Atomoxetine


Article Author:
Douglas Fedder


Article Editor:
Abdolreza Saadabadi


Editors In Chief:
Lauren Camaione


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
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Saad Nazir
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Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
1/27/2019 8:25:26 AM

Indications

Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in adults and children over the age of 6. Although atomoxetine is only FDA approved for the treatment of ADHD, it is sometimes used off-label for the treatment of adult patients with treatment-resistant depression. It is available as a generic.[1][2][3]

Mechanism of Action

Atomoxetine is a selective, presynaptic, norepinephrine reuptake inhibitor also known as a NET inhibitor. Atomoxetine is the R(-) isomer of the racemic mixture of R and S isomers. The R isomer is an approximately 9 times more potent inhibitor of norepinephrine reuptake than the S isomer. Atomoxetine achieves its therapeutic effects by increasing the levels of intra-synaptic norepinephrine in the central nervous system (CNS). Atomoxetine also increases extracellular levels of dopamine in the prefrontal cortex, believed to result from NET inhibition. Recent studies on rhesus monkeys using positron emission tomography have shown that atomoxetine also occupies serotonin transporters, but more research in this area is still needed.[4][5][6][7][8]

Specific studies regarding the intestinal permeability of atomoxetine are not available; however, 2 studies on the bioavailability of atomoxetine determined that in extensive metabolizers the bioavailability of atomoxetine was 63%, and in poor metabolizers, the bioavailability was 94%. The differences in bioavailability were attributed to differences in first-pass metabolism in the liver rather than differences in intestinal absorption. Another study comparing the bioavailability of atomoxetine capsules versus solution found no differences in bioavailability between the 2. Another study looking at the absorption of atomoxetine found no differences across a range of gastrointestinal pH levels, indicating that concurrent use of antacids and proton pump inhibitors should not be cause for concern when administering atomoxetine.

The duration of action for atomoxetine can be up to 24 hours depending on its rate of metabolism.

The volume of distribution of atomoxetine has been demonstrated to be approximate 0.85 L/kg, which is only slightly higher than the volume of total body water. For this reason, it is believed that atomoxetine is distributed into total body water. Peak concentrations of atomoxetine in plasma occurred 1 to 2 hours after administration, but may be delayed by a high-fat meal. The CNS pharmacokinetics of atomoxetine was studied in rats. Penetration of the blood-brain barrier (BBB)is crucial in the pharmacokinetics of atomoxetine, as the CNS is the site of action for atomoxetine. The ratio of brain extracellular fluid (ECF) to plasma concentrations of Atomoxetine was determined to be 0.7 +/- 0.4, suggesting that movement across the BBB is primarily via diffusion rather than an active transport mechanism.

In vitro studies have shown that atomoxetine is approximately 98.7% protein bound, with albumin making up 97.5% of this binding. The high protein binding of atomoxetine raises concerns about possible drug-to-drug interactions due to displacement from plasma proteins. In vitro studies have shown that plasma protein binding in humans was only reduced by toxic concentrations of acetylsalicylic acid (aspirin), indicating minimal clinical risk for drug-to-drug interactions.

Metabolism of atomoxetine primarily occurs in the liver via the action of CYP2D6, an enzyme that is involved in the metabolism of around 25% of all marketed drugs. CYP2D6 genes are highly polymorphic; this may lead to increased or decreased metabolism of atomoxetine in certain individuals based on their specific CYP2D6 alleles. This may lead to decreased drug efficacy or increased toxicity for these individuals at a given dosage. The primary metabolite of atomoxetine, 4-hydroxy atomoxetine, has biological activity equally potent to that of atomoxetine. The half-life of atomoxetine is approximately 5 hours and may reach up to 24 hours in poor metabolizers. The active metabolite of atomoxetine has a half-life of 6 to 8 hours and may reach up to 40 hours in poor metabolizers. Atomoxetine is excreted primarily through the urine (83%) and feces (17%).

Administration

Atomoxetine is available in 10-mg, 18-mg, 25-mg, 40-mg, 60-mg, 80-mg, and 100-mg capsules as a hydrochloride salt. Atomoxetine can be taken with or without food as a once-daily dose in the morning, or as 2 evenly divided doses in the morning and afternoon. Capsules should not be opened and should be taken whole. Initial dosing for adults is 40 mg per day, and may be increased after a minimum of 3 days to achieve therapeutic effects. A maximum daily dose is 100 mg per day. Initial dosing for children older than 6 years and less than 70 kg is 0.5 mg/kg per day. Maximum daily dose of 1.4 mg/kg per day or 100 mg, whichever is less.

Atomoxetine was the first non-stimulant medication to receive FDA approval for the treatment of ADHD. Previous medications approved to treat ADHD such as methylphenidate and other amphetamines are all classified as CNS stimulants, they may carry a higher risk of abuse and addiction than atomoxetine. Clinical studies of atomoxetine have shown a lack of abuse potential, consistent with preclinical predictions. While atomoxetine has been shown to be effective in treating ADHD, many studies have shown stimulant medications have a greater efficacy. Also, stimulant medications typically have an almost immediate clinical effect; whereas, atomoxetine may take several weeks for full therapeutic action to be noticed.

Caution should be used when administering atomoxetine to individuals with hepatic impairment. Mild hepatic impairment requires no dosing adjustments. Doses should be decreased to 50% of normal in individuals with moderate hepatic impairment (Child-Pugh class B), and to 25% of normal in individuals with severe hepatic impairment (Child-Pugh class C).

Patients may stop taking atomoxetine without tapering.[9][10]

Adverse Effects

Atomoxetine has a United States (US) boxed warning for suicidal ideation in children and adolescents. An analysis of multiple short-term trials revealed an increase in suicidal ideation in children and adolescents treated with Atomoxetine (0.4%) compared to those treated with a placebo (0%). Children and adolescents who are started on Atomoxetine should be closely monitored for suicidal ideation and unusual changes in behavior. A risk-benefit analysis should always be performed before starting anyone on atomoxetine.

Other Adverse Effects

Greater than 10%

Headache (19%), insomnia (1% to 19%), drowsiness (8% to 11%), hyperhidrosis (4% to 15%), xerostomia (17% to 35%), nausea (7% to 26%), decreased appetite (15% to 23%), abdominal pain (7% to 18%), vomiting (4% to 11%), constipation (1% to 11%), erectile dysfunction (8% to 21%)

One percent to 10%

Increased diastolic blood pressure (5% to 9%; greater than or equal to 15 mm Hg), systolic hypertension (4% to 5%), palpitations (3%), cold extremities (1% to 3%), syncope (less than or equal to 3%), flushing (greater than or equal to 2%), orthostatic hypotension (less than or equal to 2%), tachycardia (less than or equal to 2%), prolonged QT interval on ECG, fatigue (6% to 10%), dizziness (5% to 8%), depression (4% to 7%), disturbed sleep (3% to 7%), irritability (5% to 6%), jitteriness (2% to 5%), abnormal dreams (4%), chills (3%), paresthesia (adults 3%; postmarketing observation in children), anxiety (greater than or equal to 2%), hostility (children and adolescents 2%), emotional lability (1% to 2%), agitation, restlessness, sensation of cold, excoriation (2% to 4%), skin rash (2%), pruritus, uticaria, weight loss (2% to 7%), decreased libido (3%), hot flash (3%), increased thirst (2%), menstrual disease, Dyspepsia (4%), anorexia (3%), dysgeusia, flatulence Ejaculatory disorder (2% to 6%), urinary retention (1% to 6%), dysmenorrhea (3%), dysuria (2%), orgasm abnormal, pollakiuria, prostatitis, testicular pain, urinary frequency, Tremor (1% to 5%), muscle spasm, weakness, Blurred vision (1% to 4%), conjunctivitis (1% to 3%), mydriasis, and pharyngolaryngeal pain

Contraindications

Contraindications to atomoxetine include allergy to atomoxetine, use of an MAOI within the last 14 days, narrow-angle glaucoma, history of pheochromocytoma, and cardiac disorders in which increases in blood pressure or heart rate cannot be tolerated.

Women of childbearing age prescribed atomoxetine should use appropriate contraceptive measures as the adverse effects of atomoxetine use during pregnancy have not been investigated thoroughly. Women who are breastfeeding should exercise caution when taking atomoxetine as it is unknown if atomoxetine is excreted in breast milk.

Monitoring

Children prescribed atomoxetine should have their growth monitored. All patients started on atomoxetine should have their vital signs monitored. Also, all patients should be monitored for attention, hyperactivity, anxiety, aggression/hostility, and suicidal ideation.

Toxicity

Exercise caution when prescribing atomoxetine with other medications metabolized via CYP2D6 as plasma concentrations can be greatly affected leading to toxicity. Evidence regarding the toxicity of atomoxetine is limited, with much of the data coming from case studies of overdoses. Tachycardia, nausea, vomiting, and hypertension were among the most common symptoms of toxicity. Activated charcoal therapy and support of vital signs appear to be sufficient care during acute toxicity.

Enhancing Healthcare Team Outcomes

Atomoxetine is sometimes used to treat ADHD. However, all healthcare workers who look after these patients need to closely monitor the children for their growth. In addition, the vital signs must be recorded at each clinic visit. Finally, the medication can significantly affect behavior and thus the child needs to be monitored for anxiety, aggression/hostility, and suicidal ideation. If adverse effects appear, the drug should be discontinued and the child referred back to the mental health professional. The outcomes for children treated with atomoxetine is fair; some children do respond positively but adverse effects often reduce compliance. (Level V)


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Atomoxetine - Questions

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A woman enters your pharmacy with an atomoxetine prescription for her 11-year-old son. For which condition is the patient likely being treated?



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A patient has a history of resistant depression, substance abuse, and has been known to sell his medications. What could be prescribed to this patient for attention deficit hyperactivity disorder (ADHD)?



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It is decided to treat a patient with attention deficit hyperactivity disorder with atomoxetine. What is the mechanism of action of this medication?



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The patient is an 8-year-old boy is 4 feet 6 inches tall and weighs 110 pounds. What would be the correct initial dosage of atomoxetine?



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A new patient comes to you seeking treatment for his ADHD. He has a history of substance abuse that has caused permanent damage to many of his internal organs. He has a history of lung cancer from years of smoking. Also, he has a history of bacterial endocarditis and chronic hepatitis C from intravenous drug use. The patient has an ejection fraction of 55% and severe hepatic impairment (Child-Pugh class C). Which of the following is true regarding this patient and treatment with atomoxetine?



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Atomoxetine - References

References

Patra S,Nebhinani N,Viswanathan A,Kirubakaran R, Atomoxetine for attention deficit hyperactivity disorder in children and adolescents with autism: A systematic review and meta-analysis. Autism research : official journal of the International Society for Autism Research. 2019 Jan 17;     [PubMed]
Kasparbauer AM,Petrovsky N,Schmidt PM,Trautner P,Weber B,Sträter B,Ettinger U, Effects of nicotine and atomoxetine on brain function during response inhibition. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2018 Dec 12;     [PubMed]
Jensen CM,Breindahl T, Patients in medical treatment for attention deficit/hyperactivity disorder (ADHD): Are they at risk in drug screening? Attention deficit and hyperactivity disorders. 2018 Dec 7;     [PubMed]
Mardomingo Sanz MJ,Sancho Mateo C,Soler López B, [Assessment of comorbidity and social anxiety in adolescents with attention deficit hyperactivity disorder: the SELFIE study]. Anales de pediatria (Barcelona, Spain : 2003). 2018 Nov 18;     [PubMed]
Solmi M,Fornaro M,Toyoshima K,Carvalho AF,Köhler CA,Veronese N,Stubbs B,de Bartolomeis A,Correll CU, Systematic review and exploratory meta-analysis of the efficacy, safety, and biological effects of psychostimulants and atomoxetine in patients with schizophrenia or schizoaffective disorder. CNS spectrums. 2018 Nov 21;     [PubMed]
Villas-Boas CB,Chierrito D,Fernandez-Llimos F,Tonin FS,Sanches ACC, Pharmacological treatment of attention-deficit hyperactivity disorder comorbid with an anxiety disorder: a systematic review. International clinical psychopharmacology. 2018 Nov 12;     [PubMed]
Howes CF,Sharp C, Delusional infestation in the treatment of ADHD with atomoxetine. BMJ case reports. 2018 Sep 23;     [PubMed]
Aldemir R,Demirci E,Bayram AK,Canpolat M,Ozmen S,Per H,Tokmakci M, Evaluation of Two Types of Drug Treatment with QEEG in Children with ADHD. Translational neuroscience. 2018;     [PubMed]
Kobayashi H,Fujii K,Kobayashi M,Saito N,Okunushi K,Ebata R,Shiohama T,Sawada D,Shimojo N, Facial nerve palsy associated with atomoxetine-induced hypertension. Brain     [PubMed]
Sharma A, Update on Common Psychiatric Medications for Children. Pediatric annals. 2018 Aug 1;     [PubMed]

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