STRATTERA 25mg. Capsules.

BOXED WARNING

The safety and efficacy of atomoxetine in children less than 6 years of age have not been established. Atomoxetine is not approved for the treatment of major depressive disorder (MDD). An increased risk of suicidal ideation was noted during pediatric ADHD and enuresis studies with atomoxetine, including one suicide attempt but no completed suicides. Co-morbidities occurring with ADHD may increase the risk of suicidal ideation and/or behavior. Pediatric patients should be closely monitored for clinical worsening, as well as agitation, irritability, suicidal thinking or behaviors, and unusual changes in behavior. Such monitoring would generally include at least weekly in-person contact with patients during the first 4 weeks of treatment, then one visit at weeks 6, 8, and 12, then as indicated beyond 12 weeks. Additional contact by telephone may be appropriate between visits. Consideration should be given to changing or stopping the therapeutic regimen in patients who are experiencing symptoms that might be precursors to emerging suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Periodic reassessment of the need for medication is recommended. Atomoxetine should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Sudden death has been reported in association with atomoxetine treatment at usual doses in pediatric patients with structural cardiac abnormalities. A large retrospective cohort study including over 1.2 million children and young adults 2—24 years of age did not find an increased risk of serious cardiovascular events, including sudden cardiac death, myocardial infarction, or stroke in current users of drugs for the treatment of ADHD compared to nonusers (adjusted hazard ratio 0.75; 95% CI 0.31—1.85). The authors concluded that although the absolute magnitude of risk appears to be low, a modest increase in risk could not be ruled out. A cardiac assessment should be conducted prior to atomoxetine administration to evaluate appropriateness of treatment; careful screening and monitoring is recommended by the American Heart Association. The potential for growth inhibition in pediatric patients should be monitoring during atomoxetine therapy. Monitor height and weight at treatment initiation and periodically thereafter. Studies are not available to define the impact of atomoxetine on final adult height and weight, but short-term (9-week) studies have shown that up to 3.5% of body weight can be lost, and this loss may be dose-related. Data from open-label trials indicate that in general, the weight and height gain of children treated with atomoxetine lags behind that predicted by normative population data for the first 9—12 months of treatment; subsequently, weight gain rebounds and at about 3 years of treatment, patients have gained slightly more weight (0.5 kg) than predicted by their baseline data. After about 12 months, gain in height stabilizes, and at 3 years, patients have gained only slightly less (0.4 cm) than predicted. Growth patterns are similar regardless of pubertal status; however, mean weight gain has been shown to be slower for poor vs. extensive metabolizers (2.4 kg less vs. 0.2 kg less than predicted, respectively), while height gain is similar between poor and extensive metabolizers (1.1 cm less vs. 0.4 cm less than predicted, respectively). Adverse effects such as aggression and hostility have been observed in some children and adolescents receiving medications for ADHD. Although this has not been a finding of statistical significance with administration of atomoxetine compared to placebo, patients should be closely monitored for potential onset of these effects. It should be noted that not all patients with ADHD will require medication; non-drug measures are often instituted concurrently with drug therapy.

DEA CLASS

Rx

DESCRIPTION

Selective norepinephrine reuptake inhibitor (SNRI); first nonstimulant drug approved for ADHD; indicated for adults and children 6 years of age and older; common side effects include decreased appetite, headache, drowsiness, and nausea/vomiting; dosed once or twice daily.

COMMON BRAND NAMES

Strattera

HOW SUPPLIED

Atomoxetine/Atomoxetine Hydrochloride/Strattera Oral Cap: 10mg, 18mg, 25mg, 40mg, 60mg, 80mg, 100mg

DOSAGE & INDICATIONS

MAXIMUM DOSAGE

100 mg/day PO.

Safety and efficacy have not been evaluated.

Weighing more than 70 kg: 100 mg/day PO.
Weighing 70 kg or less: 1.4 mg/kg/day PO (Max: 100 mg/day PO).

6 to 12 years weighing more than 70 kg: 100 mg/day PO.
6 to 12 years weighing 70 kg or less: 1.4 mg/kg/day PO (Max: 100 mg/day PO).
1 to 5 years: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Moderate hepatic impairment (Child-Pugh Class B): Reduce initial and target dosage by 50% of normal.
Severe hepatic impairment (Child-Pugh Class C): Reduce initial and target dosage by 75% of normal.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Renal clearance is not an important predictor of atomoxetine clearance.

ADMINISTRATION

A MedGuide is available which informs patients about the cardiac and psychiatric risks associated with use, and should be provided by the authorized dispenser to each patient receiving a prescription.

STORAGE

Strattera:
– Store between 68 to 77 degrees F

CONTRAINDICATIONS / PRECAUTIONS

Atomoxetine is contraindicated in any patient with a known hypersensitivity to atomoxetine (e.g., angioedema or urticaria due to the drug) or any inactive ingredients in the product. The risk for allergic reactions is possible with any drug, although allergic reactions were uncommon in clinical trials with atomoxetine. Anaphylaxis, angioedema, rash, and urticaria have been reported in patients taking atomoxetine.

Atomoxetine is contraindicated in patients with pheochromocytoma or history of pheochromocytoma. Serious reactions, including increased blood pressure and tachyarrhythmia, have been reported during use of atomoxetine in this patient population.

Atomoxetine is contraindicated for concomitant use in patients receiving MAOI therapy.

Atomoxetine should be discontinued in patients who exhibit jaundice (yellowing of the skin or the whites of the eyes) 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). Extremely rare cases of hepatic disease have been reported to the manufacturer; in these cases the patients recovered with normal liver function after stopping the medication. Due to a positive de-challenge, it appears that atomoxetine was causally associated with the liver dysfunction. Routine liver function tests are not a standard recommendation for those who take atomoxetine. The liver toxicity is unpredictable and rare. Patients should be informed of the signs and symptoms of liver toxicity. Patients should also be told to actively monitor for liver toxicity and call their health care provider immediately if they notice such effects. Additionally, atomoxetine undergoes extensive hepatic metabolism resulting in an active metabolite. The dosage should be reduced in those with hepatic disease, including hepatitis.

The use of atomoxetine is contraindicated in patients with closed-angle glaucoma. In clinical trials, atomoxetine use was associated with an increased risk for mydriasis.

Urinary retention and urinary hesitancy (roughly 3% each) have been reported in adult ADHD controlled trials with atomoxetine. Two adult patients withdrew from atomoxetine studies due to urinary retention. In the placebo groups, no patients withdrew and no urinary hesitancy was reported. Use atomoxetine with caution in patients with benign prostatic hypertrophy (BPH), and be aware that complaints of new or worsened urinary retention or hesitancy could be related to atomoxetine. Despite the low affinity of atomoxetine for cholinergic receptors, constipation and xerostomia have also been reported. Therefore, atomoxetine should also be used cautiously in patients with bladder obstruction, GI obstruction, or ileus.

Seizures occurred in 0.1% and 0.2% of adults and pediatrics, respectively, in clinical trials that followed premarket testing. Within these trials, the seizure risk among pediatrics was greater among poor metabolizers (0.3%) than extensive metabolizers (0.2%). Causality to the drug has not been established. In some instances, seizures have been reported in those with risk factors for seizures or with a preexisting seizure disorder; therefore, atomoxetine should be used cautiously under these conditions until further information becomes available.

Patients should exercise caution when driving or operating machinery until the full effects of atomoxetine are known. Atomoxetine may cause drowsiness, dizziness or fatigue. Patients should avoid taking atomoxetine with ethanol and avoid ethanol intoxication.

A potential risk of using atomoxetine to treat ADHD in those with bipolar disorder is the possible induction of hypomania or mania. New onset manic symptoms may also emerge in those with no prior history of bipolar disorder. Until more information is available regarding the effects of atomoxetine in patients with bipolar disorder, its use in this patient population should be closely monitored. Although a causal link between the induction of mania or hypomania and the emergence of suicidal impulses has not been established, there is a concern that such symptoms may represent precursors to emerging suicidality. Prior to initiating treatment with atomoxetine, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. In psychotic individuals, atomoxetine may exacerbate behavioral disturbances, psychosis, or thought disorders. New onset psychotic symptoms may occur in individuals without a prior history of psychosis.

Atomoxetine is contraindicated in patients with severe cardiac or vascular conditions that would be expected to deteriorate from potentially significant increases in blood pressure or heart rate (e.g., 15 to 20 mmHg in blood pressure or 20 beats/minute in heart rate). Such conditions may include but are not limited to symptomatic or uncontrolled cardiac disease, advanced arteriosclerosis, symptomatic heart failure, cardiomyopathy, severe coronary artery disease, severe hypertension, serious cardiac arrhythmias (e.g., ventricular arrhythmias), structural cardiac abnormalities, ventricular dysfunction, or other serious cardiac conditions. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP), and it is recommended to avoid use of atomoxetine in patients with confirmed or suspected long QT syndrome. Cardiac disease and other factors or conditions that increase the risk of QT prolongation should be taken into consideration prior to atomoxetine administration including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or concurrent use of drugs that prolong the QT interval or cause electrolyte imbalances. Females, the elderly, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation. It is advisable to correct electrolyte imbalances prior to atomoxetine initiation. Caution is recommended when treating patients with conditions that may be worsened by increased blood pressure or heart rate such as controlled or mild hypertension, tachycardia, cardiac-related diseases, or cerebrovascular disease. Pulse and blood pressure measurements should be obtained at baseline, following dose increases, and periodically throughout atomoxetine therapy. Sudden death, myocardial infarction, and stroke have occurred in adults receiving standard dosages of atomoxetine. Sudden death has been reported in association with atomoxetine treatment at usual doses in pediatric patients with structural cardiac abnormalities or other serious heart conditions. However, a large retrospective cohort study including over 1.2 million pediatric patients and young adults 2—24 years of age did not find an increased risk of serious cardiovascular events in current users of drugs for the treatment of ADHD compared to nonusers (adjusted hazard ratio 0.75; 95% CI 0.31 to 1.85). Similar results were seen when current users of ADHD drugs were compared to former users and when current users with severe underlying cardiovascular disease were included in the analysis. The authors concluded that although the absolute magnitude of risk appears to be low, a modest increase in risk could not be ruled out. The American Heart Association (AHA) states that it is reasonable to consider the use of medications for the treatment of ADHD in pediatric patients with congenital heart disease without current hemodynamic or arrhythmic concerns or congenital heart disease that is considered stable by the patient’s pediatric cardiologist, unless the cardiologist has specific concerns. However, these patients should be closely monitored and treatment discontinuation should be considered if the patient develops any of the following conditions: heart condition associated with sudden cardiac death (SCD), arrhythmia requiring cardiopulmonary resuscitation, direct current cardioversion/defibrillation or overdrive pacing, arrhythmia associated with SCD, any clinically significant arrhythmia that is not treated or controlled, QTc on electrocardiogram (ECG) more than 0.46 sec, or heart rate or blood pressure more than 2 standard deviations above the mean for age. All patients being considered for pharmacologic treatment of ADHD should have a careful history taken, including assessment for a family history of sudden death or ventricular arrhythmia, and a physical exam to assess for the presence of cardiac disease. If cardiac disease is suspected, further cardiac evaluation including an ECG and echocardiogram is warranted. For pediatric patients, the AHA states that it is reasonable to obtain a baseline ECG as a part of the initial evaluation. If a child or adolescent has any significant findings on physical examination, ECG, or family history, consult a pediatric cardiologist before initiating the medication. Once the medication is started, a repeat ECG may be helpful if the original ECG was obtained before the child was 12 years old, if cardiac symptoms develop, or there is a change in family history.

The safety and efficacy of atomoxetine in children less than 6 years of age have not been established. Atomoxetine is not approved for the treatment of major depressive disorder (MDD). An increased risk of suicidal ideation was noted during pediatric ADHD and enuresis studies with atomoxetine, including one suicide attempt but no completed suicides. Co-morbidities occurring with ADHD may increase the risk of suicidal ideation and/or behavior. Pediatric patients should be closely monitored for clinical worsening, as well as agitation, irritability, suicidal thinking or behaviors, and unusual changes in behavior. Such monitoring would generally include at least weekly in-person contact with patients during the first 4 weeks of treatment, then one visit at weeks 6, 8, and 12, then as indicated beyond 12 weeks. Additional contact by telephone may be appropriate between visits. Consideration should be given to changing or stopping the therapeutic regimen in patients who are experiencing symptoms that might be precursors to emerging suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Periodic reassessment of the need for medication is recommended. Atomoxetine should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Sudden death has been reported in association with atomoxetine treatment at usual doses in pediatric patients with structural cardiac abnormalities. A large retrospective cohort study including over 1.2 million children and young adults 2—24 years of age did not find an increased risk of serious cardiovascular events, including sudden cardiac death, myocardial infarction, or stroke in current users of drugs for the treatment of ADHD compared to nonusers (adjusted hazard ratio 0.75; 95% CI 0.31—1.85). The authors concluded that although the absolute magnitude of risk appears to be low, a modest increase in risk could not be ruled out. A cardiac assessment should be conducted prior to atomoxetine administration to evaluate appropriateness of treatment; careful screening and monitoring is recommended by the American Heart Association. The potential for growth inhibition in pediatric patients should be monitoring during atomoxetine therapy. Monitor height and weight at treatment initiation and periodically thereafter. Studies are not available to define the impact of atomoxetine on final adult height and weight, but short-term (9-week) studies have shown that up to 3.5% of body weight can be lost, and this loss may be dose-related. Data from open-label trials indicate that in general, the weight and height gain of children treated with atomoxetine lags behind that predicted by normative population data for the first 9—12 months of treatment; subsequently, weight gain rebounds and at about 3 years of treatment, patients have gained slightly more weight (0.5 kg) than predicted by their baseline data. After about 12 months, gain in height stabilizes, and at 3 years, patients have gained only slightly less (0.4 cm) than predicted. Growth patterns are similar regardless of pubertal status; however, mean weight gain has been shown to be slower for poor vs. extensive metabolizers (2.4 kg less vs. 0.2 kg less than predicted, respectively), while height gain is similar between poor and extensive metabolizers (1.1 cm less vs. 0.4 cm less than predicted, respectively). Adverse effects such as aggression and hostility have been observed in some children and adolescents receiving medications for ADHD. Although this has not been a finding of statistical significance with administration of atomoxetine compared to placebo, patients should be closely monitored for potential onset of these effects. It should be noted that not all patients with ADHD will require medication; non-drug measures are often instituted concurrently with drug therapy.

Orthostatic hypotension and syncope have been reported in atomoxetine clinical studies. Use caution when administering atomoxetine to patients who have a history of orthostatic or postural hypotension, or any condition that may predispose a patient to postural hypotension, hypovolemia, low blood pressure, antihypertensive medications, dehydration, or abrupt heart rate or blood pressure changes.

Atomoxetine is classified as FDA pregnancy risk category C. There are no human studies to establish safety of atomoxetine during pregnancy. In rabbit organogenesis studies, decreases in live fetuses, increases in early resorption and slight maternal toxicity were noted at doses 23 times the maximum human dose (MHD) (100 mg/kg/day). The AUC of atomoxetine at this dose in rabbits is estimated to be 3.3 times (extensive metabolizers) and 0.4 times (poor metabolizers) the MHD. The no-effect dose for these findings was 30 mg/kg/day. In rat studies spanning the period 10 weeks prior to mating until lactation, decreases in pup weight and survival were seen at 25 mg/kg/day (but not 13 mg/kg/day). Incomplete ossifications were noted at 40 but not 20 mg/kg/day. Rat studies have not shown impairment of fertility during use of atomoxetine doses 6 times the MHD. According to one brief correspondence, 3 pregnancies have occurred during adult clinical trials of atomoxetine, with 2 pregnancies resulting in healthy newborns, and 1 unknown outcome because the patient was lost to follow-up. Due to a lack of pregnancy outcome data, atomoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The effect of atomoxetine on labor and delivery is unknown.

According to the manufacturer, it is not known if atomoxetine is excreted into human breast milk and caution should be exercised when administering the drug to a woman who is breast-feeding. Atomoxetine is excreted into the milk of rats. The low molecular weight and long half-life of the drug suggest that excretion into human breast milk is likely. If atomoxetine therapy cannot be avoided during breast-feeding, the nursing infant should be monitored for signs of potential toxicity, including abdominal pain, constipation, and dyspepsia. Although methylphenidate may be considered as an alternative to atomoxetine in breast-feeding women, the medical use of stimulant medications has not been evaluated by the American Academy of Pediatrics (AAP); the AAP considers stimulants such as amphetamines, when used as drugs of abuse, to be contraindicated in breast-feeding due to concerns of irritability and poor sleeping pattern in the infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.

The pharmacokinetics, safety and efficacy regarding the use of atomoxetine in the geriatric population has not been evaluated in controlled clinical trials. No prospective trials have been published which address the use of atomoxetine in sufficient numbers of adults 50 years and older, and thus atomoxetine is not considered a first-line therapy for the geriatric population.