Atomoxetine

Source: Wikipedia, the free encyclopedia.

Atomoxetine
Clinical data
Trade namesStrattera, others
Other names(R)-N-Methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine
AHFS/Drugs.comMonograph
MedlinePlusa603013
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classSelective norepinephrine reuptake inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability63 to 94%[7][8][9]
Protein binding98%[7][8][9]
MetabolismLiver, via CYP2D6[7][8][9]
Elimination half-life4.5–25 hours[7][8][9][10][11]
ExcretionKidney (80%) and faecal (17%)[7][8][9]
Identifiers
  • (3R)-N-Methyl-3-(2-methylphenoxy)-3-phenylpropan-1-amine
JSmol)
  • CC1=C(C=CC=C1)O[C@H](CCNC)C2=CC=CC=C2
  • 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 checkY
  • Key:VHGCDTVCOLNTBX-QGZVFWFLSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Atomoxetine, sold under the brand name Strattera, is a

psychostimulants.[16][17] It is also used as a cognitive and executive functioning enhancer to improve self-motivation, persistence, attention, inhibition, and working memory.[18][19][20] Use of atomoxetine is only recommended for those who are at least six years old.[12] It is taken orally.[12] Atomoxetine is a selective norepinephrine reuptake inhibitor and is believed to work by increasing norepinephrine and dopamine levels in the brain.[12][10] The effectiveness of atomoxetine is comparable to the commonly prescribed stimulant medication methylphenidate.[21][22][23][24]

Common side effects of atomoxetine include abdominal pain, loss of appetite, nausea, feeling tired, and dizziness.[12] Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide, and aggression.[12][25] There is a lack of data regarding its safety during pregnancy; as of 2019, its safety during pregnancy and for use during breastfeeding is not certain.[26][27]

It was approved for medical use in the United States in 2002.[12] In 2021, it was the 219th most commonly prescribed medication in the United States, with more than 1.9 million prescriptions.[28][29]

Medical uses

Atomoxetine is

indicated for the treatment of attention deficit hyperactivity disorder (ADHD).[5]

Attention deficit hyperactivity disorder

Atomoxetine is approved for use in children, adolescents, and adults.

stimulant treatments for ADHD is that it has little known abuse potential.[8] Meta-analyses and systematic reviews have found that atomoxetine has comparable efficacy and equal tolerability to methylphenidate in children and adolescents. In adults, efficacy and tolerability are equivalent.[21][22][23][24]

While its efficacy may be less than that of amphetamine,

drug use disorder
.

Unlike α2 adrenoceptor agonists such as guanfacine and clonidine, atomoxetine's use can be abruptly stopped without significant discontinuation effects being seen.[8]

The initial therapeutic effects of atomoxetine usually take 1 to 4 weeks to become apparent.[7][33][34] A further 2 to 4 weeks may be required for the full therapeutic effects to be seen.[35][33] Incrementally increasing response may occur up to 1 year or longer.[34][36] The maximum recommended total daily dose in children and adolescents over 70 kg and adults is 100 mg.[5]

Other uses

Cognitive disengagement syndrome

Atomoxetine may be used to treat cognitive disengagement syndrome (CDS),[37] as multiple randomised controlled clinical trials (RCTs) have found that it is an effective treatment.[38][39][40] In contrast, multiple other RCTs have shown that it responds poorly to the stimulant medication methylphenidate.[41][42][43][44]

Traumatic brain injury

Atomoxetine is sometimes used in the treatment of

Cochrane review identified only one study of atomoxetine for TBI and found no positive effects.[48] Aside from TBI, atomoxetine was found to be effective in the treatment of akinetic mutism following subarachnoid hemorrhage in a case report.[46][49]

Contraindications

Contraindications include:[8]

Adverse effects

Common side effects include abdominal pain, loss of appetite, nausea, feeling tired, and dizziness.

anorexia, weight loss, and hypertension, rating it as a "potentially least preferred agent based on safety" for treating ADHD.[50][51] As of 2019, safety in pregnancy and breastfeeding is not clear;[26]
a 2018 review stated that, "[b]ecause of lack of data, the treating physician should consider stopping atomoxetine treatment in women with ADHD during pregnancy."[27]

The U.S.

black box warning for suicidal behavior/ideation.[9] Similar warnings have been issued in Australia.[8][52] Unlike stimulant medications, atomoxetine does not have abuse liability or the potential to cause withdrawal effects on abrupt discontinuation.[8][53]

Overdose

Atomoxetine is relatively non-toxic in overdose. Single-drug overdoses involving over 1500 mg of atomoxetine have not resulted in death.[8]

Interactions

Atomoxetine is a

substrate for CYP2D6. Concurrent treatment with a CYP2D6 inhibitor such as bupropion, fluoxetine, or paroxetine has been shown to increase plasma atomoxetine by 100% or more, as well as increase N-desmethylatomoxetine levels and decrease plasma 4-hydroxyatomoxetine levels by a similar degree.[54][55][56]

Atomoxetine has been found to directly inhibit

QT prolongation has been reported with atomoxetine at therapeutic doses and in overdose; it is suggested that atomoxetine not be used with other medications that may prolong the QT interval, concomitantly with CYP2D6 inhibitors, and caution to be used in poor metabolizers.[55]

Other notable drug interactions include:[8]

Pharmacology

Pharmacodynamics

Atomoxetine (and metabolites)[59][60]
Site ATX 4-OH-ATX N-DM-ATX
SERTTooltip Serotonin transporter 77 43 ND
NETTooltip Norepinephrine transporter 5 3 92
DAT 1,451 ND ND
5-HT1A >1,000 ND ND
5-HT1B >1,000 ND ND
5-HT1D >1,000 ND ND
5-HT2 2,000 1,000 1,700
5-HT6 >1,000 ND ND
5-HT7 >1,000 ND ND
α1 11,400 20,000 19,600
α2A 29,800 >30,000 >10,000
β1 18,000 56,100 32,100
M1 >100,000 >100,000 >100,000
M2 >100,000 >100,000 >100,000
D1 >10,000 >10,000 >10,000
D2 >10,000 >10,000 >10,000
H1 12,100 >100,000 >100,000
MOR
Tooltip μ-Opioid receptor		 Antagonist 422 ND
DOR
Tooltip δ-Opioid receptor		 ND 300 ND
KOR
Tooltip κ-Opioid receptor		 Partial Agonist 95 ND
σ1 >1,000 ND ND
GABAA 200 >30,000 >10,000
NMDA 0.66 - 3,470a ND ND
Kir3.1/3.2
 10,900b ND ND
Kir3.2
 12,400b ND ND
Kir3.1/3.4
 6,500b ND ND
hERG 6,300 20,000 5,710
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All values are for human receptors unless otherwise specified. arat cortex. bXenopus oocytes. Additional sources:[61][62][10][58]

Atomoxetine inhibits the presynaptic norepinephrine transporter (NET), preventing the reuptake of norepinephrine throughout the brain along with inhibiting the reuptake of dopamine in specific brain regions such as the prefrontal cortex, where dopamine transporter (DAT) expression is minimal.[10] In rats, atomoxetine increased prefrontal cortex catecholamine concentrations without altering dopamine levels in the striatum or nucleus accumbens; in contrast, methylphenidate, a dopamine reuptake inhibitor, was found to increase prefrontal, striatal, and accumbal dopamine levels to the same degree.[61] In addition to rats, atomoxetine has also been found to induce similar region-specific catecholamine level alteration in mice.[63]

Atomoxetine's status as a

rhesus monkeys found that atomoxetine occupied >90% and >85% of neural NET and SERT, respectively.[64] However, both mouse and rat microdialysis studies have failed to find an increase in extracellular serotonin in the prefrontal cortex following acute or chronic atomoxetine treatment.[61][63] Supporting atomoxetine's selectivity, a human study found no effects on platelet serotonin uptake (a marker of SERT inhibition) and inhibition of the pressor effects of tyramine (a marker of NET inhibition).[65]

Atomoxetine has been found to act as an

ADHD.[70][71]

Atomoxetine also reversibly inhibits

GIRK currents in Xenopus oocytes in a concentration-dependent, voltage-independent, and time-independent manner.[72] Kir3.1/3.2 ion channels are opened downstream of M2, α2, D2, and A1 stimulation, as well as other Gi-coupled receptors.[72] Therapeutic concentrations of atomoxetine are within range of interacting with GIRKs, especially in CYP2D6 poor metabolizers.[72]
It is not known whether this contributes to the therapeutic effects of atomoxetine in ADHD.

4-Hydroxyatomoxetine, the major active metabolite of atomoxetine in CYP2D6 extensive metabolizers, has been found to have sub-micromolar affinity for

κ-opioid receptors.[62]
It is not known whether this action at the kappa-opioid receptor leads to CNS-related adverse effects.

Pharmacokinetics

Orally administered atomoxetine is rapidly and completely absorbed.[10] First-pass metabolism by the liver is dependent on CYP2D6 activity, resulting in an absolute bioavailability of 63% for extensive metabolizers and 94% for poor metabolizers.[10] Maximum plasma concentration is reached in 1–2 hours.[10] If taken with food, the maximum plasma concentration decreases by 10-40% and delays the tmax by 3 hours.[10] Drugs affecting gastric pH have no effect on oral bioavailability.[5]

Following intravenous delivery, atomoxetine has a volume of distribution of 0.85 L/kg (indicating distribution primarily in total body water), with limited partitioning into red blood cells.[10][73] It is highly bound to plasma proteins (98.7%), mainly albumin, along with α1-acid glycoprotein (77%) and IgG (15%).[10][58] Its metabolite N-desmethylatomoxetine is 99.1% bound to plasma proteins, while 4-hydroxyatomoxetine is only 66.6% bound.[10]

The half-life of atomoxetine varies widely between individuals, with an average range of 4.5 to 19 hours.

Ctrough) residing around 30–40°ng/mL; however, both the time to steady-state levels and Ctrough are expected to vary based on a patient's CYP2D6 profile.[75][76]

Atomoxetine, N-desmethylatomoxetine, and 4-hydroxyatomoxetine produce minimal to no inhibition of CYP1A2 and CYP2C9, but inhibit CYP2D6 in human liver microsomes at concentrations between 3.6 and 17 μmol/L.[citation needed] Plasma concentrations of 4-hydroxyatomoxetine and N-desmethylatomoxetine at steady state are 1.0% and 5% that of atomoxetine in CYP2D6 extensive metabolizers, and are 5% and 45% that of atomoxetine in CYP2D6 poor metabolizers.[5]

Atomoxetine is excreted unchanged in urine at <3% in both extensive and poor CYP2D6 metabolizers, with >96% and 80% of a total dose being excreted in urine, respectively.[10] The fractions excreted in urine as 4-hydroxyatomoxetine and its glucuronide account for 86% of a given dose in extensive metabolizers, but only 40% in poor metabolizers.[10] CYP2D6 poor metabolizers excrete greater amounts of minor metabolites, namely N-desmethylatomoxetine and 2-hydroxymethylatomoxetine and their conjugates.[10]

Major metabolites of atomoxetine in humans.[10]

Pharmacogenomics

Chinese adults homozygous for the hypoactive CYP2D6*10 allele have been found to exhibit two-fold higher area-under-the-curve (AUCs) and 1.5-fold higher maximum plasma concentrations compared to extensive metabolizers.[10]

Japanese men homozygous for CYP2D6*10 have similarly been found to experience two-fold higher AUCs compared to extensive metabolizers.[10]

Chemistry

Atomoxetine, or (−)-methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropylamine, is a white, granular powder that is highly soluble in water.

  • Strattera 60-mg capsule back
    Strattera 60-mg capsule back
  • Strattera 60-mg capsule front with Lilly logo
    Strattera 60-mg capsule front with Lilly logo

Synthesis

Original synthesis of atomoxetine, as patented by Eli Lilly and Company[77][78]

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.[79]

History

Atomoxetine 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. Atomoxetine was initially intended to be developed as an antidepressant, but it was found to be insufficiently efficacious for treating depression. It was, however, found to be effective for ADHD and was approved by the FDA in 2002, for the treatment of ADHD. Its patent expired in May 2017.[80] 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.[81] On 1 September 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States.[82] 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."[83]

In 2017 the FDA approved the generic production of atomoxetine by four pharmaceutical companies.[84]

Society and culture

The drug was originally known as tomoxetine. It was renamed to avoid

medication errors, as the name may be confused with tamoxifen.[85]

Brand names

In India, atomoxetine is sold under brand names including Axetra, Axepta, Attera, Tomoxetin, and Attentin. In Australia, Canada, Italy, Portugal, Romania, Spain, Switzerland and the US, atomoxetine is sold under the brand name Strattera. In the Czech Republic it is sold under brand names including Mylan. In Poland, it is sold under the brand name Auroxetyn. In Iran, atomoxetine is sold under brand names including Stramox. In Brazil, it is sold under the brand name Atentah. In 2017, a

generic version was approved in the United States.[84]

Research

There has been some suggestion that atomoxetine might be a helpful adjunct in people with

major depression, particularly in cases with concomitant ADHD.[86]

Atomoxetine may be used in those with ADHD and

autism.[88] As with other norepinephrine reuptake inhibitors it appears to reduce anxiety and depression symptoms, although attention has focused mainly on specific patient groups such as those with concurrent ADHD[89] or methamphetamine dependence.[90]

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Further reading