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Description
Pharmacology
Indications and Usage
Contraindications
Warnings
Precautions
Drug Interactions
Adverse Reactions
Drug Abuse and Dependence
Overdose
Dosage
Supplied
(Ed. Note: Links to news stories
on Strattera
and video are at bottom of this page.)
STRATTERA (atomoxetine HCl) is a selective norepinephrine reuptake inhibitor for treatment of ADHD in children, adolescents and adults. Atomoxetine HCl is the R(-) isomer as determined by x-ray diffraction. STRATTERA capsules are intended for oral administration only. Each capsule contains atomoxetine HCl equivalent to 10, 18, 25, 40, or 60 mg of atomoxetine. The capsules also contain pregelatinized starch and dimethicone. The capsule shells contain gelatin, sodium lauryl sulfate, and other inactive ingredients. The capsule shells also contain one or more of the following: FD&C Blue No. 2, synthetic yellow iron oxide, titanium dioxide. The capsules are imprinted with edible black ink.
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.
The pharmacokinetics of atomoxetine have been evaluated in more than 400 children and adolescents in selected clinical trials, primarily using population pharmacokinetic studies.
Absorption and distribution — Atomoxetine is rapidly absorbed after oral administration. Maximal plasma concentrations (Cmax) are reached approximately 1 to 2 hours after dosing. STRATTERA can be administered with or without food.
Special Populations:
Hepatic insufficiency - Dosage adjustment is recommended for patients
with moderate or severe hepatic insufficiency (see DOSAGE AND
ADMINISTRATION).
Renal insufficiency - Subjects with end stage renal disease had higher systemic exposure to atomoxetine than healthy subjects (about a 65% increase), but there was no difference when exposure was corrected for mg/kg dose. STRATTERA can therefore be administered to ADHD patients with end stage renal disease or lesser degrees of renal insufficiency using the normal dosing regimen.
Geriatric - The pharmacokinetics of atomoxetine have not been evaluated in the geriatric population.
Pediatric - The pharmacokinetics of atomoxetine in children and adolescents are similar to those in adults. The pharmacokinetics of atomoxetine have not been evaluated in children under 6 years of age.
Gender - Gender did not influence atomoxetine disposition.
Ethnic origin - Ethnic origin did not influence atomoxetine disposition (except that poor metabolizers are more common in Caucasians).
STRATTERA is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD).
The effectiveness of STRATTERA in the treatment of ADHD was established in 2 placebo-controlled trials in children, 2 placebo-controlled trials in children and adolescents, and 2 placebo-controlled trials in adults who met DSM-IV criteria for ADHD (see CLINICAL STUDIES and read story "Strattera Effective in Girls").
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, eg, in social, academic, or occupational functioning, and must be present in 2 or more settings, eg, school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. 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.
Special Diagnostic Considerations
The specific etiology of ADHD is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but 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.
Need for Comprehensive Treatment Program
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.
Long-Term Use
The effectiveness of STRATTERA for long-term use, ie, for more than 9 weeks in child and adolescent patients and 10 weeks in adult patients, has not been systematically evaluated in controlled trials. Therefore, 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 DOSAGE AND ADMINISTRATION).
Hypersensitivity
STRATTERA is contraindicated in patients known to be hypersensitive to atomoxetine or other constituents of the product (see WARNINGS).
Monoamine Oxidase
Inhibitors
ISTRATTERA 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.
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.
Allergic Events
Although uncommon, allergic reactions, including angioneurotic edema, urticaria, and rash, have been reported in patients taking STRATTERA.
Growth
Growth should be monitored during treatment with STRATTERA. During acute treatment studies (up to 9 weeks), STRATTERA-treated patients lost an average of 0.4 kg, while placebo patients gained an average of 1.5 kg. In a controlled trial that randomized patients to placebo or 1 of 3 atomoxetine doses, 1.3%, 7.1%, 19.3%, and 29.1% of patients lost at least 3.5% of their body weight in the placebo, 0.5, 1.2, and 1.8 mg/kg/day STRATTERA dose groups, respectively. During acute treatment studies, STRATTERA-treated patients grew an average of 0.9 cm, while placebo-treated patients grew an average of 1.1 cm. There are no long-term, placebo-controlled data to evaluate the effect of STRATTERA on growth. Weight and height were assessed during open-label studies of 12 and 18 months, and mean rates of growth were compared to normal growth curves. Patients treated with STRATTERA for at least 18 months gained an average of 6.5 kg while mean weight percentile decreased slightly from 68 to 60. For this same group of patients, the average gain in height was 9.3 cm with a slight decrease in mean height percentile from 54 to 50. Among patients treated for at least 6 months, mean weight gain was lower for poor metabolizer (PM) patients compared with extensive metabolizer (EM) patients (+0.7 kg compared with +3.0 kg), while mean growth for PM patients was 4.3 cm and mean growth for EM patients was 4.4 cm. Whether final adult height or weight is affected by treatment with STRATTERA is unknown. Patients requiring long-term therapy should be monitored and consideration should be given to interrupting therapy in patients who are not growing or gaining weight satisfactorily.
General: Effects on blood pressure and heart rate — STRATTERA should be used with caution in patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease because it can increase blood pressure and heart rate. Pulse and blood pressure should be measured at baseline, following STRATTERA dose increases, and periodically while on therapy.
In pediatric placebo-controlled trials, STRATTERA-treated subjects experienced a mean increase in heart rate of about 6 beats/minute compared with placebo subjects. At the final study visit before drug discontinuation, 3.6% (12/335) of STRATTERA-treated subjects had heart rate increases of at least 25 beats/minute and a heart rate of at least 110 beats/minute, compared with 0.5% (1/204) of placebo subjects. No pediatric subject had a heart rate increase of at least 25 beats/minute and a heart rate of at least 110 beats/minute on more than one occasion. Tachycardia was identified as an adverse event for 1.5% (5/340) of these pediatric subjects compared with 0.5% (1/207) of placebo subjects. The mean heart rate increase in extensive metabolizer (EM) patients was 6.7 beats/minute, and in poor metabolizer (PM) patients 10.4 beats/minute.
STRATTERA-treated pediatric subjects experienced mean increases of about 1.5 mm Hg in systolic and diastolic blood pressures compared with placebo. At the final study visit before drug discontinuation, 6.8% (22/324) of STRATTERA-treated pediatric subjects had high systolic blood pressure measurements compared with 3.0% (6/197) of placebo subjects. High systolic blood pressures were measured on 2 or more occasions in 8.6% (28/324) of STRATTERA-treated subjects and 3.6% (7/197) of placebo subjects. At the final study visit before drug discontinuation, 2.8% (9/326) of STRATTERA-treated pediatric subjects had high diastolic blood pressure measurements compared with 0.5% (1/200) of placebo subjects. High diastolic blood pressures were measured on 2 or more occasions in 5.2% (17/326) of STRATTERA-treated subjects and 1.5% (3/200) placebo subjects. (High systolic and diastolic blood pressure measurements were defined as those exceeding the 95th percentile, stratified by age, gender, and height percentile - National High Blood Pressure Education Working Group on Hypertension Control in Children and Adolescents.)
In adult placebo-controlled trials, STRATTERA-treated subjects experienced a mean increase in heart rate of 5 beats/minute compared with placebo subjects. Tachycardia was identified as an adverse event for 3% (8/269) of these adult atomoxetine subjects compared with 0.8% (2/263) of placebo subjects.
STRATTERA-treated adult subjects experienced mean increases in systolic (about 3 mm Hg) and diastolic (about 1 mm Hg) blood pressures compared with placebo. At the final study visit before drug discontinuation, 1.9% (5/258) of STRATTERA-treated adult subjects had systolic blood pressure measurements=150 mm Hg compared with 1.2% (3/256) of placebo subjects. At the final study visit before drug discontinuation, 0.8% (2/257) of STRATTERA-treated adult subjects had diastolic blood pressure measurements=100 mm Hg compared with 0.4% (1/257) of placebo subjects. No adult subject had a high systolic or diastolic blood pressure detected on more than one occasion.
Orthostatic hypotension has been reported in subjects taking STRATTERA. In short-term child- and adolescent-controlled trials, 1.8% (6/340) of STRATTERA-treated subjects experienced symptoms of postural hypotension compared with 0.5% (1/207) of placebo-treated subjects. STRATTERA should be used with caution in any condition that may predispose patients to hypotension.
Effects on urine outflow from the bladder - In adult ADHD controlled trials, the rates of urinary retention (3%, 7/269) and urinary hesitation (3%, 7/269) were increased among atomoxetine subjects compared with placebo subjects (0%, 0/263). Two adult atomoxetine subjects and no placebo subjects discontinued from controlled clinical trials because of urinary retention. A complaint of urinary retention or urinary hesitancy should be considered potentially related to atomoxetine.
Information for Patients: Patients should consult a physician if they are taking or plan to take any prescription or over-the-counter medicines, dietary supplements, or herbal remedies.
Patients should consult a physician if they are nursing, pregnant, or thinking of becoming pregnant while taking STRATTERA.
Nursing Mothers: Atomoxetine and/or its metabolites were excreted in the milk of rats. It is not known if atomoxetine is excreted in human milk. Caution should be exercised if STRATTERA is administered to a nursing woman.
Pediatric Use: The safety and efficacy of STRATTERA in pediatric patients less than 6 years of age have not been established. The efficacy of STRATTERA beyond 9 weeks and safety of STRATTERA beyond 1 year of treatment have not been systematically evaluated.
A study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioral and sexual development. Rats were treated with 1, 10, or 50 mg/kg/day (approximately 0.2, 2, and 8 times, respectively, the maximum human dose on a mg/m2 basis) of atomoxetine given by gavage from the early postnatal period (Day 10 of age) through adulthood. Slight delays in onset of vaginal patency (all doses) and preputial separation (10 and 50 mg/kg), slight decreases in epididymal weight and sperm number (10 and 50 mg/kg), and a slight decrease in corpora lutea (50 mg/kg) were seen, but there were no effects on fertility or reproductive performance. A slight delay in onset of incisor eruption was seen at 50 mg/kg. A slight increase in motor activity was seen on Day 15 (males at 10 and 50 and females at 50 mg/kg) and on Day 30 (females at 50 mg/kg) but not on Day 60 of age. There were no effects on learning and memory tests. The significance of these findings to humans is unknown.
Geriatric Use: The safety and efficacy of STRATTERA in geriatric patients have not been established.
Patients may take STRATTERA with or without food.
If patients miss a dose, they should take it as soon as possible, but should not take more than the prescribed total daily amount of STRATTERA in any 24-hour period.
Patients should use caution when driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected by atomoxetine.
Laboratory Tests: Routine laboratory tests are not required.
Monoamine Oxidase Inhibitors (MAOI) Do not take while using an MAOI or within 2 weeks of discontinuing and MAOI. (See above)
Albuterol - Albuterol (600 mcg iv over 2 hours) induced increases in heart rate and blood pressure. These effects were potentiated by atomoxetine (60 mg BID for 5 days) and were most marked after the initial coadministration of albuterol and atomoxetine (see Drug-Drug Interactions under PRECAUTIONS).
Alcohol - Consumption of ethanol with STRATTERA did not change the intoxicating effects of ethanol.
CYP2D6 inhibitors - Dosage adjustment of STRATTERA may be necessary when coadministered with CYP2D6 inhibitors, eg, paroxetine, fluoxetine, and quinidine (see DOSAGE AND ADMINISTRATION).
Pressor agents - Because of possible effects on blood pressure, STRATTERA should be used cautiously with pressor agents.
BEFORE USING THIS MEDICINE: INFORM YOUR DOCTOR OR PHARMACIST of all prescription and over-the-counter medicine that you are taking. Also tell your prescriber or health care professional if you are a frequent user of grapefruit juice, drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check with your health care professional before stopping or starting any of your medicines.
STRATTERA was administered to 2067 children or adolescent patients with ADHD and 270 adults with ADHD in clinical studies. During the ADHD clinical trials, 169 patients were treated for longer than 1 year and 526 patients were treated for over 6 months.
The data in the following tables and text cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with data obtained from other clinical investigations involving different treatments, uses, or investigators. The cited data provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence in the population studied.
Child and Adolescent Clinical Trials
Reasons for discontinuation of treatment due to adverse events in child and adolescent clinical trials - In acute child and adolescent placebo-controlled trials, 3.5% (15/427) of atomoxetine subjects and 1.4% (4/294) placebo subjects discontinued for adverse events. For all studies, (including open-label and long-term studies), 5% of extensive metabolizer (EM) patients and 7% of poor metabolizer (PM) patients discontinued because of an adverse event. Among STRATTERA-treated patients, aggression (0.5%, n=2); irritability (0.5%, n=2); somnolence (0.5%, n=2); and vomiting (0.5%, n=2) were the reasons for discontinuation reported by more than 1 patient.
Commonly observed adverse events in acute child and adolescent, placebo-controlled trials - Commonly observed adverse events 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 for the BID trials. Results were similar in the QD trial except as shown in Table 2, which shows both BID and QD results for selected adverse events. The most commonly observed adverse events 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: dyspepsia, nausea, vomiting, fatigue, appetite decreased, dizziness, and mood swings (see Tables 1 and 2).
The following adverse events occurred in at least 2% of PM patients and were either twice as frequent or statistically significantly more frequent in PM patients compared with EM patients: decreased appetite (23% of PMs, 16% of EMs); insomnia (13% of PMs, 7% of EMs); sedation (4% of PMs, 2% of EMs); depression (6% of PMs, 2% of EMs); tremor (4% of PMs, 1% of EMs); early morning awakening (3% of PMs, 1% of EMs); pruritus (2% of PMs, 1% of EMs); mydriasis (2% of PMs, 1% of EMs).
Adult Clinical Trials - Reasons for discontinuation of treatment due to adverse events in acute adult placebo-controlled trials — In the acute adult placebo-controlled trials, 8.5% (23/270) atomoxetine subjects and 3.4% (9/266) placebo subjects discontinued for adverse events. Among STRATTERA-treated patients, insomnia (1.1%, n=3); chest pain (0.7%, n=2); palpitations (0.7%, n=2); and urinary retention (0.7%, n=2) were the reasons for discontinuation reported by more than 1 patient.
Commonly observed adverse events in acute adult placebo-controlled trials — Commonly observed adverse events 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 3. The most commonly observed adverse events in patients treated with STRATTERA (incidence of 5% or greater and at least twice the incidence in placebo patients) were: constipation, dry mouth, nausea, appetite decreased, dizziness, insomnia, decreased libido, ejaculatory problems, impotence, urinary hesitation and/or urinary retention and/or difficulty in micturition, and dysmenorrhea (see Table 3).
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. The table below displays the incidence of sexual side effects reported by at least 2% of adult patients taking STRATTERA in placebo-controlled trials. (see Table 4)
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.
Controlled Substance Class
STRATTERA is not a controlled substance.
Physical and Psychological Dependence
In a randomized, double-blind, placebo-controlled, abuse-potential study in
adults comparing effects of STRATTERA and placebo, STRATTERA was not associated
with a pattern of response that suggested stimulant or euphoriant
properties.
Clinical study data in over 2000 children, adolescents, and adults with ADHD and over 1200 adults with depression showed only isolated incidents of drug diversion or inappropriate self-administration associated with STRATTERA. There was no evidence of symptom rebound or adverse events suggesting a drug-discontinuation or withdrawal syndrome.
Animal Experience
Drug discrimination studies in rats and monkeys showed inconsistent stimulus
generalization between atomoxetine and cocaine.
The effects of overdose greater than twice the maximum recommended daily dose in humans are unknown.
No specific information is available on the treatment of overdose with atomoxetine. Patients who overdose with atomoxetine should be monitored carefully and receive supportive care. Gastric emptying and repeated activated charcoal (with/without cathartics) may prevent systemic absorption.
HOW TO USE THIS MEDICINE:
DO NOT EXCEED THE RECOMMENDED DOSE or take this medicine for longer than prescribed.
Initial 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).
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).
The maximum recommended total daily dose in children and adolescents over 70 kg and adults is 100 mg.
Maintenance/Extended Treatment
There is no evidence available from controlled trials to indicate how long the patient with ADHD should be treated with STRATTERA. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. Nevertheless, the physician who elects to use STRATTERA for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
General Dosing Information
STRATTERA may be taken with or without food.
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 Special Populations under CLINICAL PHARMACOLOGY).
Dosing adjustment for use with a strong CYP2D6 inhibitor - In children and adolescents up to 70 kg body weight administered strong CYP2D6 inhibitors, eg, paroxetine, fluoxetine, quinidine, 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, eg, paroxetine, fluoxetine, 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.
Atomoxetine can be discontinued without being tapered.
STRATTERA capsules are supplied in 10, 18, 25, 40, and 60-mg strengths.
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
NOTE: This information is not intended to cover all possible uses, precautions, interactions, or adverse effects for this drug. If you have questions about the drug(s) you are taking, check with your health care professional.
Last updated: November 2002
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The information in this monograph is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects. This information is generalized and is not intended as specific medical advice. If you have questions about the medicines you are taking or would like more information, check with your doctor, pharmacist, or nurse.
Copyright © 2002 Healthyplace Inc. All rights reserved.
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