Atomoxetine

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Continuing Education Activity

Atomoxetine is indicated for treating attention deficit hyperactivity disorder (ADHD) in adults and children over the age of 6. Although atomoxetine is only FDA-approved for treating ADHD, it is sometimes used off-label for the treatment of adult patients with treatment-resistant depression. This activity outlines the indications, mechanism of action, safe administration, adverse effects, contraindications, and monitoring of atomoxetine.

Objectives:

  • Identify the mechanism of action of atomoxetine.
  • Outline the contraindications of atomoxetine.
  • Review the appropriate follow-up monitoring for atomoxetine therapy.
  • Summarize some interprofessional team strategies for improving care coordination and communication to enhance patient outcomes and minimize adverse events with atomoxetine.

Indications

Atomoxetine is indicated for treating attention deficit hyperactivity disorder (ADHD) in adults and children over the age of 6. Although atomoxetine is only FDA-approved for treating ADHD, it is sometimes used off-label for the treatment of adult patients with treatment-resistant depression. It is also available as a generic formulation.[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. The R(-) isomer is an approximately nine times more potent inhibitor of norepinephrine reuptake than the S(+) isomer. Atomoxetine achieves its therapeutic effects by increasing the concentrations of intra-synaptic norepinephrine in the central nervous system (CNS). Atomoxetine also increases extracellular concentrations 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]

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. Patients can take atomoxetine with or without food as a once-daily dose in the morning or as two 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 can 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 six years and less than 70 kg is 0.5 mg/kg per day. The maximum daily dose of 1.4 mg/kg per day or 100 mg, whichever is less.

Atomoxetine is the first non-stimulant medication to receive FDA approval for the treatment of ADHD. Previous medicines approved to treat ADHD, such as methylphenidate and other amphetamines, are CNS stimulants. Therefore, 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 demonstrated to be effective in treating ADHD, many studies have shown stimulant medications have greater efficacy. Also, stimulant medications typically have an almost immediate clinical effect; whereas, atomoxetine may take several weeks for full noticeable therapeutic action. Patients may stop taking atomoxetine without tapering.[9][10]

Special Population

  • Caution is necessary when administering atomoxetine to individuals with hepatic impairment. Mild hepatic impairment requires no dosing adjustments. Doses should decrease to 50% of normal in individuals with moderate hepatic impairment (Child-Pugh class B) and 25% in individuals with severe hepatic impairment (Child-Pugh class C).
  • Patients with renal impairment usually do not need dose adjustment per manufacturer's product labeling. 
  • Atomoxetine is pregnancy category C medicine.
  • No serious adverse events were reported in the breastfed infants, but alternate drugs may be preferred.[11]

Pharmacokinetics

  • Specific studies regarding the intestinal permeability of atomoxetine are not available; however, two 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 two. 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.[12]
  • The volume of distribution of atomoxetine is approximately 0.85 L/kg, which is only slightly higher than the volume of total body water. For this reason, the belief is 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. Researchers studied the CNS pharmacokinetics of atomoxetine in rats. The 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 the brain extracellular fluid (ECF) to atomoxetine plasma concentrations suggests that movement across the BBB is primarily via diffusion rather than an active transport mechanism.[13]
  • 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. However, in vitro studies have demonstrated 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.[12]
  • The duration of action for atomoxetine can be up to 24 hours, depending on its rate of metabolism. Approximately 7% of Caucasians and less than 1% of Asians are poor metabolizers of CYP2D6, and this polymorphism results in altered atomoxetine pharmacokinetics. Oral bioavailability can become altered, e.g., 63% in extensive metabolizers of CYP2D6 and 94% in poor metabolizers, and the estimated half-life can become altered, e.g.,  5.2 hours in extensive metabolizers and 21.6 hours in poor metabolizers.[12]
  • The primary metabolite of atomoxetine, 4-hydroxy atomoxetine, is biologically equipotent to 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%).[14]

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 start on atomoxetine require close monitoring for suicidal ideation and unusual changes in behavior. Clinicians should always perform a risk-benefit analysis before starting anyone on atomoxetine.[15]

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%)[16][17]

One percent to 10%

Increased diastolic blood pressure (5% to 9%; greater than or equal to 15 mmHg), 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 QTc 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%), 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%), abnormal orgasm, 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.[18][19][20][21][22][23]

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, which cannot tolerate increases in blood pressure or heart rate.

Because of the potential for interaction with CYP2D6 inhibitors (paroxetine, fluoxetine, and quinidine) dose of atomoxetine needs to be adjusted to prevent side effects from a higher concentration of atomoxetine.[24]

Women of childbearing age should use appropriate contraceptive measures as the adverse effects of atomoxetine have not been investigated thoroughly during pregnancy. Women who are breastfeeding should exercise caution when taking atomoxetine as it is unknown if atomoxetine is excreted in breast milk.[25]

Monitoring

Children prescribed atomoxetine should have their growth monitored. All patients started on atomoxetine should have their vital signs monitored. Also, all patients require monitoring for attention, hyperactivity, anxiety, aggression/hostility, and suicidal ideation.[26]

Toxicity

Exercise caution when prescribing atomoxetine with other medications metabolized via CYP2D6 as plasma concentrations can be significantly 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. [12][27]

The concomitant administration of atomoxetine and MAOIs, e.g., phenelzine, is contraindicated because the combination may increase the risk of serious and potentially fatal adverse events, including hyperthermia, rigidity, myoclonus, autonomic instability, extreme agitation, and mental status changes, leading to delirium and coma. A two-week washout period should occur between the discontinuation and initiation of either of these agents.[28]

Enhancing Healthcare Team Outcomes

When atomoxetine is used to treat ADHD, the health care team MDs, DOs, NPs, and PAs need to prescribe carefully and monitor patients regularly, e.g., children's growth. Pharmacists should perform medication reconciliation and watch for potential drug interaction to report to the clinician. Nursing staff should record vital signs for patients at each clinic visit and provide consultation. Additionally, the medication can significantly affect behavior, and thus the clinicians need to monitor patients for anxiety, aggression/hostility, and suicidal ideation, especially in children. If adverse effects appear, discontinuing the drug might be necessary, and the patient should be referred to a mental health clinician for a follow-up consultation. The outcomes for patients treated with atomoxetine can be fair; some patients respond positively, but adverse effects often reduce adherence. Thus communication between the healthcare team is vital for optimal patient outcomes. [Level 5]


Article Details

Article Author

Douglas Fedder

Article Author

Himanshu Patel

Article Editor:

Abdolreza Saadabadi

Updated:

10/25/2021 11:58:49 AM

PubMed Link:

Atomoxetine

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