Atomoxetine

Atomoxetine is a drug approved for the treatment of attention-deficit hyperactivity disorder (ADHD). It is a selective norepinephrine reuptake inhibitor or 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. 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. On September 1, 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States. 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."

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 shown in clinical trials to offer 24-hour coverage of symptoms associated with ADHD in adults and children.

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 (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. 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.

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 microdyalisis 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. Atomoxetine has little affinity for serotonergic, cholinergic, or adrenergic receptors.

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 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.

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, palpitations, increases in heart rate and blood pressure.

Occasionally after prolonged use some patients have experienced slow onset mild depression, tiredness and forgetfulness while using Strattera. There were also reports of this medicine causing indications of short-term memory loss from some patients.

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.

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

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 caused by a change (loss or drop) in weight and must be watched carefully.

Discontinuation effects
Strattera can be discontinued without being tapered.

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. "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."


 * "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.

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."

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."

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.

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.

Studies have also shown that discontinuing use can lead to minor cases of cramps, fatigue, and memory loss.

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. 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.

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.

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.

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.

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, "stomache pumping" or medically known as lavage, is no longer an accepted procedure in emergency departments for overdose. Atomoxetine is highly protein bound so dialysis is unlikely to be of benefit.

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.

Synthesis


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