STRATAN

Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor used for the treatment of attention deficit hyperactivity disorder (ADHD).

Also known as the marketed product

Strattera, atomoxetine is used with other treatment modalities (psychological, educational, cognitive behaviour therapy, etc) to improve developmentally inappropriate symptoms associated with ADHD including distractibility, short attention span, hyperactivity, emotional lability, and impulsivity.

Although the underlying pathophysiology that causes

ADHD remains unclear, evidence suggests that dysregulation in noradrenergic and dopaminergic pathways plays a critical role in suboptimal executive functioning within prefrontal regions of the brain, which are involved in attention and memory.

Atomoxetine has been shown to specifically increase NA and DA within the prefrontal cortex, but not in the nucleus accumbens (NA) or striatum.

This is beneficial in the treatment of ADHD as DA activation in the subcortical NA and striatum is associated with many stimulant-associated side effects and an increase in abuse potential, which is a limiting factor associated with the use of stimulant medications such as Methylphenidate, Dextroamphetamine, and Lisdexamfetamine.

Use of non-stimulant medications such as atomoxetine is therefore thought to offer a clinical advantage over the use of traditional medications for the management of ADHD.

More recently, positron emission tomography (PET) imaging studies in rhesus monkeys have shown that atomoxetine also binds to the serotonin transporter (SERT), 9 and blocks the N-methyl-d-aspartate (NMDA) receptor, 10 indicating a role for the glutamatergic system in the pathophysiology of ADHD.

Long-acting formulations of psychostimulants (such as Methylphenidate, Dextroamphetamine, and Lisdexamfetamine ) are typically considered the most effective and first-line treatment for ADHD in adults and children as recommended by CADDRA (Canadian ADHD Resource Alliance).

However, these stimulant medications are limited by dose-related side effects and concerns of abuse.

Many contain a blackbox warning stating that CNS stimulants, including methylphenidate-containing products and amphetamines, have a high potential for abuse and dependence.

In particular, increased dopamine in key areas caused by these stimulant medications is associated with their reinforcing and addictive properties, and even amplifies the potency and reinforcing effects of other drugs of abuse such as amphetamines, making ADHD sufferers more susceptible to their addictive effects.

Concerns about abuse potential have spurred research into medications with fewer effects on DA and the use of non-stimulant ADHD medications including atomoxetine, Modafinil and Guanfacine.

The non-stimulant norepinephrine/dopamine reuptake inhibitor Bupropion (commonly used for the treatment of depression and for smoking cessation) has also been shown to be effective in the treatment of ADHD.

Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults.

Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor used for the treatment of attention deficit hyperactivity disorder (ADHD).

Atomoxetine has been shown to specifically increase norepinephrine and dopamine within the prefrontal cortex, which results in improved ADHD symptoms. 8, 8, 18 Due to atomoxetine's noradrenergic activity, it also has effects on the cardiovascular system such as increased blood pressure and tachycardia.

Sudden deaths, stroke, and myocardial infarction have been reported in patients taking atomoxetine at usual doses for ADHD.

Atomoxetine should be used with caution in patients whose underlying medical conditions could be worsened by increases in blood pressure or heart rate such as certain patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease.

It should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experienced clinically important increases in blood pressure or heart rate.

Although the role of atomoxetine in these cases is unknown, consideration should be given to not treating patients with clinically significant cardiac abnormalities.

Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during atomoxetine treatment should undergo a prompt cardiac evaluation.

In general, particular care should be taken in treating ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in patients at risk for bipolar disorder.

Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by atomoxetine at usual doses.

If such symptoms occur, consideration should be given to a possible causal role of atomoxetine, and discontinuation of treatment should be considered.

Atomoxetine capsules increased the risk of suicidal ideation in short-term studies in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD).

All pediatric patients being treated with atomoxetine should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

Postmarketing reports indicate that atomoxetine can cause severe liver injury.

Although no evidence of liver injury was detected in clinical trials of about 6000 patients, there have been rare cases of clinically significant liver injury that were considered probably or possibly related to atomoxetine use in postmarketing experience.

Rare cases of liver failure have also been reported, including a case that resulted in a liver transplant.

Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted.

Laboratory testing to determine liver enzyme levels should be done upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu like” symptoms).

The pharmacokinetic profile of atomoxetine is highly dependent on cytochrome P450 2D6 genetic polymorphisms of the individual.

A large fraction of the population (up to 10% of Caucasians and 2% of people of African descent and 1% of Asians) are poor metabolizers (PMs) of CYP2D6 metabolized drugs.

These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of 21.6 hours) of atomoxetine compared with people with normal CYP2D6 activity.

Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in extensive metabolizers (EMs) and 94% in poor metabolizers (PMs).

Mean maximal plasma concentrations (Cmax) are reached approximately 1-2 hours after dosing with a maximal concentration of 350 ng/ml with an AUC of 2 mcg.h/ml.

The reported volume of distribution of oral atomoxetine was 1.6-2.6 L/kg. The steady-state volume of distribution of intravenous atomoxetine was approximately 0.85 L/kg.

Atomoxetine undergoes biotransformation primarily through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway.

People with reduced activity in the

CYP2D6 pathway (also known as poor metabolizers or PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (also known as extensive metabolizers, or EMs).

PMs, the AUC of atomoxetine at steady-state is approximately 10-fold higher and Cmax is about 5-fold greater than for EMs.

The major oxidative metabolite formed regardless of CYP2D6 status is 4-hydroxy-atomoxetine, which is rapidly glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter, but circulates in plasma at much lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentration in PMs).

In individuals that lack

CYP2D6 activity, 4-hydroxyatomoxetine is still the primary metabolite, but is formed by several other cytochrome P450 enzymes and at a slower rate.

Another minor metabolite, N-Desmethyl-atomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has much less pharmacological activity than atomoxetine and lower plasma concentrations (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in PMs).

Hover over products below to view reaction partners Atomoxetine 4-hydroxyatomoxetine 4-hydroxyatomoxetine-O-glucuronide N-desmethylatomoxetine N-desmethyl-4-hydroxyatomoxetine.

Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the feces (less than 17% of the dose).

Only a small fraction (less than 3%) of the atomoxetine dose is excreted as unchanged atomoxetine, indicating extensive biotransformation.

The reported half-life depends on the

CYP2D6 genetic polymorphisms of the individual and can range from 3-5.6 hours.

The clearance rate of atomoxetine depends the CYP2D6 genetic polymorphisms of the individual and can range of 0.27-0.67 L.h/kg.

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There is limited clinical trial experience with atomoxetine overdose.

During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of atomoxetine capsules and at least one other drug.

There have been no reports of death involving overdose of atomoxetine capsules alone, including intentional overdoses at amounts up to 1400 mg. In some cases of overdose involving atomoxetine, seizures have been reported.

The most commonly reported symptoms accompanying acute and chronic overdoses of atomoxetine capsules were gastrointestinal symptoms, somnolence, dizziness, tremor, and abnormal behavior.

Hyperactivity and agitation have also been reported.

Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, blood pressure increased, mydriasis, dry mouth) have also been observed.

Most events were mild to moderate.

Less commonly, there have been reports of QT prolongation and mental changes, including disorientation and hallucinations.

If symptoms of overdose are suspected, a Certified Poison Control Center should be consulted for up to date guidance and advice.

Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose.

• Hypersensitivity to atomoxetine or other constituents of product.

• Atomoxetine capsules use within 2 weeks after discontinuing MAOI or other drugs that affect brain monoamine concentrations.

• Pheochromocytoma or history of pheochromocytoma.

Disorders that might deteriorate with clinically important increases in HR and BP. 4.1 Hypersensitivity Atomoxetine capsules are contraindicated in patients known to be hypersensitive to atomoxetine or other constituents of the product. 4.2 Monoamine Oxidase Inhibitors (MAOI) Atomoxetine capsules should not be taken with an MAOI, or within 2 weeks after discontinuing an MAOI.

Treatment with an

MAOI should not be initiated within 2 weeks after discontinuing atomoxetine capsules.

With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI.

Some cases presented with features resembling neuroleptic malignant syndrome.

Such reactions may occur when these drugs are given concurrently or in close proximity. 4.3 Narrow Angle Glaucoma In clinical trials, atomoxetine capsules use was associated with an increased risk of mydriasis and therefore its use is not recommended in patients with narrow angle glaucoma. 4.4 Pheochromocytoma Serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with pheochromocytoma or a history of pheochromocytoma who received atomoxetine capsules.

Therefore, atomoxetine capsules should not be taken by patients with pheochromocytoma or a history of pheochromocytoma. 4.5 Severe Cardiovascular.

Disorders Atomoxetine capsules should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experience increases in blood pressure or heart rate that could be clinically important (for example, 15 to 20 mm Hg in blood pressure or 20 beats per minute in heart rate). .

Initial, Target and Maximum Daily Dose (Acute and Maintenance/Extended Treatment) Body Weight Initial Daily Dose Target Total Daily Dose Maximum Total Daily Dose Children and adolescents up to 70 kg 0.5 mg/kg 1.2 mg/kg 1.4 mg/kg Children and adolescents over 70 kg and adults 40 mg 80 mg 100 mg Dosing adjustment — Hepatic Impairment, Strong CYP2D6 Inhibitor, and in patients known to be CYP2D6 poor metabolizers (PMs). 2.1 Acute Treatment Dosing of children and adolescents up to 70 kg body weight.

• Atomoxetine capsules should be initiated at a total daily dose of approximately 0.5 mg/kg and increased after a minimum of 3 days to a target total daily dose of approximately 1.2 mg/kg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening.

No additional benefit has been demonstrated for doses higher than 1.2 mg/kg/day.

The total daily dose in children and adolescents should not exceed 1.4 mg/kg or 100 mg, whichever is less.

Dosing of children and adolescents over 70 kg body weight and adults.

• Atomoxetine capsules should be initiated at a total daily dose of 40 mg and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening.

After to 4 additional weeks, the dose may be increased to a maximum of 100 mg in patients who have not achieved an optimal response.

There are no data that support increased effectiveness at higher doses.

The maximum recommended total daily dose in children and adolescents over 70 kg and adults is 100 mg. 2.2 Maintenance/Extended Treatment It is generally agreed that pharmacological treatment of ADHD may be needed for extended periods.

The benefit of maintaining pediatric patients (ages to 15 years) with ADHD on atomoxetine capsules after achieving a response in a dose range of 1.2 to 1.8 mg/kg/day was demonstrated in a controlled trial.

Patients assigned to atomoxetine capsules in the maintenance phase were generally continued on the same dose used to achieve a response in the open label phase.

The physician who elects to use atomoxetine capsules for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. 2.3 General Dosing Information Atomoxetine capsules may be taken with or without food.

Atomoxetine capsules can be discontinued without being tapered.

Atomoxetine capsules are not intended to be opened, they should be taken whole.

The safety of single doses over 120 mg and total daily doses above 150 mg have not been systematically evaluated. 2.4 Dosing in Specific Populations Dosing adjustment for hepatically impaired patients — For those ADHD patients who have hepatic insufficiency (HI), dosage adjustment is recommended as follows: For patients with moderate HI (Child-Pugh Class B), initial and target doses should be reduced to 50% of the normal dose (for patients without HI).

For patients with severe

HI (Child-Pugh Class C), initial dose and target doses should be reduced to 25% of normal.

Dosing adjustment for use with a strong CYP2D6 inhibitor or in patients who are known to be CYP2D6 PMs — In children and adolescents up to 70 kg body weight administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, or in patients who are known to be CYP2D6 PMs, atomoxetine capsule should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.

In children and adolescents over 70 kg body weight and adults administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, atomoxetine capsule should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.

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There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including atomoxetine, during pregnancy.

Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting Risk Summary Available published studies with atomoxetine use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Some animal reproduction studies of atomoxetine had adverse developmental outcomes.

One of 3 studies in pregnant rabbits dosed during organogenesis resulted in decreased live fetuses and an increase in early resorptions, as well as slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery.

These effects were observed at plasma levels (AUC) 3 times and 0.4 times the human plasma levels in extensive and poor metabolizers receiving the maximum recommended human dose (MRHD), respectively.

In rats dosed prior to mating and during organogenesis a decrease in fetal weight (female only) and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses were observed at a dose approximately 5 times the MRHD on a mg/m 2 basis.

In one of 2 studies in which rats were dosed prior to mating through the periods of organogenesis and lactation, decreased pup weight and decreased pup survival were observed at doses corresponding to to 6 times the MRHD on a mg/m 2 basis.

No adverse fetal effects were seen in pregnant rats dosed during the organogenesis period.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Pregnant rabbits were treated with up to 100 mg/kg/day of atomoxetine by gavage throughout the period of organogenesis.

At this dose, in of 3 studies, a decrease in live fetuses and an increase in early resorptions was observed.

Slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery were observed.

These findings were observed at doses that caused slight maternal toxicity.

The no-effect dose for these findings was 30 mg/kg/day. The 100 mg/kg dose is approximately 23 times the MRHD on a mg/m 2 basis; plasma levels (AUC) of atomoxetine at this dose in rabbits are estimated to be 3.3 times (extensive metabolizers) or 0.4 times (poor metabolizers) those in humans receiving the MRHD.

Rats were treated with up to approximately 50 mg/kg/day of atomoxetine (approximately 6 times the MRHD on a mg/m 2 basis) in the diet from 2 weeks (females) or 10 weeks (males) prior to mating through the periods of organogenesis and lactation.

In of 2 studies, decreases in pup weight and pup survival were observed.

The decreased pup survival was also seen at 25 mg/kg (but not at 13 mg/kg).

In a study in which rats were treated with atomoxetine in the diet from 2 weeks (females) or 10 weeks (males) prior to mating throughout the period of organogenesis, a decrease in fetal weight (female only) and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses were observed at 40 mg/kg/day (approximately 5 times the MRHD on a mg/m 2 basis) but not at 20 mg/kg/day. No adverse fetal effects were seen when pregnant rats were treated with up to 150 mg/kg/day (approximately 17 times the MRHD on a mg/m 2 basis) by gavage throughout the period of organogenesis.

Anyone considering the use of atomoxetine in a child or adolescent must balance the potential risks with the clinical need.

The pharmacokinetics of atomoxetine in children and adolescents are similar to those in adults.

The safety, efficacy, and pharmacokinetics of atomoxetine in pediatric patients less than 6 years of age have not been evaluated.

A study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioral and sexual development.

Rats were treated with 1, 10, or 50 mg/kg/day (approximately 0.2, 2, and 8 times, respectively, the maximum human dose on a mg/m 2 basis) of atomoxetine given by gavage from the early postnatal period (Day of age) through adulthood.

Slight delays in onset of vaginal patency (all doses) and preputial separation (10 and 50 mg/kg), slight decreases in epididymal weight and sperm number (10 and 50 mg/kg), and a slight decrease in corpora lutea (50 mg/kg) were seen, but there were no effects on fertility or reproductive performance.

A slight delay in onset of incisor eruption was seen at 50 mg/kg. A slight increase in motor activity was seen on Day 15 (males at and 50 mg/kg and females at 50 mg/kg) and on Day 30 (females at 50 mg/kg) but not on Day of age.

There were no effects on learning and memory tests.

The significance of these findings to humans is unknown.

The safety, efficacy and pharmacokinetics of atomoxetine in geriatric patients have not been evaluated.