Atomoxetine

Introduction Overview

Generic Name

atomoxetine

Brand Name

Strattera

Dosage Form

capsule (10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, 100 mg)

Drug Class

Adrenergic uptake inhibitors for ADHD

Pharmacokinetics

Absorption: Atomoxetine, the active ingredient in Strattera, is well absorbed orally, with peak plasma concentrations occurring approximately 1 to 2 hours post-dose. Its bioavailability is high, although first-pass metabolism reduces the amount of unchanged drug entering systemic circulation. The rate and extent of absorption are not significantly affected by food intake, enabling dosing with or without meals. Animal and human studies have shown that absorption is consistent, making oral capsules an effective delivery method.

Distribution: Atomoxetine exhibits moderate plasma protein binding, primarily to albumin, estimated at around 98%. It distributes widely throughout the body, including crossing the blood-brain barrier to exert its central nervous system effects. The volume of distribution at steady state approximates 0.85 to 1.35 L/kg, suggesting moderate tissue penetration. Distribution may vary with patient characteristics such as age and body weight; however, these variations are clinically insignificant in most patients.

Metabolism: Atomoxetine is extensively metabolized in the liver predominantly via the cytochrome P450 enzyme CYP2D6 into 4-hydroxyatomoxetine, which is then conjugated. Genetic polymorphisms in CYP2D6 result in different metabolism phenotypes: extensive metabolizers (EMs) and poor metabolizers (PMs). PMs experience higher plasma concentrations and longer half-lives of atomoxetine, necessitating possible dose adjustments. Concomitant use of strong CYP2D6 inhibitors similarly raises atomoxetine levels, warranting caution.

Elimination: The elimination half-life of atomoxetine ranges from approximately 5.2 hours in EMs to 24 hours in PMs. The drug and its metabolites are primarily excreted in the urine, with minor fecal elimination. Around 96% of an administered dose is recovered in urine over one week, predominantly as metabolites. Renal impairment has minimal effect on elimination due to hepatic metabolism being the main route. The pharmacokinetic profile supports once or twice daily dosing regimens for sustained therapeutic effects.

Dosage Forms

Available Dosage Forms: Strattera is formulated as an oral capsule available in multiple strengths including 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, and 100 mg. These capsules should be swallowed whole and not crushed, chewed, or opened due to the risk associated with exposure to the capsule contents.

Dosages for Adults and Adolescents: For adults and adolescents, the usual starting dose is 40 mg once daily. After at least 3 days, the dose is typically increased to 80 mg per day, either given as a single dose or divided into two doses in the morning and late afternoon/early evening. If necessary, and after 2 to 4 weeks, the dose may be further increased up to 100 mg daily in patients who have not achieved optimal therapeutic response. Therapeutic monitoring and titration should be individualized based on efficacy and tolerability.

Specific Patient Populations: Pediatric patients weighing 70 kg or less start at 0.5 mg/kg/day, increasing to 1.2 mg/kg/day after a minimum of 3 days at initial dose, with a maximum dose of 1.4 mg/kg/day or 100 mg/day, whichever is lower. Pediatric patients over 70 kg follow adult dosing guidelines. Dose adjustments are advised in patients with hepatic impairment because atomoxetine clearance is significantly reduced in such individuals. Also, dose consideration is necessary for patients who are poor metabolizers or taking strong CYP2D6 inhibitors to avoid toxicity. Strattera has not been studied in children under 6 years old and is not recommended in this population.

Mechanism Of Action

Strattera (atomoxetine) primarily functions as a selective norepinephrine reuptake inhibitor (NRI). It inhibits the presynaptic norepinephrine transporter (NET) protein responsible for the reuptake of norepinephrine from the synaptic cleft back into presynaptic neurons. By blocking this transporter, atomoxetine increases extracellular norepinephrine concentrations in key brain regions associated with attention and impulse control, such as the prefrontal cortex. This enhancement of noradrenergic neurotransmission improves focus, attention span, and reduces hyperactive and impulsive behaviors characteristic of ADHD.

Unlike stimulant medications commonly used for ADHD, Strattera is not a dopamine reuptake inhibitor and does not significantly increase dopaminergic neurotransmission in brain areas associated with the reward pathway. This selective mechanism reduces the risk of abuse, dependence, and stimulant-related adverse effects, making it a valuable non-stimulant alternative.

Beyond norepinephrine modulation, emerging research indicates atomoxetine may indirectly influence dopaminergic transmission in the prefrontal cortex due to the interaction between norepinephrine and dopamine transporters, further contributing to its therapeutic effects. Clinical studies demonstrate that steady-state administration leads to sustained elevations in synaptic norepinephrine, correlating with improvements in ADHD symptoms over weeks.

Comparatively, atomoxetine’s mechanism distinguishes it from stimulant agents like amphetamines or methylphenidate, which increase dopamine and norepinephrine release and block their reuptake more broadly. This difference underpins its unique clinical profile, particularly in patients contraindicated for stimulants or those with a history of substance abuse. The selective noradrenergic effect aligns with its distinct side effect and safety profile observed in extensive clinical trials.

Pharmacological Actions

Selective inhibition of presynaptic norepinephrine transporter increasing norepinephrine availability in the synaptic cleft
Enhancement of noradrenergic neurotransmission in the prefrontal cortex leading to improved attention and impulse control
Non-stimulant activity without significant dopaminergic reward pathway activation, reducing abuse potential
Modulation of adrenergic pathways contributing to reduced hyperactivity and impulsivity in ADHD
Indirect effects on dopaminergic transmission in cortical areas via norepinephrine transporter inhibition
Improved synaptic neurotransmitter balance associated with executive function and cognitive control
No significant effect on serotonin reuptake or monoamine oxidase activity
Demonstrates a delayed onset of full therapeutic efficacy, with symptom improvements observed over several weeks
Lacks sympathomimetic effects typical of stimulant drugs, minimizing cardiovascular stimulation
Provides a sustained 24-hour symptom control with once or twice daily dosing

Therapeutic Or Clinical Uses

Treatment of attention-deficit hyperactivity disorder (ADHD) in children aged 6 years and older, adolescents, and adults
Improvement of attention span, reduction in impulsivity and hyperactivity in ADHD patients
Adjunct to psychological, educational, and social measures to manage ADHD symptoms
Non-stimulant therapeutic option for patients contraindicated for stimulant medications
Management of ADHD in patients with a history of substance abuse due to low abuse potential
Off-label use in treatment-resistant depression in adults in some clinical scenarios
Potential use in patients who do not tolerate or do not respond adequately to stimulant therapy
Use in patients with a risk of stimulant-related side effects such as cardiovascular issues or anxiety
Part of individualized ADHD treatment plans considering patient preference and safety profile
Alternative for long-term maintenance treatment of ADHD symptoms

Side Or Adverse Effects

Nausea and vomiting
Upset stomach and gastrointestinal discomfort
Constipation
Dry mouth
Loss of appetite leading to potential weight loss
Mood changes including irritability and mood swings
Fatigue or feeling tired
Dizziness
Urination problems including difficulty or painful urination
Impotence or erectile dysfunction in males
New or worsening psychiatric symptoms such as anxiety, panic attacks, agitation, hostility, or depression
Rare but serious allergic reactions including swelling and difficulty breathing
Rare instances of liver toxicity presenting as upper right abdominal pain, jaundice, or dark urine
Possible cardiovascular effects including chest pain, increased heart rate, and hypertension
Prolonged and painful erections (priapism), a rare but serious side effect

Precautions

Use caution in patients with preexisting cardiovascular conditions such as hypertension, heart disease, or congenital heart defects
Monitor closely for emergence or worsening of suicidal ideation, especially in children, adolescents, and young adults
Avoid use in patients with narrow-angle glaucoma due to potential to increase intraocular pressure
Assess hepatic function prior to initiation and consider dose adjustments in hepatic impairment
Beware of potential allergic reactions in patients sensitive to atomoxetine or capsule excipients
Regular monitoring of blood pressure and heart rate during treatment
Careful use advised in individuals with a history of bipolar disorder or psychosis
Avoid abrupt discontinuation; tapering may be required to reduce withdrawal symptoms
Be alert for new behavioral symptoms such as aggression or hostility that might emerge during therapy
Caution advised when prescribing to patients with pheochromocytoma or adrenal gland tumors
Ensure dosage adherence to prevent overdose and adverse effects
Exercise care in patients with low blood pressure or orthostatic hypotension
Consider potential effects on growth in pediatric patients; monitor height and weight regularly
Inform patients about the importance of not opening, crushing, or chewing capsules
Counsel regarding potential interactions with other medications and avoid concomitant MAO inhibitors

Warnings

Contraindicated in patients with narrow-angle glaucoma, severe heart or blood vessel problems, or pheochromocytoma
Avoid use in combination with monoamine oxidase inhibitors (MAOIs) within 14 days before or after treatment due to risk of hypertensive crisis
Increased risk for stroke, heart attack, and sudden death in patients with underlying heart disease or high blood pressure
Potential for new or worsening psychosis or mania, especially in patients with a history of mental illness
Risk of suicidal ideation and behavior, particularly in children, adolescents, and young adults during initial treatment or dose changes
Risk of severe liver injury; patients should be monitored for signs of hepatotoxicity
Use with caution in patients with elevated blood pressure or cardiovascular risk factors
Exposure to capsule contents can cause eye irritation; handle broken capsules carefully
Potential risk of orthostatic hypotension and syncope
May impair ability to perform hazardous tasks such as driving until individual response is known
Possible interactions increasing effects of blood pressure medications or other drugs affecting norepinephrine
Avoid use in patients with hypersensitivity to atomoxetine or its components
Patients with family history of sudden cardiac death require careful evaluation before treatment
Monitoring required for liver function tests if clinically indicated during therapy
Patients should be advised to report emergent symptoms of chest pain, shortness of breath, or palpitations promptly

Contraindication

Known hypersensitivity to atomoxetine or any component of Strattera capsules
Narrow-angle glaucoma
Severe cardiovascular disorders including severe hypertension, coronary artery disease, and congenital heart defects
Pheochromocytoma or other adrenal gland tumors
Concurrent or recent (within 14 days) use of monoamine oxidase inhibitors (MAOIs)
History of serious hypersensitivity reactions to atomoxetine
Patients with history of serious cardiac arrhythmias or unstable cardiac conditions
Known poor metabolizers of CYP2D6 without careful dose adjustment
Severe liver impairment without proper dose modification

Drug Interactions

Monoamine oxidase inhibitors (MAOIs) – risk of hypertensive crisis; concurrent use contraindicated
Strong CYP2D6 inhibitors such as paroxetine, fluoxetine, or quinidine – can increase atomoxetine plasma concentration requiring dose adjustments
Antihypertensive medications may have altered effects due to atomoxetine’s potential to raise blood pressure and heart rate
Certain asthma medications including sympathomimetics may increase cardiovascular side effects
Cold or allergy medications containing decongestants like pseudoephedrine or phenylephrine can enhance sympathomimetic effects
CYP2D6 inducers or inhibitors can alter metabolism and clearance of atomoxetine
Drugs prolonging QT interval should be used cautiously due to additive cardiac effects
Alcohol may exacerbate side effects such as dizziness and sedation
Other central nervous system medications including antidepressants may have additive effects on mood or risk of side effects
Medications affecting liver enzyme activity could influence atomoxetine levels
Co-administration with drugs affecting blood pressure requires close cardiovascular monitoring
Potential interaction with medications metabolized by CYP enzymes via enzyme induction or inhibition
Use caution with other agents known to cause urinary retention or erectile dysfunction
Patients should inform healthcare providers of all medications and supplements to prevent unrecognized interactions
Frequent monitoring is recommended when starting or stopping medications that affect CYP2D6

Preparations Of The Drug

Oral capsules containing atomoxetine hydrochloride available in strengths: 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, and 100 mg
Capsules should be swallowed whole and not chewed, crushed, or opened to prevent irritation or exposure
Available in unit-dose packaging for ease of dispensing and dosing accuracy
Immediate-release formulation allowing for flexible dosing once or twice daily
Generic formulations of atomoxetine available with similar pharmacokinetic profiles and dosing instructions
Packaged with child-resistant containers to minimize accidental ingestion
Stable at room temperature storage between 15 to 30 °C (59 to 86 °F)
Manufactured by Eli Lilly and Company (marketed by Lilly USA, LLC)
Available through prescription with careful monitoring and dispensing instructions
Capsule excipients designed to ensure bioavailability and patient tolerability
No liquid or alternative dosage forms currently available; capsules are the only recommended formulation
Provided with patient information leaflets detailing dosing, side effects, and handling precautions
Proper disposal recommended for unused or expired capsules to prevent unintended exposure
Handling precautions emphasize avoiding contact of capsule contents with eyes or broken skin
Often dispensed in standard quantities tailored for titration schedules and maintenance therapy