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atomoxetine hydrochloride capsule
----------Strattera 18 mg
(atomoxetine HCl) is a selective norepinephrine reuptake inhibitor. Atomoxetine HCl 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 C17H21NO•HCl, which corresponds to a molecular weight of 291.82
Atomoxetine HCl is a white to practically white solid, which has a solubility of 27.8 mg/mL in water.
STRATTERA capsules are intended for oral administration only.
12 CLINICAL PHARMACOLOGY
The precise mechanism by which atomoxetine produces its
therapeutic effects in Attention-Deficit/Hyperactivity Disorder (ADHD) is
unknown, but is thought to be related to selective inhibition of the
pre-synaptic norepinephrine transporter, as determined in ex vivo uptake and
neurotransmitter depletion studies.
An exposure-response analysis encompassing doses of atomoxetine (0.5, 1.2 or 1.8 mg/kg/day) or placebo demonstrated atomoxetine exposure correlates with efficacy as measured by the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator administered and scored. The exposure-efficacy relationship was similar to that observed between dose and efficacy with median exposures at the two highest doses resulting in near maximal changes from baseline [see Clinical Studies (14.2)].12.3 Pharmacokinetics
Atomoxetine is well-absorbed after oral administration and is
minimally affected by food. It is eliminated primarily by oxidative metabolism
through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway and subsequent
glucuronidation. Atomoxetine has a half-life of about 5 hours. A fraction of the
population (about 7% of Caucasians and 2% of African Americans) are poor
metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced
activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak
plasma concentrations, and slower elimination (plasma half-life of about
24 hours) of atomoxetine compared with people with normal activity [extensive
metabolizers (EMs)]. Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine,
and quinidine, cause similar increases in exposure.
Absorption and distribution — Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in EMs and 94% in PMs. Maximal plasma concentrations (Cmax) are reached approximately 1 to 2 hours after dosing.
STRATTERA can be administered with or without food. Administration of
STRATTERA with a standard high-fat meal in adults did not affect the extent of
oral absorption of atomoxetine (AUC), but did decrease the rate of absorption,
resulting in a 37% lower Cmax, and delayed Tmax by 3 hours. In clinical trials with children and
adolescents, administration of STRATTERA with food resulted in a 9% lower Cmax.
At therapeutic concentrations, 98% of atomoxetine in plasma is bound to protein, primarily albumin.
Metabolism and elimination —
Atomoxetine is metabolized primarily through the CYP2D6 enzymatic pathway.
People with reduced activity in this pathway (PMs) have higher plasma
concentrations of atomoxetine compared with people with normal activity (EMs).
For PMs, AUC of atomoxetine is approximately 10-fold and Css,max is about 5-fold greater than EMs. Laboratory tests are
available to identify CYP2D6 PMs. Coadministration of STRATTERA with potent
inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine, results in a
substantial increase in atomoxetine plasma exposure, and dosing adjustment may
be necessary [see Warnings and Precautions (5.13)]. Atomoxetine did not inhibit or induce the
Mean apparent plasma clearance of atomoxetine after oral administration in adult EMs is 0.35 L/hr/kg and the mean half-life is 5.2 hours. Following oral administration of atomoxetine to PMs, mean apparent plasma clearance is 0.03 L/hr/kg and mean half-life is 21.6 hours. For PMs, AUC of atomoxetine is approximately 10-fold and Css,max is about 5-fold greater than EMs. The elimination half-life of 4-hydroxyatomoxetine is similar to that of N-desmethylatomoxetine (6 to 8 hours) in EM subjects, while the half-life of N-desmethylatomoxetine is much longer in PM subjects (34 to 40 hours).
Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the feces (less than 17% of the dose). Only a small fraction of the STRATTERA dose is excreted as unchanged atomoxetine (less than 3% of the dose), indicating extensive biotransformation.
1 INDICATIONS AND USAGE 1.1 Attention-Deficit/Hyperactivity Disorder (ADHD)
STRATTERA is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD).
The efficacy of STRATTERA 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.
STRATTERA 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 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.
4 CONTRAINDICATIONS 4.1 Hypersensitivity
STRATTERA is 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)
STRATTERA 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 STRATTERA. 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, STRATTERA use was associated with an increased risk of mydriasis and therefore its use is not recommended in patients with narrow angle glaucoma.
6 ADVERSE REACTIONS 6.1 Clinical Trials Experience
STRATTERA 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 STRATTERA-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 — STRATTERA 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 STRATTERA (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (STRATTERA incidence greater than placebo) are listed in Table 1. Results were similar in the BID and the QD trial except as shown in Table 2, 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 STRATTERA (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 1 and 2).
Male and female sexual dysfunction — Atomoxetine appears to impair sexual function in some patients. Changes in sexual desire, sexual performance, and sexual satisfaction are not well assessed in most clinical trials because they need special attention and because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate the actual incidence. Table 3 above displays the incidence of sexual side effects reported by at least 2% of adult patients taking STRATTERA in placebo-controlled trials.
There are no adequate and well-controlled studies examining sexual dysfunction with STRATTERA treatment. While it is difficult to know the precise risk of sexual dysfunction associated with the use of STRATTERA, physicians should routinely inquire about such possible side effects.6.2 Postmarketing Spontaneous Reports
The following adverse reactions have been identified during post approval use of STRATTERA. Unless otherwise specified, these adverse reactions have occurred in adults and children and adolescents. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cardiovascular system — QT prolongation, syncope.
General disorders and administration site conditions — Lethargy.
Nervous system disorders — Hypoaesthesia; paraesthesia in children and adolescents; sensory disturbances; tics.
Psychiatric disorders — Depression and depressed mood; anxiety.
Seizures — Seizures have been reported in the postmarketing period. The postmarketing seizure cases include patients with pre-existing seizure disorders and those with identified risk factors for seizures, as well as patients with neither a history of nor identified risk factors for seizures. The exact relationship between STRATTERA and seizures is difficult to evaluate due to uncertainty about the background risk of seizures in ADHD patients.
Skin and subcutaneous tissue disorders — Hyperhidrosis.
Urogenital system — Male pelvic pain; urinary hesitation in children and adolescents; urinary retention in children and adolescents.
10 OVERDOSAGE 10.1 Human Experience
No fatal overdoses occurred in clinical trials. There is limited clinical trial experience with STRATTERA overdose. During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of STRATTERA and at least one other drug. There have been no reports of death involving overdose of STRATTERA alone, including intentional overdoses at amounts up to 1400 mg. In some cases of overdose involving STRATTERA, seizures have been reported. The most commonly reported symptoms accompanying acute and chronic overdoses of STRATTERA were somnolence, agitation, hyperactivity, abnormal behavior, and gastrointestinal symptoms. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., mydriasis, tachycardia, dry mouth) have also been observed. Less commonly, there have been reports of QT prolongation and mental changes, including disorientation and hallucinations.10.2 Management of Overdose
An airway should be established. Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after ingestion. Activated charcoal may be useful in limiting absorption. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose.
2 DOSAGE AND ADMINISTRATION 2.1 Acute Treatment
Dosing of children and adolescents up to 70 kg body weight — STRATTERA 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 — STRATTERA 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.
It is generally agreed that pharmacological treatment of ADHD may be needed for extended periods. The benefit of maintaining pediatric patients (ages 6-15 years) with ADHD on STRATTERA 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 STRATTERA 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 STRATTERA 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
STRATTERA may be taken with or without food.
STRATTERA can be discontinued without being tapered.
STRATTERA capsules are not intended to be opened, they should be taken whole [see Patient Counseling Information (17.6)].
The safety of single doses over 120 mg and total daily doses above 150 mg
have not been systematically evaluated.
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, STRATTERA 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.
In children and adolescents over 70 kg body weight and adults administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, STRATTERA should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied
16.2 Storage and Handling
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
BOXED WARNINGWARNING: SUICIDAL IDEATION IN CHILDREN AND ADOLESCENTS
STRATTERA (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 STRATTERA 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. STRATTERA is approved for ADHD in pediatric and adult patients. STRATTERA is not approved for major depressive disorder.
Pooled analyses of short-term (6 to 18 weeks) placebo-controlled trials of STRATTERA 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 STRATTERA compared to placebo. The average risk of suicidal ideation in patients receiving STRATTERA 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)].
STRATTERA - atomoxetine
Read the Medication Guide that comes with STRATTERA® before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your treatment or your child's treatment with STRATTERA.
The following have been reported with use of STRATTERA:
1. Suicidal thoughts and actions in children and teenagers:
Children and teenagers sometimes think about suicide, and many report trying to kill themselves. Results from STRATTERA clinical studies with over 2200 child or teenage ADHD patients suggest that some children and teenagers may have a higher chance of having suicidal thoughts or actions. Although no suicides occurred in these studies, 4 out of every 1000 patients developed suicidal thoughts. Tell your child or teenager's doctor if your child or teenager (or there is a family history of):
The chance for suicidal thoughts and actions may be higher:
Prevent suicidal thoughts and action in your child or teenager by:
Watch for the following signs in your child or teenager during STRATTERA treatment:
Call your child or teenager's doctor right away if they have any of the above signs, especially if they are new, sudden, or severe. Your child or teenager may need to be closely watched for suicidal thoughts and actions or need a change in medicine.
2. Severe liver damage:
STRATTERA can cause liver injury in some patients. Call your doctor right away if you or your child has the following signs of liver problems:
3. Heart-related problems:
Tell your doctor if you or your child has any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting STRATTERA.
Your doctor should check your blood pressure or your child's blood pressure and heart rate regularly during treatment with STRATTERA.
Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking STRATTERA.
4. New mental (psychiatric) problems in children and teenagers:
Call your child or teenager's doctor right away about any new mental symptoms because adjusting or stopping STRATTERA treatment may need to be considered.
What Is STRATTERA?
STRATTERA is a selective norepinephrine reuptake inhibitor medicine. It is used for the treatment of attention deficit and hyperactivity disorder (ADHD). STRATTERA may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD.
STRATTERA should be used as a part of a total treatment program for ADHD that may include counseling or other therapies.
STRATTERA has not been studied in children less than 6 years old.
Who should not take STRATTERA?
STRATTERA should not be taken if you or your child:
STRATTERA may not be right for you or your child. Before starting STRATTERA tell your doctor or your child's doctor about all health conditions (or a family history of) including:
Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding.
Can STRATTERA be taken with other medicines?
Tell your doctor about all the medicines that you or your child takes including prescription and nonprescription medicines, vitamins, and herbal supplements. STRATTERA and some medicines may interact with each other and cause serious side effects. Your doctor will decide whether STRATTERA can be taken with other medicines.
Especially tell your doctor if you or your child takes:
Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist.
Do not start any new medicine while taking STRATTERA without talking to your doctor first.
How should STRATTERA be taken?
What are possible side effects of STRATTERA?
See “What is the most important information I should know about STRATTERA?” for information on reported suicidal thoughts and actions, other mental problems, severe liver damage, and heart problems.
Other serious side effects include:
Common side effects in children and teenagers include:
Common side effects in adults include:
Other information for children, teenagers, and adults:
This is not a complete list of possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store STRATTERA?
General information about STRATTERA
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use STRATTERA for a condition for which it was not prescribed. Do not give STRATTERA to other people, even if they have the same condition. It may harm them.
This Medication Guide summarizes the most important information about STRATTERA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about STRATTERA that was written for healthcare professionals. For more information about STRATTERA call 1-800-Lilly-Rx (1-800-545-5979) or visit www.strattera.com.
What are the ingredients in STRATTERA?
Active ingredient: atomoxetine hydrochloride.
Nardil® is a registered trademark of Pfizer Inc.
Parnate® is a registered trademark of GlaxoSmithKline.
Emsam® is a registered trademark of Somerset Pharmaceuticals Inc.
This Medication Guide has been approved by the US Food and Drug Administration.
Patient Information revised July 29, 2010
Eli Lilly and Company
Copyright 2003, 2010, Eli Lilly and Company. All rights reserved.
PV 5855 AMPRevised: 08/2010Eli Lilly and Company
Revised: 07/2010 Lake Erie Medical DBA Quality Care Products LLC
Reproduced with permission of U.S. National Library of Medicine
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