Atomoxetine

Atomoxetine

Systematic (IUPAC) name
(3R)-N-methyl-3-(2-methylphenoxy)-3-phenylpropan-1-amine; (R)-N-methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine
Clinical data
Trade names	Strattera
AHFS/Drugs.com	monograph
MedlinePlus	a603013
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	63 to 94%
Protein binding	98%
Metabolism	Hepatic, via CYP2D6
Biological half-life	5.2 hours
Excretion	Renal (80%) and faecal (17%)
Identifiers
CAS Number	83015-26-3 N
ATC code	N06BA09 (WHO)
PubChem	CID: 54841
IUPHAR/BPS	7118
DrugBank	DB00289 Y
ChemSpider	49516 Y
UNII	ASW034S0B8 Y
KEGG	D07473 Y
ChEBI	CHEBI:127342 Y
ChEMBL	CHEMBL641 Y
Chemical data
Formula	C17H21NO
Molecular mass	255.36 g/mol 291.81 g/mol (hydrochloride)
SMILES CC1=C(C=CC=C1)O[C@H](CCNC)C2=CC=CC=C2
InChI InChI=1S/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 Y Key:VHGCDTVCOLNTBX-QGZVFWFLSA-N Y
NY (what is this?)  (verify)

Atomoxetine (brand name: Strattera) is a norepinephrine reuptake inhibitor approved for the treatment of attention deficit hyperactivity disorder (ADHD).

Medical use

Attention deficit hyperactivity disorder

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 primary advantage over the standard stimulant treatments for ADHD is that it has little known abuse potential.

The initial therapeutic effects of atomoxetine usually take 2–4 weeks to become apparent. A further 2–4 weeks may be required for the full therapeutic effects to be seen. Its efficacy may be less than that of stimulant medications.

Unlike α₂ adrenoceptor agonists such as guanfacine and clonidine, atomoxetine's use can be abruptly stopped without significant withdrawal effects being seen.

Investigational uses

There has been some suggestion that atomoxetine might be a helpful adjunct in people with major depression, especially in cases where ADHD occurs comorbidly to major depression. Several randomised double-blind placebo-controlled trials found that atomoxetine was an efficacious treatment for various disorders like pediatric bedwetting, binge eating disorder, and is an efficacious weight loss medication.

Adverse effects

Incidence of adverse effects:

Very common (>10% incidence) adverse effects include:

• Nausea (26%)
• Dry mouth (20%)
• Appetite loss (16%)
• Insomnia (15%)
• Fatigue (10%)
• Headache
• Cough

Common (1-10% incidence) adverse effects include:

• Constipation (8%)
• Dizziness (8%)
• Erectile dysfunction (8%)
• Somnolence (8%)
• Abdominal pain (7%)
• Urinary hesitation (6%)
• Tachycardia (high heart rate) (5-10%)
• Hypertension (high blood pressure) (5-10%)
• Irritability (5%)
• Abnormal Dreams (4%)
• Dyspepsia (4%)
• Ejaculation disorder (4%)
• Hyperhidrosis (4%)
• Vomiting (4%)
• Hot flashes (3%)
• Paraesthesia (3%)
• Menstrual disorder (3%)
• Weight loss (2%)
• Depression
• Sinus headache
• Dermatitis
• Mood swings

Uncommon (0.1-1% incidence) adverse effects include:

• Suicide-related events
• Hostility
• Emotional lability
• Aggression
• Psychosis
• Syncope (fainting)
• Tremor
• Migraine
• Hypoaesthesia
• Seizure
• Palpitations
• Sinus tachycardia
• QT interval prolongation
• Increased blood bilirubin
• Allergic reactions

Rare (0.01-0.1% incidence) adverse effects including

• Raynaud's phenomenon
• Abnormal/increased liver function tests
• Jaundice
• Hepatitis
• Liver injury
• Acute liver failure
• Urinary retention
• Priapism
• Male genital pain

The FDA of the US has issued a black box warning for suicidal behaviour/ideation. Similar warnings have been issued in Australia. Unlike stimulant medications, atomoxetine does not have abuse liability or the potential to cause withdrawal effects on abrupt discontinuation.

Contraindications

Contraindications include:

• Hypersensitivity to atomoxetine or any of the excipients in the product
• Symptomatic cardiovascular disease including:

-moderate to severe hypertension

-atrial fibrillation

-atrial flutter

-ventricular tachycardia

-ventricular fibrillation

-ventricular flutter

-advanced arteriosclerosis

• Severe cardiovascular disorders
• Phaeochromocytoma
• Concomitant treatment with monoamine oxidase inhibitors
• Narrow angle glaucoma
• Poor metabolizers (due to the metabolism of atomoxetine by CYP2D6)

Interactions

Atomoxetine is a substrate for CYP2D6 and hence concurrent treatment with CYP2D6 inhibitors such as bupropion (Wellbutrin) or fluoxetine (Prozac) is not recommended, as this can lead to significant elevations of plasma atomoxetine levels. CYP2D6 is not very susceptible to enzyme induction. Other possible drug interactions include:

• Antihypertensive and pressor agents, due to the potential pressor effect of indirect sympathomimetics such as atomoxetine.
• Norepinephrine-acting agents such as α₁ adrenoceptor agonists or norepinephrine reuptake inhibitors due to the potential for additive or synergistic pharmacologic effects.
• β-adrenoceptor agonists due to the potential for the effects of these drugs to be potentiated by atomoxetine.
• Highly plasma protein-bound drugs due to the potential of atomoxetine to displace these drugs from plasma proteins and hence potentiate their adverse effects. Examples include diazepam, paroxetine and phenytoin.

Overdose

Atomoxetine is relatively non-toxic in overdose. Single-drug overdoses involving over 1500 mg of atomoxetine have not resulted in death. The most common symptoms of overdose include:

• Gastrointestinal symptoms
• Somnolence
• Dizziness
• Tremor
• Abnormal behaviour
• Hyperactivity
• Agitation
• Dry mouth
• Tachycardia
• Hypertension
• Mydriasis

Less common symptoms:

• Seizures
• QTc interval prolongation

The recommended treatment for atomoxetine overdose includes use of activated charcoal to prevent further absorption of the drug.

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.

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 pregelatinized starch and dimethicone. The capsule shells contain gelatin, sodium lauryl sulfate, FD&C Blue No. 2, yellow iron oxide, titanium dioxide, red iron oxide, edible black ink, and trace amounts of other inactive ingredients.

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  Strattera 60-mg capsule back

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  Strattera 60-mg capsule front with Lilly logo

Pharmacology

Atomoxetine inhibits NET, SERT, and DAT with respective K_i values of 5, 77, and 1451 nM.In microdialysis studies, it increased NE and DA levels by three-fold in the prefrontal cortices, but did not alter DA levels in the striatum or nucleus accumbens. Atomoxetine's selective increase in NE and DA are due to a lack of high concentrations of DAT in the prefrontal cortex, and the nucleus accumbens's relative paucity of NE neurons. Atomoxetine also acts as an NMDA receptor antagonist at clinically relevant doses. The role of NMDA receptor antagonism in atomoxetine's therapeutic profile remains to be further elucidated, but recent literature has further implicated glutaminergic dysfunction as central in ADHD pathophysiology and etiology.

4-Hydroxyatomoxetine, the principle metabolite of atomoxetine, exhibits relatively weak affinity for μ-opioid receptors and κ-opioid receptors. Creighton et al. reported antagonism of μ-opioid receptors and a partial agonist effect at κ-opioid receptors. The clinical significance of these effects are not known.

Atomoxetine has been found to inhibit both brain and cardiac G protein-coupled inwardly-rectifying potassium channels, a characteristic it shares with the related drug reboxetine.

Binding profile

Protein	Ki (nM) for atomoxetine	Ki (nM) for 4-hydroxyatomoxetine
SERT	77	?
NET	5	?
DAT	1451	?
5-HT receptors	>1000	?
Alpha adrenergic receptors	>1000	?
Beta adrenergic receptors	>1000	?
D1 & D2	>1000	?
M1 & M2	>1000	?
H1 & H2	>1000	?
δ1 opioid receptor	?	300
κ1 opioid receptor	?	95
μ opioid receptor	?	422
σ1 receptor	>1000	?

History

This compound is manufactured, marketed, and sold in the United States as the hydrochloride salt (atomoxetine HCl) under the brand name Strattera by Eli Lilly and Company, the original patent-filing company and current U.S. patent owner. Strattera was approved by the FDA in 2006 for the treatment of ADHD. No generic is manufactured directly in the United States since it is under patent until 2017. On 12 August 2010, Lilly lost a lawsuit that challenged its patent on Strattera, increasing the likelihood of an earlier entry of a generic into the US market. On 1 September 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States. In a 29 July 2011 conference call, however, Sun Pharmaceutical's Chairman stated "Lilly won that litigation on appeal so I think [generic Strattera]’s deferred."

Brand names

In India, atomoxetine is sold under brand names including Tomoxetin, Attentrol, Axepta, Atokem, and Attentin. In Romania, atomoxetine is sold under the brand name Strattera and as a generic made by Sun Pharmaceuticals.

External links

• Strattera by Eli Lilly and Company
• RxList.com – Strattera
• Detailed Strattera Consumer Information: Uses, Precautions, Side Effects
• All disclosed Lilly trials
• MSDS for Atomoxetine HCl
• Strattera Related Published Studies