Strattera

Strattera Special Precautions

atomoxetine

Manufacturer:

Eli Lilly

Distributor:

DKSH
Full Prescribing Info
Special Precautions
Suicidal Ideation and Behaviour: Pooled analyses of short-term (6 to 18 weeks) placebo-controlled trials of Strattera in children and adolescents showed a greater risk of suicidal ideation during treatment in those receiving Strattera. There were a total of 12 trials (11 in ADHD and 1 in enuresis) involving over 2200 patients. The average risk of suicidal ideation in patients treated with Strattera was 0.4% (5/1357) compared with 0% (0/851) in patients treated with placebo. There was 1 suicide attempt in patients treated with Strattera and none in patients treated with placebo. No suicides occurred in these trials. All events of suicidal ideation and behaviour associated with Strattera occurred in children 12 years of age and younger. It is unknown whether the risk of suicidality in children extends to longer-term use of Strattera. A similar meta-analysis in adult patients treated with Strattera for either ADHD or major depressive disorder (MDD) did not reveal an increased risk of suicidal ideation or behaviour in association with the use of Strattera.
All children being treated with Strattera should be monitored closely for suicidality, clinical worsening, and unusual changes of behaviour, especially during the first few months of treatment or at times of dose change. The following symptoms have been reported with Strattera: 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 ideation and behaviour has not been established, there is a concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including discontinuing Strattera, 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 patients' presenting symptoms. These patients should be referred to a paediatric psychiatrist for assessment and supervision.
Families and caregivers of children and adolescents being treated with Strattera should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behaviour, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers.
Based on clinical trials conducted in children and adolescents (<18 years of age) to establish the efficacy of the drug over placebo for the treatment of ADHD, the number needed to treat calculations suggest that a clinician should expect to treat 2 to 3 patients to see one patient respond and 4 to 5 patients to see one patient respond that would not have with placebo treatment. This is balanced against suicidal ideation occurring in 1 out of about every 271-272 patients treated.
Aggressive Behaviour or Hostility: Hostility (predominantly aggression, oppositional behaviour and anger) and emotional lability are often observed in patients with ADHD and has been reported in clinical trials and the post-marketing experience of some medications indicated for the treatment of ADHD. Although there is no conclusive evidence that atomoxetine causes aggressive behaviour or hostility, aggressive behaviour or hostility was more frequently observed in clinical trials among children, adolescents and adults treated with atomoxetine compared to placebo (not statistically significant). Patients beginning treatment for ADHD should be monitored for the appearance or worsening of aggressive behaviour or hostility. Referral of patients to a psychiatrist for regular assessment and supervision during treatment should also be considered.
Possible Allergic Events: Although uncommon, allergic reactions, including anaphylactic reactions, rash, angioneurotic oedema and urticaria, have been reported in patients taking Strattera.
Seizures: The pre-clinical and clinical trial data for Strattera do not suggest that Strattera is proconvulsive. However, seizures have been very rarely reported in post-marketing spontaneous reports. Strattera should be used with caution in patients with a history of seizures. Discontinuation of Strattera should be considered in any patient developing seizures or if there is an increase in seizure frequency where no other cause is identified.
Cardiovascular Effects: Patients should be screened for pre-existing or underlying cardiovascular or cerebovascular conditions before initiation of treatment with atomoxetine and monitored for new conditions of the heart or brain during the course of treatment.
Strattera can affect heart rate and blood pressure. It is recommended that the heart rate and blood pressure be measured before treatment is started, after the dose is increased or decreased and periodically during treatment to detect possible clinically important increases.
Most patients taking Strattera experience a modest increase in heart rate (mean <10 bpm) and/or increase in blood pressure (mean <5mmHg) that are not clinically important (see Adverse Reactions). However, data from ADHD clinical trials show that some patients (approximately 5 to 10% of children and adults) do experience clinically important changes in heart rate (20 beats per minute or greater) or blood pressure (15 to 20 mm Hg or greater).
Strattera should be used with caution in patients whose underlying medical conditions could be worsened by increases in blood pressure or heart rate, such as patients with hypertension, tachycardia or cardiovascular or cerebrovascular disease.
Strattera should not be used in patients with severe cardiovascular disorders whose condition would be expected to deteriorate if they experienced increases in blood pressure or heart rate that could be clinically important (see Contraindications).
In addition, Strattera should be used with caution in patients with congenital QT prolongation, acquired QT prolongation (for example, due to concomitant use of a drug that prolongs the QT), or a family history of QT prolongation (see Pharmacology: Pharmacodynamics: Clinical Trials: Cardiac Electrophysiology under Actions).
Because orthostatic hypotension has also been reported, Strattera should be used with caution in any condition that may predispose patients to orthostatic hypotension or conditions associated with abrupt heart rate or blood pressure changes (see Contraindications).
Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems: A pharmacological potential exists for all ADHD drugs to increase the risk of sudden/cardiac death. Although confirmation of an incremental risk for adverse cardiac events arising from treatment with ADHD medications is lacking, prescribers should consider this potential risk.
All drugs with sympathomimetic effects prescribed in the management of ADHD should be used with caution in patients who are: a) involved in strenuous exercise or activities, b) use stimulants, or c) have a family history of sudden/cardiac death. Strattera is a drug with peripheral sympathomimetic effects and should not generally be used in children, adolescents, or adults with known structural cardiac abnormalities. Prior to the initiation of treatment, a personal and family cardiac and psychiatric history should be obtained. In patients with relevant risk factors and based on the clinician's judgment, further evaluation by a specialist should be considered.
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, Strattera 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.
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 Strattera subjects compared with placebo subjects (0%, 0/263). A complaint of urinary retention or urinary hesitancy should be considered potentially related to Strattera. Use with caution in patients with enlarged prostates or other conditions predisposing to urinary retention.
Priapism: Rare post-marketing cases of priapism, defined as painful and non-painful penile erection lasting more than 4 hours, have been reported for paediatric and adult patients treated with Strattera. The erections resolved in cases in which follow-up information was available, some following discontinuation of Strattera. Prompt medical attention is required in the event of suspected priapism.
Effects on Growth (Height and Weight): Data from longer-term trials (≥2 years) suggest that any effect of Strattera on growth is minimal and is most strongly associated with initiation of treatment. At 24 months, patients displayed a marked absolute mean weight gain (approximately 10.7kg), which corresponded to a slight decrease relative to baseline normative weights (-2.8 percentiles). The decrease at endpoint from the weight that would have been reached had the baseline normative weight been maintained was 0.9kg. At 24 months, there was also marked absolute mean height gain (approximately 13.1cm), which corresponded to a slight decrease relative to baseline normative heights (-2.2 percentiles). The decrease at endpoint from the height predicted by baseline normative height and the mean observed height was approximately 0.5cm.
In the placebo-controlled study, LYAF, a statistically significant effect was seen for both height and weight corresponding to decreases relative to baseline normative heights (-2.68 percentiles for atomoxetine group vs 0.76 for placebo group) and normative weights (-3.93 percentiles for atomoxetine group vs 5.44 percentiles for placebo group). A similar response was seen in the open-label study LYAB with weight and height increases lower than normative rates (-2.0 percentile for height and -3 percentiles for weight). Analysis of effects by baseline weight and height shows that patients in the lowest quartile for weight and height are the least affected by Strattera. The potential effect of treatment with Strattera on final adult stature is unknown. Periodic monitoring of height and weight are recommended for patients requiring long-term therapy.
Hepatic Effects: Very rarely, spontaneous reports of liver injury, manifested by elevated hepatic enzymes and bilirubin with jaundice, have been reported. In some very rare cases, severe liver injury, including acute liver failure, has also been reported. Strattera should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted.
Hepatic or Renal Impairment: See Pharmacology: Pharmacokinetics under Actions and Dosage & Administration.
Carcinogenicity and Mutagenicity: Atomoxetine hydrochloride was not carcinogenic in rats and mice when given in the diet for 2 years. The time-weighted average doses of up to 47 and 458 mg/kg/day were approximately 6 (rat) and 30 (mouse) times the maximum recommended daily oral dose in children and approximately 4 (rat) and 17 (mouse) times the maximum recommended daily oral dose in adults, on a mg/m2 basis. Systemic exposure (plasma AUC) to active moiety (atomoxetine + 4-hydroxyatomoxetine) in rats was estimated to be less than that in EMs or PMs receiving the maximum dose, and exposure in mice was estimated to be 1 to 3 times that in EMs but less than that in PMs.
Atomoxetine hydrochloride was not genotoxic in a battery of tests including bacterial reverse mutation assays, a mouse lymphoma assay, a chromosomal aberration test in Chinese hamster ovary cells, in vivo micronucleus test in mice, unscheduled DNA synthesis test in rat hepatocytes and in vivo sister chromatid exchange test in bone marrow of Chinese hamsters. However, there was a slight increase in the percentage of Chinese hamster ovary cells with diplochromosomes, suggesting endoreduplication (numerical aberration). The metabolite N-desmethylatomoxetine hydrochloride was negative in the Ames test, mouse lymphoma assay and unscheduled DNA synthesis test.
Patients with Concomitant Illness: In a controlled study of paediatric patients with ADHD and comorbid chronic motor tics or Tourette's Disorder, Strattera-treated patients did not experience worsening of tics compared to placebo-treated patients. In a controlled study of adolescent patients with ADHD and comorbid Major Depressive Disorder, Strattera-treated patients did not experience worsening of depression compared to placebo-treated patients. In two controlled studies (one in paediatric patients and one in adult patients) of patients with ADHD and comorbid anxiety disorders, Strattera-treated patients did not experience worsening of anxiety compared to placebo-treated patients. There have been rare post-marketing reports of anxiety and depression or depressed mood and very rare reports of tics (see Adverse Reactions).
Drug Abuse and Dependence: Physical and Psychological Dependence: A randomised, double-blind, placebo-controlled, abuse-potential study was conducted in recreational drug users (n=16) of the ages 18 to 36 who did not meet DSM-IV criteria for substance abuse. Atomoxetine was administered in single doses. The study results suggest that Strattera does not have a significant potential for abuse.
Clinical study data in over 3000 children, adolescents and adults with ADHD and over 1200 adults with depression did not demonstrate any pattern 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 generalisation between atomoxetine and cocaine. Atomoxetine substituted for the discriminative stimulus effect of cocaine in some monkeys (0.6-5.6 mg/kg, 0.1-0.8 times the maximum adult dose on a mg/m2 basis) and rats (at 5-50 mg/kg, 0.4-3.8 times the maximum adult dose on a mg/m2 basis). The main 4-hydroxyatomoxetine metabolite has moderate affinity (Ki 95-422nM) for opioid receptors.
Effects on Ability to Drive and Use Machinery: Patients should be advised to use caution when driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected by Strattera.
Use in Pregnancy: Pregnancy Category B3: Pregnant rabbits were treated orally with up to 100 mg/kg/day atomoxetine throughout the period of organogenesis. At this dose, a decrease in live foetuses and/or an increase in early resorptions were observed, along with evidence of slight maternal toxicity. Slight increases in the incidences of major blood vessel variations were observed in 1 of 3 studies; the no-effect dose for the cardiovascular findings was 30 mg/kg/day. The 100 mg/kg/day dose is 14 times the maximum human dose on a mg/m2 basis; exposure (plasma AUC) to active moiety (atomoxetine + 4-hydroxyatomoxetine) at this dose is estimated to be less than that in EMs or PMs receiving the maximum human adult dose.
Rats were treated with up to 57 (males) and 46 (females) mg/kg/day of atomoxetine (4 times the maximum human adult dose on a mg/m2 basis) in the diet from 2 (females) or 10 (males) weeks prior to mating through the periods of organogenesis and lactation. In one study, decreases in fetal and pup body weight and fetal skeletal anomalies were seen at 41-98 mg/kg/day (3-7 times the maximum tolerated human adult dose on a mg/m2 basis) along with maternal toxicity and incisor overgrowth/teeth clipped was seen at 7 mg/kg/day or greater. In a second study, decreases in pup weight were seen at 46-70 mg/kg/day (4-5 times the maximum human adult dose on a mg/m2 basis) and reduced pup survival at 23-39 mg/kg/day (2-3 times the maximum adult dose on a mg/m2 basis) along with maternal toxicity. No adverse fetal effects were seen when pregnant rats were treated with up to 150 mg/kg/day (11 times the maximum human dose on a mg/m2 basis) by gavage during the period of organogenesis only.
No adequate and well-controlled studies have been conducted in pregnant women. Strattera should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus.
Impairment of Fertility: Atomoxetine hydrochloride did not impair fertility when administered to rats from 10 days of age through adulthood at oral doses up to 50 mg/kg/day (up to 7 times the maximum recommended daily oral dose in children and 4 times the maximum recommended daily oral dose in adults, on a mg/m2 basis). In addition, there was no evidence of impaired fertility in two studies in adult rats given atomoxetine in the diet at time-weighted average doses up to 57 mg/kg/day in males and 46 mg/kg/day in females (up to 6-8 times the maximum recommended daily oral dose in children and 4 times the maximum recommended daily oral dose in adults, on a mg/m2 basis).
Labour and Delivery: Parturition (gestational length or live birth indices) in rats was not affected by atomoxetine. The effect of Strattera on labour and delivery in humans is unknown.
Use in Lactation: Atomoxetine and/or its metabolites are excreted in the milk of rats. It is not known if atomoxetine is excreted in human milk. Treatment of rats with atomoxetine prior to mating through the periods of organogenesis and lactation was associated with adverse effects on pups (see Use in Pregnancy & Lactation). Caution should be exercised if Strattera is administered to a nursing woman.
Use in Children: Children and Adolescents: The safety and efficacy of Strattera in paediatric patients less than 6 years of age have not been established. The safety and efficacy of Strattera has been established in acute studies (up to 9 weeks) and long-term studies (up to 2 years). The efficacy of Strattera beyond 18 months of treatment and safety of Strattera beyond 2 years of treatment have not been systematically evaluated. When considering treatment with Strattera for extended periods, physicians should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see Maintenance/Extended Treatment under Dosage & Administration).
Young rats were treated with atomoxetine to evaluate effects on growth and neurobehavioural and sexual development. Rats were treated with 1, 10 and 50 mg/kg/day atomoxetine (0.1, 1 and 6 times, respectively, the maximum paediatric dose on a mg/m2 basis) by gavage from the early post-natal period (day 10 of age) through adulthood (day 85 of age). 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 noted, 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 given 10 and 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 in humans is unknown.
Use in the Elderly: Elderly Use: The safety and efficacy of Strattera in elderly patients (over 65) have not been established.
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