Atomoxetine

255.355

255.35

1533716-785-6

ASW034S0B8

DTXSID9044297

N06BA09|N - Nervous system

2922299090

21.3

3.9

Solid

1.0±0.1 g/cm3

161-165 ºC

389.0±37.0 °C at 760 mmHg

164.1±16.0 °C

1.552

3.90e-03 g/L

Store at 25 deg C (77 deg F); excursions permitted to 15 to 30 deg C (59 to 86 deg F).

1.31X10-5 mm Hg at 25 deg C (est)

10.13None

Henry's Law constant = 1.13X10-8 atm-cu m/mol at 25 °C (est)

10.13|pKa = 9.80 (secondary amine) (est)

164.2 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

Hydroxyl radical reaction rate constant = 1.22X10-10 cu cm/molec-sec at 25 °C (est)

22-24/25

P201, P202, P261, P264, P270, P271, P273, P280, P281, P301+P310, P304+P340, P305+P351+P338, P308+P313, P310, P311, P321, P330, P391, P403+P233, P405, P501

H301

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including atomoxetine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Atomoxetine hydrochloride/

Barton J; Atomoxetine: A New Pharmacotherapeutic Approach in the Management of Attention Deficit/Hyperactivity Disorder; Arch Dis Child 90 (Suppl 1): i26-9 (2005)|Kratochvil CJ et al; Atomoxetine in the Treatment of Attention Deficit Hyperactivity Disorder; Expert Rev Neurother 4 (4): 601-11 (2004)

|Danger|H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P261, P264, P270, P271, P273, P280, P281, P301+P310, P304+P340, P305+P351+P338, P308+P313, P310, P311, P321, P330, P391, P403+P233, P405, and P501|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

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.|IDENTIFICATION AND USE: Atomoxetine, as Strattera, is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). HUMAN EXPOSURE AND TOXICITY: Atomoxetine increased the risk of suicidal ideation in short-term studies in children or adolescents with ADHD. Symptoms accompanying acute and chronic overdoses of atomoxetine include gastrointestinal symptoms, somnolence, dizziness, tremor, abnormal behavior, hyperactivity, agitation, and signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, blood pressure increased, mydriasis, dry mouth). Less commonly, there have been reports of QT prolongation and mental changes, including disorientation and hallucinations. Atomoxetine may cause clinically significant hepatotoxicity either by metabolic idiosyncrasy or by inducing autoimmune hepatitis. There have been fatalities reported involving a mixed ingestion overdose of Strattera and at least one other drug. Sudden deaths, stroke, and myocardial infarction have been reported in both children and adults with structural cardiac abnormalities or other serious heart problems. ANIMAL STUDIES: The median lethal oral dose of atomoxetine hydrochloride in animals was estimated to be 25 mg/kg for cats, >37.5 mg/kg for dogs, and 0.190 mg/kg in rats and mice. Premonitory signs of toxicity following single oral doses of atomoxetine in animals included mydriasis and reduced pupillary light reflex, mucoid stools, salivation, vomiting, ataxia, tremors, myoclonic jerking, and convulsions. Chronic toxicity studies of up to 1 year were conducted in adult rats and dogs. There was no major target organ toxicity observed in dogs given oral doses up to 16 mg/kg/day or in rats given atomoxetine in the diet at time-weighted average doses up to 47 mg/kg/day. These doses are 4-5 times the maximum recommended daily oral dose in adults. Mild hepatic effects, characterized by mottling and pallor of the liver, increased relative liver weights, hepatocellular vacuolation, and slightly increased serum ALT values, occurred in male rats given time weighted average doses >/= 14 mg/kg/day. No hepatic effects were observed in dogs. Clinical signs of mydriasis, reduced pupillary light reflex, emesis, and tremors were observed in dogs, and these effects were minimal in adult dogs given >/= 8 mg/kg/day. No evidence of drug-associated teratogenicity or retarded fetal development was produced in rabbits or rats administered atomoxetine hydrochloride throughout organogenesis at oral doses up to 100 mg/kg/day and 150 mg/kg/day (13 times the maximum recommended daily oral dose in adults). In a rat fertility study, decreased pup weight and survival was observed, predominantly during the first week postpartum following maternal dietary atomoxetine timeweighted average doses of 23 mg/kg/day or higher. Atomoxetine hydrochloride was negative in a battery of genotoxicity studies that included a reverse point mutation assay (Ames Test), an in vitro mouse lymphoma assay, a chromosomal aberration test in Chinese hamster ovary cells, an unscheduled DNA synthesis test in rat hepatocytes, and an in vivo micronucleus test in mice. However, there was a slight increase in the percentage of Chinese hamster ovary cells with diplochromosomes, suggesting endoreduplication (numerical aberration). Atomoxetine hydrochloride was not carcinogenic in rats and mice when given in the diet for 2 years at time-weighted average doses up to 47 and 458 mg/kg/day, respectively.

Atomoxetine has been linked to serum aminotransferase elevations in a small proportion of patients (~0.5%). More importantly, there have been several reports of clinically apparent acute liver injury due to atomoxetine. The onset of injury was within 3 to 12 weeks of starting the medication. The typical pattern of serum enzyme elevations was hepatocellular with marked increases in serum aminotransferase levels (often >20 times upper limit of normal) and clinical features that resembled acute viral hepatitis. Most cases have been self-limited, but instances of acute liver failure sometimes requiring emergency liver transplantation have been reported. Immunoallergic features were not found, but several patients with acute injury had antinuclear antibody and at least one patient had other features that resembled autoimmune hepatitis (with typical liver histology and high levels of immunoglobulins in serum).

Strattera should be administered with caution to patients being treated with systemically-administered (oral or intravenous) albuterol (or other beta2 agonists) because the action of albuterol on the cardiovascular system can be potentiated resulting in increases in heart rate and blood pressure. Albuterol (600 mcg iv over 2 hours) induced increases in heart rate and blood pressure. These effects were potentiated by atomoxetine (60 mg BID for 5 days) and were most marked after the initial coadministration of albuterol and atomoxetine. However, these effects on heart rate and blood pressure were not seen in another study after the coadministration with inhaled dose of albuterol (200-800 ug) and atomoxetine (80 mg QD for 5 days) in 21 healthy Asian subjects who were excluded for poor metabolizer status.|The manufacturer states that atomoxetine is contraindicated in patients currently receiving or having recently received (i.e., within 2 weeks) monoamine oxidase (MAO) inhibitor therapy. In addition, at least 2 weeks should elapse after discontinuing atomoxetine before initiating MAO inhibitor therapy. Severe, potentially 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) have been reported in patients receiving other drugs that affect brain monoamine concentrations concomitantly with MAO inhibitor therapy.|Potential pharmacokinetic interaction (decreased metabolism of atomoxetine) when atomoxetine is used concomitantly with drugs that inhibit the activity of the cytochrome P-450 2D6 (CYP2D6) isoenzyme. Inhibitors of CYP2D6 may increase plasma concentrations of atomoxetine in patients with the extensive-metabolizer phenotype to such an extent that plasma concentrations of the drug are similar to those achieved in poor metabolizers. When atomoxetine is used concomitantly with potent CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine), or in patients with poor-metabolizer phenotypes of the CYP2D6 isoenzyme, the manufacturer states that dosage adjustment of atomoxetine should be considered. However, in vitro studies suggest that concomitant use of atomoxetine with CYP2D6 inhibitors will not increase plasma concentrations of atomoxetine in patients with the poor-metabolizer phenotype.|Potential pharmacologic interaction (increased hypertensive effects) with concomitant use of pressor agents (e.g., dopamine, dobutamine) and atomoxetine. Use with caution.|For more Interactions (Complete) data for ATOMOXETINE (6 total), please visit the HSDB record page.

... A fraction of the population (about 7% of Caucasians and 2% of African-Americans) are poor metabolizers (PMs) of CYP2D6 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 about 24 hours) of atomoxetine compared with those who have normal activity (extensive metabolizers (EMs)).|The manufacturer also states that atomoxetine should not be used in patients with angle-closure glaucoma, since the drug was associated with an increased risk of mydriasis in some patients during controlled clinical trials.|Seizures have been reported in the postmarketing period. The postmarketing seizure cases include patients with pre-existing seizure disorders and those with identified risk factors for seizures, as well as patients with neither a history of nor identified risk factors for seizures. The exact relationship between Strattera and seizures is difficult to evaluate due to uncertainty about the background risk of seizures in ADHD patients.|Strattera 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).|For more Populations at Special Risk (Complete) data for ATOMOXETINE (7 total), please visit the HSDB record page.

At therapeutic concentrations, 98.7% of plasma atomoxetine is bound to protein, with 97.5% of that being bound to albumin, followed by alpha-1-acid glycoprotein and immunoglobulin G.

While data specific to atomoxetine were not available(SRC, 2005), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through subsoils into aquifers(1).

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

Atomoxetine is a selective norepinephrine reuptake inhibitor used primarily for therapy of attention deficit hyperactivity disorder. Atomoxetine has been linked to a low rate of serum aminotransferase elevations and to rare cases of acute, clinically apparent liver injury.

Central Nervous System Stimulants

Adrenergic Uptake Inhibitors|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Atomoxetine is included in the database.|Strattera is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). /Included in US product labeling/|/EXPL THER/ /The purpose of this study was/ to observe the efficacy and safety of atomoxetine hydrochloride in children with narcolepsy. Totally 66 patients with narcolepsy who were conformed international classification of sleep disturbances (ICSD-2) diagnostic criteria treated with atomoxetine hydrochloride seen from November 2010 to December 2014 were enrolled into this study, 42 of them were male and 24 female, mean age of onset was 7.5 years (3.75-13.00 years), mean duration before diagnosis was 1.75 years (0.25-5.00 years). Complete blood count, liver and kidney function, multiple sleep latency test (MSLT), polysomnography (PGS), neuroimaging and electroencephalography (EEG) were performed for each patient. For some of the children HLA-DR2 gene and serum markers of infection were tested. The 66 cases were followed up from 2 to 49 months (average 18 months) to observe the clinical efficacy and adverse reactions. In 62 cases excessive daytime sleepiness was improved, in 11 cases (16.7%) it was controlled (16.7%), in 29 cases (43.9%) the treatment was obviously effective and in 22 (33.3%) it was effective; cataplexy occurred in 54 cases, in 18 (33.3%) it was controlled, in 19 (35.2%) the treatment was obviously effective and in 10 (18.5%) effective; night sleep disorders existed in 55 cases, in 47 cases it was improved, in 14 (25.5%) it was controlled, in 20 (36.4%) the treatment was obviously effective and in 13 (23.6%) effective; hypnagogic or hypnopompic hallucination was present in 13 cases, in only 4 these symptoms were controlled. Sleep paralysis existed in 4 cases, it was controlled in only 1 case. In 18 cases attention and learning efficiency improved.Anorexia occurred in 18 cases, mood disorder in 5 cases, depression in 2 cases, nocturia, muscle tremors, involuntary tongue movement each occurred in 1 case. P-R interval prolongation and atrial premature contraction were found in 1 case. Atomoxetine hydrochloride showed good effects in patients with narcolepsy on excessive daytime sleepiness, cataplexy and night sleep disorders, the effects on hallucinations and sleep paralysis were not significant. Adverse reactions were slight, anorexia and mood disorder were common. As a non-central nervous system stimulant, atomoxetine hydrochloride does not induce drug dependence and has no prescription limits; it has good tolerability, safety and effectiveness, it can be a good alternative in treatment of children with narcolepsy.|For more Therapeutic Uses (Complete) data for ATOMOXETINE (6 total), please visit the HSDB record page.

/BOXED WARNING/ WARNING: SUICIDAL IDEATION IN CHILDREN AND ADOLESCENTS. Strattera (atomoxetine) increased the risk of suicidal ideation in short-term studies in children or adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). Anyone considering the use of Strattera in a child or adolescent must balance this risk with the clinical need. Co-morbidities occurring with ADHD may be associated with an increase in the risk of suicidal ideation and/or behavior. Patients who are started on therapy should be monitored closely for suicidality (suicidal thinking and behavior), clinical worsening, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Strattera is approved for ADHD in pediatric and adult patients. Strattera is not approved for major depressive disorder. Pooled analyses of short-term (6 to 18 weeks) placebo-controlled trials of Strattera in children and adolescents (a total of 12 trials involving over 2200 patients, including 11 trials in ADHD and 1 trial in enuresis) have revealed a greater risk of suicidal ideation early during treatment in those receiving Strattera compared to placebo. The average risk of suicidal ideation in patients receiving Strattera was 0.4% (5/1357 patients), compared to none in placebo-treated patients (851 patients). No suicides occurred in these trials.|Postmarketing reports indicate that Strattera 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 Strattera use in postmarketing experience. Rare cases of liver failure have also been reported, including a case that resulted in a liver transplant. Because of probable underreporting, it is impossible to provide an accurate estimate of the true incidence of these reactions. Reported cases of liver injury occurred within 120 days of initiation of atomoxetine in the majority of cases and some patients presented with markedly elevated liver enzymes [>20 X upper limit of normal (ULN)], and jaundice with significantly elevated bilirubin levels (>2 X ULN), followed by recovery upon atomoxetine discontinuation. In one patient, liver injury, manifested by elevated hepatic enzymes up to 40 X ULN and jaundice with bilirubin up to 12 X ULN, recurred upon rechallenge, and was followed by recovery upon drug discontinuation, providing evidence that Strattera likely caused the liver injury. Such reactions may occur several months after therapy is started, but laboratory abnormalities may continue to worsen for several weeks after drug is stopped. The patient described above recovered from his liver injury, and did not require a liver transplant.|Strattera 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 manufacturer states that atomoxetine is contraindicated in patients currently receiving or having recently received (i.e., within 2 weeks) monoamine oxidase (MAO) inhibitor therapy. In addition, at least 2 weeks should elapse after discontinuing atomoxetine before initiating MAO inhibitor therapy. Severe, potentially 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) have been reported in patients receiving other drugs that affect brain monoamine concentrations concomitantly with MAO inhibitor therapy.|For more Drug Warnings (Complete) data for ATOMOXETINE (26 total), please visit the HSDB record page.

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. 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).

Drugs that block the transport of adrenergic transmitters into axon terminals or into storage vesicles within terminals. The tricyclic antidepressants (ANTIDEPRESSIVE AGENTS, TRICYCLIC) and amphetamines are among the therapeutically important drugs that may act via inhibition of adrenergic transport. Many of these drugs also block transport of serotonin. (See all compounds classified as Adrenergic Uptake Inhibitors.)

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 to 2 hours after dosing with a maximal concentration of 350 ng/ml with an AUC of 2 mcg.h/ml.|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 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.|The clearance rate of atomoxetine depends the CYP2D6 genetic polymorphisms of the individual and can range of 0.27-0.67 L.h/kg.|Steady-state volume of distribution (intravenous administration): 8.5 L/kg. Atomexetine distributes primarily into total body water; volume of distribution is similar across patient weight range after normalizing for body weight.|Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in extensive metabolizers and 94% in poor metabolizers. Maximal plasma concentrations (Cmax) are reached approximately 1 to 2 hours after dosing.|/MILK/ Atomoxetine and/or its metabolites are distributed into milk in rats; it is not known whether the drug is distributed into milk in humans.|... Atomoxetine has high aqueous solubility and biological membrane permeability that facilitates its rapid and complete absorption after oral administration. Absolute oral bioavailability ranges from 63 to 94%, which is governed by the extent of its first-pass metabolism. Three oxidative metabolic pathways are involved in the systemic clearance of atomoxetine: aromatic ring-hydroxylation, benzylic hydroxylation and N-demethylation. Aromatic ring-hydroxylation results in the formation of the primary oxidative metabolite of atomoxetine, 4-hydroxyatomoxetine, which is subsequently glucuronidated and excreted in urine. The formation of 4-hydroxyatomoxetine is primarily mediated by the polymorphically expressed enzyme cytochrome P450 (CYP) 2D6. This results in two distinct populations of individuals: those exhibiting active metabolic capabilities (CYP2D6 extensive metabolizers) and those exhibiting poor metabolic capabilities (CYP2D6 poor metabolizers) for atomoxetine. The oral bioavailability and clearance of atomoxetine are influenced by the activity of CYP2D6; nonetheless, plasma pharmacokinetic parameters are predictable in extensive and poor metabolizer patients. After single oral dose, atomoxetine reaches maximum plasma concentration within about 1-2 hours of administration. In extensive metabolizers, atomoxetine has a plasma half-life of 5.2 hours, while in poor metabolizers, atomoxetine has a plasma half-life of 21.6 hours. The systemic plasma clearance of atomoxetine is 0.35 and 0.03 L/h/kg in extensive and poor metabolizers, respectively. Correspondingly, the average steady-state plasma concentrations are approximately 10-fold higher in poor metabolizers compared with extensive metabolizers. Upon multiple dosing there is plasma accumulation of atomoxetine in poor metabolizers, but very little accumulation in extensive metabolizers. The volume of distribution is 0.85 L/kg, indicating that atomoxetine is distributed in total body water in both extensive and poor metabolizers. Atomoxetine is highly bound to plasma albumin (approximately 99% bound in plasma). Although steady-state concentrations of atomoxetine in poor metabolizers are higher than those in extensive metabolizers following administration of the same mg/kg/day dosage, the frequency and severity of adverse events are similar regardless of CYP2D6 phenotype.Atomoxetine administration does not inhibit or induce the clearance of other drugs metabolized by CYP enzymes. In extensive metabolizers, potent and selective CYP2D6 inhibitors reduce atomoxetine clearance; however, administration of CYP inhibitors to poor metabolizers has no effect on the steady-state plasma concentrations of atomoxetine.|For more Absorption, Distribution and Excretion (Complete) data for ATOMOXETINE (8 total), please visit the HSDB record page.

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). For 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).|Atomoxetine is metabolized primarily through the CYP2D6 enzymatic pathway. People with reduced activity in this pathway (PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (EMs). For PMs, AUC of atomoxetine is approximately 10-fold and Css, max is about 5-fold greater than EMs. Laboratory tests are available to identify CYP2D6 PMs.|The major oxidative metabolite formed, regardless of CYP2D6 status, is 4-hydroxyatomoxetine, which is 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 extensive metabolizers (EMs) and 0.1% of atomoxetine concentration in PMs). 4-Hydroxyatomoxetine is primarily formed by CYP2D6, but in PMs, 4-hydroxyatomoxetine is formed at a slower rate by several other cytochrome P450 enzymes. N-Desmethylatomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has substantially less pharmacological activity compared with atomoxetine and circulates in plasma at lower concentrations (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in poor metabolizers (PMs)).|The role of the polymorphic cytochrome p450 2D6 (CYP2D6) in the pharmacokinetics of atomoxetine hydrochloride [(-)-N-methyl-gamma-(2-methylphenoxy)benzenepropanamine hydrochloride; LY139603] has been documented following both single and multiple doses of the drug. In this study, the influence of the CYP2D6 polymorphism on the overall disposition and metabolism of a 20-mg dose of (14)C-atomoxetine was evaluated in CYP2D6 extensive metabolizer (EM; n = 4) and poor metabolizer (PM; n = 3) subjects under steady-state conditions. Atomoxetine was well absorbed from the gastrointestinal tract and cleared primarily by metabolism with the preponderance of radioactivity being excreted into the urine. In EM subjects, the majority of the radioactive dose was excreted within 24 hr, whereas in PM subjects the majority of the dose was excreted by 72 hr. The biotransformation of atomoxetine was similar in all subjects undergoing aromatic ring hydroxylation, benzylic oxidation, and N-demethylation with no CYP2D6 phenotype-specific metabolites. The primary oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which was subsequently conjugated forming 4-hydroxyatomoxetine-O-glucuronide. Due to the absence of CYP2D6 activity, the systemic exposure to radioactivity was prolonged in PM subjects (t(1/2) = 62 hr) compared with EM subjects (t(1/2) = 18 hr). In EM subjects, atomoxetine (t(1/2) = 5 hr) and 4-hydroxyatomoxetine-O-glucuronide (t(1/2) = 7 hr) were the principal circulating species, whereas atomoxetine (t(1/2) = 20 hr) and N-desmethylatomoxetine (t(1/2) = 33 hr) were the principal circulating species in PM subjects. Although differences were observed in the excretion and relative amounts of metabolites formed, the primary difference observed between EM and PM subjects was the rate at which atomoxetine was biotransformed to 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 of the Strattera dose is excreted as unchanged atomoxetine (less than 3% of the dose), indicating extensive biotransformation.|For more Metabolism/Metabolites (Complete) data for ATOMOXETINE (8 total), please visit the HSDB record page.

The reported half-life depends on the CYP2D6 genetic polymorphisms of the individual and can range from 3 to 5.6 hours.|The plasma elimination half life in normal (extensive) metabolizers is about 5 hours. In person who are poor metabolizers (7% of whites and 2% of blacks), the drug plasma levels are much higher and the plasma elimination half life is 24 hours.|Mean apparent plasma clearance of atomoxetine after oral administration in adult extensive metabolizers (EMs) is 0.35 L/hr/kg and the mean half-life is 5.2 hours. Following oral administration of atomoxetine to poor metabolizers (PMs), mean apparent plasma clearance is 0.03 L/hr/kg and mean half-life is 21.6 hours. For PMs, AUC of atomoxetine is approximately 10-fold and Css, max is about 5-fold greater than EMs. The elimination half-life of 4-hydroxyatomoxetine is similar to that of N-desmethylatomoxetine (6 to 8 hours) in EM subjects, while the half-life of N-desmethylatomoxetine is much longer in PM subjects (34 to 40 hours).|... In extensive metabolizers, atomoxetine has a plasma half-life of 5.2 hours, while in poor metabolizers, atomoxetine has a plasma half-life of 21.6 hours. ...|... Twenty-one cytochrome P450 2D6 extensive metabolizer patients participated in these single-dose and steady-state pharmacokinetic evaluations. Atomoxetine was rapidly absorbed, with peak plasma concentrations occurring 1 to 2 hours after dosing. Half-life averaged 3.12 and 3.28 hours after a single dose and at steady state, respectively. ...

Atomoxetine is known to be a potent and selective inhibitor of the norepinephrine transporter (NET), which prevents cellular reuptake of norepinephrine throughout the brain, which is thought to improve the symptoms of ADHD. More recently, positron emission tomography (PET) imaging studies in rhesus monkeys have shown that atomoxetine also binds to the serotonin transporter (SERT), and blocks the N-methyl-d-aspartate (NMDA) receptor, indicating a role for the glutamatergic system in the pathophysiology of ADHD.|The selective norepinephrine (NE) transporter inhibitor atomoxetine (formerly called tomoxetine or LY139603) has been shown to alleviate symptoms in Attention Deficit/Hyperactivity Disorder (ADHD). We investigated the mechanism of action of atomoxetine in ADHD by evaluating the interaction of atomoxetine with monoamine transporters, the effects on extracellular levels of monoamines, and the expression of the neuronal activity marker Fos in brain regions. Atomoxetine inhibited binding of radioligands to clonal cell lines transfected with human NE, serotonin (5-HT) and dopamine (DA) transporters with dissociation constants (K(i)) values of 5, 77 and 1451 nM, respectively, demonstrating selectivity for NE transporters. In microdialysis studies, atomoxetine increased extracellular (EX) levels of NE in prefrontal cortex (PFC) 3-fold, but did not alter 5-HT(EX) levels. Atomoxetine also increased DA(EX) concentrations in PFC 3-fold, but did not alter DA(EX) in striatum or nucleus accumbens. In contrast, the psychostimulant methylphenidate, which is used in ADHD therapy, increased NE(EX) and DA(EX) equally in PFC, but also increased DA(EX) in the striatum and nucleus accumbens to the same level. The expression of the neuronal activity marker Fos was increased 3.7-fold in PFC by atomoxetine administration, but was not increased in the striatum or nucleus accumbens, consistent with the regional distribution of increased DA(EX). We hypothesize that the atomoxetine-induced increase of catecholamines in PFC, a region involved in attention and memory, mediates the therapeutic effects of atomoxetine in ADHD. In contrast to methylphenidate, atomoxetine did not increase DA in striatum or nucleus accumbens, suggesting it would not have motoric or drug abuse liabilities.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. 2. Treat agitation, seizures, coma, and hyperthermia if they occur. 3. Continuously monitor the temperature, other vital signs, and the ECG for a minimum of 6 hours. /Amphetamines/|For more Antidote and Emergency Treatment (Complete) data for ATOMOXETINE (7 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Postmarketing reports indicate that Strattera 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 Straterra use in postmarketing experience. Rare cases of liver failure have also been reported, including a case that resulted in a liver transplant. Because of probable underreporting, it is impossible to provide an accurate estimate of the true incidence of these reactions. Reported cases of liver injury occurred within 120 days of initiation of atomoxetine in the majority of cases and some patients presented with markedly elevated liver enzymes [>20 X upper limit of normal (ULN)], and jaundice with significantly elevated bilirubin levels (>2 X ULN), followed by recovery upon atomoxetine discontinuation. In one patient, liver injury, manifested by elevated hepatic enzymes up to 40 X ULN and jaundice with bilirubin up to 12 X ULN, recurred upon rechallenge, and was followed by recovery upon drug discontinuation, providing evidence that Strattera likely caused the liver injury. Such reactions may occur several months after therapy is started, but laboratory abnormalities may continue to worsen for several weeks after drug is stopped. The patient described above recovered from his liver injury, and did not require a liver transplant.|/SIGNS AND SYMPTOMS/ Strattera (atomoxetine) increased the risk of suicidal ideation in short-term studies in children or adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD).|/SIGNS AND SYMPTOMS/ There is limited clinical trial experience with Strattera overdose. During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of Strattera and at least one other drug. There have been no reports of death involving overdose of Strattera alone, including intentional overdoses at amounts up to 1400 mg. In some cases of overdose involving Strattera, seizures have been reported. The most commonly reported symptoms accompanying acute and chronic overdoses of Strattera 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.|/CASE REPORTS/ An eight-year-old female with attention deficient hyperactive disorder (ADHD) was treated with atomoxetine hydrochloride. She complained of increased abdominal pain and occasional emesis; her transaminases and bilirubin were markedly elevated. She was admitted to a tertiary-care pediatric hospital and treated for drug-induced hepatitis. Atomoxetine was discontinued and supportive care was instituted. A liver biopsy showed hepatitis with moderate piecemeal necrosis. Clinical status and liver function tests improved over 13 days of hospitalization. ...|For more Human Toxicity Excerpts (Complete) data for ATOMOXETINE (18 total), please visit the HSDB record page.

139603, LY

Table: Atomoxetine Hydrochloride Preparations [Table#6945]

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients