had already been cited several times between 2008 and 2010 for other violations, which they did not properly address upon receiving warnings.¹⁶  Thus, the USFDA withheld approval of all pending NDAs being manufactured at this location and Sun Pharma never released the generic version of Strattera.¹⁵

            On May 30, 2017, the USFDA approved the first generic versions of Strattera, at various strengths, to treat ADHD, manufactured by four different pharmaceutical companies: Apotex Inc., Teva Pharamceuticals USA Inc., Aurobindo Pharma Limited, and Glenmark Pharmaceutcial Limited.¹⁴  These generic drugs demonstrated the same quality and strength as Eli Lilly’s Strattera.¹⁴  Atomoxetine is distributed with a Medication Guide that outlines the proper use of the drug as well as the aforementioned potential risks that accompany use.¹⁴  These include an increased risk for suicidal ideation, severe liver damage, and serious cardiovascular events, all of which should be closely monitored for in patients using this drug.¹⁴

Bibliography

1.     Caballero, Joshua, and Milap C. Nahata. “Atomoxetine Hydrochloride for the Treatment of Attention-Deficit/Hyperactivity Disorder.” Clinical Therapeutics, vol. 25, no. 12, 22 Oct. 2003, pp. 3065–3083., doi:10.1016/s0149-2918(03)90092-0.

2.     Kratochvil, Christopher J., et al. “Atomoxetine and Methylphenidate Treatment in Children With ADHD: A Prospective, Randomized, Open-Label Trial.” Journal of the American Academy of Child & Adolescent Psychiatry, vol. 41, no. 7, July 2002, pp. 776–784., doi:10.1097/00004583-200207000-00008.

3.     Bymaster, Frank P., et al. “Atomoxetine Increases Extracellular Levels of Norepinephrine and Dopamine in Prefrontal Cortex of Rat A Potential Mechanism for Efficacy in Attention Deficit/Hyperactivity Disorder.” Neuropsychopharmacology, vol. 27, no. 5, 12 Apr. 2002, pp. 699–711., doi:10.1016/s0893-133x(02)00346-9.

4.     Garnock-Jones, Karly P., and Gillian M. Keating. “Atomoxetine.” Pediatric Drugs, vol. 11, no. 3, June 2009, pp. 203–226., doi:10.2165/00148581-200911030-00005.

5.     Chamberlain, Samuel R., et al. “Atomoxetine Modulates Right Inferior Frontal Activation During Inhibitory Control: A Pharmacological Functional Magnetic Resonance Imaging Study.” Biological Psychiatry, vol. 65, 2009, pp. 550–555., doi:10.1016/j.biopsych.2008.10.014.

6.     Michelson, David, et al. “CYP2D6 And Clinical Response to Atomoxetine in Children and Adolescents With ADHD.” Journal of the American Academy of Child & Adolescent Psychiatry, vol. 46, no. 2, Feb. 2007, pp. 242–251., doi:10.1097/01.chi.0000246056.837-91.b6.

7.     Boot, John, et al. “Discovery and Structure–Activity Relationships of Novel Selective Norepinephrine and Dual Serotonin/Norepinephrine Reuptake Inhibitors.” Bioorganic & Medicinal Chemistry Letters, vol. 15, 2005, pp. 699–703., doi:10.1016/j.bmcl.2004.11.025.

8.     Hanwella, Raveen, et al. “Comparative Efficacy and Acceptability of Methylphenidate and Atomoxetine in Treatment of Attention Deficit Hyperactivity Disorder in Children and Adolescents: a Meta-Analysis.” BMC Psychiatry, vol. 11, no. 176, 10 Nov. 2011, doi:10.1186/1471-244x-11-176

9.      “Strattera (Atomoxetine HCl).” CenterWatch, www.centerwatch.com/drug-information/fda-approved-drugs/drug/813/strattera-atomoxetine-hcl.

10.  Thomas M. Burton – Staff Reporter of The Wall Street Journal. “Lilly's ADHD Drug, Strattera, Receives Approval From FDA.” The Wall Street Journal, Dow Jones & Company, 27 Nov. 2002, www.wsj.com/articles/SB1038356016518835988.

11.  IBJ Staff and Associated Press. “Eli Lilly Loses Patent Lawsuit for Strattera.” Indianapolis Business Journal | IBJ.com, Indianapolis Business Journal | IBJ.com, 13 Aug. 2010, www.ibj.com/articles/21678-eli-lilly-loses-patent-lawsuit-for-strattera.

12.  “Strattera Lawsuits - Suicide Lawyers, Strattera Side Effects.” Parker Waichman LLP, 5 May 2018, www.yourlawyer.com/defective-drugs/strattera/strattera/.

13.  “A Guide to Drug Safety Terms at FDA.” Consumer Health Information, FDA, Nov. 2012, www.fda.gov/consumer.

14.  “Press Announcements - FDA Approves First Generic Strattera for the Treatment of ADHD.” US Food and Drug Administration Home Page, Center for Biologics Evaluation and Research, 30 May 2017, www.fda.gov/newsevents/newsroom/pressannouncements/ucm561096.htm.

15.  Meganathan, Siddharthan.  “Sun Pharma received USFDA approval for generic Strattera capsules.” International Business Times, 1 Sept. 2010, www.web.archive.org/web/20110407100949/http://www.ibtimes.com/.

16.  “Sun Pharmaceutical Industries Inc - Warning Letter.” Inspections, Compliance, Enforcement, and Criminal Investigations, Department of Health and Human Services, 25 Aug. 2010, www.fdanews.com/ext/resources/files/archives/s/Sun_Pharma_WL.pdf.