Prescription Drug Information: Atomoxetine (Page 2 of 7)

5.2 Severe Liver Injury

Postmarketing reports indicate that atomoxetine can cause severe liver injury. Although no evidence of liver injury was detected in clinical trials of about 6000 patients, there have been rare cases of clinically significant liver injury that were considered probably or possibly related to atomoxetine use in postmarketing experience. Rare cases of liver failure have also been reported, including a case that resulted in a liver transplant. 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 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.
Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted. Laboratory testing to determine liver enzyme levels should be done upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu like” symptoms) [see Warnings and Precautions (5.12); Patient Counseling Information (17)].

5.3 Serious Cardiovascular Events

Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems
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.
Assessing Cardiovascular Status in Patients being Treated with Atomoxetine
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.

5.4 Effects on Blood Pressure and Heart Rate

Atomoxetine should be used with caution in patients whose underlying medical conditions could be worsened by increases in blood pressure or heart rate such as certain patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease. It should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experienced clinically important increases in blood pressure or heart rate [see Contraindications (4.5)]. Pulse and blood pressure should be measured at baseline, following atomoxetine dose increases, and periodically while on therapy to detect possible clinically important increases.
The following table provides short-term, placebo-controlled clinical trial data for the proportions of patients having an increase in: diastolic blood pressure ≥15 mm Hg; systolic blood pressure ≥20 mm Hg; heart rate greater than or equal to 20 bpm, in both the pediatric and adult populations (see Table 1).
Table 1a
a Abbreviations: bpm=beats per minute; DBP=diastolic blood pressure; HR=heart rate; mm Hg=millimeters mercury; SBP=systolic blood pressure.
b Proportion of patients meeting threshold at any one time during clinical trial.

Pediatric Acute Placebo-Controlled

Adult Acute Placebo-Controlled

Maximumb

Endpoint

Maximumb

Endpoint

Atomoxetine

Placebo

Atomoxetine

Placebo

Atomoxetine

Placebo

Atomoxetine

Placebo

%

%

%

%

%

%

%

%

DBP (≥15 mm Hg)

21.5

14.1

9.3

4.8

12.6

8.7

4.8

3.5

SBP (≥20 mm Hg)

12.5

8.7

4.9

3.3

12.4

7.8

4.2

3.2

HR (≥20 bpm)

23.4

11.5

12.2

3.8

22.4

8.3

10.2

2.0

In placebo-controlled registration studies involving pediatric patients, tachycardia was identified as an adverse event for 0.3% (5/1597) of these atomoxetine patients compared with 0% (0/934) of placebo patients. The mean heart rate increase in extensive metabolizer (EM) patients was 5.0 beats/minute, and in poor metabolizer (PM) patients 9.4 beats/minute.
In adult clinical trials where EM/PM status was available, the mean heart rate increase in PM patients was significantly higher than in EM patients (11 beats/minute versus 7.5 beats/minute). The heart rate effects could be clinically important in some PM patients.
In placebo-controlled registration studies involving adult patients, tachycardia was identified as an adverse event for 1.5% (8/540) of atomoxetine patients compared with 0.5% (2/402) of placebo patients.
In adult clinical trials where EM/PM status was available, the mean change from baseline in diastolic blood pressure in PM patients was higher than in EM patients (4.21 versus 2.13 mm Hg) as was the mean change from baseline in systolic blood pressure (PM: 2.75 versus EM: 2.40 mm Hg). The blood pressure effects could be clinically important in some PM patients.
Orthostatic hypotension and syncope have been reported in patients taking atomoxetine. In child and adolescent registration studies, 0.2% (12/5596) of atomoxetine -treated patients experienced orthostatic hypotension and 0.8% (46/5596) experienced syncope. In short-term child and adolescent registration studies, 1.8% (6/340) of atomoxetine -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 registration studies. Atomoxetine 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.

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