When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Please note: Sections 2 & 3 have been re-formatted in line with QRD requirements, no content changes made.
4. Clinical particulars
4.3 Contra-indications
Added:
Atomoxetine should not be used in patients with pheochromocytoma or a history of pheochromocytoma [See 4.4 Special Warnings and Special Precautions for Use – Cardiovascular Effects].
Added: Atomoxetine should not be used in patients with severe cardiovascular or cerebrovascular disorders whose condition would be expected to deteriorate if they experienced increases in blood pressure or heart rate that could be clinically important (for example, 15 to 20 mm Hg in blood pressure or 20 beats per minute in heart rate) [See 4.4 Special Warnings and Special Precautions for Use – Cardiovascular Effects]. Severe cardiovascular disorders may include severe hypertension, heart failure, arterial occlusive disease, angina, haemodynamically significant congenital heart disease, cardiomyopathies, myocardial infarction, potentially life-threatening arrhythmias and channelopathies (disorders caused by the dysfunction of ion channels). Severe cerebrovascular disorders may include cerebral aneurysm or stroke.
Atomoxetine should not be used in patients with severe cardiovascular or cerebrovascular disorders whose condition would be expected to deteriorate if they experienced increases in blood pressure or heart rate that could be clinically important (for example, 15 to 20 mm Hg in blood pressure or 20 beats per minute in heart rate) [See 4.4 Special Warnings and Special Precautions for Use – Cardiovascular Effects]. Severe cardiovascular disorders may include severe hypertension, heart failure, arterial occlusive disease, angina, haemodynamically significant congenital heart disease, cardiomyopathies, myocardial infarction, potentially life-threatening arrhythmias and channelopathies (disorders caused by the dysfunction of ion channels). Severe cerebrovascular disorders may include cerebral aneurysm or stroke.
4.4 Special warnings and precautions for use
Section reordered
Cardiovascular effects:
Added (bold):
Use with caution in any condition that may predispose patients to hypotension or conditions associated with abrupt heart rate or blood pressure changes.
Possible allergic events: Although uncommon, allergic reactions, including anaphylactic reactions, rash, angioneurotic oedema, and urticaria, have been reported in patients taking atomoxetine.
New-onset or worsening of Comorbid Depression, Anxiety and Tics: In a controlled study of paediatric patients with ADHD and co morbid chronic motor tics or Tourette’s Disorder, atomoxetine-treated patients did not experience worsening of tics compared to placebo-treated patients. In a controlled study of adolescent patients with ADHD and co morbid Major Depressive Disorder, atomoxetine-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 co-morbid anxiety disorders, atomoxetine-treated patients did not experience worsening of anxiety compared to placebo-treated patients.
There have been rare postmarketing reports of anxiety and depression or depressed mood and very rare reports of tics in patients taking atomoxetine (see section 4.8 Undesirable Effects).
Patients who are being treated for ADHD with atomoxetine should be monitored for the appearance or worsening of anxiety symptoms, depressed mood and depression or tics.
Hepatic effects
Added (bold) Deleted (strikethrough):
Strattera should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted. Very rarely, spontaneous reports of liver injury, toxicity, manifested by elevated hepatic enzymes and bilirubin with jaundice, has have been reported. Also very rarely, In some very rare cases, severe liver injury, including acute liver failure, has have also been reported. Strattera should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted.
4.5 Interaction with other medicinal products and other forms of interaction
CYP2D6 inhibitors (SSRIs (e.g. fluoxetine, paroxetine), quinidine, terbinafine): In patients receiving these drugs, atomoxetine exposure may be 6-to 8-fold increased and Css max 3 to 4 times higher, because it Atomoxetine is primarily metabolised by the CYP2D6 pathway to 4‑hydroxyatomoxetine. In CYP2D6 extensive metaboliser patients, potent inhibitors of CYP2D6 increase atomoxetine steady‑state plasma concentrations to exposures similar to those observed in CYP2D6 poor metaboliser patients. In extensive metaboliser individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and Css, max is about 3- to 4- fold greater than atomoxetine alone. Dose adjustment and slower titration and final lower dosage of atomoxetine may be necessary in those patients who are also already taking CYP2D6 inhibitor drugs.
Salbutamol (or other beta2 agonists):
Contradictory findings regarding this interaction were found. Systemically administered Salbutamol (600 μg i.v. over 2 hrs) in combination with atomoxetine (60 mg twice daily for 5 days) induced increases in heart rate and blood pressure. during the combination of salbutmol (600 μg i.v. over 2 hrs) and atomoxetine (60 mg twice daily for 5 days) and increased within time. and were This effect was most marked after the initial coadministration of salbutamol and atomoxetine but returned towards baseline at the end of 8 hours. However, in a separate study the effects on blood pressure and heart rate of a standard inhaled dose of salbutamol (200 μg) were not increased by the short term coadministration of atomoxetine (80 mg once daily for 5 days) in a study of healthy Asian adults who were extensive atomoxetine metabolisers.
Attention should be paid to monitoring heart rate and blood pressure, and dose adjustments may be justified for either atomoxetine or salbutamol (or other beta2 agonists) in the event of significant increases in heart rate and blood pressure during coadministration of these drugs.
Seizures are a potential risk with atomoxetine. Caution is advised with concomitant use of medicinal drugs which are known to lower the seizure threshold (such as tricyclic antidepressants or SSRIs, neuroleptics, phenothiazines or butyrophenone, mefloquine, chloroquine, buproprion or tramadol). (see section 4.4). In addition, caution is advised when stopping concomitant treatment with benzodiazepines due to potential withdrawal seizures.
Pressor Agents or drugs that increase blood pressure: Because of possible increase in effects on blood pressure, atomoxetine should be used cautiously with pressor agents or medications that may increase blood pressure (such as salbutamol). Attention should be paid to monitoring of blood pressure, and review of treatment for either atomoxetine or pressor agents may be justified in the case of significant change in blood pressure.
Deleted (strikethrough):
Effects of atomoxetine on other drugs:
Cytochrome P450 Enzymes: Atomoxetine did not cause clinically significant inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9. In vitro studies indicate that atomoxetine does not cause clinically significant induction of CYP1A2 and CYP3A.
4.8 Undesirable effects
Children and adolescents:
System Organ Class
Very Common
Common
Uncommon
Post-Marketing Experience Spontaneous
Reports*
Psychiatric Disorders
Irritability, mood swings, insomnia3
Suicide-related events, aggression,
hostility,
emotional lability**
Early morning awakening
Psychosis (including hallucinations),**
Agitation.**
depression and
depressed
mood,**
anxiety**
tics**
Nervous System Disorders
Headache, somnolence2
Dizziness
Syncope, tremor, migraine
Seizure,***
paraesthesia,
hypoaesthesia,
Hepatobiliary disorders
Abnormal/increased liver function tests, jaundice, hepatitis, liver injury, acute hepatic failure, blood bilirubin increased **
Adults:
Added (bold): System Organ Class Very Common Common Uncommon Post-Marketing Experience Spontaneous Reports* Psychiatric Disorders Insomnia2 Libido decreased, sleep disorder Early morning awakening Suicide-related events, aggression, hostility and emotional lability,** psychosis (including hallucinations),** Agitation,** depression and depressed mood,** anxiety** tics** Nervous System Disorders Dizziness, sinus headache, paraesthesia, tremor Syncope, migraine Seizure,*** Hypoaesthesia, Hepatobiliary disorders Abnormal/increased liver function tests, jaundice, hepatitis, liver injury, acute hepatic failure, blood bilirubin increased ** 4.9 Overdose Signs and symptoms:During postmarketing, there have been reports of non-fatal acute and chronic overdoses of atomoxetine alone. The most commonly reported symptoms accompanying acute and chronic overdoses were gastrointestinal symptoms somnolence, dizziness, tremor agitation, hyperactivity,and abnormal behaviour., and gastrointestinal symptoms. Hyperactivity and agitation have also been reported. Most events were mild to moderate. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, blood pressure increased, mydriasis, tachycardia, dry mouth) were also observed and reports of pruritis and rash have been received. All patients recovered from these events. Most events were mild to moderate. In some cases of overdose involving atomoxetine, seizures have been reported and very rarely QT prolongation. There have also been reports of fatal, acute overdoses involving a mixed ingestion of atomoxetine and at least one other drug. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Atomoxetine does not worsen tics in patients with ADHD and comorbid chronic motor tics or Tourette’s Disorder. Added: Active Comparator Studies In a randomised, double-blind, parallel group, 6 week paediatric study to test the noninferiority of atomoxetine to a standard extended-release methylphenidate comparator, the comparator was shown to be associated with superior response rates compared to atomoxetine. The percentage of patients classified as responders was 23.5% (placebo), 44.6% (atomoxetine) and 56.4% (methylphenidate). Both atomoxetine and the comparator were statistically superior to placebo and methylphenidate was statistically superior to atomoxetine (p=0.016). However, this study excluded patients who were stimulant nonresponders. 5.2 Pharmacokinetic properties Added: Cytochrome P450 Enzymes: Atomoxetine did not cause clinically significant inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Re-ordered but no content changes 10. DATE OF REVISION OF THE TEXT 25 November 2011
Insomnia2
Libido decreased, sleep disorder
Suicide-related events, aggression, hostility and emotional lability,** psychosis (including hallucinations),**
Agitation,**
depression
and depressed
mood,** anxiety**
Dizziness, sinus headache, paraesthesia, tremor
Syncope, migraine
Hypoaesthesia,
4.9 Overdose
Signs and symptoms:During postmarketing, there have been reports of non-fatal acute and chronic overdoses of atomoxetine alone. The most commonly reported symptoms accompanying acute and chronic overdoses were gastrointestinal symptoms somnolence, dizziness, tremor agitation, hyperactivity,and abnormal behaviour., and gastrointestinal symptoms. Hyperactivity and agitation have also been reported. Most events were mild to moderate. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, blood pressure increased, mydriasis, tachycardia, dry mouth) were also observed and reports of pruritis and rash have been received. All patients recovered from these events. Most events were mild to moderate. In some cases of overdose involving atomoxetine, seizures have been reported and very rarely QT prolongation. There have also been reports of fatal, acute overdoses involving a mixed ingestion of atomoxetine and at least one other drug.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Atomoxetine does not worsen tics in patients with ADHD and comorbid chronic motor tics or Tourette’s Disorder.
Active Comparator Studies
In a randomised, double-blind, parallel group, 6 week paediatric study to test the noninferiority of atomoxetine to a standard extended-release methylphenidate comparator, the comparator was shown to be associated with superior response rates compared to atomoxetine. The percentage of patients classified as responders was 23.5% (placebo), 44.6% (atomoxetine) and 56.4% (methylphenidate). Both atomoxetine and the comparator were statistically superior to placebo and methylphenidate was statistically superior to atomoxetine (p=0.016). However, this study excluded patients who were stimulant nonresponders.
Cytochrome P450 Enzymes: Atomoxetine did not cause clinically significant inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9.
Re-ordered but no content changes
10. DATE OF REVISION OF THE TEXT
25 November 2011
Active Comparator Studies In a randomised, double-blind, parallel group, 6 week paediatric study to test the noninferiority of atomoxetine to a standard extended-release methylphenidate comparator, the comparator was shown to be associated with superior response rates compared to atomoxetine. The percentage of patients classified as responders was 23.5% (placebo), 44.6% (atomoxetine) and 56.4% (methylphenidate). Both atomoxetine and the comparator were statistically superior to placebo and methylphenidate was statistically superior to atomoxetine (p=0.016). However, this study excluded patients who were stimulant nonresponders. 5.2 Pharmacokinetic properties Added: Cytochrome P450 Enzymes: Atomoxetine did not cause clinically significant inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Re-ordered but no content changes 10. DATE OF REVISION OF THE TEXT 25 November 2011
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of last renewal: 27 May 2009
New date:
23 October 2009
4.2 Posology and method of administration
Special Populations
Deleted:
The safety and efficacy of Strattera in children under 6 years of age have not been established. Therefore Strattera should not be used in children under 6 years of age.
Children under six years of age:
The safety and efficacy of Strattera in children under 6 years of age have not been established. Therefore Strattera should not be used in children under 6 years of age (see section 4.4).
Sudden death and pre-existing structural cardiac abnormalities or other serious heart problems
Sudden death has been reported in children and adolescents with structural cardiac abnormalities who were taking atomoxetine at usual doses. Although some serious structural cardiac abnormalities alone carry an increased risk of sudden death, atomoxetine should only be used with caution in children or adolescents with known serious structural cardiac abnormalities and in consultation with a cardiac specialist.
Added (headings to each paragraph in 4.4):
Deleted (strikethrough) Added (bold):
Suicide-related behaviour: Suicide related behaviour (suicide attempts and suicidal ideation) has been reported in patients treated with atomoxetine. In double blind clinical trials, suicide related behaviours occurred at a frequency of 0.44% in were uncommon but more frequently observed among children and adolescents treated with atomoxetine treated patients (6 out of 1357 patients treated, one case of suicide attempt and five of suicidal ideation). Therecompared to those treated with placebo, where there were no events in the placebo group (n=851). The age range of children experiencing these events was 7 to 12 years. It should be noted that the number of adolescent patients included in the clinical trials was low. Patients who are being treated for ADHD should be carefully monitored for the appearance or worsening of suicide related behaviour.
Psychotic or manic symptoms: Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, mania or agitation in children and adolescents without a prior history of psychotic illness or mania can be caused by atomoxetine at usual doses. If such symptoms occur, consideration should be given to a possible causal role of atomoxetine, and discontinuation of treatment should be considered. The possibility that Strattera will cause the exacerbation of pre-existing psychotic or manic symptoms cannot be excluded.
Aggressive behaviour, hostility or emotional lability: Hostility (predominantly aggression, oppositional behaviour and anger) and emotional lability were more frequently observed in clinical trials among children and adolescents treated with Strattera compared to those treated with placebo. Patients should be closely monitored for the appearance or worsening of aggressive behaviour, hostility or emotional lability.
Patients who are being treated for ADHD should be carefully monitored for the appearance or worsening of suicide related behaviour, hostility and emotional lability. As with other psychotropic medication, the possibility of rare, serious psychiatric adverse effects cannot be excluded.
Children under six years of age: Strattera should not be used in patients less than six years of age as efficacy and safety have not been established in this age group.
Salbutamol: Atomoxetine should be administered with caution to patients being treated with high dose nebulised or systemically administered (oral or intravenous) salbutamol (or other beta2 agonists) because the action of salbutamol on the cardiovascular system can be potentiated. Systemically administered Salbutamol (600 mg i.v. over 2 hrs) induced increases in heart rate and blood pressure. These effects were potentiated by atomoxetine (60 mg twice daily for 5 days) and were most marked after the initial coadministration of salbutamol and atomoxetine. In a study of healthy Asian adults who were extensive atomoxetine metabolisers, the effects on blood pressure and heart rate of a standard inhaled dose of salbutamol (200 mg) were not clinically significant compared to intravenous administration and not increased by the short term coadministration of atomoxetine (80 mg once daily for 5 days). Heart rate after multiple inhalations of salbutamol (800 mg) was similar in the presence or absence of atomoxetine.
Children and adolescents: Abdominal painIn paediatric placebo-controlled trials, headache, abdominal pain1 and decreased appetite are the adverse events most commonly associated with atomoxetine, and are reported by about 19%, 18% and 16% of patients respectively, but seldom lead to drug discontinuation (discontinuation rates are 0.3 1% for headache, 0.2 % for abdominal pain and 0.0% for decreased appetite). These effects are Abdominal pain and decreased appetite are usually transient.
Nausea or, vomiting and somnolence2 can occur in about 9% and 10% to 11% of patients respectively, particularly during the first month of therapy. However, these episodes were usually mild to moderate in severity and transient, and did not result in a significant number of discontinuation from therapy (discontinuation raterates 0.5%).
In paediatric placebo‑controlled trials, patients taking atomoxetine experienced a mean increase in heart rate of about 6 beats/minute and mean increases in systolic and diastolic blood pressure of about 2 mm Hg compared with placebo. In adult placebo‑controlled trials, patients taking atomoxetine experienced a mean increase in heart rate of 65 beats/minute and mean increases in systolic (about 32 mm Hg) and diastolic (about 1 mm Hg) blood pressures compared with placebo.
Because of its effect on noradrenergic tone, orthostatic hypotension (0.2%, N=7) and syncope (0.8%, N=26) have been reported in patients taking atomoxetine. Atomoxetine should be used with caution in any condition that may predispose patients to hypotension.
NOTE: Table changed in full (please see SPC):
CYP2D6 poor metabolisers (PM): The following adverse events occurred in at least 2% of CYP2D6 poor metaboliser (PM) patients and were either twice as frequent or statistically significantly more frequent in PM patients compared with CYP2D6 extensive metaboliser (EM) patients: appetite decreased (24.1% of PMs, 17.0% of EMs); insomnia (10.5% of PMs, 6.8% of EMs);combined (including insomnia, middle insomnia and initial insomnia, 14.9% of PMs, 9.7% of EMs); depression combined (including depression, major depression, depressive symptom, depressed mood and dysphoria, 6.5% of PMs and 4.1% of EMs), weight decreased (7.3% of PMs, 4.4% of EMs), constipation 6.8% of PMs, 4.3% of EMs); tremor (4.5% of PMs, 0.9% of EMs); sedation (3.9% of PMs, 2.1% of EMs); excoriation (3.9% of PMs, 1.7% of EMs); enuresis (3.0% of PMs, 1.2% of EMs); depressed mood (3.0% of PMs, 1.0% of EMs); tremor (5.1% of PMs, 1.1% of EMs); early morning awakening (3.0% of PMs, 1.1% of EMs); conjunctivitis (3.02.5% of PMs, 1.52% of EMs); syncope (2.15% of PMs, 0.7% of EMs); early morning awakening (2.3% of PMs, 0.8% of EMs); mydriasis (2.50% of PMs, 0.76% of EMs). The following events did not meet above criteria but were reported by more PM patients than EM patients:is noteworthy: generalised anxiety (2.5disorder (0.8% of PMs, 2.2 and 0.1% of EMs); depression (2.5% of PMs, 1.9% of EMs). In addition, in trials lasting up to 10 weeks, weight loss was more pronounced in PM patients (mean of 0.6 kg in EM and 1.1kg in PM).
In adults, the adverse events reported most frequently with atomoxetine treatment were gastrointestinal or genitourinary and insomnia.
Strattera has been studied in trials involving in over 40005000 children and adolescents with ADHD. The acute efficacy of Strattera in the treatment of ADHD was initially established in six randomised, double-blind, placebo-controlled trials of six to nine weeks duration.
12 December 2008
*Addition of high strength (80mg) throughout.
1. NAME OF THE MEDICINAL PRODUCT
80mg Added:
STRATTERA 10 mg, 18 mg, 25 mg, 40 mg, 60 mg or 80 mg hard capsules.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
The active substance is atomoxetine hydrochloride. Each STRATTERA 10 mg, 18 mg, 25 mg, 40 mg, 60 mg or 80 mg capsule contains atomoxetine hydrochloride equivalent to 10 mg, 18 mg, 25 mg, 40 mg, 60 mg or 80 mg of atomoxetine.
Changed:
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL form
STRATTERA 80 mg capsules are opaque brown (cap) and opaque white (body), imprinted with “Lilly 3250” and “80 mg” in black ink.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
80 mg: Yellow iron oxide E172, Red iron oxide E172, Titanium dioxide E171
10 mg, 18 mg, 25 mg and 80 mg: Titanium dioxide E 171
8. MARKETING AUTHORISATION NUMBER(S)
STRATTERA 80 mg hard capsules: PA 47/95/7
04 July 2008
7. MARKETING AUTHORISATION HOLDER
Eli Lilly and Company Limited
Lilly House,
Priestley Road,
Basingstoke,
Hampshire RG24 9NL
United Kingdom
New date
November 2007
Changed
Hard capsule to Capsule, hard.
Added following paragraph
Where patients are continuing treatment with atomoxetine beyond 1 year, re-evaluation of the need for therapy by a specialist in the treatment of ADHD is recommended.
Changes in bold text
Hepatic insufficiency: For patients with moderate hepatic insufficiency (Child-Pugh class B), initial and target doses should be reduced to 50% of the usual dose. For patients with severe hepatic insufficiency (Child-Pugh class C), initial dose and target doses should be reduced to 25% of usual dose (see section 5.2).
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 usual dosing regimen. Atomoxetine may exacerbate hypertension in patients with end stage renal disease (see section 5.2).
Approximately 7% of Caucasians have a genotype corresponding to a non-functional CYP2D6 enzyme (called CYP2D6 poor metabolisers). Patients with this genotype have a several-fold higher exposure to atomoxetine when compared to patients with a functional enzyme. Poor metabolisers are therefore at higher risk of adverse events (see sections 4.8 and 5.2). For patients with a known poor metaboliser genotype, a lower starting dose and slower up titration of the dose may be considered.
Deletions in strikethrough text and changes in bold text
CYP2D6 inhibitors (SSRIs [eg, fluoxetine, paroxetine, quinidine, terbinafine]): Atomoxetine is primarily metabolised by the CYP2D6 pathway to 4-hydroxyatomoxetine. In CYP2D6 extensive metaboliser patients, selective potent inhibitors of CYP2D6 may increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in CYP2D6 poor metaboliser patients. In vitro studies suggest that co-administration of cytochrome P450 inhibitors to CYP2D6 poor metabolisers will not increase the plasma concentrations of atomoxetine. In extensive metaboliser individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and Css,max is about 3- to 4-fold greater than atomoxetine alone. . Dosage adjustment and Sslower titration of atomoxetine may be necessary in those patients who are also taking CYP2D6 inhibitor drugs. If a CYP2D6 inhibitor is prescribed or discontinued after titration to the appropriate atomoxetine dose has occurred, the clinical response and tolerability should be re-evaluated for that patient to determine if dose adjustment is needed.
Added
Caution is advised when combining atomoxetine with potent inhibitors of cytochrome P450 enzymes, other than CYP2D6 in patients who are poor CYP2D6 metabolisers, as the risk of clinically relevant increases in atomoxetine exposure in vivo is unknown.
In vitro studies indicate that atomoxetine does not cause clinically significant induction of CYP1A2 and CYP3A.
4.6 Pregnancy and lactation
Deletions in strikethrough text
Animal studies in general do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition, or postnatal development (see section 5.3).
Added the adverse event, Priapism under the SOC, Reproductive system and breast disorders in the adverse reactions tables
CYP2D6 poor metabolisers (PM):
Signs and symptoms: There is limited clinical trial experience with atomoxetine overdose and no fatalities were observed. During post-marketing, there have been reports of non-fatal, acute and chronic overdoses of atomoxetine alone. The most commonly reported symptoms accompanying acute and chronic overdoses were somnolence, agitation, hyperactivity, abnormal behaviour, and gastro-intestinal symptoms. All Most events were mild to moderate. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (eg, mydriasis, tachycardia, dry mouth) have were also observed and reports of pruritus and rash have been observed received. All patients recovered from these events. In some cases of overdose involving atomoxetine, seizures have been reported and very rarely QT prolongation. There have also been reports of fatal, acute overdoses, involving a mixed ingestion of atomoxetine and at least one other drug.
There is limited clinical trial experience with atomoxetine overdose. No fatal overdoses occurred in clinical trials.
Management of overdose: An airway should be established. Activated charcoal may be useful in limiting absorption if the patient presents within 1 hour of ingestion. 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. The patient should be observed for a minimum of 6 hours. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose.
However, any effect on this transporter is likely to be minimal, as the majority of 4-hydroxyatomoxetine is further metabolised such that it circulates in plasma at much lower concentrations (1% of atomoxetine concentration in EM extensive metabolisers and 0.1% of atomoxetine concentration in PM poor metabolisers).
5.2 Pharmacokinetic properties
Biotransformation: Atomoxetine undergoes biotransformation primarily through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway. Individuals with reduced activity of this pathway (poor metabolisers) represent about 7% of the Caucasian population and have higher plasma concentrations of atomoxetine compared with people with normal activity (extensive metabolisers). For poor metabolisers, AUC of atomoxetine is approximately 10-fold greater and Css,max is about 5-fold greater than extensive metabolisers. The major oxidative metabolite formed is 4-hydroxyatomoxetine that is rapidly glucuronidated. 4-hydroxyatomoxetine is equipotent to atomoxetine but circulates in plasma at much lower concentrations. Although 4-hydroxyatomoxetine is primarily formed by CYP2D6, in individuals that lack CYP2D6 activity, 4-hydroxyatomoxetine can be formed by several other cytochrome P450 enzymes, but at a slower rate. Atomoxetine does not inhibit or induce CYP2D6 at therapeutic doses.
Added following paragraphs
Special populations
Hepatic impairment results in a reduced atomoxetine clearance, increased atomoxetine exposure (AUC increased 2-fold in moderate impairment and 4-fold in severe impairment), and a prolonged half-life of parent drug compared to healthy controls with the same CYP2D6 extensive metaboliser genotype. In patients with moderate to severe hepatic impairment (Child Pugh class B and C), initial and target doses should be adjusted (see section 4.2).
Atomoxetine mean plasma concentrations for end stage renal disease (ESRD) subjects were generally higher than the mean for healthy control subjects, shown by Cmax (7% difference) and AUC0-¥ (about 65% difference) increases. After adjustment for body weight, the differences between the two groups are minimised. Pharmacokinetics of atomoxetine and its metabolites in individuals with ESRD suggest that no dose adjustment would be necessary (see section 4.2).
5.3 Preclinical safety data
Due to the dose limitation imposed by the clinical (or exaggerated pharmacological) response of the animals to the drug, combined with metabolic differences among species, maximum tolerated doses in animals used in non-clinical studies produced atomoxetine exposures similar to or slightly above those that are achieved in CYP2D6 poor metabolising patients, at the maximum recommended daily dose.
6.6 Instructions for use and handling Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product
No special requirements. Atomoxetine capsules are not intended to be opened. Atomoxetine is an ocular irritant. In the event of capsules content coming in contact with the eye, the affected eye should be flushed immediately with water, and medical advice obtained. Hands and any potentially contaminated surfaces should be washed as soon as possible.
23 January 2007