Atomoxetine Hydrochloride

ATOMOXETINE HYDROCHLORIDE — atomoxetine hydrochloride capsule
Sun Pharma Global FZE

WARNING: SUICIDAL IDEATION IN CHILDREN AND ADOLESCENTS

Atomoxetine hydrochloride (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 hydrochloride 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 hydrochloride is approved for ADHD in pediatric and adult patients. Atomoxetine hydrochloride is not approved for major depressive disorder.

Pooled analyses of short-term (6 to 18 weeks) placebo-controlled trials of atomoxetine hydrochloride 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 hydrochloride compared to placebo. The average risk of suicidal ideation in patients receiving atomoxetine hydrochloride 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)].

1 INDICATIONS AND USAGE

1.1 Attention-Deficit/Hyperactivity Disorder (ADHD)

Atomoxetine hydrochloride capsules are indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD).

[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.

1.3 Need for Comprehensive Treatment Program

Atomoxetine hydrochloride capsules are 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.

2 DOSAGE AND ADMINISTRATION

2.1 Acute Treatment

Dosing of children and adolescents up to 70 kg body weight — Atomoxetine hydrochloride capsules 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 hydrochloride capsules 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)].

2.2 Maintenance/Extended Treatment

It is generally agreed that pharmacological treatment of ADHD may be needed for extended periods. The physician who elects to use atomoxetine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

2.3 General Dosing Information

Atomoxetine hydrochloride capsules may be taken with or without food.

Atomoxetine hydrochloride capsules can be discontinued without being tapered.

Atomoxetine hydrochloride capsules are not intended to be opened, they should be taken whole [see Patient Counseling Information (17.6)].

2.4 Dosing in Specific Populations

Dosing adjustment for hepatically impaired patients — For those ADHD patients who have hepatic insufficiency (HI), dosage adjustment is recommended as follows: For patients with moderate HI (Child-Pugh Class B), initial and target doses should be reduced to 50% of the normal dose (for patients without HI). For patients with severe HI (Child-Pugh Class C), initial dose and target doses should be reduced to 25% of normal [see Use In Specific Populations (8.6)].

Dosing adjustment for use with a strong CYP2D6 inhibitor or in patients who are known to be CYP2D6 PMs — In children and adolescents up to 70 kg body weight administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, or in patients who are known to be CYP2D6 PMs, atomoxetine hydrochloride capsules should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.

3 DOSAGE FORMS AND STRENGTHS

Each capsule contains atomoxetine HCl equivalent to 10 mg (Opaque White, Opaque White), 18 mg (Opaque Yellow, Opaque White), 25 mg (Opaque Blue, Opaque White), 40 mg (Opaque Blue, Opaque Blue), 60 mg (Opaque Blue, Opaque Yellow), 80 mg (Opaque Brown, Opaque White), or 100 mg (Opaque Brown, Opaque Brown) of atomoxetine.

4 CONTRAINDICATIONS

4.1 Hypersensitivity

Atomoxetine hydrochloride capsules are contraindicated in patients known to be hypersensitive to atomoxetine or other constituents of the product [see Warnings and Precautions (5.7)].

4.2 Monoamine Oxidase Inhibitors (MAOI)

Atomoxetine hydrochloride capsules 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 hydrochloride capsules. 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 hydrochloride capsules use was associated with an increased risk of mydriasis and therefore its use is not recommended in patients with narrow angle glaucoma.

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Ideation

Atomoxetine hydrochloride increased the risk of suicidal ideation in short-term studies in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). Pooled analyses of short-term (6 to 18 weeks) placebo-controlled trials of atomoxetine hydrochloride in children and adolescents have revealed a greater risk of suicidal ideation early during treatment in those receiving atomoxetine hydrochloride. There were a total of 12 trials (11 in ADHD and 1 in enuresis) involving over 2200 patients (including 1357 patients receiving atomoxetine hydrochloride and 851 receiving placebo). The average risk of suicidal ideation in patients receiving atomoxetine hydrochloride was 0.4% (5/1357 patients), compared to none in placebo-treated patients. There was 1 suicide attempt among these approximately 2200 patients, occurring in a patient treated with atomoxetine hydrochloride. No suicides occurred in these trials. All reactions occurred in children 12 years of age or younger. All reactions occurred during the first month of 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 hydrochloride for either ADHD or major depressive disorder (MDD) did not reveal an increased risk of suicidal ideation or behavior in association with the use of atomoxetine hydrochloride.

All pediatric patients being treated with atomoxetine hydrochloride should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms have been reported with atomoxetine hydrochloride: 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. Thus, patients being treated with atomoxetine hydrochloride should be observed for the emergence of such symptoms.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who are experiencing emergent suicidality or symptoms that might be precursors to emerging suicidality, especially if these symptoms are severe or abrupt in onset, or were not part of the patient’s presenting symptoms.

Families and caregivers of pediatric patients being treated with atomoxetine hydrochloride should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.

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