ATOMOXETINE HYDROCHLORIDE capsule

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

ATOMOXETINE HYDROCHLORIDE (UNII: 57WVB6I2W0) (ATOMOXETINE - UNII:ASW034S0B8)

Available from:

Apotex Corp.

INN (International Name):

ATOMOXETINE HYDROCHLORIDE

Composition:

ATOMOXETINE 10 mg

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Atomoxetine capsules are indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). The efficacy of atomoxetine capsules was established in seven clinical trials in outpatients with ADHD: four 6 to 9-week trials in pediatric patients (ages 6 to 18), two 10-week trial in adults, and one maintenance trial in pediatrics (ages 6 to 15) [see Clinical Studies (14)] . 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 is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Drug treatment is not intended for use in the patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential in children and adolescents with this diagnosis and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe drug treatment medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms. Atomoxetine capsules are contraindicated in patients known to be hypersensitive to atomoxetine or other constituents of the product [see Warnings and Precautions (5.8)] . Atomoxetine should not be taken with an MAOI, or within 2 weeks after discontinuing an MAOI. Treatment with an MAOI should not be initiated within 2 weeks after discontinuing atomoxetine. With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity [see Drug Interactions (7.1)] . In clinical trials, atomoxetine use was associated with an increased risk of mydriasis and therefore its use is not recommended in patients with narrow angle glaucoma. Serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with pheochromocytoma or a history of pheochromocytoma who received atomoxetine. Therefore, atomoxetine should not be taken by patients with pheochromocytoma or a history of pheochromocytoma. Atomoxetine 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) [see Warnings and Precautions (5.4)]. Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including atomoxetine, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhd-medications/. Risk Summary Available published studies with atomoxetine use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Some animal reproduction studies of atomoxetine had adverse developmental outcomes. One of 3 studies in pregnant rabbits dosed during organogenesis resulted in decreased live fetuses and an increase in early resorptions, as well as slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery. These effects were observed at plasma levels (AUC) 3 times and 0.4 times the human plasma levels in extensive and poor metabolizers receiving the maximum recommended human dose (MRHD), respectively. In rats dosed prior to mating and during organogenesis a decrease in fetal weight (female only) and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses were observed at a dose approximately 5 times the MRHD on a mg/m2 basis. In one of 2 studies in which rats were dosed prior to mating through the periods of organogenesis and lactation, decreased pup weight and decreased pup survival were observed at doses corresponding to 5-6 times the MRHD on a mg/m2 basis. No adverse fetal effects were seen in pregnant rats dosed during the organogenesis period (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-­20%, respectively. Data Animal Data 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 MRHD on a mg/m2 basis; plasma levels (AUC) of atomoxetine at this dose in rabbits are estimated to be 3.3 times (extensive metabolizers) or 0.4 times (poor metabolizers) those in humans receiving the MRHD. Rats were treated with up to approximately 50 mg/kg/day of atomoxetine (approximately 6 times the MRHD on a mg/m2 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 MRHD on a mg/m2 basis) but not at 20 mg/kg/day. No adverse fetal effects were seen when pregnant rats were treated with up to 150 mg/kg/day (approximately 17 times the MRHD on a mg/m2 basis) by gavage throughout the period of organogenesis. Risk Summary There are no data on the presence of atomoxetine or its metabolite in human milk, the effects on the breastfed child, or the effects on milk production. Atomoxetine is present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for atomoxetine and any potential adverse effects on the breastfed child from atomoxetine or from the underlying maternal condition. Anyone considering the use of atomoxetine in a child or adolescent must balance the potential risks with the clinical need [see Boxed Warning and Warnings and Precautions (5.1)] . The pharmacokinetics of atomoxetine in children and adolescents are similar to those in adults. The safety, efficacy, and pharmacokinetics of atomoxetine in pediatric patients less than 6 years of age have not been evaluated. A study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioral and sexual development. Rats were treated with 1, 10, or 50 mg/kg/day (approximately 0.2, 2, and 8 times, respectively, the maximum human dose on a mg/m2 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. The safety, efficacy and pharmacokinetics of atomoxetine in geriatric patients have not been evaluated. Atomoxetine exposure (AUC) is increased, compared with normal subjects, in EM subjects with moderate (Child-Pugh Class B) (2-fold increase) and severe (Child-Pugh Class C) (4-fold increase) hepatic insufficiency. Dosage adjustment is recommended for patients with moderate or severe hepatic insufficiency [see Dosage and Administration (2.3)] . EM subjects with end stage renal disease had higher systemic exposure to atomoxetine than healthy subjects (about a 65% increase), but there was no difference when exposure was corrected for mg/kg dose. Atomoxetine can therefore be administered to ADHD patients with end stage renal disease or lesser degrees of renal insufficiency using the normal dosing regimen. Gender did not influence atomoxetine disposition. Ethnic origin did not influence atomoxetine disposition (except that PMs are more common in Caucasians). Tics in patients with ADHD and comorbid Tourette’s Disorder — 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 to 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 [see Adverse Reactions (6.2)] . Anxiety in patients with ADHD and comorbid Anxiety Disorders – In two post-marketing, double-blind, placebo-controlled trials, it has been demonstrated that treating patients with ADHD and comorbid anxiety disorders with atomoxetine does not worsen their anxiety. In a 12-week double-blind, placebo-controlled trial, 176 patients, aged 8-17, who met DSM-IV criteria for ADHD and at least one of the anxiety disorders of separation anxiety disorder, generalized anxiety disorder or social phobia were randomized. Following a 2-week double-blind placebo lead-in, atomoxetine was initiated at 0.8 mg/kg/day with increase to a target dose of 1.2 mg/kg/day (median dose 1.30 mg/kg/day +/- 0.29 mg/kg/day). Atomoxetine did not worsen anxiety in these patients as determined by the Pediatric Anxiety Rating Scale (PARS). Of the 158 patients who completed the double-blind placebo lead-in, 26 (16%) patients discontinued the study. In a separate 16-week, double-blind, placebo-controlled trial, 442 patients aged 18 to 65, who met DSM-IV criteria for adult ADHD and social anxiety disorder (23% of whom also had Generalized Anxiety Disorder) were randomized. Following a 2-week double-blind placebo lead-in, atomoxetine was initiated at 40 mg/day to a maximum dose of 100 mg/day (mean daily dose 83 mg/day +/- 19.5 mg/day). Atomoxetine did not worsen anxiety in these patients as determined by the Liebowitz Social Anxiety Scale (LSAS). Of the 413 patients who completed the double-blind placebo lead-in, 149 (36.1%) patients discontinued the study. There have been postmarketing reports of anxiety [see Adverse Reactions (6.2)] . Atomoxetine is not a controlled substance. In a randomized, double-blind, placebo-controlled, abuse-potential study in adults comparing effects of atomoxetine and placebo, atomoxetine was not associated with a pattern of response that suggested stimulant or euphoriant properties. 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. There was no evidence of symptom rebound or adverse reactions suggesting a drug-discontinuation or withdrawal syndrome. Animal Experience — Drug discrimination studies in rats and monkeys showed inconsistent stimulus generalization between atomoxetine and cocaine.

Product summary:

Atomoxetine capsules, USP 10 mg are available for oral administration as hard gelatin capsules with a white opaque body and a white opaque cap, imprinted “APO AM10” in black ink. They are supplied as follows: NDC Number Size 60505-2830-3 Bottles of 30 Atomoxetine capsules, USP 18 mg are available for oral administration as hard gelatin capsules with a white opaque body and a gold opaque cap, imprinted “APO AM18” in black ink. They are supplied as follows: NDC Number Size 60505-2831-3 Bottles of 30 Atomoxetine capsules, USP 25 mg are available for oral administration as hard gelatin capsules with a white opaque body and a blue opaque cap, imprinted “APO AM25” in black ink. They are supplied as follows: NDC Number Size 60505-2832-3 Bottles of 30 Atomoxetine capsules, USP 40 mg are available for oral administration as hard gelatin capsules with a blue opaque body and a blue opaque cap, imprinted “APO AM40” in black ink. They are supplied as follows: NDC Number Size 60505-2833-3 Bottles of 30 Atomoxetine capsules, USP 60 mg are available for oral administration as hard gelatin capsules with a gold opaque body and a blue opaque cap, imprinted “APO AM60” in black ink. They are supplied as follows: NDC Number Size 60505-2834-3 Bottles of 30 Atomoxetine capsules, USP 80 mg are available for oral administration as hard gelatin capsules with a white opaque body and an orange opaque cap, imprinted “APO AM80” in black ink. They are supplied as follows: NDC Number Size 60505-2835-3 Bottles of 30 Atomoxetine capsules, USP 100 mg are available for oral administration as hard gelatin capsules with an orange opaque body and an orange opaque cap, imprinted “APO AM100” in black ink. They are supplied as follows: NDC Number Size 60505-2836-3 Bottles of 30 Store atomoxetine capsules, USP at 20°C to 25°C (68°F to 77°F) excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Authorization status:

Abbreviated New Drug Application

Patient Information leaflet

ATOMOXETINE HYDROCHLORIDE- ATOMOXETINE HYDROCHLORIDE CAPSULE
Apotex Corp.
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MEDICATION GUIDE
Atomoxetine Capsules, USP
(a" toe mox’ e teen)
Read the Medication Guide that comes with atomoxetine capsules before
you or your child starts taking it
and each time you get a refill. There may be new information. This
Medication Guide does not take the
place of talking to your doctor about your treatment or your child’s
treatment with atomoxetine.
What is the most important information I should know about atomoxetine
capsules?
The following have been reported with use of atomoxetine:
1.Suicidal thoughts and actions in children and teenagers:
Children and teenagers sometimes think about suicide, and many report
trying to kill themselves. Results
from atomoxetine clinical studies with over 2200 child or teenage ADHD
patients suggest that some
children and teenagers may have a higher chance of having suicidal
thoughts or actions. Although no
suicides occurred in these studies, 4 out of every 1000 patients
developed suicidal thoughts. Tell your
child or teenager’s doctor if your child or teenager (or there is a
family history of):
•
has bipolar illness (manic-depressive illness)
•
had suicide thoughts or actions before starting atomoxetine capsules
The chance for suicidal thoughts and actions may be higher:
•
early during atomoxetine treatment
•
during dose adjustments
Prevent suicidal thoughts and action in your child or teenager by:
•
paying close attention to your child or teenager’s moods, behaviors,
thoughts, and feelings during
atomoxetine treatment
•
keeping all follow-up visits with your child or teenager’s doctor as
scheduled
Watch for the following signs in your child or teenager during
atomoxetine treatment:
•
anxiety
•
agitation
•
panic attacks
•
trouble sleeping
•
irritability
•
hostility
•
aggressiveness
•
impulsivity
•
restlessness
•
mania
•
depression
•
suicide thoughts
Call your child or teenager’s doctor right away if they have any of
the above signs,

Summary of Product characteristics

ATOMOXETINE HYDROCHLORIDE- ATOMOXETINE HYDROCHLORIDE CAPSULE
APOTEX CORP.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
ATOMOXETINE CAPSULES
SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR
ATOMOXETINE CAPSULES.
ATOMOXETINE CAPSULES, FOR ORAL USE
INITIAL U.S. APPROVAL: 2002
WARNING: SUICIDAL IDEATION IN CHILDREN AND ADOLESCENTS
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING._
INCREASED RISK OF SUICIDAL IDEATION IN CHILDREN OR ADOLESCENTS _(5.1)_
NO SUICIDES OCCURRED IN CLINICAL TRIALS _(5.1)_
PATIENTS STARTED ON THERAPY SHOULD BE MONITORED CLOSELY_ (5.1)_
RECENT MAJOR CHANGES
Dosage and Administration, Screen for Bipolar Disorder Prior to
Starting Atomoxetine Capsules (2.4)
1/2022
Warnings and Precautions, Emergence of New Psychotic or Manic Symptoms
(5.5) 1/2022
Warnings and Precautions, Screening Patients for Bipolar Disorder
(5.6) 1/2022
Warnings and Precautions, Aggressive Behavior or Hostility (5.7)
1/2022
INDICATIONS AND USAGE
Atomoxetine is a selective norepinephrine reuptake inhibitor indicated
for the treatment of Attention-
Deficit/Hyperactivity Disorder (ADHD). (1.1)
DOSAGE AND ADMINISTRATION
Initial, Target and Maximum Daily Dose (2.1)
(Acute and Maintenance/Extended Treatment)
BODY WEIGHT
INITIAL DAILY
DOSE
TARGET TOTAL DAILY
DOSE
MAXIMUM TOTAL DAILY
DOSE
Children and adolescents up to 70 kg
0.5 mg/kg
1.2 mg/kg
1.4 mg/kg
Children and adolescents over 70 kg
and adults
40 mg
80 mg
100 mg
Dosing adjustment — Hepatic Impairment, Strong CYP2D6 Inhibitor, and
in patients known to be CYP2D6
poor metabolizers (PMs). (2.5, 12.3)
DOSAGE FORMS AND STRENGTHS
Each capsule contains atomoxetine hydrochloride equivalent to 10, 18,
25, 40, 60, 80, or 100 mg of
atomoxetine. (3, 11, 16)
CONTRAINDICATIONS
Hypersensitivity to atomoxetine or other constituents of product.
(4.1)
Atomoxetine use within 2 weeks after discontinuing MAOI or other drugs
that affect brain monoamine
concentrations. (4.2, 7.1)
Narrow Angle Glaucoma. (4