Atomoxetine Hydrochloride

FDA Drug Information • Also known as: Atomoxetine Hydrochloride, Strattera

Brand Names: Atomoxetine Hydrochloride, Strattera
Dosage Form: CAPSULE
Product Type: DRUG FOR FURTHER PROCESSING

⚠ Boxed Warning (Black Box)

WARNING: SUICIDAL IDEATION IN CHILDREN AND ADOLESCENTS 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 atomoxetine 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. Atomoxetine is approved for ADHD in pediatric and adult patients. Atomoxetine is not approved for major depressive disorder. Pooled analyses of short-term (6 to 18 weeks) placebo-controlled trials of atomoxetine 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 atomoxetine compared to placebo. The average risk of suicidal ideation in patients receiving atomoxetine was 0.4% (5/1357 patients), compared to none in placebo-treated patients (851 patients). No suicides occurred in these trials [see Warnings and Precautions ( 5.1 )] . 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)

Description

11 DESCRIPTION Atomoxetine is a selective norepinephrine reuptake inhibitor. Atomoxetine hydrochloride, USP is the R (-) isomer as determined by x-ray diffraction. The chemical designation is (-)- N -Methyl-3-phenyl-3-( o -tolyloxy)- propylamine hydrochloride. The molecular formula is C 17 H 21 NO

HCl, which corresponds to a molecular weight of 291.82. The chemical structure is: Atomoxetine hydrochloride, USP is a white to practically white solid, which has a solubility of 27.8 mg/mL in water. Atomoxetine capsules, USP are intended for oral administration only. Each capsule contains atomoxetine hydrochloride, USP equivalent to 10, 18, 25, 40, 60, 80, or 100 mg of atomoxetine. The capsules also contain pregelatinized starch. The capsule shells contain gelatin and titanium dioxide. The capsule shells may also contain one or more of the following: FD&C Blue No. 2 (25 mg, 40 mg, and 60 mg), iron oxide red (80 mg and 100 mg), and iron oxide yellow (18 mg, 25 mg, 40 mg, 60 mg, 80 mg and 100 mg). The capsules are imprinted with edible black ink (comprised of ammonia solution, iron oxide black, potassium hydroxide, propylene glycol, and shellac.). atomstructure

What Is Atomoxetine Hydrochloride Used For?

1 INDICATIONS AND USAGE Atomoxetine is a selective norepinephrine reuptake inhibitor indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). ( 1.1 ) 1.1 Attention-Deficit/Hyperactivity Disorder (ADHD) 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 )] . 1.2 Diagnostic Considerations 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. 1.3 Need for Comprehensive Treatment Program 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...

Dosage and Administration

2 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) 2.1 Acute Treatment Dosing of children and adolescents up to 70 kg body weight — Atomoxetine 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 [see Clinical Studies ( 14 )] . The total daily dose in children and adolescents should not exceed 1.4 mg/kg or 100 mg, whichever is less. Dosing of children and adolescents over 70 kg body weight and adults — Atomoxetine 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 [see Clinical Studies ( 14 )] . The maximum recommended total daily dose in children and adolescents over 70 kg and adults is 100 mg. 2.2 Maintenance/Extended Treatment It is generally agreed that pharmacological treatment of ADHD may be needed for extended periods. The benefit of maintaining pediatric patients (ages 6 to 15 years) with ADHD on atomoxetine after achieving a response in a dose range of 1.2 to 1.8 mg/kg/day was demonstrated in a controlled trial. Patients assigned to atomoxetine in the maintenance phase were generally continued on the same dose used to achieve a response in the open label phase. The physician who elects to use atomoxetine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient [see Clinical Studies ( 14.1 )] . 2.3 General Dosing Information Atomoxetine capsules may be taken with or without food. Atomoxetine capsules can be discontinued without being tapered. Atomoxetine capsules are not intended to be opened, they should be taken whole [see Patient Counseling Information ( 17 )] . The safety of single doses over 120 mg and total daily doses above 150 mg have not been systematically evaluated. 2.4 Screen for Bipolar Disorder Prior to Starting Atomoxetine Capsules Prior to initiating treatment with atomoxetine capsules, screen patients for a...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS Most common adverse reactions (≥5% and at least twice the incidence of placebo patients) Child and Adolescent Clinical Trials - Nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence. (6.1) Adult Clinical Trials - Constipation, dry mouth, nausea, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Atomoxetine 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. Child and Adolescent Clinical Trials Reasons for discontinuation of treatment due to adverse reactions in child and adolescent clinical trials — In acute child and adolescent placebo-controlled trials, 3.0% (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-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 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 (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (atomoxetine incidence greater than placebo) are listed in Table 2. Results were similar in the BID and the QD trial except as shown in Table 3, 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 (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 Tables 2 and 3). Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of pediatric patients experienced potentially clinically important changes in heart rate (≥20 beats per min) or blood pressure (≥15 to 20 mm Hg) [see Contraindications ( 4 ) and Warnings and Precautions ( 5 )] . Table 2: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine in Acute (up to 18 weeks) Child and Adolescent Trials Adverse Reaction a Percentage of Patients Reporting Reaction Atomoxetine (N=1597) Placebo (N=934) Gastrointestinal Disorders Abdominal pain b 18 10 Vomiting 11 6 Nausea 10 5 General Disorders and Administration Site Conditions Fatigue 8 3...

Drug Interactions

7 DRUG INTERACTIONS Monoamine Oxidase Inhibitors. (4.2, 7.1) CYP2D6 Inhibitors – Concomitant use may increase atomoxetine steady–state plasma concentrations in EMs. (7.2) Antihypertensive Drugs and Pressor Agents – Possible effects on blood pressure. (7.3) Albuterol (or other beta 2 agonists) – Action of albuterol on cardiovascular system can be potentiated. (7.4) 7.1 Monoamine Oxidase Inhibitors 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 Contraindications ( 4.2 )] . 7.2 Effect of CYP2D6 Inhibitors on Atomoxetine 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 ss, max is about 3- to 4-fold greater than atomoxetine alone. In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine. 7.3 Antihypertensive Drugs and Pressor Agents Because of possible effects on blood pressure, atomoxetine should be used cautiously with antihypertensive drugs and pressor agents (e.g., dopamine, dobutamine) or other drugs that increase blood pressure. 7.4 Albuterol Atomoxetine should be administered with caution to patients being treated with systemically-administered (oral or intravenous) albuterol (or other beta 2 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 to 800 mcg) and atomoxetine (80 mg QD for 5 days) in 21 healthy Asian subjects who were excluded for poor metabolizer status. 7.5 Effect of Atomoxetine on P450 Enzymes Atomoxetine did not cause clinically important inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9. CYP3A Substrate (e.g., Midazolam) — Coadministration of atomoxetine (60 mg BID for 12 days) with midazolam, a model compound for CYP3A4 metabolized drugs (single...

Contraindications

4 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. ( 4.3 ) Pheochromocytoma or history of pheochromocytoma. ( 4.4 ) Severe Cardiovascular Disorders that might deteriorate with clinically important increases in HR and BP. ( 4.5 ) 4.1 Hypersensitivity Atomoxetine capsules are contraindicated in patients known to be hypersensitive to atomoxetine or other constituents of the product [see Warnings and Precautions ( 5.8 )] . 4.2 Monoamine Oxidase Inhibitors (MAOI) 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 )] . 4.3 Narrow Angle Glaucoma 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. 4.4 Pheochromocytoma Serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with pheochromocytoma or a history of pheochromocytoma who received atomoxetine. Therefore, atomoxetine should not be taken by patients with pheochromocytoma or a history of pheochromocytoma. 4.5 Severe Cardiovascular Disorders Atomoxetine should not be used in...

Pregnancy and Breastfeeding

8.1 Pregnancy 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/m 2 basis. In one of 2 studies in which rats were dosed prior to mating through the periods of organogenesis and lactation, decreased pup weight and decreased pup survival were observed at doses corresponding to 5-6 times the MRHD on a mg/m 2 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...

Overdosage

10 OVERDOSAGE 10.1 Human Experience There is limited clinical trial experience with atomoxetine overdose. During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of atomoxetine and at least one other drug. There have been no reports of death involving overdose of atomoxetine 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 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 [see Clinical Pharmacology ( 12.2 )] . 10.2 Management of Overdose Consult with a Certified Poison Control Center 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 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: 70518-4313-00 NDC: 70518-4313-01 PACKAGING: 30 in 1 BOX PACKAGING: 1 in 1 POUCH 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]. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.