Atomoxetine, sold under the brand name Strattera, among others, is a
medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field an ...
used to treat
attention deficit hyperactivity disorder (ADHD).
It may be used alone or along with
psychostimulants.
It is also used as a
cognitive enhancer
Nootropics ( , or ) (colloquial: smart drugs and cognitive enhancers, similar to adaptogens) are a wide range of natural or synthetic supplements or drugs and other substances that are claimed to improve cognitive function or to promote rela ...
to improve alertness, attention, and memory.
Use of atomoxetine is only recommended for those who are at least six years old.
[ It is taken by mouth.][ Atomoxetine is a ]norepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epine ...
and is believed to work by increasing norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...
and dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...
levels in the brain.
Common side effects of atomoxetine include abdominal pain, loss of appetite, nausea, feeling tired, and dizziness.[ Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, ]suicide
Suicide is the act of intentionally causing one's own death. Mental disorders (including depression, bipolar disorder, schizophrenia, personality disorders, anxiety disorders), physical disorders (such as chronic fatigue syndrome), and ...
, and aggression. There is a lack of data regarding its safety during pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ...
; as of 2019, its safety during pregnancy and for use during breastfeeding
Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...
is not certain.[
It was approved for medical use in the United States in 2002.][ In 2020, it was the 287th most commonly prescribed medication in the United States, with more than 1million prescriptions.
]
Medical uses
Atomoxetine is indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD).
Attention deficit hyperactivity disorder
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
Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
treatments for ADHD is that it has little known abuse potential. While it has been shown to significantly reduce inattentive and hyperactive symptoms, the responses were lower than the response to stimulants. Additionally, 40% of participants who were treated with atomoxetine experienced residual ADHD symptoms.
While its efficacy may be less than that of stimulant medications, there is some evidence that it may be used in combination with stimulants.[ Doctors may prescribe non-stimulants including atomoxetine when a person has bothersome side effects from stimulants; when a stimulant was not effective; in combination with a stimulant to increase effectiveness;] or when there is concern about the abuse potential of psychostimulants in a patient with a history of drug use disorder
Substance use disorder (SUD) is the persistent use of drugs (including alcohol) despite substantial harm and adverse consequences as a result of their use. Substance use disorders are characterized by an array of mental/emotional, physical, and b ...
.
Unlike α2 adrenoceptor agonists such as guanfacine and clonidine
Clonidine, sold under the brand name Catapres among others, is an α2-adrenergic agonist medication used to treat high blood pressure, ADHD, drug withdrawal ( alcohol, opioids, or nicotine), menopausal flushing, diarrhea, spasticity, an ...
, atomoxetine's use can be abruptly stopped without significant discontinuation effects being seen.
The initial therapeutic effects of atomoxetine usually take 1 to 4 weeks to become apparent. A further 2 to 4 weeks may be required for the full therapeutic effects to be seen. Incrementally increasing response may occur up to 1 year or longer. The maximum recommended total daily dose in children and adolescents over 70 kg and adults is 100 mg.
Contraindications
Contraindications include:
* Symptomatic cardiovascular disease including:
** Moderate to severe hypertension
** Atrial fibrillation
** Atrial flutter
** Ventricular tachycardia
Ventricular tachycardia (V-tach or VT) is a fast heart rate arising from the lower chambers of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple episodes over a short perio ...
** Ventricular fibrillation
Ventricular fibrillation (V-fib or VF) is an abnormal heart rhythm in which the Ventricle (heart), ventricles of the heart Fibrillation, quiver. It is due to disorganized electrical conduction system of the heart, electrical activity. Ventricular ...
** Ventricular flutter
** Advanced arteriosclerosis
* Severe cardiovascular disorders
* Uncontrolled hyperthyroidism
* Pheochromocytoma
* Concomitant treatment with monoamine oxidase inhibitors
* Narrow angle glaucoma
Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye re ...
Adverse effects
Common side effects include abdominal pain, loss of appetite, nausea, feeling tired, and dizziness. Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide
Suicide is the act of intentionally causing one's own death. Mental disorders (including depression, bipolar disorder, schizophrenia, personality disorders, anxiety disorders), physical disorders (such as chronic fatigue syndrome), and ...
, and aggression. A 2020 meta-analysis found that atomoxetine was associated with anorexia, weight loss, and hypertension, rating it as a "potentially least preferred agent based on safety" for treating ADHD. As of 2019, safety in pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ...
and breastfeeding
Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...
is not clear; a 2018 review stated that, " cause of lack of data, the treating
physician should consider stopping atomoxetine treatment in women with ADHD during pregnancy."
The U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(FDA) has issued a black box warning for suicidal behavior/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.
Incidence of adverse effects
Very common (>10% incidence) adverse effects include:
* Diarrhea (43%)
* Nausea (26%)
* Xerostomia (Dry mouth) (20%)
* Appetite loss (16%)
* Insomnia (15%)
* Fatigue (10%)
* Headache
* Cough
* Vomiting (in children and adolescents)
Common (1–10% incidence) adverse effects include:
Uncommon (0.1–1% incidence) adverse effects include:
Rare (0.01–0.1% incidence) adverse effects including:
* Raynaud's phenomenon
* Abnormal/increased liver function tests
* Jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme met ...
* Hepatitis
Hepatitis is inflammation of the liver parenchyma, liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), Anorexia (symptom), poor appetite ...
* Liver injury
* Acute liver failure
* Urinary retention
* Priapism
* Male genital pain
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.
Interactions
Atomoxetine is a substrate
Substrate may refer to:
Physical layers
*Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached
** Substrate (locomotion), the surface over which an organism lo ...
for CYP2D6
Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.
CYP2 ...
. 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.
Atomoxetine has been found to directly inhibit hERG potassium currents with an IC50 of 6.3 μM, which has the potential to cause arrhythmia. 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.[
Other notable drug interactions include:]
* Antihypertensive
Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests that ...
agents, due to atomoxetine acting as an indirect sympathomimetic
* Indirect-acting sympathomimetics, such as pseudoephedrine, norepinephrine reuptake inhibitors, or MAOIs
* Direct-acting sympathomimetics, such as phenylephrine or other α1 adrenoceptor agonists, including pressors such as dobutamine or isoprenaline and β2 adrenoceptor agonists
* Highly plasma protein-bound drugs: atomoxetine has the potential to displace these drugs from plasma proteins which may potentiate their adverse or toxic effects. ''In vitro'', atomoxetine does not affect the plasma protein binding of aspirin, desipramine, diazepam, paroxetine, phenytoin, or warfarin
Pharmacology
Pharmacodynamics
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.[ In rats, atomoxetine increased ]prefrontal cortex
In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA ...
catecholamine
A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol ( benzene with two hydroxyl side groups next to each other) and a side-chain amine.
Catechol can be either a free molecule or a ...
concentrations without altering dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...
levels in the striatum or nucleus accumbens; in contrast, methylphenidate
Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent ...
, a dopamine reuptake inhibitor
A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular do ...
, was found to increase prefrontal, striatal, and accumbal dopamine levels to the same degree. In addition to rats, atomoxetine has also been found to induce similar region-specific catecholamine level alteration in mice.
Atomoxetine's status as a serotonin transporter (SERT) inhibitor at clinical doses in humans is uncertain. A PET imaging
Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...
study on rhesus monkeys found that atomoxetine occupied >90% and >85% of neural NET and SERT, respectively. 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.[ 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).
Atomoxetine has been found to act as an NMDA receptor antagonist in rat cortical neurons at therapeutic concentrations.] It causes a use-dependent open-channel block and its binding site overlaps with the Mg2+ binding site.[ Atomoxetine's ability to increase prefrontal cortex firing rate in anesthetized rats could not be blocked by D1 or α2-adrenergic receptor antagonists, but could be potentiated by NMDA or an α1-adrenergic receptor antagonist, suggesting a glutaminergic mechanism. In Sprague Dawley rats, atomoxetine reduces NR2B protein content without altering transcript levels.] Aberrant glutamate and NMDA receptor function have been implicated in the etiology of ADHD.
Atomoxetine also reversibly inhibits GIRK currents in ''Xenopus'' oocytes in a concentration-dependent, voltage-independent, and time-independent manner. Kir3.1/3.2 ion channel
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...
s are opened downstream of M2, α2, D2, and A1 stimulation, as well as other Gi-coupled receptors.[ Therapeutic concentrations of atomoxetine are within range of interacting with GIRKs, especially in CYP2D6 poor metabolizers.][ 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 ]opioid receptor
Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatosta ...
s, acting as an antagonist at μ-opioid receptors and a partial agonist at κ-opioid receptors. 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.[ First-pass metabolism by the liver is dependent on ]CYP2D6
Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.
CYP2 ...
activity, resulting in an absolute bioavailability of 63% for extensive metabolizers and 94% for poor metabolizers.[ Maximum plasma concentration is reached in 1–2 hours.][ If taken with food, the maximum plasma concentration decreases by 10-40% and delays the tmax by 3 hours.][ Drugs affecting gastric pH have no effect on oral bioavailability.]
Atomoxetine has a volume of distribution of 0.85 L/kg, with limited partitioning into red blood cells.[ It is highly bound to plasma proteins (98.7%), mainly albumin, along with α1-acid glycoprotein (77%) and IgG (15%).][ Its metabolite ''N''-desmethylatomoxetine is 99.1% bound to plasma proteins, while 4-hydroxyatomoxetine is only 66.6% bound.][
The half-life of atomoxetine varies widely between individuals, with an average range of 4.5 to 19 hours.] As atomoxetine is metabolized by CYP2D6, exposure may be increased 10-fold in CYP2D6 poor metabolizers.[ Among CYP2D6 extensive metabolizers, the half-life of atomoxetine averaged 5.34 hours and the half-life of the active metabolite N-desmethylatomoxetine was 8.9 hours.] By contrast, among CYP2D6 poor metabolizers the half-life of atomoxetine averaged 20.0 hours and the half-life of N-desmethylatomoxetine averaged 33.3 hours.
Atomoxetine, ''N''-desmethylatomoxetine, and 4-hydroxyatomoxetine produce minimal to no inhibition of CYP1A2 and CYP2C9, but inhibit CYP2D6
Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.
CYP2 ...
in human liver microsomes at concentrations between 3.6 and 17 μmol/L. 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.
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.[ 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.][ CYP2D6 poor metabolizers excrete greater amounts of minor metabolites, namely ''N''-desmethylatomoxetine and 2-hydroxymethylatomoxetine and their conjugates.][
]
Pharmacogenomics
Chinese adults homozygous for the hypoactive CYP2D6*10 allele have been found to exhibit two-fold higher area-under-the-curve In the field of pharmacokinetics, the area under the curve (AUC) is the definite integral of the concentration of a drug in blood plasma as a function of time (this can be done using liquid chromatography–mass spectrometry). In practice, the drug ...
(AUCs) and 1.5-fold higher maximum plasma concentrations compared to extensive metabolizers.[
Japanese men homozygous for CYP2D6*10 have similarly been found to experience two-fold higher AUCs compared to extensive metabolizers.][
]
Chemistry
Atomoxetine, or (−)-methyl[(3''R'')-3-(2-methylphenoxy)-3-phenylpropylamine, is a white, granular powder that is highly soluble in water.
File:Strattera 60mg capsule back.jpg, Strattera 60-mg capsule back
File:Lilly Strattera 60mg Capsule.jpg, Strattera 60-mg capsule front with Lilly logo
Synthesis
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.
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 drug development, 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. 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 eneric Stratteras deferred."
In 2017 the FDA approved the generic production of atomoxetine by four pharmaceutical companies.
Society and culture
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 Iran, atomoxetine is sold under brand names including Stramox. In 2017, a generic version was approved in the United States.
Research
There has been some suggestion that atomoxetine might be a helpful adjunct in people with major depression, particularly in cases with concomitant ADHD.
Atomoxetine may be used in those with ADHD and bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
although such use has not been well studied. Some benefit has also been seen in people with ADHD and autism
The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
. 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 or methamphetamine dependence.
References
Further reading
*
External links
*
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