Eli Lilly and Company Limited

9.             DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Added:

Date of latest renewal:           27 May 2009

10.          DATE OF REVISION OF THE TEXT

New date:

27 May 2009

4.                  Clinical particulars

                                                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.

Added:

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).

4.4          Special warnings and precautions for use

Added:

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.

Added:

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.

Deleted (strikethrough) Added (bold):

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.

Added:

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.

4.5          Interaction with other medicinal products and other forms of interaction

Added (bold):

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.

4.8               Undesirable effects

Deleted (strikethrough) Added (bold):

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. 

Deleted (strikethrough) Added (bold):

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):

Deleted (strikethrough) Added (bold):

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).

Adults:

In adults, the adverse events reported most frequently with atomoxetine treatment were gastrointestinal or genitourinary and insomnia.

NOTE: Table changed in full (please see SPC):

5.            PHARMACOLOGICAL PROPERTIES

5.1          Pharmacodynamic properties

Deleted (strikethrough) Added (bold):

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. 

10.          DATE OF REVISION OF THE TEXT

New date:

22 October 2008

7.             MARKETING AUTHORISATION HOLDER

Changed:

Eli Lilly and Company Limited

Lilly House,

Priestley Road,

Basingstoke,

Hampshire RG24 9NL

United Kingdom

10.          DATE OF REVISION OF THE TEXT

New date:

19 October 2007

3.             PHARMACEUTICAL FORM

‘Hard capsules’ changed to ‘Capsules, hard’.

4.             CLINICAL PARTICULARS

4.2                Posology and method of administration

Added:

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.

Added:

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 section 4.8 and section 5.2).  For patients with a known poor metaboliser genotype, a lower starting dose and slower up titration of the dose may be considered.

4.5          Interaction with other medicinal products and other forms of interaction

Added (new text in bold):

CYP2D6 inhibitors (SSRIs [eg, fluoxetine, paroxetine, quinidine, terbinafine]): 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 C_ss,max is about 3- to 4-fold greater than atomoxetine alone.  Dose adjustment and slower 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.

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.

Added:

In vitro studies indicate that atomoxetine does not cause clinically significant induction of CYP1A2 and CYP3A.

4.6          Pregnancy and lactation

Removed (deleted text indicated by strikethrough):

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).

4.8                Undesirable effects

Added (to both tables under Post-Marketing Experience Spontaneous Reports):

Priapism

4.9          Overdose

Added (new text in bold):

Signs and symptoms: 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.  Most events were mild to moderate.  Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (eg, mydriasis, tachycardia, dry mouth) were also observed and reports of pruritus and rash have been 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.  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.

5.             PHARMACOLOGICAL PROPERTIES

5.2          Pharmacokinetic properties

Added:

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 C_ss,max is about 5-fold greater than extensive metabolisers.

Added:

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 C_max (7% difference) and AUC_0-¥ (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

Added:

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.             PHARMACEUTICAL PARTICULARS

6.4          Special precautions for storage

Deleted:

Do not store above 25°C.

Replaced by:

This medicinal product does not require any special storage conditions.

6.6        Instructions for use and handling

Deleted:

No special requirements.

Replaced by:

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.

10.          DATE OF REVISION OF THE TEXT

New date:

23 January 2007

4.             CLINICAL PARTICULARS

4.1          Therapeutic indications

Added:

Treatment must be initiated by a specialist in the treatment of ADHD.

4.2                Posology and method of administration

Removed:

Additional information for the safe use of this product: Treatment must be initiated by or under the supervision of a physician with appropriate knowledge and experience in treating ADHD.

Replaced by:

Additional information for the safe use of this product: Atomoxetine should be used in accordance with national clinical guidance on treatment of ADHD where available.

4.4          Special warnings and precautions for use

Added:

Atomoxetine should be used with caution in patients with congenital or acquired long QT or a family history of QT prolongation (see section 4.5 and section 4.8).

Seizures are a potential risk with atomoxetine.  Atomoxetine should be introduced with caution in patients with a history of seizure.  Discontinuation of atomoxetine should be considered in any patient developing a seizure or if there is an increase in seizure frequency where no other cause is identified.

4.5          Interaction with other medicinal products and other forms of interaction

Added:

There is the potential for an increased risk of QT interval prolongation when atomoxetine is administered with other QT prolonging drugs (such as neuroleptics, class IA and III anti-arrhythmics, moxifloxacin, erythromycin, methadone, mefloquine, tricyclic antidepressants, lithium, or cisapride), drugs that cause electrolyte imbalance (such as thiazide diuretics), and drugs that inhibit CYP2D6.

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 antidepressants, neuroleptics, mefloquine, bupropion, or tramadol) (see section 4.4).

4.8                Undesirable effects

Tables re-organised into body system by frequency.  Addition of post-marketing spontaneous reports, including seizure, QT prolongation, Raynaud’s phenomenon, abnormal liver function tests, jaundice, hepatitis.  Addition of suicide-related events, aggression, hostility, and emotional lability as ‘Uncommon’ to Undesirable effects table - children and adolescents, and as ‘Post Marketing Spontaneous Reports’ to Undesirable effects table - adults.

10.          DATE OF REVISION OF THE TEXT

New date:

10 April 2006