Atomoxetine Hydrochloride Information
Atomoxetine hydrochloride () Indications And Usage
Atomoxetine hydrochloride () capsules are indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD).
The efficacy of Atomoxetine hydrochloride () capsules was established in six clinical trials in outpatients with ADHD: four 6 to 9-week trials in pediatric patients (ages 6 to 18) and two 10-week trials in adults [see ].
A diagnosis of ADHD (DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that cause impairment and that were present before age 7 years. The symptoms must be persistent, must be more severe than is typically observed in individuals at a comparable level of development, must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and must be present in 2 or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder.
The specific etiology of ADHD is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but also of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of DSM-IV characteristics.
For the Inattentive Type, at least 6 of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes, lack of sustained attention, poor listener, failure to follow through on tasks, poor organization, avoids tasks requiring sustained mental effort, loses things, easily distracted, forgetful. For the Hyperactive-Impulsive Type, at least 6 of the following symptoms must have persisted for at least 6 months: fidgeting/squirming, leaving seat, inappropriate running/climbing, difficulty with quiet activities, “on the go,” excessive talking, blurting answers, can’t wait turn, intrusive. For a Combined Type diagnosis, both inattentive and hyperactive-impulsive criteria must be met.
Atomoxetine hydrochloride () Dosage And Administration
Atomoxetine hydrochloride () 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.
Atomoxetine hydrochloride () 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 2 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.
Atomoxetine hydrochloride () capsules may be taken with or without food.
Atomoxetine hydrochloride () capsules can be discontinued without being tapered.
Atomoxetine hydrochloride () 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.
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 .
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 hydrochloride () 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 hydrochloride () 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.
Atomoxetine hydrochloride () Dosage Forms And Strengths
Each capsule contains Atomoxetine hydrochloride () equivalent to 10 mg (Opaque White, Opaque White), 18 mg (Gold, Opaque White), 25 mg (Opaque Blue, Opaque White), 40 mg (Opaque Blue, Opaque Blue), 60 mg (Opaque Blue, Gold), 80 mg (Opaque Brown, Opaque White), or 100 mg (Opaque Brown, Opaque Brown) of atomoxetine.
Atomoxetine hydrochloride () Warnings And Precautions
Atomoxetine hydrochloride () increased the risk of suicidal ideation in short-term studies in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). Pooled analyses of short-term (6 to 18 weeks) placebo-controlled trials of Atomoxetine hydrochloride () in children and adolescents have revealed a greater risk of suicidal ideation early during treatment in those receiving Atomoxetine hydrochloride () . There were a total of 12 trials (11 in ADHD and 1 in enuresis) involving over 2200 patients (including 1357 patients receiving Atomoxetine hydrochloride () and 851 receiving placebo). The average risk of suicidal ideation in patients receiving Atomoxetine hydrochloride () was 0.4% (5/1357 patients), compared to none in placebo-treated patients. There was 1 suicide attempt among these approximately 2200 patients, occurring in a patient treated with Atomoxetine hydrochloride () . . All reactions occurred in children 12 years of age or younger. All reactions occurred during the first month of treatment. It is unknown whether the risk of suicidal ideation in pediatric patients extends to longer-term use. A similar analysis in adult patients treated with Atomoxetine hydrochloride () for either ADHD or major depressive disorder (MDD) did not reveal an increased risk of suicidal ideation or behavior in association with the use of Atomoxetine hydrochloride () .
All pediatric patients being treated with Atomoxetine hydrochloride () 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.
The following symptoms have been reported with Atomoxetine hydrochloride () : anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania. Although a causal link between the emergence of such symptoms and the emergence of suicidal impulses has not been established, there is a concern that such symptoms may represent precursors to emerging suicidality. Thus, patients being treated with Atomoxetine hydrochloride () should be observed for the emergence of such symptoms.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who are experiencing emergent suicidality or symptoms that might be precursors to emerging suicidality, especially if these symptoms are severe or abrupt in onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of pediatric patients being treated with Atomoxetine hydrochloride () should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.
Postmarketing reports indicate that Atomoxetine hydrochloride () 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 hydrochloride () use in postmarketing experience. 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 Atomoxetine hydrochloride () 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. However, severe liver injury due to any drug may potentially progress to acute liver failure resulting in death or the need for a liver transplant.
Children and Adolescents
Sudden death has been reported in association with atomoxetine treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, atomoxetine generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the noradrenergic effects of atomoxetine.
Adults
Sudden deaths, stroke, and myocardial infarction have been reported in adults taking atomoxetine at usual doses for ADHD. Although the role of atomoxetine in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Consideration should be given to not treating adults with clinically significant cardiac abnormalities.
Children, adolescents, or adults who are being considered for treatment with atomoxetine should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). 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.
Atomoxetine hydrochloride () should be used with caution in patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease because it can increase blood pressure and heart rate. Pulse and blood pressure should be measured at baseline, following Atomoxetine hydrochloride () dose increases, and periodically while on therapy.
In pediatric placebo-controlled trials, Atomoxetine hydrochloride () -treated subjects experienced a mean increase in heart rate of about 6 beats/minute compared with placebo subjects. At the final study visit before drug discontinuation, 2.5% (36/1434) of Atomoxetine hydrochloride () -treated subjects had heart rate increases of at least 25 beats/minute and a heart rate of at least 110 beats/minute, compared with 0.2% (2/850) of placebo subjects. There were 1.1% (15/1417) pediatric atomoxetine-treated subjects with a heart rate increase of at least 25 beats/minute and a heart rate of at least 110 beats/minute on more than one occasion. Tachycardia was identified as an adverse event for 0.3% (5/1597) of these pediatric subjects compared with 0% (0/934) of placebo subjects. The mean heart rate increase in extensive metabolizer (EM) patients was 5 beats/minute, and in poor metabolizer (PM) patients 9.4 beats/minute.
Atomoxetine hydrochloride () -treated pediatric subjects experienced mean increases of about 1.6 and 2.4 mm Hg in systolic and diastolic blood pressures, respectively compared with placebo. At the final study visit before drug discontinuation, 4.8% (59/1226) of Atomoxetine hydrochloride () -treated pediatric subjects had high systolic blood pressure measurements compared with 3.5% (26/748) of placebo subjects. High systolic blood pressures were measured on 2 or more occasions in 4.4% (54/1226) of Atomoxetine hydrochloride () -treated subjects and 1.9% (14/748) of placebo subjects. At the final study visit before drug discontinuation, 4% (50/1262) of Atomoxetine hydrochloride () -treated pediatric subjects had high diastolic blood pressure measurements compared with 1.1% (8/759) of placebo subjects. High diastolic blood pressures were measured on 2 or more occasions in 3.5% (44/1262) of Atomoxetine hydrochloride () -treated subjects and 0.5% (4/759) of placebo subjects. (High systolic and diastolic blood pressure measurements were defined as those exceeding the 95 percentile, stratified by age, gender, and height percentile - National High Blood Pressure Education Working Group on Hypertension Control in Children and Adolescents.)
In adult placebo-controlled trials, Atomoxetine hydrochloride () -treated subjects experienced a mean increase in heart rate of 5 beats/minute compared with placebo subjects. Tachycardia was identified as an adverse event for 1.5% (8/540) of these adult atomoxetine subjects compared with 0.5% (2/402) of placebo subjects.
Atomoxetine hydrochloride () -treated adult subjects experienced mean increases in systolic (about 2 mm Hg) and diastolic (about 1 mm Hg) blood pressures compared with placebo. At the final study visit before drug discontinuation, 2.2% (11/510) of Atomoxetine hydrochloride () -treated adult subjects had systolic blood pressure measurements ≥150 mm Hg compared with 1% (4/393) of placebo subjects. At the final study visit before drug discontinuation, 0.4% (2/510) of Atomoxetine hydrochloride () -treated adult subjects had diastolic blood pressure measurements ≥100 mm Hg compared with 0.5% (2/393) of placebo subjects. No adult subject had a high systolic or diastolic blood pressure detected on more than one occasion.
Orthostatic hypotension and syncope have been reported in patients taking Atomoxetine hydrochloride () . In child and adolescent trials, 0.2% (12/5596) of Atomoxetine hydrochloride () -treated patients experienced orthostatic hypotension and 0.8% (46/5596) experienced syncope. In short-term child and adolescent controlled trials, 1.8% (6/340) of Atomoxetine hydrochloride () -treated patients experienced orthostatic hypotension compared with 0.5% (1/207) of placebo-treated patients. Syncope was not reported during short-term child and adolescent placebo-controlled ADHD trials. Atomoxetine hydrochloride () should be used with caution in any condition that may predispose patients to hypotension, or conditions associated with abrupt heart rate or blood pressure changes.
There have been spontaneous postmarketing reports of Raynaud’s phenomenon (new onset and exacerbation of preexisting condition).
Data on the long-term effects of Atomoxetine hydrochloride () on growth come from open-label studies, and weight and height changes are compared to normative population data. In general, the weight and height gain of pediatric patients treated with Atomoxetine hydrochloride () lags behind that predicted by normative population data for about the first 9-12 months of treatment. Subsequently, weight gain rebounds and at about 3 years of treatment, patients treated with Atomoxetine hydrochloride () have gained 17.9 kg on average, 0.5 kg more than predicted by their baseline data. After about 12 months, gain in height stabilizes, and at 3 years, patients treated with Atomoxetine hydrochloride () have gained 19.4 cm on average, 0.4 cm less than predicted by their baseline data (see below).
Figure 1: Mean Weight and Height Percentiles Over Time for Patients With Three Years of Atomoxetine hydrochloride () Treatment
This growth pattern was generally similar regardless of pubertal status at the time of treatment initiation. Patients who were pre-pubertal at the start of treatment (girls ≤8 years old, boys ≤9 years old) gained an average of 2.1 kg and 1.2 cm less than predicted after three years. Patients who were pubertal (girls >8 to ≤13 years old, boys >9 to ≤14 years old) or late pubertal (girls >13 years old, boys >14 years old) had average weight and height gains that were close to or exceeded those predicted after three years of treatment.
Growth followed a similar pattern in both extensive and poor metabolizers (EMs, PMs). PMs treated for at least two years gained an average of 2.4 kg and 1.1 cm less than predicted, while EMs gained an average of 0.2 kg and 0.4 cm less than predicted.
In short-term controlled studies (up to 9 weeks), Atomoxetine hydrochloride () -treated patients lost an average of 0.4 kg and gained an average of 0.9 cm, compared to a gain of 1.5 kg and 1.1 cm in the placebo-treated patients. In a fixed-dose controlled trial, 1.3%, 7.1%, 19.3%, and 29.1% of patients lost at least 3.5% of their body weight in the placebo, 0.5, 1.2, and 1.8 mg/kg/day dose groups.
Growth should be monitored during treatment with Atomoxetine hydrochloride () .
Routine laboratory tests are not required.
Poor metabolizers (PMs) of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of Atomoxetine hydrochloride () compared with extensive metabolizers (EMs). Approximately 7% of a Caucasian population are PMs. Laboratory tests are available to identify CYP2D6 PMs. The blood levels in PMs are similar to those attained by taking strong inhibitors of CYP2D6. The higher blood levels in PMs lead to a higher rate of some adverse effects of Atomoxetine hydrochloride () .
Atomoxetine hydrochloride () Adverse Reactions
Atomoxetine hydrochloride () was administered to 5382 children or adolescent patients with ADHD and 1007 adults with ADHD in clinical studies. During the ADHD clinical trials, 1625 children and adolescent patients were treated for longer than 1 year and 2529 children and adolescent patients were treated for over 6 months.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Reasons for discontinuation of treatment due to adverse reactions in child and adolescent clinical trials
In acute child and adolescent placebo-controlled trials, 3% (48/1613) of atomoxetine subjects and 1.4% (13/945) placebo subjects discontinued for adverse reactions. For all studies, (including open-label and long-term studies), 6.3% of extensive metabolizer (EM) patients and 11.2% of poor metabolizer (PM) patients discontinued because of an adverse reaction. Among Atomoxetine hydrochloride () -treated patients, irritability (0.3%, N=5); somnolence (0.3%, N=5); aggression (0.2%, N=4); nausea (0.2%, N=4); vomiting (0.2%, N=4); abdominal pain (0.2%, N=4); constipation (0.1%, N=2); fatigue (0.1%, N=2); feeling abnormal (0.1%, N=2); and headache (0.1%, N=2) were the reasons for discontinuation reported by more than 1 patient.
Seizures
Atomoxetine hydrochloride () has not been systematically evaluated in pediatric patients with seizure disorder as these patients were excluded from clinical studies during the product’s premarket testing. In the clinical development program, seizures were reported in 0.2% (12/5073) of children whose average age was 10 years (range 6 to 16 years). In these clinical trials, the seizure risk among poor metabolizers was 0.3% (1/293) compared to 0.2% (11/4741) for extensive metabolizers.
Commonly observed adverse reactions in acute child and adolescent, placebo-controlled trials
Commonly observed adverse reactions associated with the use of Atomoxetine hydrochloride () (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (Atomoxetine hydrochloride () incidence greater than placebo) are listed in . Results were similar in the BID and the QD trial except as shown in , which shows both BID and QD results for selected adverse reactions based on statistically significant Breslow-Day tests. The most commonly observed adverse reactions in patients treated with Atomoxetine hydrochloride () (incidence of 5% or greater and at least twice the incidence in placebo patients, for either BID or QD dosing) were: nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence (see and ).
Table 1: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine hydrochloride () in Acute (up to 18 weeks) Child and Adolescent Trials
Reactions reported by at least 2% of patients treated with atomoxetine, and greater than placebo. The following reactions did not meet this criterion but were reported by more atomoxetine-treated patients than placebo-treated patients and are possibly related to atomoxetine treatment: blood pressure increased, early morning awakening, flushing, mydriasis, sinus tachycardia, asthenia, palpitations, mood swings, constipation. The following reactions were reported by at least 2% of patients treated with atomoxetine, and equal to or less than placebo: pharyngolaryngeal pain, insomnia (insomnia includes the terms, insomnia, initial insomnia, middle insomnia). The following reaction did not meet this criterion but shows a statistically significant dose relationship: pruritus.
b
c
Table 2: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine hydrochloride () in Acute (up to 18 weeks) Child and Adolescent Trials
Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort.
b
c
The following adverse reactions occurred in at least 2% of PM patients and were either twice as frequent or statistically significantly more frequent in PM patients compared with EM patients: insomnia (15% of PMs, 10% of EMs); weight decreased (7% of PMs, 4% of EMs); constipation (7% of PMs, 4% of EMs); depression (7% of PMs, 4% of EMs); tremor (5% of PMs, 1% of EMs); excoriation (4% of PMs, 2% of EMs); conjunctivitis (3% of PMs, 1% of EMs); syncope (3% of PMs, 1% of EMs); early morning awakening (2% of PMs, 1% of EMs); mydriasis (2% of PMs, 1% of EMs).
1
Adult Clinical Trials
In the acute adult placebo-controlled trials, 11.3% (61/541) atomoxetine subjects and 3% (12/405) placebo subjects discontinued for adverse reactions. Among Atomoxetine hydrochloride () -treated patients, insomnia (0.9%, N=5); nausea (0.9%, N=5); chest pain (0.6%, N=3); fatigue (0.6%, N=3); anxiety (0.4%, N=2); erectile dysfunction (0.4%, N=2); mood swings (0.4%, N=2); nervousness (0.4%, N=2); palpitations (0.4%, N=2); and urinary retention (0.4%, N=2) were the reasons for discontinuation reported by more than 1 patient.
Atomoxetine hydrochloride () has not been systematically evaluated in adult patients with a seizure disorder as these patients were excluded from clinical studies during the product’s premarket testing. In the clinical development program, seizures were reported on 0.1% (1/748) of adult patients. In these clinical trials, no poor metabolizers (0/43) reported seizures compared to 0.1% (1/705) for extensive metabolizers.
Commonly observed adverse reactions associated with the use of Atomoxetine hydrochloride () (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (Atomoxetine hydrochloride () incidence greater than placebo) are listed in . The most commonly observed adverse reactions in patients treated with Atomoxetine hydrochloride () (incidence of 5% or greater and at least twice the incidence in placebo patients) were: constipation, dry mouth, nausea, fatigue, decreased appetite, insomnia, erectile dysfunction, urinary hesitation and/or urinary retention and/or dysuria, dysmenorrhea, and hot flush (see ).
Table 3: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine hydrochloride () in Acute (up to 25 weeks) Adult Trials
Reactions reported by at least 2% of patients treated with atomoxetine, and greater than placebo. The following reactions did not meet this criterion but were reported by more atomoxetine-treated patients than placebo-treated patients and are possibly related to atomoxetine treatment: early morning awakening, peripheral coldness, tachycardia, prostatitis, testicular pain, and orgasm abnormal. The following reactions were reported by at least 2% of patients treated with atomoxetine, and equal to or less than placebo: headache, pharyngolaryngeal pain, irritability.
b
c
d
e
f
Atomoxetine appears to impair sexual function in some patients. Changes in sexual desire, sexual performance, and sexual satisfaction are not well assessed in most clinical trials because they need special attention and because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate the actual incidence. above displays the incidence of sexual side effects reported by at least 2% of adult patients taking Atomoxetine hydrochloride () in placebo-controlled trials.
There are no adequate and well-controlled studies examining sexual dysfunction with Atomoxetine hydrochloride () treatment. While it is difficult to know the precise risk of sexual dysfunction associated with the use of Atomoxetine hydrochloride () , physicians should routinely inquire about such possible side effects.
The following adverse reactions have been identified during post approval use of Atomoxetine hydrochloride () . Unless otherwise specified, these adverse reactions have occurred in adults and children and adolescents. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
QT prolongation, syncope.
Lethargy.
Hypoaesthesia, paraesthesia in children and adolescents; sensory disturbances; tics.
Depression and depressed mood; anxiety.
Seizures have been reported in the postmarketing period. The postmarketing seizure cases include patients with preexisting 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 Atomoxetine hydrochloride () and seizures is difficult to evaluate due to uncertainty about the background risk of seizures in ADHD patients.
Hyperhidrosis.
Male pelvic pain; urinary hesitation in children and adolescents; urinary retention in children and adolescents.
Atomoxetine hydrochloride () Drug Interactions
In extensive metabolizers (EMs), inhibitors of CYP2D6 (e.g., paroxetine, fluoxetine, and quinidine) increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in poor metabolizers (PMs). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and C is about 3- to 4-fold greater than atomoxetine alone.
In vitro
Atomoxetine did not cause clinically important inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9.
Coadministration of Atomoxetine hydrochloride () (60 mg BID for 12 days) with midazolam, a model compound for CYP3A4 metabolized drugs (single dose of 5 mg), resulted in 15% increase in AUC of midazolam. No dose adjustment is recommended for drugs metabolized by CYP3A.
Coadministration of Atomoxetine hydrochloride () (40 or 60 mg BID for 13 days) with desipramine, a model compound for CYP2D6 metabolized drugs (single dose of 50 mg), did not alter the pharmacokinetics of desipramine. No dose adjustment is recommended for drugs metabolized by CYP2D6.
In vitro
Atomoxetine hydrochloride () Use In Specific Populations
Pregnant rabbits were treated with up to 100 mg/kg/day of atomoxetine by gavage throughout the period of organogenesis. At this dose, in 1 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 maximum human dose on a mg/m 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 maximum human dose.
Rats were treated with up to approximately 50 mg/kg/day of atomoxetine (approximately 6 times the maximum human dose on a mg/m basis) in the diet from 2 weeks (females) or 10 weeks (males) prior to mating through the periods of organogenesis and lactation. In 1 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 maximum human dose on a mg/m 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 maximum human dose on a mg/m basis) by gavage throughout the period of organogenesis.
No adequate and well-controlled studies have been conducted in pregnant women. Atomoxetine hydrochloride () should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.
Anyone considering the use of Atomoxetine hydrochloride () 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 hydrochloride () 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 basis) of atomoxetine given by gavage from the early postnatal period (Day 10 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 10 and 50 mg/kg and females at 50 mg/kg) and on Day 30 (females at 50 mg/kg) but not on Day 60 of age. There were no effects on learning and memory tests. The significance of these findings to humans is unknown.
Atomoxetine administered in a flexible dose range of 0.5 to 1.5 mg/kg/day (mean dose of 1.3 mg/kg/day) and placebo were compared in 148 randomized pediatric (age 7-17 years) subjects with a DSM-IV diagnosis of ADHD and comorbid tic disorder in an 18 week, double-blind, placebo-controlled study in which the majority (80%) enrolled in this trial with Tourette's Disorder (Tourette's Disorder: 116 subjects; chronic motor tic disorder: 29 subjects). A non-inferiority analysis revealed that atomoxetine did not worsen tics in these patients as determined by the Yale Global Tic Severity Scale Total Score (YGTSS). Out of 148 patients who entered the acute treatment phase, 103 (69.6%) patients discontinued the study. The primary reason for discontinuation in both the atomoxetine (38 of 76 patients, 50.0%) and placebo (45 of 72 patients, 62.5%) treatment groups was identified as lack of efficacy with most of the patients discontinuing at Week 12. This was the first visit where patients with a CGI-S≥4 could also meet the criteria for "clinical non-responder" (CGI-S remained the same or increased from study baseline) and be eligible to enter an open-label extension study with atomoxetine. There have been postmarketing reports of tics
Atomoxetine hydrochloride () Drug Abuse And Dependence
Clinical study data in over 2000 children, adolescents, and adults with ADHD and over 1200 adults with depression showed only isolated incidents of drug diversion or inappropriate self-administration associated with Atomoxetine hydrochloride () . There was no evidence of symptom rebound or adverse reactions suggesting a drug-discontinuation or withdrawal syndrome.
Drug discrimination studies in rats and monkeys showed inconsistent stimulus generalization between atomoxetine and cocaine.
Atomoxetine hydrochloride () Description
Atomoxetine hydrochloride is a selective norepinephrine reuptake inhibitor. Atomoxetine hydrochloride is the (-) isomer as determined by x-ray diffraction. The chemical designation is (-)--Methyl-3-phenyl-3-(-tolyloxy)-propylamine hydrochloride. The molecular formula is CHNO•HCl, which corresponds to a molecular weight of 291.82. The chemical structure is:
Atomoxetine hydrochloride is a white to practically white solid, which has a solubility of 27.8 mg/mL in water.
Atomoxetine hydrochloride () capsules are intended for oral administration only.
Each capsule contains Atomoxetine hydrochloride () equivalent to 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, and 100 mg of atomoxetine. In addition, each capsule contains the following inactive ingredients: dimethicone and pregelatinized starch.
The capsule shell for 10 mg consists of gelatin, sodium lauryl sulfate and titanium dioxide.
The capsule shell for 18 mg consists of D&C yellow # 10, FD&C red #3, gelatin, sodium lauryl sulfate and titanium dioxide.
The capsule shell for 25 mg and 40 mg consists of FD&C blue #1, FD&C red #3, gelatin, sodium lauryl sulfate and titanium dioxide.
The capsule shell for 60 mg consists of D&C yellow # 10, FD&C blue #1, FD&C red #3, gelatin, sodium lauryl sulfate and titanium dioxide.
The capsule shell for 80 mg and 100 mg consists of D&C yellow #10, FD&C red #3, gelatin, sodium lauryl sulfate and titanium dioxide.
Atomoxetine hydrochloride () capsules 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg or 100 mg are printed with edible black ink. The black ink is comprised of black iron oxide, propylene glycol, and shellac.
Atomoxetine hydrochloride () Clinical Pharmacology
Atomoxetine is well-absorbed after oral administration and is minimally affected by food. It is eliminated primarily by oxidative metabolism through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway and subsequent glucuronidation. Atomoxetine has a half-life of about 5 hours. A fraction of the population (about 7% of Caucasians and 2% of African Americans) 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 about 24 hours) of atomoxetine compared with people with normal activity [extensive metabolizers (EMs)]. Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine, and quinidine, cause similar increases in exposure.
The pharmacokinetics of atomoxetine have been evaluated in more than 400 children and adolescents in selected clinical trials, primarily using population pharmacokinetic studies. Single-dose and steady-state individual pharmacokinetic data were also obtained in children, adolescents, and adults. When doses were normalized to a mg/kg basis, similar half-life, C, and AUC values were observed in children, adolescents, and adults. Clearance and volume of distribution after adjustment for body weight were also similar.
Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in EMs and 94% in PMs. Maximal plasma concentrations (C) are reached approximately 1 to 2 hours after dosing.
Atomoxetine hydrochloride () can be administered with or without food. Administration of Atomoxetine hydrochloride () with a standard high-fat meal in adults did not affect the extent of oral absorption of atomoxetine (AUC), but did decrease the rate of absorption, resulting in a 37% lower C, and delayed T by 3 hours. In clinical trials with children and adolescents, administration of Atomoxetine hydrochloride () with food resulted in a 9% lower C.
The steady-state volume of distribution after intravenous administration is 0.85 L/kg indicating that atomoxetine distributes primarily into total body water. Volume of distribution is similar across the patient weight range after normalizing for body weight.
At therapeutic concentrations, 98% of atomoxetine in plasma is bound to protein, primarily albumin.
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 C is about 5-fold greater than EMs. Laboratory tests are available to identify CYP2D6 PMs. Coadministration of Atomoxetine hydrochloride () with potent inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine, results in a substantial increase in atomoxetine plasma exposure, and dosing adjustment may be necessary . Atomoxetine did not inhibit or induce the CYP2D6 pathway.
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 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 PMs).
Mean apparent plasma clearance of atomoxetine after oral administration in adult EMs is 0.35 L/hr/kg and the mean half-life is 5.2 hours. Following oral administration of atomoxetine to 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 C 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).
Atomoxetine is excreted primarily as 4-hydroxyatomoxetine--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 Atomoxetine hydrochloride () dose is excreted as unchanged atomoxetine (less than 3% of the dose), indicating extensive biotransformation.
[See ]
Atomoxetine hydrochloride () Clinical Studies
The effectiveness of Atomoxetine hydrochloride () in the treatment of ADHD was established in 4 randomized, double-blind, placebo-controlled studies of pediatric patients (ages 6 to 18). Approximately one-third of the patients met DSM-IV criteria for inattentive subtype and two-thirds met criteria for both inattentive and hyperactive/impulsive subtypes.
Signs and symptoms of ADHD were evaluated by a comparison of mean change from baseline to endpoint for Atomoxetine hydrochloride () and placebo-treated patients using an intent-to-treat analysis of the primary outcome measure, the investigator administered and scored ADHD Rating Scale-IV-Parent Version (ADHDRS) total score including hyperactive/impulsive and inattentive subscales. Each item on the ADHDRS maps directly to one symptom criterion for ADHD in the DSM-IV.
In Study 1, an 8-week randomized, double-blind, placebo-controlled, dose-response, acute treatment study of children and adolescents aged 8 to 18 (N=297), patients received either a fixed dose of Atomoxetine hydrochloride () (0.5, 1.2, or 1.8 mg/kg/day) or placebo. Atomoxetine hydrochloride () was administered as a divided dose in the early morning and late afternoon/early evening. At the 2 higher doses, improvements in ADHD symptoms were statistically significantly superior in Atomoxetine hydrochloride () -treated patients compared with placebo-treated patients as measured on the ADHDRS scale. The 1.8 mg/kg/day Atomoxetine hydrochloride () dose did not provide any additional benefit over that observed with the 1.2 mg/kg/day dose. The 0.5 mg/kg/day Atomoxetine hydrochloride () dose was not superior to placebo.
In Study 2, a 6-week randomized, double-blind, placebo-controlled, acute treatment study of children and adolescents aged 6 to 16 (N=171), patients received either Atomoxetine hydrochloride () or placebo. Atomoxetine hydrochloride () was administered as a single dose in the early morning and titrated on a weight-adjusted basis according to clinical response, up to a maximum dose of 1.5 mg/kg/day. The mean final dose of Atomoxetine hydrochloride () was approximately 1.3 mg/kg/day. ADHD symptoms were statistically significantly improved on Atomoxetine hydrochloride () compared with placebo, as measured on the ADHDRS scale. This study shows that Atomoxetine hydrochloride () is effective when administered once daily in the morning.
In 2 identical, 9-week, acute, randomized, double-blind, placebo-controlled studies of children aged 7 to 13 (Study 3, N=147; Study 4, N=144), Atomoxetine hydrochloride () and methylphenidate were compared with placebo. Atomoxetine hydrochloride () was administered as a divided dose in the early morning and late afternoon (after school) and titrated on a weight-adjusted basis according to clinical response. The maximum recommended Atomoxetine hydrochloride () dose was 2 mg/kg/day. The mean final dose of Atomoxetine hydrochloride () for both studies was approximately 1.6 mg/kg/day. In both studies, ADHD symptoms statistically significantly improved more on Atomoxetine hydrochloride () than on placebo, as measured on the ADHDRS scale.
Examination of population subsets based on gender and age (
The effectiveness of Atomoxetine hydrochloride () in the treatment of ADHD was established in 2 randomized, double-blind, placebo-controlled clinical studies of adult patients, age 18 and older, who met DSM-IV criteria for ADHD.
Signs and symptoms of ADHD were evaluated using the investigator-administered Conners Adult ADHD Rating Scale Screening Version (CAARS), a 30-item scale. The primary effectiveness measure was the 18-item Total ADHD Symptom score (the sum of the inattentive and hyperactivity/impulsivity subscales from the CAARS) evaluated by a comparison of mean change from baseline to endpoint using an intent-to-treat analysis.
In 2 identical, 10-week, randomized, double-blind, placebo-controlled acute treatment studies (Study 5, N=280; Study 6, N=256), patients received either Atomoxetine hydrochloride () or placebo. Atomoxetine hydrochloride () was administered as a divided dose in the early morning and late afternoon/early evening and titrated according to clinical response in a range of 60 to 120 mg/day. The mean final dose of Atomoxetine hydrochloride () for both studies was approximately 95 mg/day. In both studies, ADHD symptoms were statistically significantly improved on Atomoxetine hydrochloride () , as measured on the ADHD Symptom score from the CAARS scale.
Examination of population subsets based on gender and age (
Atomoxetine hydrochloride () How Supplied/storage And Handling
Atomoxetine hydrochloride () capsules are available as follows:
10 mg, hard gelatin capsules with opaque white cap and body containing white to off white colored powder equivalent to 10 mg of atomoxetine. The cap is printed with ‘SZ’ and the body is printed with ‘518’ in black ink.
NDC 0781-2260-31, bottle of 30 capsules
NDC 0781-2260-22, bottle of 2000 capsules
18 mg, hard gelatin capsules with gold cap and opaque white body containing white to off white colored powder equivalent to 18 mg of atomoxetine. The cap is printed with ‘SZ’ and the body is printed with ‘519’ in black ink.
NDC 0781-2261-31, bottle of 30 capsules
NDC 0781-2261-22, bottle of 2000 capsules
25 mg, hard gelatin capsules with opaque blue cap and opaque white body containing white to off white colored powder equivalent to 25 mg of atomoxetine. The cap is printed with ‘SZ’ and the body is printed with ‘520’ in black ink.
NDC 0781-2262-31, bottle of 30 capsules
NDC 0781-2262-22, bottle of 2000 capsules
40 mg, hard gelatin capsules with opaque blue cap and body containing white to off white colored powder equivalent to 40 mg of atomoxetine. The cap is printed with ‘SZ’ and the body is printed with ‘521’ in black ink.
NDC 0781-2263-31, bottle of 30 capsules
NDC 0781-2263-22, bottle of 2000 capsules
60 mg, hard gelatin capsules with opaque blue cap and gold body containing white to off white colored powder equivalent to 60 mg of atomoxetine. The cap is printed with ‘SZ’ and the body is printed with ‘522’ in black ink.
NDC 0781-2264-31, bottle of 30 capsules
NDC 0781-2264-22, bottle of 2000 capsules
80 mg, hard gelatin capsules with opaque brown cap and opaque white body containing white to off white colored powder equivalent to 80 mg of atomoxetine. The cap is printed with ‘SZ’ and the body is printed with ‘523’ in black ink.
NDC 0781-2265-31, bottle of 30 capsules
NDC 0781-2265-22, bottle of 2000 capsules
100 mg, hard gelatin capsules with opaque brown cap and body containing white to off white colored powder equivalent to 100 mg of atomoxetine. The cap is printed with ‘SZ’ and the body is printed with ‘524’ in black ink.
NDC 0781-2266-31, bottle of 30 capsules
NDC 0781-2266-22, bottle of 2000 capsules
Atomoxetine hydrochloride () Patient Counseling Information
See FDA-approved Medication Guide.
Physicians should instruct their patients to read the Medication Guide before starting therapy with Atomoxetine hydrochloride () and to reread it each time the prescription is renewed.
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Atomoxetine hydrochloride () and should counsel them in its appropriate use. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Atomoxetine hydrochloride () .
Atomoxetine hydrochloride () Medication Guide
Tell your doctor if you or your child has any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting Atomoxetine hydrochloride () .
Your doctor should check your blood pressure or your child’s blood pressure and heart rate regularly during treatment with Atomoxetine hydrochloride () .
Atomoxetine hydrochloride () is a selective norepinephrine reuptake inhibitor medicine. It is used for the treatment of attention deficit and hyperactivity disorder (ADHD). Atomoxetine hydrochloride () may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD.
Atomoxetine hydrochloride () should be used as a part of a total treatment program for ADHD that may include counseling or other therapies.
Atomoxetine hydrochloride () has not been studied in children less than 6 years old.
Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding.
Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist.
See ” for information on reported suicidal thoughts and actions, other mental problems, severe liver damage, and heart problems.
This is not a complete list of possible side effects.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Atomoxetine hydrochloride () for a condition for which it was not prescribed. Do not give Atomoxetine hydrochloride () to other people, even if they have the same condition. It may harm them.
This Medication Guide summarizes the most important information about Atomoxetine hydrochloride () . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Atomoxetine hydrochloride () that was written for healthcare professionals. For more information about Atomoxetine hydrochloride () , call Sandoz Inc. at 1-800-525-8747.
The capsule shell for 10 mg consists of gelatin, sodium lauryl sulfate and titanium dioxide.
The capsule shell for 18 mg consists of D&C yellow # 10, FD&C red #3, gelatin, sodium lauryl sulfate and titanium dioxide.
The capsule shell for 25 mg and 40 mg consists of FD&C blue #1, FD&C red #3, gelatin, sodium lauryl sulfate and titanium dioxide.
The capsule shell for 60 mg consists of D&C yellow # 10, FD&C blue #1, FD&C red #3, gelatin, sodium lauryl sulfate and titanium dioxide.
The capsule shell for 80 mg and 100 mg consists of D&C yellow #10, FD&C red #3, gelatin, sodium lauryl sulfate and titanium dioxide.
Atomoxetine hydrochloride () capsules, 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg and 100 mg are printed with edible black ink. The black ink is comprised of black iron oxide, propylene glycol, and shellac.
Nardil is a registered trademark of Pfizer Inc.
Parnate is a registered trademark of GlaxoSmithKline.
Emsam is a registered trademark of Somerset Pharmaceuticals Inc.
Manufactured in India by Sandoz Private Ltd.
for Sandoz Inc., Princeton, NJ 08540
Rev. October 2010
Atomoxetine hydrochloride () Principal Display Panel - Mg
NDC 0781-2260-31
Medication Guide provided separately
30 Capsules
Atomoxetine hydrochloride () Principal Display Panel - Mg
NDC 0781-2261-31
Medication Guide provided separately
30 Capsules
Atomoxetine hydrochloride () Principal Display Panel - Mg
NDC 0781-2262-31
Medication Guide provided separately
30 Capsules
Atomoxetine hydrochloride () Principal Display Panel - Mg
NDC 0781-2263-31
Medication Guide provided separately
30 Capsules
Atomoxetine hydrochloride () Principal Display Panel - Mg
NDC 0781-2264-31
Medication Guide provided separately
30 Capsules
Atomoxetine hydrochloride () Principal Display Panel - Mg
NDC 0781-2265-31
Medication Guide provided separately
30 Capsules
Atomoxetine hydrochloride () Principal Display Panel - Mg
NDC 0781-2266-31
Medication Guide provided separately
30 Capsules
