Atomoxetine: uses, appearance and warnings

Atomoxetine capsules are indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) in adults and pediatric patients 6 years of age and older. Atomoxetine capsules is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with ADHD Atomoxetine capsules are selective norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of ADHD in adults and pediatric patients 6 years of age and older. ( 1 )

Capsules: • 10 mg of atomoxetine (Opaque White, Opaque White) • 18 mg of atomoxetine (Opaque Yellow, Opaque White) • 25 mg of atomoxetine (Opaque Blue, Opaque White) • 40 mg of atomoxetine (Opaque Blue, Opaque Blue) • 60 mg of atomoxetine (Opaque Blue, Opaque Yellow) • 80 mg of atomoxetine (Opaque Reddish Brown, Opaque White) • 100 mg of atomoxetine (Opaque Reddish Brown, Opaque Reddish Brown) Capsules: contain 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, or 100 mg of atomoxetine. ( 3 , 11 , 16 )

16.1 How Supplied Table 10 displays the available atomoxetine capsules strengths. Table 10: Atomoxetine Capsules Strengths Strength a Color Identification NDC Bottles of 30 with child-resistant closure 10 mg opaque white, opaque white 265/10 16714-755-01 18 mg opaque yellow, opaque white 266/18 18 16714-756-01 25 mg opaque blue, opaque white 267/25 16714-757-01 40 mg opaque blue, opaque blue 268/40 16714-758-01 60 mg opaque blue, opaque yellow 268/40 16714-759-01 80 mg opaque reddish brown, opaque white 270/80 16714-760-01 100 mg opaque reddish brown, opaque reddish brown 271/100 16714-761-01 a Strength is based on the base (atomoxetine). 16.2 Storage and Handling Store at 20 ° C to 25 ° C (68 ° F to 77 ° F); excursions permitted to 15 ° C to 30 ° C (59 ° F to 86 ° F) [see USP Controlled Room Temperature]. 16.1 How Supplied Table 10 displays the available atomoxetine capsules strengths. Table 10: Atomoxetine Capsules Strengths Strength a Color Identification NDC Bottles of 30 with child-resistant closure 10 mg opaque white, opaque white 265/10 16714-755-01 18 mg opaque yellow, opaque white 266/18 18 16714-756-01 25 mg opaque blue, opaque white 267/25 16714-757-01 40 mg opaque blue, opaque blue 268/40 16714-758-01 60 mg opaque blue, opaque yellow 268/40 16714-759-01 80 mg opaque reddish brown, opaque white 270/80 16714-760-01 100 mg opaque reddish brown, opaque reddish brown 271/100 16714-761-01 a Strength is based on the base (atomoxetine).

Atomoxetine capsules is contraindicated in patients: • With known hypersensitivity reaction to atomoxetine capsules or other constituents of atomoxetine capsules. Hypersensitivity reactions included anaphylaxis, angioneurotic edema, urticaria, and rash [see Warnings and Precautions ( 5.8 )] . • Taking, or within 14 days of stopping, a monoamine oxidase inhibitor (MAOI) [see Drug Interactions ( 7 )] . • With narrow angle glaucoma. In clinical trials, atomoxetine capsules use was associated with an increased risk of mydriasis. • With pheochromocytoma or a history of pheochromocytoma. Serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with pheochromocytoma or a history of pheochromocytoma who received atomoxetine capsules. • With severe cardiac or vascular disorders whose condition would be expected to deteriorate if they had a clinically important increase in blood pressure or heart rate (e.g., 15 to 20 mm Hg in blood pressure or 20 beats per minute in heart rate) [ see Warnings and Precautions ( 5.4 ) ]. Contraindicated in patients (4): • With known hypersensitivity to atomoxetine or other constituents of atomoxetine • Taking or within 14 days of stopping, a monoamine oxidase inhibitor (MAOI) • With narrow angle glaucoma • With pheochromocytoma or history of pheochromocytoma • With severe cardiac or vascular disorders whose condition would be expected to deteriorate with clinically important increases in blood pressure or heart rate

• Severe Liver Injury: atomoxetine should be discontinued and not restarted in patients with jaundice or laboratory evidence of liver injury. ( 5.2 ) • Serious Cardiovascular Reactions : Prior to atomoxetine treatment, patients should have a careful history and physical exam to assess for presence of cardiovascular (CV) disease. atomoxetine generally should not be used in pediatric patients with known serious cardiac abnormalities, cardiomyopathy, serious arrhythmias. Consideration should be given to not using atomoxetine in adults with clinically significant cardiac abnormalities. Patients who develop symptoms suggestive of cardiac disease during atomoxetine treatment should stop atomoxetine and undergo a prompt cardiac evaluation. ( 5.3 ) • Increase in Blood Pressure and Heart Rate : Heart rate and blood pressure should be measured at baseline, following atomoxetine dosage increase, and periodically while on therapy. ( 5.4 ) • New Psychotic or Manic Symptoms and Activation of Mania: If psychotic or manic symptoms occur, consider discontinuing atomoxetine. ( 5.5 ) • Aggressive Behavior or Hostility: Monitor for the appearance or worsening of aggressive behavior or hostility. ( 5.7 ) • Effects on Urine Outflow: Urinary retention or hesitancy may occur. ( 5.9 ) • Priapism: Prompt medical attention is required in the event of suspected priapism. ( 5.10 ) • Effect on Growth in Pediatric Patients: Closely monitor growth (e.g., weight, height) in pediatric patients. ( 5.11 ) 5.1 Suicidal Thoughts and Behaviors in Pediatric Patients 6 Years of Age and Older • All atomoxetine-treated pediatric patients should be monitored and observed closely for clinical worsening, suicidal thoughts and behavior, and unusual changes in behavior, especially during the initial few months of atomoxetine therapy, or at times of dosage changes, either increases or decreases. • Families and caregivers of atomoxetine-treated pediatric patients should be alerted about the need to monitor patients daily for the emergence of agitation, irritability, unusual changes in behavior, and mental health-related symptoms, as well as the emergence of suicidal thoughts and behavior, and to report such symptoms immediately to a health care provider. • Consider changing the therapeutic regimen, including stopping atomoxetine, in patients who experience emergent suicidality or symptoms that might be precursors to emerging suicidal thoughts and behavior, especially if these symptoms are severe or abrupt in onset, or were not part of the patient’s presenting symptoms. Atomoxetine increased the risk of suicidal ideation in pediatric patients 6 years and older with ADHD in pooled placebo-controlled short-term studies (6 to 18 weeks). In 12 studies (11 studies in patients with ADHD and 1 study in another population) with over 2,200 pediatric patients, the mean incidence of suicidal ideation in atomoxetine-treated pediatric patients was 0.4% (5/1,357) (including one patient with a suicide attempt) compared to 0% (0/851) in placebo-treated pediatric patients. No suicides occurred in these studies. All the suicidal ideations occurred in pediatric patients 6 to 12 years of age, and all occurred during the first month of atomoxetine 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 for ADHD did not reveal an increased risk of suicidal ideation or behavior. The following psychiatric symptoms have been reported with atomoxetine: 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. 5.2 Severe Liver Injury Atomoxetine should be discontinued and not restarted in patients with jaundice or laboratory evidence of liver injury, Liver enzyme and function tests should be obtained upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu like” symptoms). Postmarketing reports indicate that atomoxetine can cause severe liver injury. Although no evidence of liver injury was detected in clinical trials of about 6,000 patients, there have been rare cases of clinically significant liver injury that were considered probably or possibly related to atomoxetine use during postmarketing use. • Rare cases of liver failure have been reported during postmarketing use, including a case that resulted in a liver transplant. • Reported cases of liver injury occurred within 120 days of initiation of atomoxetine in most cases and some patients presented with markedly elevated liver enzymes (>20 times upper limit of normal (ULN)), and jaundice with significantly elevated bilirubin levels (>2 times ULN), followed by recovery upon atomoxetine discontinuation. In one patient, liver injury, manifested by elevated hepatic enzymes up to 40 times ULN and jaundice with bilirubin up to 12 times ULN, recurred upon rechallenge, and was followed by recovery upon atomoxetine discontinuation, providing evidence that atomoxetine likely caused the liver injury. Such reactions may occur several months after atomoxetine is started, but laboratory abnormalities may continue to worsen for several weeks after atomoxetine is stopped. …

Most common adverse reactions (≥5% and at least twice the incidence of placebo patients): • Pediatric Clinical Studies: Nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence. ( 6.1 ) • Adult Clinical Studies: Constipation, dry mouth, nausea, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation. ( 6.1 ) Patients should be instructed to use caution when driving a car or operating hazardous machinery (because of somnolence) until they are reasonably certain that their performance is not affected by atomoxetine . ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1800-206-7821 or FDA at 1-800-FDA-1088 or. …

See Table 8 for clinically significant drug interactions with atomoxetine and other drugs. Table 8: Clinically Significant Drug Interactions with atomoxetine and Other Drugs Monoamine Oxidase Inhibitors (MAOIs) Prevention or Management Atomoxetine is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue, or in patients who stopped an MAOI within 14 days. Mechanism and Clinical Effect(s) As with other drugs affecting brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (hyperthermia, rigidity, myoclonus, autonomic instability with fluctuations of vital signs, extreme agitation progressing to delirium/coma) with concomitant use of atomoxetine and an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. …