STRATTERA 10MG CAPSULES

Active substance: ATOMOXETINE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
STRATTERA 10 mg hard capsules.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains atomoxetine hydrochloride equivalent to 10 mg of
atomoxetine.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Capsule, hard
STRATTERA 10 mg capsules: hard capsule, opaque white, imprinted with “Lilly
3227” and “10 mg” in black ink.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Strattera is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in
children of 6 years and older, in adolescents and in adults as part of a comprehensive treatment
programme. Treatment must be initiated by a specialist in the treatment of ADHD, such as a
paediatrician, child/adolescent psychiatrist, or psychiatrist. Diagnosis should be made according to
current DSM criteria or the guidelines in ICD.
In adults, the presence of symptoms of ADHD that were pre-existing in childhood should be
confirmed. Third-party corroboration is desirable and Strattera should not be initiated when the
verification of childhood ADHD symptoms is uncertain. Diagnosis cannot be made solely on the
presence of one or more symptoms of ADHD. Based on clinical judgment, patients should have
ADHD of at least moderate severity as indicated by at least moderate functional impairment in 2 or
more settings (for example, social, academic, and/or occupational functioning), affecting several
aspects of an individual’s life.
Additional information for the safe use of this product:
A comprehensive treatment programme typically includes psychological, educational and social
measures and is aimed at stabilising patients with a behavioural syndrome characterised by symptoms
which may include chronic history of short attention span, distractability, emotional lability,
impulsivity, moderate to severe hyperactivity, minor neurological signs and abnormal EEG. Learning
may or may not be impaired.

Pharmacological treatment is not indicated in all patients with this syndrome and the decision to use
the drug must be based on a very thorough assessment of the severity of the patient’s symptoms and
impairment in relation to the patient’s age and the persistence of symptoms.

4.2

Posology and method of administration
For oral use. Strattera can be administered as a single daily dose in the morning, with
or without food. Patients who do not achieve a satisfactory clinical response
(tolerability [e.g. nausea or somnolence] or efficacy) when taking Strattera as a single
daily dose might benefit from taking it as twice daily evenly divided doses in the
morning and late afternoon or early evening.
Dosing of children/adolescents up to 70 kg Body Weight:
Strattera should be initiated at a total daily dose of approximately 0.5mg/kg. The initial dose
should be maintained for a minimum of 7 days prior to upward dose titration according to
clinical response and tolerability. The recommended maintenance dose is approximately
1.2mg/kg/day (depending on the patient’s weight and available dosage strengths of
atomoxetine). No additional benefit has been demonstrated for doses higher than
1.2mg/kg/day. The safety of single doses over 1.8mg/kg/day and total daily doses above 1.8
mg/kg have not been systematically evaluated.In some cases it might be appropriate to
continue treatment into adulthood.
Dosing of children/adolescents over 70 kg Body Weight:
Strattera should be initiated at a total daily dose of 40 mg. The initial dose should be
maintained for a minimum of 7 days prior to upward dose titration according to clinical
response and tolerability. The recommended maintenance dose is 80mg. No additional benefit
has been demonstrated for doses higher than 80 mg. The maximum recommended total daily
dose is 100 mg. The safety of single doses over 120mg and total daily doses above 150mg
have not been systematically evaluated.
Dosing of Adults:
Strattera should be initiated at a total daily dose of 40 mg. The initial dose should be
maintained for a minimum of 7 days prior to upward dose titration according to clinical
response and tolerability. The recommended maintenance daily dose is 80mg to 100mg. The
maximum recommended total daily dose is 100 mg. The safety of single doses over 120mg
and total daily doses above 150mg have not been systematically evaluated.
Additional information for the safe use of this product:

Pre-treatment screening:
Prior to prescribing it is necessary to take an appropriate medical history and conduct
a baseline evaluation of a patient’s cardiovascular status, including blood pressure and
heart rate (see sections 4.3 and 4.4).
Ongoing monitoring:
Cardiovascular status should be regularly monitored with blood pressure and pulse
recorded after each adjustment of dose and then at least every 6 months. For
paediatric patients the use of a centile chart is recommended. For adults, current
reference guidelines for hypertension should be followed. (See section 4.4.)
Withdrawal of Treatment

In the study programme no distinct withdrawal symptoms have been described. In cases of
significant adverse effects, atomoxetine may be stopped abruptly; otherwise the drug may be
tapered off over a suitable time period.
Treatment with Strattera need not be indefinite. Re-evaluation of the need for continued
therapy beyond 1 year should be performed, particularly when the patient has reached a stable
and satisfactory response.

Special Populations
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.
Older people: the use of atomoxetine in patients over 65 years of age has not been
systematically evaluated.

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)
4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Atomoxetine should not be used in combination with monoamine oxidase inhibitors (MAOI).
Atomoxetine should not be used within a minimum of 2 weeks after discontinuing therapy
with MAOI. Treatment with MAOI should not be initiated within 2 weeks after discontinuing
atomoxetine.
Atomoxetine should not be used in patients with narrow angle glaucoma, as in clinical trials
the use of atomoxetine was associated with an increased incidence of mydriasis.
Atomoxetine should not be used in patients with severe cardiovascular or cerebrovascular
disorders [see section 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 pheochromocytoma or a history of
pheochromocytoma [see section 4.4 Special Warnings and Special Precautions for Use –
Cardiovascular Effects].
4.4

Special warnings and precautions for use

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
were uncommon but more frequently observed among children and adolescents treated with
atomoxetine compared to those treated with placebo, where there were no events. In adult
double-blind clinical trials there was no difference in frequency of suicide related behaviour
between atomoxetine and placebo. Patients who are being treated for ADHD should be
carefully monitored for the appearance or worsening of suicide related behaviour.
Sudden death and pre-existing cardiac abnormalities
Sudden death has been reported in patients 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 patients with known serious structural cardiac abnormalities and in consultation with a
cardiac specialist.
Cardiovascular effects

Atomoxetine can affect heart rate and blood pressure.
Most patients taking atomoxetine experience a modest increase in heart rate (mean <10 bpm)
and/or increase in blood pressure (mean <5 mm Hg) (see section 4.8).
However, combined data from controlled and uncontrolled ADHD clinical trials show that
approximately 8-12% of children and adolescents, and 6-10% adults experience more
pronounced changes in heart rate (20 beats per minute or greater) and blood pressure (15-20
mmHg or greater). Analysis of these clinical trial data showed that approximately 15-26% of
children and adolescents, and 27-32% of adults experiencing such changes in blood pressure
and heart rate during atomoxetine treatment had sustained or progressive increases. Longterm sustained changes in blood pressure may potentially contribute to clinical consequences
such as myocardial hypertrophy.
As a result of these findings, patients who are being considered for treatment with
atomoxetine should have a careful history and physical exam to assess for the presence of
cardiac disease, and should receive further specialist cardiac evaluation if initial findings
suggest such history or disease.
It is recommended that heart rate and blood pressure be measured and recorded before
treatment is started and, during treatment, after each adjustment of dose and then at least
every 6 months to detect possible clinically important increases. For paediatric patients the

use of a centile chart is recommended. For adults, current reference guidelines for
hypertension should be followed.
Atomoxetine should not be used in patients with severe cardiovascular or cerebrovascular
disorders (see section 4.3Contraindications – Severe Cardiovascular and Cerebrovascular
Disorders). Atomoxetine should be used with caution in patients whose underlying medical
conditions could be worsened by increases in blood pressure and heart rate, such as patients
with hypertension, tachycardia, or cardiovascular or cerebrovascular disease.
Patients who develop symptoms suggestive of cardiac disease during atomoxetine treatment
should undergo a prompt specialist cardiac evaluation.
In addition, atomoxetine should be used with caution in patients with congenital or acquired
long QT or a family history of QT prolongation (see sections 4.5 and 4.8).
As orthostatic hypotension has also been reported, atomoxetine should be used with caution
in any condition that may predispose patients to hypotension or conditions associated with
abrupt heart rate or blood pressure changes.
Cerebrovascular effects
Patients with additional risk factors for cerebrovascular conditions (such as a history of
cardiovascular disease, concomitant medications that elevate blood pressure) should be
assessed at every visit for neurological signs and symptoms after initiating treatment with
atomoxetine.
Hepatic effects
Very rarely, spontaneous reports of liver injury, manifested by elevated hepatic enzymes and
bilirubin with jaundice, have been reported. Also very rarely, severe liver injury, including
acute liver failure, have been reported. Strattera should be discontinued in patients with
jaundice or laboratory evidence of liver injury, and should not be restarted.
Psychotic or manic symptoms
Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking,
mania or agitation in patients 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) was more frequently
observed in clinical trials among children, adolescents and adults treated with Strattera
compared to those treated with placebo. Emotional lability was more frequently observed in
clinical trials among children 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.
Possible allergic events
Although uncommon, allergic reactions, including anaphylactic reactions, rash, angioneurotic
oedema, and urticaria, have been reported in patients taking atomoxetine.

Seizures
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.
Growth and development
Growth and development should be monitored in children and adolescents during treatment
with atomoxetine. Patients requiring long-term therapy should be monitored and
consideration should be given to dose reduction or interrupting therapy in children and
adolescents who are not growing or gaining weight satisfactorily.
Clinical data do not suggest a deleterious effect of atomoxetine on cognition or sexual
maturation, however the amount of available long-term data is limited. Therefore, patients
requiring long-term therapy should be carefully monitored.
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).
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.
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.
Other therapeutic use
Strattera is not indicated for the treatment of major depressive episodes and/or anxiety as the
results of clinical trials in adults in these conditions,where ADHD is not present, did not
show an effect compared to placebo (see section 5.1).

4.5

Interaction with other medicinal products and other forms of interaction
Effects of other drugs on atomoxetine:
MAOIs: Atomoxetine should not be used with MAOIs (see section 4.3).

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 is metabolised by the CYP2D6 pathway. Slower titration and final
lower dosage of atomoxetine may be necessary in patients who are already 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 reevaluated 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
Salbutamol (or other beta2 agonists):
Atomoxetine should be administered with caution to patients treated with high dose nebulised
or systemically administered salbutamol (or other beta2 agonists) because cardiovascular
effects can be potentiated.
Contradictory findings regarding this interaction were found. Systemically administered
Salbutamol (600 g i.v. over 2 hrs) in combination with atomoxetine (60 mg twice daily for 5
days) induced increases in heart rate and blood pressure. 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 g) 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. Similarly heart rate after multiple
inhalations of salbutamol (800 g) did not differ in the presence or absence of atomoxetine.

μ

μ

μ

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.
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 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.
Anti-hypertensive drugs
Atomoxetine should be used cautiously with antihypertensive drugs. Because of a possible
increase in blood pressure, atomoxetine may decrease the effectiveness of antihypertensive
drugs / drugs used to treat hypertension. Attention should be paid to monitoring of blood
pressure and review of treatment of atomoxetine or antihypertensive drugs may be justified in
the case of significant changes of blood pressure.
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.
Drugs that Affect Noradrenaline: Drugs that affect noradrenaline should be used cautiously
when co-administered with atomoxetine because of the potential for additive or synergistic
pharmacological effects. Examples include antidepressants such as imipramine, venlafaxine
and mirtazapine, or the decongestants pseudoephedrine or phenylephrine.
Drugs that Affect Gastric pH: Drugs that elevate gastric pH (magnesium hydroxide/aluminum
hydroxide, omeprazole) had no effect on atomoxetine bioavailability.
Drugs Highly Bound to Plasma Protein: In vitro drug-displacement studies were conducted
with atomoxetine and other highly bound drugs at therapeutic concentrations. Warfarin,
acetylsalicylic acid, phenytoin, or diazepam did not affect the binding of atomoxetine to
human albumin. Similarly, atomoxetine did not affect the binding of these compounds to
human albumin.
4.6

Pregnancy and lactation

Pregnancy
Animal studies in general do not indicate direct harmful effects with respect to pregnancy,
embryonal/foetal development, parturition or postnatal development (see section 5.3). For
atomoxetine clinical data on exposed pregnancies are limited. Such data are insufficient to
indicate either an association or a lack of association between atomoxetine and adverse
pregnancy and/or lactation outcomes. Atomoxetine should not be used during pregnancy
unless the potential benefit justifies the potential risk to the foetus.
Breast-feeding
Atomoxetine and/or its metabolites were excreted in the milk of rats. It is not known if
atomoxetine is excreted in human milk. Because of the lack of data, atomoxetine should be
avoided during breastfeeding.

4.7

Effects on ability to drive and use machines

Data on the effects on the ability to drive and use machines are limited. Atomoxetine has
been associated with increased rates of fatigue, somnolence, and dizziness relative to placebo
in paediatric and adult patients. 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 atomoxetine.
4.8

Undesirable effects

Children and adolescents:
In 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 0.1% for headache, 0.2 % for abdominal pain and 0.0% for
decreased appetite). Abdominal pain and decreased appetite are usually transient.

Associated with decreased appetite, some patients experienced growth retardation early in
therapy in terms of both weight and height gain. On average, after an initial decrease in
weight and height gain, patients treated with atomoxetine recovered to mean weight and
height as predicted by group baseline data over the long-term treatment.
Nausea, vomiting and somnolence2 can occur in about 10% to 11% of patients 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
rates ≤ 0.5%).

In both paediatric and adult placebo-controlled trials, patients taking atomoxetine
experienced increases in heart rate, systolic and diastolic blood pressure (see section 4.4).
Because of its effect on noradrenergic tone, orthostatic hypotension (0.2%) and syncope
(0.8%) have been reported in patients taking atomoxetine. Atomoxetine should be used with
caution in any condition that may predispose patients to hypotension.
The following table of undesirable effects is based on adverse event reporting and laboratory
investigations from clinical trials and post marketing spontaneous reports in children and
adolescents:
Table: Adverse reactions
Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon
(≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

System Organ
Class

Very common

Common

Uncommon

Rare

≥1/10

≥1/100 to <1/10

≥1/1,000 to <1/100

≥1/10,000 to <1/1,000

Metabolism
and Nutrition
Disorders
Psychiatric
Disorders

Appetite
decreased.

Nervous
System
Disorders

Headache,
somnolence2.

Irritability, mood
swings,
insomnia3,
agitation *,
anxiety,
depression and
depressed mood
*, tics *.
Dizziness.

Syncope, tremor,
migraine,
paraesthesia*,
hypoaesthesia*,
Seizure**.

Palpitations, sinus
tachycardia.
QT interval
prolongation **.
Raynaud’s
phenomenon.
Abdominal
pain1, vomiting,
nausea.

Constipation,
dyspepsia.

Blood bilirubin
increased*.

Hepatobiliary
disorders

Skin and
Subcutaneous
Tissue
Disorders
Renal and
urinary
disorders
Reproductive
System and
Breast
Disorders

Suicide-related
events, aggression,
hostility,
emotional
lability*, Psychosis
(including
hallucinations)*.

Mydriasis.

Eye Disorders
Cardiac
Disorders

Vascular
disorders
Gastro
intestinal
Disorders

Anorexia (loss
of appetite).

Dermatitis,
pruritus, rash.

Abnormal/increased
liver function tests,
jaundice, hepatitis,
liver injury, acute
hepatic failure*.

Hyperhidrosis,
allergic reactions.

Urinary hesitation,
urinary retention.
Priapism, male genital
pain.

Fatigue,
lethargy.

General
Disorders and
Administration
Site Conditions
Investigations

Blood pressure
increased4,
Heart rate
increased4.

Asthenia.

Weight
decreased.

1

Also includes abdominal pain upper, stomach discomfort, abdominal discomfort and
epigastric discomfort.
2
Also includes sedation
3
Includes initial, middle and terminal (early morning wakening) insomnia
4
Heart rate and blood pressure findings are based on measured vital signs.
*
See section 4.4
**
See section 4.4 and section 4.5
CYP2D6 poor metabolisers (PM)
The following adverse events occurred in at least 2% of CYP2D6 poor metaboliser (PM) patients and
were 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 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);
conjunctivitis (2.5% of PMs, 1.2% of EMs); syncope (2.5% of PMs, 0.7% of EMs); early morning
awakening (2.3% of PMs, 0.8% of EMs); mydriasis (2.0% of PMs, 0.6% of EMs). The following
event did not meet above criteria but is noteworthy: generalised anxiety disorder (0.8% of PMs and
0.1% 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 adult ADHD clinical trials, the following system organ classes had the highest frequency
of adverse events during treatment with atomoxetine: gastrointestinal, nervous system and
psychiatric disorders. The most common adverse events (≥5%) reported were appetite
decreased (14.9%), insomnia (11.3%) headache (16.3%), dry mouth (18.4%) and nausea
(26.7%). The majority of these events were mild or moderate in severity and the events most
frequently reported as severe were nausea, insomnia, fatigue and headache. A complaint of
urinary retention or urinary hesitancy in adults should be considered potentially related to
atomoxetine.
The following table of undesirable effects is based on adverse event reporting and laboratory
investigations from clinical trials and post marketing spontaneous reports in adults.
Table: Adverse reactions
Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon
(≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

System Organ
Class

Very common

Common

Uncommon

Rare

≥1/10

≥1/100 to <1/10

≥1/1,000 to <1/100

≥1/10,000 to
<1/1,000

Metabolism and
Nutrition
Disorders
Psychiatric
Disorders

Appetite
decreased.
Insomnia2.

Agitation*, libido
decreased, sleep
disorder,
depression and
depressed mood*,
anxiety,

Nervous System
Disorders

Headache.

Dizziness,
dysgeusia,
paraesthesia,
somnolence
(including
sedation), tremor.
Palpitations,
tachycardia.
Flushing. Hot
flush.
Abdominal pain1,
constipation,
dyspepsia,
flatulence,
vomiting.

Cardiac
Disorders
Vascular
disorders
Gastrointestinal
Disorders

Dry mouth,
nausea.

Suicide-related
events*,
aggression,
hostility and
emotional
lability*,
restlessness,
tics*.
Syncope,
migraine.
hypoaesthesia *.

QT interval
prolongation**.
Peripheral
coldness.

Reproductive
System and
Breast Disorders

Seizure**.

Raynaud’s
phenomenon.

Abnormal/increased
liver function tests,
jaundice, hepatitis,
liver injury, acute
hepatic failure,
blood bilirubin
increased*.

Hepato-biliary
disorders

Skin and
Subcutaneous
Tissue Disorders
Musculoskeletal
and connective
tissue disorders
Renal and
urinary
disorders

Psychosis
(including
hallucinations) *.

Dermatitis,
hyperhydrosis,
rash.

Allergic
reactions4,
pruritis, urticaria.
Muscle spasms.

Dysuria,
pollakuria,
urinary
hesitation,
urinary retention.
Dysmenorrhoea,
ejaculation
disorder, erectile
dysfunction,
prostatitis, male

Micturation
urgency.

Ejaculation
failure,
menstruation
irregular, orgasm
abnormal.

Priapism.

General
Disorders and
Administration
Site Conditions
Investigations

Blood pressure
increased3,
Heart rate
increased3.

genital pain.
Asthenia, fatigue,
lethargy, chills
feeling jittery,
irritability, thirst.
Weight
decreased.

Feeling cold.

1

Also includes abdominal pain upper, stomach discomfort, abdominal discomfort and
epigastric discomfort.
2
Also includes initial insomnia, middle insomnia and terminal (early morning wakening)
insomnia.
3
Heart rate and blood pressure findings are based on measured vital signs.
4
Includes anaphylactic reactions and angioneurotic oedema.
*
See section 4.4
**
See section 4.4 and section 4.5
CYP2D6 poor metabolisers (PM)
The following adverse events occurred in at least 2% of CYP2D6 poor metaboliser (PM) patients and
were statistically significant more frequent in PM patients compared with CYP2D6 extensive
metaboliser (EM) patients: vision blurred (3.9% of PMs, 1.3% of EMs), dry mouth (34.5% of PMs,
17.4% of EMs), constipation (11.3% of PMs, 6.7% of EMs), feeling jittery (4.9% of PMs, 1.9% of
EMs), decreased appetite (23.2% of PMs, 14.7% of EMs), uterine leiomyoma (2.3% of PMs, 0.1% of
EMs), tremor (5.4% of PMs, 1.2% of EMs), insomnia (19.2% of PMs, 11.3% of EMs), sleep disorder
(6.9% of PMs, 3.4% of EMs), middle insomnia (5.4% of PMs, 2.7% of EMs), terminal insomnia (3 %
of PMs, 0.9% of EMs), urinary retention (5.9% of PMs, 1.2% of EMs), erectile dysfunction (20.9% of
PMs, 8.9% of EMs), ejaculation disorder (6.1% of PMs, 2.2% of EMs), hyperhidrosis (14.8% of PMs,
6.8% of EMs), peripheral coldness (3% of PMs, 0.5% of EMs).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via the national reporting system
listed in Appendix V.

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 and abnormal
behaviour. Hyperactivity and agitation have also been reported. Signs and symptoms
consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia,
blood pressure increased, mydriasis, dry mouth) were also observed and reports of pruritis
and rash have been received. 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.

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

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Centrally acting sympathomimetics

ATC code: N06BA09
Mechanism of action and Pharmacodynamic effects
Atomoxetine is a highly selective and potent inhibitor of the pre-synaptic noradrenaline
transporter, its presumed mechanism of action, without directly affecting the serotonin or
dopamine transporters. Atomoxetine has minimal affinity for other noradrenergic receptors or
for other neurotransmitter transporters or receptors. Atomoxetine has two major oxidative
metabolites: 4-hydroxyatomoxetine and N-desmethylatomoxetine. 4-Hydroxyatomoxetine is
equipotent to atomoxetine as an inhibitor of the noradrenaline transporter but unlike
atomoxetine, this metabolite also exerts some inhibitory activity at the serotonin transporter.
However, any effect on this transporter is likely to be minimal as the majority of 4hydroxyatomoxetine is further metabolised such that it circulates in plasma at much lower
concentrations (1% of atomoxetine concentration in extensive metabolisers and 0.1% of
atomoxetine concentration in poor metabolisers). N-Desmethylatomoxetine has substantially
less pharmacological activity compared with atomoxetine. It circulates in plasma at lower
concentrations in extensive metabolisers and at comparable concentrations to the parent drug
in poor metabolisers at steady state.
Atomoxetine is not a psychostimulant and is not an amphetamine derivative. In a randomised,
double-blind, placebo-controlled, abuse-potential study in adults comparing effects of
atomoxetine and placebo, atomoxetine was not associated with a pattern of response that
suggested stimulant or euphoriant properties.
Clinical efficacy and safety
Paediatric Population
Strattera has been studied in trials in over 5000 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. Signs and
symptoms of ADHD were evaluated by a comparison of mean change from baseline to
endpoint for Strattera treated and placebo treated patients. In each of the six trials,
atomoxetine was statistically significantly superior to placebo in reducing ADHD signs and
symptoms.
Additionally, the efficacy of atomoxetine in maintaining symptom response was
demonstrated in a 1 year, placebo-controlled trial with over 400 children and adolescents,

primarily conducted in Europe (approximately 3 months of open label acute treatment
followed by 9 months of double-blind, placebo-controlled maintenance treatment). The
proportion of patients relapsing after 1 year was 18.7% and 31.4% (atomoxetine and placebo,
respectively). After 1 year of atomoxetine treatment, patients who continued atomoxetine for
6 additional months were less likely to relapse or to experience partial symptom return
compared with patients who discontinued active treatment and switched to placebo (2% vs.
12% respectively). For children and adolescents periodic assessment of the value of ongoing
treatment during long-term treatment should be performed.
Strattera was effective as a single daily dose and as a divided dose administered in the
morning, and late afternoon/early evening. Strattera administered once daily demonstrated
statistically significantly greater reduction in severity of ADHD symptoms compared with
placebo as judged by teachers and parents.
The European Medicines Agency has deferred the obligation to submit the results of studies with
Strattera in one subset of the paediatric population 4 to 6 years, in the treatment of ADHD. (see
section 4.2 for information on paediatric use)

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.
Adult population
Strattera has been studied in trials in over 4800 adults who met DSM-IV diagnostic criteria
for ADHD. The acute efficacy of Strattera in the treatment of adults was established in six
randomised, double-blind, placebo-controlled trials of ten to sixteen weeks’ duration.
Signs and symptoms of ADHD were evaluated by a comparison of mean change from
baseline to endpoint for atomoxetine treated and placebo treated patients. In each of the six
trials, atomoxetine was statistically significantly superior to placebo in reducing ADHD
signs and symptoms (Table X). Atomoxetine-treated patients had statistically
significantly greater improvements in clinical global impression of severity (CGI-S) at
endpoint compared to placebo-treated patients in all of the 6 acute studies, and statistically
significantly greater improvements in ADHD-related functioning in all 3 of the acute
studies in which this was assessed (Table X). Long-term efficacy was confirmed in 2 sixmonth placebo controlled studies, but not demonstrated in a third (Table X).
Table X

Study

Mean Changes in Efficacy Measures for Placebo-Controlled Studies

Treatment

Acute Studies
LYAA ATX
PBO
LYAO ATX

Changes from Baseline in Patients with at Least One Postbaseline Value (LOCF)
CAARS-Inv:SV or
CGI-S
AAQoL
AISRSa
Mean
Mean
Mean
p-value
p-value
N
p-value
Change
Change
Change
133
134
124

-9.5
-6.0
-10.5

.006
.002

-0.8
-0.4
-0.9

.011

-

-

.002

-

-

PBO
124
-6.7
-0.5
LYBY ATX
72
-13.6
.007
-1.0
.048
PBO
75
-8.3
-0.7
LYDQ ATX
171
-8.7
<.001
-0.8
.022
14.9
.030
PBO
158
-5.6
-0.6
11.1
LYDZ ATX
192
-10.7
<.001
-1.1
<.001
15.8
.005
PBO
198
-7.2
-0.7
11.0
LYEE
ATX
191
-14.3
<.001
-1.3
<.001
12.83
<.001
PBO
195
-8.8
-0.8
8.20
Long-Term Studies
LYBV ATX
185
-11.6
.412
-1.0
.173
13.90
.045
PBO
109
-11.5
-0.9
11.18
LYCU ATX
214
-13.2
.005
-1.2
.001
13.14
.004
PBO
216
-10.2
-0.9
8.62
LYCW ATX
113
-14.3
<.001
-1.2
<.001
PBO
120
-8.3
-0.7
Abbreviations: AAQoL = Adult ADHD Quality of Life Total Score; AISRS = Adult ADHD Investigator
Symptom Rating Scale Total Score; ATX = atomoxetine; CAARS-Inv:SV = Conners Adult ADHD Rating
Scale, Investigator Rated, screening version Total ADHD Symptom Score; CGI-S = Clinical Global Impression
of Severity; LOCF = last observation carried forward; PBO = placebo.
a ADHD symptom scales; results shown for Study LYBY are for AISRS; results for all others are for CAARSInv:SV.

In sensitivity analyses using a baseline-observation-carried-forward method for patients with
no postbaseline measure (i.e. all patients treated), results were consistent with results shown
in Table X.
In analyses of clinically meaningful response in all 6 acute and both successful long-term
studies, using a variety of a priori and post hoc definitions, atomoxetine-treated patients
consistently had statistically significantly higher rates of response than placebo-treated
patients (Table Y).
Table Y
Number (n) and Percent of Patients Meeting Criteria for Response in
Pooled Placebo-Controlled Studies
Response Defined by
Improvement of at least 1 point on
CGI-S
N
n (%)
p-value

Response Defined by
40% Improvement on CAARSInv:SVat Endpoint
N
n (%)
p-value

Group
Treatment
Pooled Acute Studiesa
ATX
640
401 (62.7%)
<.001
841
347 (41.3%)
<.001
PBO
652
283 (43.4%)
851
215 (25.3%)
Pooled Long-Term Studiesa
ATX
758
482 (63.6%)
<.001
663
292 (44.0%)
<.001
PBO
611
301 (49.3%)
557
175 (31.4%)
a
Includes all studies in Table X except: Acute CGI-S response analysis excludes 2 studies in patients with
comorbid disorders (LYBY, LYDQ); Acute CAARS response analysis excludes 1 study in which the CAARS
was not administered (LYBY).

In two of the acute studies, patients with ADHD and comorbid alcoholism or social anxiety
disorder were studied and in both studies ADHD symptoms were improved. In the study with
comorbid alcohol abuse, there were no differences between atomoxetine and placebo with
respect to alcohol use behaviors. In the study with co-morbid anxiety, the comorbid condition
of anxiety did not deteriorate with atomoxetine treatment.
The efficacy of atomoxetine in maintaining symptom response was demonstrated in a study
where after an initial active treatment period of 24 weeks, patients who met criteria for

clinically meaningful response (as defined by improvement on both CAARS-Inv:SV and
CGI-S scores) were randomized to receive atomoxetine or placebo for an additional 6 months
of double-blind treatment. Higher proportions of atomoxetine-treated patients than placebotreated patients met criteria for maintaining clinically meaningful response at the end of 6
months (64.3% vs. 50.0%; p=.001). Atomoxetine-treated patients demonstrated statistically
significantly better maintenance of functioning than placebo-treated patients as shown by
lesser mean change on the Adult ADHD Quality of Life (AAQoL) total score at the 3-month
interval (p=.003) and at the 6-month interval (p=.002).
QT/QTc study
A thorough QT/QTc study, conducted in healthy adult CYP2D6 poor metabolizer (PM)
subjects dosed up to 60mg of atomoxetine BID, demonstrated that at maximum expected
concentrations the effect of atomoxetine on QTc interval was not significantly different from
placebo. There was a slight increase in QTc interval with increased atomoxetine
concentration.
5.2

Pharmacokinetic properties
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.
Absorption: Atomoxetine is rapidly and almost completely absorbed after oral
administration, reaching mean maximal observed plasma concentration (Cmax)
approximately 1 to 2 hours after dosing. The absolute bioavailability of atomoxetine
following oral administration ranged from 63% to 94% depending upon interindividual differences in the modest first pass metabolism. Atomoxetine can be
administered with or without food.
Distribution: Atomoxetine is widely distributed and is extensively (98%) bound to
plasma proteins, primarily albumin.
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 4hydroxyatomoxetine 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.
Cytochrome P450 Enzymes: Atomoxetine did not cause clinically significant
inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A,
CYP2D6, and CYP2C9.

Elimination: The mean elimination half-life of atomoxetine after oral administration is
3.6 hours in extensive metabolisers and 21 hours in poor metabolisers. Atomoxetine
is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine.
Linearity/non-linearity: pharmacokinetics of atomoxetine are linear over the range of
doses studied in both extensive and poor metabolisers.
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 minimized.
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
Preclinical data revealed no special hazard for humans based on conventional studies
of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, or
reproduction and development. 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
nonclinical studies produced atomoxetine exposures similar to or slightly above those
that are achieved in CYP2D6 poor metabolizing patients at the maximum
recommended daily dose.
A study was conducted in young rats to evaluate the effects of atomoxetine on growth
and neurobehavioral and sexual development. Slight delays in onset of vaginal
patency (all doses) and preputial separation (≥10mg/kg/day) and slight decreases in
epididymal weight and sperm number (≥10mg/kg/day) were seen; however, there
were no effects on fertility or reproductive performance. The significance of these
findings to humans is unknown.
Pregnant rabbits were treated with up to 100 mg/kg/day of atomoxetine by gavage
throughout the period of organogenesis. At this dose, in 1 of 3 studies, decrease in live
fetuses, increase in early resorption, slight increases in the incidences of atypical
origin of carotid artery and absent subclavian artery were observed. These findings
were observed at doses that caused slight maternal toxicity. The incidence of these
findings is within historical control values. The no-effect dose for these findings was
30 mg/kg/day. Exposure (AUC) to unbound atomoxetine in rabbits, at 100mg/kg/day
was approximately 3.3 times (CYP2D6 extensive metabolisers) and 0.4 times

(CYP2D6 poor metabolisers) those in humans at the maximum daily dose of
1.4mg/kg/day. The findings in one of three rabbit studies were equivocal and the
relevance to man is unknown.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Starch, pregelatinised (Maize)
Dimeticone
Capsule shell:
Sodium laurilsulfate
Gelatin
Capsule Shell Cap colourants:
10 mg: Titanium dioxide E 171
Capsule Shell Body colourants:
10 mg: Titanium dioxide E 171
Edible Black Ink SW-9008 (containing Shellac and Black Iron Oxide E172) or Edible
Black Ink SW-9010(containing Shellac and Black Iron Oxide E172).

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
Polyvinyl chloride (PVC)/polyethylene (PE)/ Polychlorotrifluoroethylene, PCTFE
blister sealed with aluminium foil lid.
Available in pack sizes of 7, 14, 28 and 56 capsules. Not all pack sizes may be
marketed.

6.6

Special precautions for disposal
The 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.

7

MARKETING AUTHORISATION HOLDER
Eli Lilly and Company Limited
Lilly House, Priestley Road,
Basingstoke, Hampshire,
RG24 9NL,
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
STRATTERA 10 mg hard capsules: PL 00006/0375

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
27/05/2009

10

DATE OF REVISION OF THE TEXT
24/05/2013

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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