Atomoxetine

Mechanism of Action

Atomoxetine is a selective, presynaptic, norepinephrine reuptake inhibitor known as a NET inhibitor. Atomoxetine is the R(-) isomer. The R(-) isomer is an approximately nine times more potent norepinephrine reuptake inhibitor than the S(+) isomer.[4] Atomoxetine inhibits the presynaptic norepinephrine transporter (NET), preventing the reuptake of NE throughout the brain and inhibiting dopamine reuptake in specific brain regions such as the prefrontal cortex (PFC). The novel mechanism of atomoxetine also includes several new brain imaging studies and animal model studies.[5]

Pharmacokinetics

Absorption: Atomoxetine is well-absorbed after oral administration and is minimally affected by food. Administration of atomoxetine capsules with a standard high-fat meal in adults did not affect the extent of oral absorption of atomoxetine (AUC) but reduced absorption rate, resulting in a 37% lower Cmax, and delayed Tmax by 3 hours. 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, implying that concurrent use of antacids and proton pump inhibitors should not be cause for concern when administering atomoxetine.[4]

Distribution: At therapeutic concentrations, 98% of atomoxetine in plasma is bound to protein, primarily albumin. The volume of distribution(Vd) is 0.85 L/kg implying that atomoxetine distributes primarily into total body water. The volume of distribution is similar across the patient weight range after normalizing for body weight. 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 brain extracellular fluid (ECF) ratio to atomoxetine plasma concentrations suggests that movement across the BBB is primarily via diffusion rather than an active transport mechanism.[6] 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 human plasma protein binding was only reduced by toxic concentrations of acetylsalicylic acid (aspirin), indicating minimal clinical risk for drug-to-drug interactions.[4]

Metabolism: Atomoxetine is metabolized predominantly through the CYP2D6 enzymatic pathway. Coadministration of atomoxetine capsules with potent inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine, results in a marked increase in atomoxetine plasma exposure, and dosing adjustment may be necessary. The main oxidative metabolite is 4-hydroxyatomoxetine. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter but has lower plasma concentrations. 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 alter, e.g., 63% in extensive metabolizers of CYP2D6 and 94% in poor metabolizers. The estimated half-life can alter, e.g., 5.2 hours in extensive metabolizers and 21.6 hours in poor metabolizers.[4]

Excretion: 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%).[7]

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 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.[8][9]

Special Population

• Dosage adjustment based on Pharmacogenetics: Patients who are CYP2D6 poor metabolizers should be prescribed 40 mg per day. The dose may be increased to 80 mg per day after four weeks if there is an inadequate response. 

• Hepatic Impairment: Atomoxetine exposure (AUC) is increased, compared with normal subjects, in subjects with moderate (Child-Pugh Class B) (2-fold increase) and severe (Child-Pugh Class C) (4-fold increase) hepatic insufficiency. Dosage adjustment is recommended for patients with moderate or severe hepatic insufficiency. Hence for moderate hepatic impairment(Child-Pugh class B), 50% dose reduction is recommended. For severe hepatic impairment (Child-Pugh class C), a 75% dose reduction is recommended.

• Renal Impairment: Patients with renal impairment usually do not need dose adjustment per the manufacturer's product labeling. 

• Pregnancy Considerations: Atomoxetine is pregnancy category C medicine.

• Breastfeeding considerations: No serious adverse events were reported in the breastfed infants, but alternate drugs for the treatment of ADHD are preferred.[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 increased 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.[11]

Common Adverse Drug Reactions (Greater than 10%)

• Headache (19%)[12]
• Insomnia (1% to 19%)
• Hyperhidrosis (4% to 15%)
• Xerostomia (17% to 35%)
• Delayed ejaculation and priapism(8% to 21%)[13]
• Nausea (7% to 26%)
• Decreased appetite (15% to 23%)
• Abdominal pain (7% to 18%)
• Vomiting (4% to 11%)[14]

Adverse Drug Reactions (1% to 10%)

• Palpitations (3%), cold extremities (1% to 3%), prolonged QTc interval on ECG, increased diastolic blood pressure (5% to 9%), greater than or equal to 15 mmHg), systolic hypertension (4% to 5%), syncope (less than or equal to 3%), orthostatic hypotension (less than or equal to 2%), tachycardia (less than or equal to 2%)[15]

• 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, seizures[16]

• Excoriation (2% to 4%), rash (2%), pruritus, urticaria,flushing (greater than or equal to 2%)weight loss (2% to 7%),  hot flash (3%), increased thirst (2%), menstrual disease, dyspepsia (4%), anorexia (3%), dysgeusia, flatulence,  urinary retention (1% to 6%), dysmenorrhea (3%), dysuria (2%),  pollakiuria, testicular pain, urinary frequency, tremor (1% to 5%), muscle spasm, weakness, blurred vision (1% to 4%), conjunctivitis (1% to 3%)decreased libido (3%), ejaculatory disorder (2% to 6%)[17]

• Hepatotoxicity (hepatocellular with marked increases in serum aminotransferase level) Likelihood score: C (probable cause of clinically apparent liver injury)[18]

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 can not tolerate increases in blood pressure or heart rate.

• Drug Interactions: 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.[19]

• Women of childbearing age should use appropriate contraceptive measures as the adverse effects of atomoxetine have not been investigated thoroughly during pregnancy. Women breastfeeding should exercise caution when taking atomoxetine as it is unknown if atomoxetine is excreted in breast milk.[20]

Boxed Warning (Package Insert)

• Suicidal ideation in adolescents & children: Atomoxetine raised the risk of suicidal ideation in children or adolescents with (ADHD). Placebo-controlled trials of atomoxetine in adolescents & children have shown a greater risk of suicidal ideation earlier during treatment in those receiving atomoxetine than in placebo. Therefore, patients who are started on therapy should be observed closely for suicidality. Clinicians should instruct caregivers on the need for close observation and communication with the clinician. The average risk of suicidal ideation in patients taking atomoxetine capsules was 0.4%.

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.[21]

• New mental (psychiatric) problems in children and teenagers: new psychotic symptoms (such as hearing voices, believing things that are not true, being suspicious).

• Monitor for emergence of bipolar disorder/hypomania while the patient is on atomoxetine.[22]

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.[4][23]

• 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. It includes 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.[24] The clinician should consult with a Certified Poison Control Center. Atomoxetine is highly protein-bound; hence dialysis is not likely to be useful in treating overdose.

Enhancing Healthcare Team Outcomes

When atomoxetine is used to treat ADHD, the health care team MDs, DOs, NPs, and PAs need to prescribe it carefully and monitor patients regularly, e.g., children's growth. Pharmacists should perform medication reconciliation and watch for potential drug interactions 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 healthcare team needs 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 clinician should refer the patient to a psychiatrist 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 safety and optimal patient outcomes.[Level 5]