Apo-Atomoxetine

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Atomoxetine hydrochloride 28.5 mg equivalent to atomoxetine 25 mg
Available from:
Apotex NZ Ltd
INN (International Name):
Atomoxetine hydrochloride 28.5 mg (equivalent to atomoxetine 25 mg)
Dosage:
25 mg
Pharmaceutical form:
Capsule
Composition:
Active: Atomoxetine hydrochloride 28.5 mg equivalent to atomoxetine 25 mg Excipient: Gelatin   Indigo carmine Iron oxide yellow Starch Titanium dioxide   Water  
Prescription type:
Prescription
Manufactured by:
Apotex Pharmachem Inc
Therapeutic indications:
Indicated for the treatment of Attention Deficit/Hyperactivity Disorder (ADHD) as defined by DSM-IV criteria in children 6 years of age and older, adolescents and adults.
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/PVdC clear film 10ML 250/60, with aluminium foil - 28 capsules - 24 months from date of manufacture stored at or below 25°C - Bottle, plastic, 950cc HDPE round, white, opaque bottle. Blue or White polypropylene screw cap 53mm-400mm with liner - 1000 capsules - 24 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-9453b
Authorization date:
2013-12-12

Read the complete document

New Zealand Datasheet

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 1 of 19

Presentation

APO-ATOMOXETINE 10mg is hard gelatin capsule with white opaque body and white

opaque cap. Imprinted “APO AM10” in black ink.

APO-ATOMOXETINE 18mg is hard gelatin capsule with white opaque body and gold opaque

cap. Imprinted “APO AM18” in black ink.

APO-ATOMOXETINE 25mg is hard gelatin capsule with white opaque body and blue opaque

cap. Imprinted “APO AM25” in black ink.

APO-ATOMOXETINE 40mg is hard gelatin capsule with blue opaque body and blue opaque

cap. Imprinted “APO AM40” in black ink.

APO-ATOMOXETINE 60mg is hard gelatin capsule with gold opaque body and blue opaque

cap. Imprinted “APO AM60” in black ink

APO-ATOMOXETINE 80mg is hard gelatin capsule with white opaque body and orange

opaque cap. Imprinted “APO AM80” in black ink.

APO-ATOMOXETINE 100mg is hard gelatin capsule with orange opaque body and orange

opaque cap. Imprinted “APO AM100” in black ink.

Indications

APO-ATOMOXETINE is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder

(ADHD) as defined by DSM-IV criteria in children 6 years of age and older, adolescents and

adults.

Dosage and Administration

Instructions for Use/Handling

APO-ATOMOXETINE capsules are not

intended to be opened.

Atomoxetine is an ocular

irritant.

In the event

capsule 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.

Initial Treatment

Children and Adolescents up to 70 kg Body Weight

APO-ATOMOXETINE should be initiated at a total daily dose of approximately 0.5 mg/kg and

increased after

a minimum of

three days to a target

total

daily dose of

approximately 1.2

mg/kg administered either as a single daily dose in the morning or as evenly divided doses in

the morning and late afternoon/early evening. After an additional

two to four weeks, the total

daily dose may be increased to a maximum of 1.4 mg/kg in patients who have not achieved

an optimal

response (see Clinical

Trials section).

The maximum recommended total

daily

dose in children and adolescents is 1.4 mg/kg or 100 mg, whichever is less.

Children and Adolescents over 70 kg Body Weight and Adults

APO-ATOMOXETINE should be initiated at a total

daily dose of 40 mg and increased after a

minimum of

three days to a target

total

daily dose of

approximately 80 mg administered

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 2 of 19

either as a single daily dose in the morning or as evenly divided doses in the morning and

late afternoon/early evening.

After

an additional

two to four

weeks,

the dose may be

increased to a maximum of 100 mg in patients who have not achieved an optimal

response

(see Clinical

Trials section).

The maximum recommended total

daily dose in children and

adolescents over 70 kg is 100 mg.

Interrupted Treatment

therapy

interrupted for

more than 1 week,

treatment

should be started at

recommended starting dose. (Refer to Initial Treatment).

Maintenance/Extended Treatment

There is no evidence available from controlled trials to indicate how long the patient

with

ADHD should be treated with APO-ATOMOXETINE.

is generally agreed,

however,

that

pharmacological

treatment of ADHD may be needed for extended periods. Nevertheless, the

physician who elects to use APO-ATOMOXETINE for extended periods should periodically re-

evaluate the long-term usefulness of the medicine for the individual patient.

Renal or Hepatic Impairment

those ADHD patients who have hepatic insufficiency or

end stage renal

disease,

cautious titration of

APO-ATOMOXETINE to the desired clinical

response is recommended.

APO-ATOMOXETINE clearance may be reduced in patients with hepatic insufficiency. APO-

ATOMOXETINE may exacerbate hypertension in patients with end stage renal disease.

Hepatic Insufficiency

In clinical

trials single doses of atomoxetine were administered to subjects with moderate to

severe hepatic insufficiency (Child-Pugh Class B and C)

resulting in reduced atomoxetine

clearance,

increased atomoxetine exposure (AUC)

and prolonged half-life of

parent

drug

compared with healthy subjects. However, the maximum exposure observed in subjects with

hepatic insufficiency did not exceed that observed in the population of healthy CYP2D6 poor

metabolisers.

For those ADHD patients who have hepatic insufficiency,

cautious titration of

APO-ATOMOXETINE to the desired clinical response is recommended.

Renal Insufficiency

In clinical

trials single doses of

atomoxetine were administered to subjects with end stage

renal

disease,

resulting in higher

atomoxetine exposure (AUC)

than in healthy subjects.

However, the maximum exposure observed in subjects with end stage renal

disease did not

exceed that

observed in the population of

healthy CYP2D6 poor

metabolisers.

APO-

ATOMOXETINE may exacerbate hypertension in patients with end stage renal

disease. For

those ADHD patients

who have end stage renal

disease,

cautious

titration of

APO-

ATOMOXETINE to the desired clinical

response is recommended, with particular attention to

those with hypertension that

may experience deterioration in the control

their

blood

pressure.

Paediatric Use

The pharmacokinetics of atomoxetine have not

been evaluated in children under 6 years of

age.

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 3 of 19

General Dosing Information

APO-ATOMOXETINE is intended for oral

administration and may be taken with or without

food. The safety of

single doses over 120 mg and total

daily doses above 150 mg have not

been systematically evaluated.

APO-ATOMOXETINE may be discontinued without tapering the dose.

Maximum Tolerated Daily Dose

The maximum recommended total daily dose in children and adolescents is 1.4 mg/kg or 100

whichever

is less.

The maximum recommended total

daily dose in children and

adolescents over 70 kg is 100 mg.

Clinical Trials

Children and Adolescents

The efficacy of

atomoxetine in the treatment

ADHD in children and adolescents was

established

four

randomised,

double-blind,

placebo-controlled

studies

paediatric

patients (ages 6 to 18 years) who met DSM-IV criteria for ADHD.

Approximately one third of

the patients met

DSM-IV criteria for inattentive subtype and two

thirds met criteria for both inattentive and hyperactive/impulsive subtypes.

Signs and symptoms of

ADHD were evaluated by a comparison of

mean change from

baseline to endpoint for atomoxetine-treated and placebo-treated patients using an intent-to-

treat analysis. The primary outcome measure being the investigator administered and scored

ADHD Rating Scale-IV-Parent Version (ADHDRS) total

score including hyperactive/impulsive

and inattentive subscales. Each item on the ADHDRS maps directly to one symptom criterion

ADHD in the DSM-IV.

A second assessment,

the Clinical

Global

Impression Severity

(CGI-S) scale, reflects the impression of

a skilled observer about the overall

clinical

state of

the patient.

The skilled observer was required to be fully familiar with the manifestations of

ADHD.

In Study LYAC,

an 8-week randomised,

double-blind,

placebo-controlled acute treatment

study of

children and adolescents aged 8 to 18 years (n=297),

patients received either

fixed dose of

atomoxetine (0.5 mg/kg/day,

1.2 mg/kg/day,

1.8 mg/kg/day)

placebo.

Atomoxetine

administered

divided

dose

early

morning

late

afternoon/early evening. Treatment with atomoxetine showed an overall

improvement

in the

reductions from baseline in mean ADHDRS total

score.

The average score decreased by

25% on 0.5 mg/kg/day,

35% on 1.2 mg/kg/day and 34% on 1.8 mg/kg/day atomoxetine,

compared to 15% with placebo. At the two higher doses, improvements in ADHD symptoms

were superior

and statistically significant

(p<0.001 vs.

placebo)

in atomoxetine-treated

patients compared with placebo-treated patients as measured on the ADHDRS and CGI-S

scales.

Atomoxetine was effective in reducing both inattentive and hyperactive/impulsive

symptoms. The results of Study LYAC are summarised in Figure 1.

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 4 of 19

Figure 1. Atomoxetine Response by Dose.

In Study LYAT,

a 6-week randomised,

double-blind,

placebo-controlled acute treatment

study of

children and adolescents aged 6 to 16 years (n=171),

patients received either

atomoxetine or

placebo.

Atomoxetine was administered as a single dose in the early

morning and titrated on a weight-adjusted basis

according to clinical

response.

maximum atomoxetine dose was 1.5 mg/kg/day.

The mean final

dose of

atomoxetine was

approximately 1.3 mg/kg/day.

Treatment

with atomoxetine showed an overall

improvement

in the reductions from baseline in mean ADHDRS total

score. The average score decreased

34% on

atomoxetine,

compared

13% with

placebo

(p<0.001

placebo).

Improvements in ADHD symptoms were superior and statistically significant in atomoxetine

treated patients compared with placebo-treated patients as measured on the ADHDRS

scale beginning at

one week and through the end of

the study.

Improvements in ADHD

symptoms

were

also

superior

atomoxetine

treated

patients

CGI-S scale.

Atomoxetine was effective in reducing both inattentive and hyperactive/impulsive symptoms.

This study demonstrates that

atomoxetine is effective when administered once daily in the

morning. The results of Study LYAT are summarised in Figure 2.

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 5 of 19

Figure 2. Once-daily administration of atomoxetine

In Study LYAW,

a 7-week randomised,

double-blind,

placebo-controlled acute treatment

study of

children and adolescents aged 6 to 16 years (n=153),

patients received either

atomoxetine or

placebo.

Atomoxetine was administered as a single dose in the early

morning and titrated on a weight-adjusted basis

according to clinical

response.

maximum atomoxetine dose was 1.8 mg/kg/day.

The mean final

dose of

atomoxetine was

approximately 1.3 mg/kg/day.

Treatment

with atomoxetine showed an overall

improvement

in the reductions from baseline in mean ADHDRS total

score based on teacher reports. The

average score decreased by 37% on atomoxetine, compared to 19% with placebo (p<0.001

placebo).

Improvements in ADHD symptoms at

school

were superior

and statistically

significant

in atomoxetine treated patients

compared with placebo-treated patients

measured on the ADHDRS scale beginning at one week and through the end of

the study.

Improvements in ADHD symptoms were also superior in atomoxetine -treated patients on

CGI-S

scale.

Atomoxetine

effective

reducing

both

inattentive

hyperactive/impulsive symptoms.

This study demonstrates that

atomoxetine is effective

when administered once daily in the morning.

In two identical,

9-week,

acute,

randomised,

double-blind,

placebo-controlled studies of

children aged 7 to 13 years (Study HFBD,

n=147;

Study HFBK,

n=144),

atomoxetine or

methylphenidate was compared with placebo.

The primary comparison of

interest

in both

studies was atomoxetine vs.

placebo.

Atomoxetine was administered as a divided dose in

the early morning and late afternoon (after school) and titrated on a weight-adjusted basis

according to clinical

response.

The maximum recommended atomoxetine dose was 2.0

mg/kg/day.

The mean final

dose of

atomoxetine for

both studies was approximately 1.6

mg/kg/day.

Treatment

with atomoxetine showed an overall

improvement

from baseline in

mean ADHDRS total

score.

The average score decreased by

38% on atomoxetine,

compared to 13% with placebo (p<0.0001 vs.

placebo)

in study HFBD and 38% on

atomoxetine, compared to 16% with placebo (p<0.0003 vs. placebo) in study HFBK. In both

studies,

improvements in ADHD symptoms were superior

and statistically significant

atomoxetine -treated patients compared with placebo-treated patients as measured on the

ADHDRS and CGI-S scales.

Atomoxetine was effective in reducing both inattentive and

hyperactive/impulsive symptoms.

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 6 of 19

Adults

The efficacy of atomoxetine for the treatment of ADHD in adults (18 years of age and older)

meeting DSM-IV criteria and with a childhood history of ADHD was established in two, short-

term (10 weeks),

randomised,

double-blind,

placebo-controlled studies;

and one,

long-term

(up to 3 years),

open-label

study.

There are no long term,

randomised,

double-blind,

placebo-controlled studies in adults.

Signs and symptoms of

ADHD were evaluated using the investigator administered Conners

Adult ADHD Rating Scale Screening Version (CAARS), a 30-item scale. The primary efficacy

measure was the 18-item Total

ADHD Symptom score (the sum of

the inattentive and

hyperactivity/impulsivity

subscales)

evaluated by

a comparison of

mean change from

baseline to endpoint using an intent-to-treat analysis.

Studies LYAA and LYAO -

In two identical,

10-week,

randomised,

double-blind,

placebo-

controlled acute treatment

studies (Study LYAA,

N=280;

Study LYAO,

N=256),

patients

received either atomoxetine or placebo. Atomoxetine was administered as a divided dose in

the early

morning and late afternoon/early

evening and titrated according to clinical

response.

The maximum atomoxetine dose was 120 mg/day.

The mean final

dose of

atomoxetine for

both studies was approximately 95 mg/day.

Treatment

with atomoxetine

showed an overall

improvement

from baseline in mean CAARS total

score.

The average

score decreased by 28% on atomoxetine,

compared to 18% with placebo (p<0.001 vs

placebo) in study LYAA and 30% on atomoxetine, compared to 20% with placebo (p<0.001

vs placebo) in study LYAO. In both studies, improvements in ADHD symptoms were superior

and statistically significant

in atomoxetine -treated patients compared with placebo-treated

patients as measured on the CAARS scale.

Study LYAR -

was an open-label,

multi-center

investigation of

the long-term safety and

tolerability of

atomoxetine in patients aged 18 years or older who meet

the DSM-IV criteria

ADHD.

This was an open label

extension of

the LYAA and LYAO studies.

Average

symptom severity decreased by 30.6% (p<0.001) as measured by the CAARS investigator

rated scale for 18 item total

ADHD symptoms. The adverse event profile was similar to that

observed in short-term studies with most treatment emergent adverse events reported to be

of mild or moderate severity.

Examination of

population subsets (gender, age, or prior stimulant treatment) did not reveal

any differential responsiveness on the basis of these subgroupings.

Contraindications

Hypersensitivity

APO-ATOMOXETINE

contraindicated

patients

with

known

hypersensitivity

atomoxetine or any excipient in this product.

Monoamine Oxidase Inhibitors

APO-ATOMOXETINE should not

be taken with monoamine oxidase inhibitors (MAOIs)

within two weeks after discontinuing MAOIs.

Treatment

with MAOIs should not

be initiated

within two weeks after discontinuing APO-ATOMOXETINE.

With other medicines that affect brain monoamine concentrations, there have been reports of

serious, sometimes fatal, reactions when taken in combination with MAOIs. These reactions

include

hyperthermia,

rigidity,

myoclonus,

autonomic

instability

with

possible

rapid

fluctuations

vital

signs

and mental

status

changes

that

include extreme agitation

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 7 of 19

progressing

delirium and

coma.

Some

cases

presented

with features

resembling

neuroleptic malignant syndrome. Such reactions may occur when these medicines are given

concurrently or in close proximity.

Narrow Angle Glaucoma

In clinical

studies, the use of atomoxetine was associated with an increased risk of mydriasis

and therefore atomoxetine is not recommended in patients with narrow angle glaucoma.

APO-ATOMOXETINE is contraindicated in patients with:

Severe Cardiovascular

Disorders— Atomoxetine should not

be used in patients with

severe cardiovascular disorders whose condition would be expected to deteriorate if they

experienced increases in blood pressure or in 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).

(Also see PRECAUTIONS).

Symptomatic

cardiovascular

disease:

moderate

severe

hypertension,

atrial

fibrillation, atrial

flutter, ventricular tachycardia, ventricular fibrillation, or ventricular flutter,

advanced arteriosclerosis (Also see PRECAUTIONS)

Uncontrolled hyperthyroidism

Phaeochromocytoma:

APO-ATOMOXETINE should

used

patients

with

pheochromocytoma or a history of pheochromocytoma (Also see PRECAUTIONS)

Warnings and Precautions

Suicidal Ideation and Behaviour

Short-term placebo controlled studies evaluated over

2200 children and adolescents with

Attention Deficit

Hyperactivity Disorder (ADHD).

Among the 1357 patients on atomoxetine,

there was a positive signal

for suicidal

thoughts (5 patients) and behaviours (1 patient) in

children 12 years of age and younger compared to placebo (0/851). No suicides occurred in

these trials. Anyone considering the use of

atomoxetine in children must balance the risk of

suicidality (suicidal

thoughts or

behaviours)

against

the clinical

need.

Patients who are

started on atomoxetine should be closely monitored for suicidality (see PRECAUTIONS).

Allergic Reactions

Although uncommon, allergic reactions, including anaphylactic reactions, rash, angioneurotic

oedema and urticaria, have been reported in patients taking atomoxetine.

Hepatic Effects

Post-marketing reports indicate that atomoxetine can cause severe liver injury in rare cases,

including acute liver failure.

Very rarely,

spontaneous reports of

liver injury,

manifested by

elevated hepatic enzymes and bilirubin with jaundice,

have been reported.

More than 2

million patients have received atomoxetine during the first two years of global

post-marketing

experience.

During such time,

there have been two reported cases of

markedly elevated

hepatic enzymes and bilirubin, in the absence of other obvious explanatory factors. In one of

these cases, liver injury recurred upon rechallenge, and was followed by recovery upon drug

discontinuation.

The patients

described above recovered from their

liver

injury.

Such

reactions may occur

several

months after

therapy is started,

laboratory abnormalities

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 8 of 19

may continue to worsen for several

weeks after drug is stopped.

As with other medications

which can cause severe drug-related liver

injury,

is possible that

a small

percentage of

patients may progress to acute liver

failure resulting in death or

the need for

a liver

transplant.

APO-ATOMOXETINE should be discontinued in patients with jaundice or laboratory evidence

of liver injury, and should not be restarted. Laboratory testing to determine liver enzyme levels

should be conducted on the first

symptom or

sign of

liver

dysfunction (e.g.,

pruritus,

dark

urine, jaundice, right upper quadrant tenderness, or unexplained "flu-like" symptoms).

Precautions

Suicidal Ideation and Behaviour

Suicidal

ideation (suicidal

thoughts)

was statistically more frequently observed in clinical

trials

among

children

adolescents

treated

with

atomoxetine

(5/1357;

[0.37%])

compared to those treated with placebo (0/851;

[0%]).

There was one report

suicidal

behaviour in a patient in this age group treated with atomoxetine compared with no reports

in patients treated with placebo.

reports of

suicidal

ideation or

behaviour

in this age

group occurred in children 12 years of

age or younger.

No suicides occurred during these

trials.

patients

being

treated

with

APO-ATOMOXETINE should be

observed for

emergence of

suicidal

thoughts or behaviours,

especially during the initial

few months of

treatment or at times of dose changes. Families and caregivers of children and adolescents

being treated with atomoxetine should be informed of the need to monitor these patients for

emergence of suicidal

thoughts or behaviours that may include signs of agitation, irritability

or unusual

changes of behaviour. If any of these symptoms develop medical

advice should

be sought immediately.

Aggressive Behaviour or Hostility

Hostility (predominantly aggression, oppositional

behaviour and anger) and emotional

lability

are often observed in patients with ADHD and have been reported in clinical

trials and post-

marketing experience for some ADHD medications. Although there is no conclusive evidence

that

atomoxetine causes aggressive behaviour or hostility,

during clinical

trials these events

were more frequently observed in children, adolescents and adults treated with atomoxetine

compared to those receiving

placebo (not

statistically

significant).

Patients

beginning

treatment

ADHD should be monitored for

the appearance or

worsening of

aggressive

behaviour or hostility.

Seizures

The pre-clinical

and clinical

trial

data for

atomoxetine do not

suggest

that

atomoxetine is

proconvulsive.

However,

seizures

have

been

very

rarely

reported

post-marketing

spontaneous reports.

Atomoxetineshould be used with caution in patients with a history of

seizures.

Discontinuation of

atomoxetine should be considered in any patient

developing

seizures or if there is an increase in seizure frequency where no other cause is identified.

Cardiovascular Effects

APO-ATOMOXETINE can affect

heart

rate and blood pressure.

is recommended that

heart

rate and blood pressure be measured before treatment

is started and periodically

during treatment to detect possible clinically important increases.

Most

patients taking atomoxetine experience a modest

increase in heart

rate (mean <10

bpm) and/or increase in blood pressure (mean <5 mm Hg) that

are not

clinically important

(See ADVERSE EFFECTS).

However,

data from ADHD clinical

trials show that

some

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 9 of 19

patients (approximately 5 to 10% of

children and adults) do experience clinically important

changes in heart rate (20 beats per minute or greater) or blood pressure (15 to 20 mm Hg or

greater).

Atomoxetine should be used with caution in patients whose underlying medical

conditions

could be worsened by increases in blood pressure or

heart

rate,

such as patients with

hypertension,

tachycardia,

cardiovascular

cerebrovascular

disease.

should not

used in patients with severe cardiovascular disorders whose condition would be expected to

deteriorate if

they experienced increases in blood pressure or

heart

rate that

could be

clinically important. (See CONTRAINDICATIONS)

APO-ATOMOXETINE should not

be used in patients with severe cardiovascular disorders

whose condition would be expected to deteriorate if

they experienced increases in blood

pressure or heart rate that could be clinically important. (See CONTRAINDICATIONS)

In addition, APO-ATOMOXETINE should be used with caution in patients with congenital

prolongation, acquired QT prolongation (for example, due to concomitant use of

a drug that

prolongs

the QT),

with

a family

history

QT prolongation.

Because

orthostatic

hypotension has also been reported,

APO-ATOMOXETINE should be used with caution in

condition that

predispose patients

to orthostatic

hypotension,

conditions

associated with abrupt heart rate or blood pressure changes. (See CONTRAINDICATIONS)

APO-ATOMOXETINE

should

used

with

caution

patients

with

history

hyperthyroidism.

Sudden Death and Pre-existing Structural Cardiac Abnormalities

Sudden death has been reported in association with some CNS stimulatory drugs used for

ADHD treatment at usual doses in children with structural cardiac abnormalities.

A pharmacological

potential

exists for all

ADHD drugs to increase the risk of sudden/cardiac

death.

Although confirmation of

an incremental

risk for adverse cardiac events arising from

treatment with ADHD medications is lacking, prescribers should consider this potential risk.

drugs with sympathomimetic effects prescribed in the management

ADHD should be

used with caution in patients who: a) are involved in strenuous exercise or activities, b) use

stimulants,

or c) have a family history of

sudden/cardiac death.

APO-ATOMOXETINE is a

drug with peripheral

sympathomimetic effects and should not

generally be used in children,

adolescents,

or adults with known structural

cardiac abnormalities.

Prior to the initiation of

treatment,

a personal

and family history should be obtained.

In patients with relevant

risk

factors and based on the clinician’s judgment,

further

cardiovascular

evaluation may be

considered.

Effects on Co morbid Chronic Tics or Tourette’s Disorder

A randomised,

double-blind study of

atomoxetine and placebo in paediatric outpatients with

ADHD and co morbid tic disorders showed that

atomoxetine did not

worsen tics in patients

with ADHD and co morbid chronic motor tics or Tourette’s Disorder.

There have been very

rare postmarketing reports of tics with atomoxetine treatment.

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

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Page 10 of 19

Effects on Comorbid Anxiety

Two randomised,

double-blind,

placebo-controlled studies of

atomoxetine,

one in children

and adolescents with ADHD and comorbid anxiety and one in adults with comorbid social

anxiety disorder, showed that atomoxetine did not worsen anxiety in patients with ADHD and

comorbid anxiety.

There have been rare postmarketing reports of

anxiety with atomoxetine

treatment.

Effects on Comorbid Major Depressive Disorder

In a controlled study of

adolescent

patients with ADHD and comorbid major

depressive

disorder, atomoxetine treated patients did not experience worsening of depression compared

to placebo-treated patients.

There have been rare postmarketing reports of

depression or

depressed mood with atomoxetine treatment.

Hepatic Insufficiency

(see Dosage and Administration sections).

Renal

Insufficiency

(see Dosage and Administration sections). In adult ADHD controlled

trials, the rates of urinary retention and urinary hesitation were increased among atomoxetine

treated patients compared with placebo patients.

A complaint

urinary retention or urinary

hesitancy should be considered potentially related to atomoxetine.

The safety and efficacy of

atomoxetine in paediatric patients less than 6 years of

age have

been established.

The efficacy

atomoxetine beyond 18 months

and safety

atomoxetine beyond two years of

treatment

have not

been systematically evaluated.

safety and efficacy of atomoxetine in elderly patients have not been established.

Carcinogenesis, Mutagenesis, Impairment of Fertility

There is no evidence of

carcinogenicity,

mutagenicity,

or impairment

fertility from in vitro

and animal

studies with atomoxetine.

Atomoxetine was not

carcinogenic in rats and mice

when given in the diet

2 years at

time-weighted average doses up to 47 and 458

mg/kg/day.

These doses are approximately 6 (rat)

and 31 (mouse)

times the maximum

recommended daily oral

dose in children and approximately 4 (rat) and 20 (mouse) times the

maximum recommended daily oral dose in adults, on a mg/m

basis.

Atomoxetine was not

mutagenic in a battery of

tests including the following:

Ames and

gradient

plate

bacterial

mutation

assays,

mouse

lymphoma

cell

mutation

assay,

chromosomal

aberration test

in Chinese hamster

ovary cells,

in vivo micronucleus test

mice,

unscheduled DNA synthesis test

in rat

hepatocytes and in vivo sister

chromatid

exchange test in bone marrow of Chinese hamsters.

Atomoxetine did not

impair fertility when administered to rats from 10 days of

age through

adulthood at oral

doses up to 50 mg/kg/day (up to 7 times the maximum recommended daily

oral

dose in children and 4 times the maximum recommended daily oral

dose in adults, on a

mg/m

basis).

In addition,

no evidence of

impaired fertility was observed in either

fertility studies in adult

rats provided atomoxetine hydrochloride in the diet

time-weighted

average doses up to 57 mg/kg/day (up to 8 times the maximum recommended daily oral

dose in children and 5 times the maximum recommended daily oral

dose in adults,

on a

mg/m

basis).

Use in Pregnancy

Category B3

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

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Page 11 of 19

No evidence of

medicine-associated teratogenicity or

retarded foetal

development

produced in rabbits or

rats administered atomoxetine throughout

organogenesis at

oral

doses

mg/kg/day

mg/kg/day

least

times

maximum

recommended daily oral dose in children and 13 times the maximum recommended daily oral

dose in adults, on a mg/m

basis). In a rat fertility study, decreased pup weight and survival

was observed,

predominantly during the first

week postpartum following maternal

dietary

atomoxetine time-weighted average doses of

23 mg/kg/day or

higher.

No adverse effects

were observed in surviving pups.

No adequate and well-controlled studies have been conducted in pregnant

women.

APO-

ATOMOXETINE should not

be used during pregnancy unless the potential

benefit

justifies

the potential risk to the foetus.

Use in Lactation

Atomoxetine and/or

its metabolites were excreted in the milk of

rats.

is not

known if

atomoxetine is excreted in human milk. Caution should be exercised if APO-ATOMOXETINE

is administered to a nursing woman.

Effects on ability to drive and use machines

Patients should be advised to use caution when driving a car

operating hazardous

machinery until

they are reasonably certain that

their performance is not

affected by APO-

ATOMOXETINE.

Medicine Abuse and Dependence

Atomoxetine is not

a controlled substance and is not

a stimulant.

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

study data in over 2000 children, adolescents and adults with ADHD and over 1200

adults

with

depression

demonstrate

pattern

medicine

diversion

inappropriate self-administration associated with atomoxetine.

There was no evidence of

symptom rebound or

adverse events suggesting a medicine-discontinuation or

withdrawal

syndrome.

Adverse Effects

Child and Adolescent Clinical Trials

The most

commonly observed adverse events associated with the use of

atomoxetine

(incidence of

2% or greater) and not

observed at

an equivalent

incidence among placebo-

treated patients (atomoxetine incidence at least twice placebo) are listed in Table 1.

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

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Page 12 of 19

Table 1

Treatment-Emergent Adverse Effects Associated with the Use of Atomoxetine in Acute

(up to 9 weeks) Child and Adolescent Trials

Adverse Effect

Percentage of Patients Reporting Effect

System Organ Class/Adverse Effect

Atomoxetine

(n=425)

Placebo

(n=292)

Gastrointestinal Disorders

Constipation

Dyspepsia

Infections and Infestations

Influenza

Metabolism and Nutritional Disorders

Appetite decreased

Nervous System Disorders

Dizziness

Psychiatric Disorders

Mood swings

Skin and Subcutaneous Tissue Disorders

Dermatitis

following

events

meet

above

criteria

were

reported

more

atomoxetine-treated patients than placebo-treated patients and are possibly related to

atomoxetine treatment:

Very common (≥ 10%): abdominal

pain (including abdominal

pain

upper,

stomach discomfort,

abdominal

discomfort

and epigastric discomfort),

vomiting,

nausea,

blood pressure increased,

heart rate increased (heart

rate and blood pressure are

based on measured vital

signs),

somnolence (including sedation),

headache Common (

1% and < 10%):

anorexia,

insomnia (also includes initial

insomnia,

middle insomnia and

terminal

insomnia),

irritability,

mydriasis,

pruritus,

rash,

weight

decreased,

depression (also

includes major depression, depressive symptoms, depressed mood, and dysphoria), fatigue

and Uncommon (≥ 0.1% and < 1%): flushing, palpitations, sinus tachycardia, conjunctivitis,

syncope (also includes syncope vasovagal), tremor, asthenia.

In a post-hoc meta-analysis of

the placebo-controlled paediatric clinical

trial

database,

suicidal

ideation (suicidal

thoughts)

statistically

more frequently

observed among

children and adolescents treated with atomoxetine (5/1357;

[0.37%])

compared to those

treated with placebo (0/851; [0%]). There was one report of suicidal

behaviour in a patient in

this age group treated with atomoxetine compared with no reports in patients treated with

placebo (see PRECAUTIONS Suicidal Ideation and Behaviour).

The following adverse events occurred in at

least

2% of

child and adolescent

CYP2D6 poor

metaboliser

(PM)

patients

statistically

significantly more frequent

in PM patients

compared with CYP2D6 extensive metaboliser

(EM)

patients:

weight

decreased (7.3% of

PMs, 4.4% of EMs), constipation (6.8% of PMs, 4.3% of EMs), insomnia (11% of PMs, 6.1%

EMs),

depression (6.5% of

PMs,

4.1% of

EMs),

tremor

(4.5% of

PMs,

0.9% of

EMs);

middle insomnia (2.8% of

PMs,

1.3% of

EMs);

syncope (2.5% of

PMs,

0.7% of

EMs);

conjunctivitis (2.5% of PMs, 1.2% of EMs); early morning awakening (2.3% of PMs, 0.8% of

EMs); mydriasis (2.0% of PMs, 0.6% of EMs); sedation (3.9% of PMs, 2.1% of EMs).

Growth – Pediatric patients treated with atomoxetine in ADHD clinical trials had a mean initial

decrease in weight

and height

gain.

Subsequently,

over

the long-term period,

patients

recovered to the mean weight and height predicted by group baseline data.

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

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Page 13 of 19

Adult Clinical Trials

The most

commonly observed adverse events associated with the use of

atomoxetine

(incidence of

2% or greater) and not

observed at

an equivalent

incidence among placebo-

treated patients (atomoxetine incidence at least twice placebo) are listed in Table 2 below.

Treatment-Emergent Adverse Events Associated with the Use of Atomoxetine in Acute

(up to 10 weeks) Adult Trials

Adverse Event

1

Percentage of Patients Reporting

Event

System Organ Class/Adverse Event

Atomoxetine

(n=269)

Placebo

(n=263)

Cardiac Disorders

Palpitations

Gastrointestinal Disorders

Dry mouth

Nausea

Constipation

Flatulence

General

Disorders

and

Administration

Site

Conditions

Rigors

Investigations

Weight decreased

Metabolism and Nutritional Disorders

Appetite decreased

Nervous System Disorders

Dizziness

Headache

Psychiatric Disorders

Insomnia

Middle insomnia

Libido decreased

Sleep disorder

Renal and Urinary Disorders

Urinary hesitation

Urinary retention

Difficulty in micturition

Reproductive System and Breast Disorders

Erectile dysfunction

Dysmenorrhoea

Impotence

Prostatitis

Orgasm abnormal

Menstruation irregular

Skin and Subcutaneous Tissue Disorders

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

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Page 14 of 19

Hyperhydrosis

Vascular Disorders

Hot flush

Events reported by at least 2% of patients treated with atomoxetine and at least twice the placebo incidence.

Based on total number of males (atomoxetine, n=174; placebo, n=172).

Based on total number of females (atomoxetine, n=95; placebo, n=91).

The following events did not

meet

this criterion but

were reported by more atomoxetine-

treated patients than placebo-treated patients and are possibly related to atomoxetine

treatment,

Very common (≥10%):

blood pressure increased,

heart

rate increased (heart

rate and blood pressure are based on measured vital

signs),

Common (≥ 1% and <10%):

abdominal

pain (includes abdominal

pain upper, stomach discomfort, abdominal

discomfort,

and epigastric discomfort),

rash,

dyspepsia,

vomiting,

asthenia,

feeling jittery,

irritability,

thirst,

dysgeusia,

somnolence (including sedation),

tremor,

agitation,

pollakuria,

flushing,

terminal

insomnia,

ejaculation disorder,

ejaculation failure,

testicular

pain,

urine flow

decreased, fatigue, lethargy, tachycardia, paraesthesia, chills and Uncommon (≥0.1% and

<1%): feeling cold,

muscle spasms,

peripheral

coldness,

restlessness,

micturition urgency,

pruritis, urticaria, blurred vision.

The following adverse events occurred in at

least

2% of

adult

CYP2D6 poor

metaboliser

(PM) patients and were statistically significantly more frequent

in PM patients compared to

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);

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 (3.0% 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%

EMs);

hyperhidrosis (14.8% of

PMs,

6.8% of

EMs);

peripheral

coldness (3.0% of

PMs,

0.5% of EMs).

Post-marketing Experience

The following list of undesirable effects (adverse drug reactions) is based on post-marketing

spontaneous reports, and corresponding reporting rates have been provided.

General Disorders and Administration Site Conditions – Very rare (<0.01%): lethargy.

Investigations – Rare (>0.01% to <0.1%): blood pressure increased.

Psychiatric – Rare (>0.01% to <0.1%): completed suicide, suicide attempt, suicidal ideation,

aggression/hostility, psychosis/mania, depression and depressed mood, anxiety. Very rare

(<0.01%): sensory disturbances including hallucinations.

Vascular Disorders – Very rare (<0.01%):

peripheral

vascular instability and/or Raynaud’s

phenomenon, potential to exacerbate pre-existing Raynaud’s phenomenon.

Urogenital System – Very rare (<0.01%): painful or prolonged erection, male genital pain,

urinary hesitation in children and adolescents, urinary retention in children and adolescents.

Cardiovascular system — Very rare (<0.01%): QT prolongation, syncope.

Nervous system – Very rare (<0.01%): seizures, paraesthesia in children and adolescents,

hypoaethesia, tics.

Skin and Subcutaneous Disorders – Very rare (<0.01%): Hyperhydrosis.

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

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Page 15 of 19

Interactions

Pharmacokinetics Interactions

Atomoxetine did not

cause clinically significant

inhibition or

induction of

cytochrome P450

enzymes,

including CYP1A2,

CYP3A,

CYP2D6 and CYP2C9.

Atomoxetine is principally

metabolised by the CYP2D6 pathway.

In CYP2D6 extensive metabolisers,

inhibitors of

CYP2D6 increase atomoxetine steady-state plasma concentrations to exposures similar to

those observed in CYP2D6 poor metabolisers.

In vitro studies suggest that co-administration of cytochrome P450 inhibitors to CYP2D6 poor

metabolisers will

increase the plasma concentrations of

atomoxetine.

Slower titration of

atomoxetine may be necessary in those patients who are also taking CYP2D6 inhibitor

medicines.

Midazolam

Co-administration of

atomoxetine with midazolam resulted in small

increases in midazolam

plasma concentrations. These changes were smaller than those caused by weak inhibitors of

CYP3A and therefore,

no dose adjustment

is recommended for medicines metabolised by

CYP3A.

Medicines Highly Bound to Plasma Protein

In vitro medicine-displacement

studies were conducted with atomoxetine and other

highly

bound medicines at

therapeutic concentrations.

Atomoxetine did not

affect

the binding of

warfarin,

acetylsalicylic acid,

phenytoin or

diazepam to human albumin.

Similarly,

these

compounds did not affect the binding of atomoxetine to human albumin.

Medicines that Affect Gastric pH

Medicines that elevate gastric pH (magnesium hydroxide/aluminium hydroxide, omeprazole)

had no effect on atomoxetine bioavailability.

Pharmacodynamic Interactions

Methylphenidate

Co-administration of

methylphenidate with Atomoxetine did not

increase cardiovascular

effects beyond those seen with methylphenidate administration alone.

Monoamine Oxidase Inhibitors

APO-ATOMOXETINE should not

be taken with monoamine oxidase inhibitors (MAOIs)

within two weeks after discontinuing MAOIs.

Treatment

with MAOIs should not

be initiated

within two weeks after discontinuing APO-ATOMOXETINE. (See Contraindications section

for further information.)

Anti-hypertensive drugs and Vasopressor Agents

Because of

possible effects on blood pressure,

APO-ATOMOXETINE should be used

cautiously with Anti-hypertensive drugs and vasopressor agents or other drugs that increase

blood pressure.

Medicines that Affect Noradrenaline

Medicines that

affect

noradrenaline should be used cautiously when co-administered with

APO-ATOMOXETINE because of

the potential

additive or

synergistic pharmacological

effects.

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

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Page 16 of 19

Beta-Adrenergic Receptor Agonists

APO-ATOMOXETINE should be administered with caution to patients being treated with

systemically-administered salbutamol

other

beta2 agonists)

because the action of

salbutamol on the cardiovascular system can be potentiated.

Tricyclic Antidepressants

APO-ATOMOXETINE

increase

adverse

cardiovascular

effects

tricyclic

antidepressants if co-administered.

Desipramine

tricyclic

antidepressants)

pharmacokinetics,

which

dependent

CYP2D6

metabolism,

were

altered

steady-state

atomoxetine

concentrations.

However,

because desipramine has noradrenergic effects,

these medicines should not

used in combination.

Alcohol

Consumption of

ethanol

with APO-ATOMOXETINE does not change the intoxicating effects

of ethanol.

Overdosage

Post

marketing data has 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. Most events were mild to moderate. In

some cases of

overdose involving atomoxetine,

seizures and very rarely QT prolongation

have been reported.

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.

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. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful

the treatment of overdose.

Further Information

Actions

Pharmacodynamics

APO-ATOMOXETINE is a non-stimulant treatment for Attention-Deficit/Hyperactivity Disorder

(ADHD).

[ADHD was formerly known as Attention Deficit

Disorder

(ADD)

with or

without

hyperactivity.]

Atomoxetine is a potent

inhibitor of

the pre-synaptic noradrenaline transporter with minimal

affinity

other

noradrenergic

receptors

other

neurotransmitter

transporters

receptors. In ex vivo uptake and neurotransmitter depletion studies,

atomoxetine was found

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

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Page 17 of 19

to selectively inhibit

the pre-synaptic noradrenaline transporter without

directly affecting the

serotonin or

dopamine transporters.

Atomoxetine has minimal

affinity for

other

receptor

systems.

Atomoxetine is primarily oxidised to 4-hydroxyatomoxetine,

which is also a potent

inhibitor of the pre-synaptic noradrenaline transporter. A thorough QT/QTc study, conducted

in healthy adult CYP2D6 poor metabolizer (PM) subjects dosed up to 60 mg of atomoxetine

BID,

demonstrated that

maximum expected concentrations the effect

atomoxetine on

QTc interval

was not significantly different from placebo. There was a slight increase in QTc

interval with increased atomoxetine concentration.

Pharmacokinetics

Single-dose and steady-state individual

pharmacokinetic

data have been obtained in

children,

adolescents and adults.

After administration of

the same mg/kg dose to children,

adolescents and adults,

similar

half-life,

mean maximum observed plasma concentration

(Cmax)

and the extent

oral

absorption (AUC)

values were observed.

Clearance and

volume of distribution after adjustment for body weight were also similar.

Absorption

Atomoxetine has high permeability and is rapidly and almost completely absorbed after oral

dosing reaching Cmax approximately 1 to 2 hours after dosing. APO-ATOMOXETINE can be

administered

with

without

food.

clinical

trials

with

children

adolescents,

administration

APO-ATOMOXETINE

with

food

resulted

9% lower

Cmax.

Administration of APO-ATOMOXETINE with a standard high-fat meal

in adults did not affect

the AUC,

did decrease the rate of

absorption resulting in a 37% lower

Cmax.

absolute bioavailability of

atomoxetine following oral

administration of

APO-ATOMOXETINE

ranged from 63% to 94% depending upon inter-individual

differences in the modest first pass

metabolism.

Distribution

The steady-state volume of

distribution after intravenous administration was approximately

0.85 L/kg indicating atomoxetine distributes primarily into total

body water.

In children and

adolescents,

volume of

distribution increased nearly proportionally to increases in body

weight.

Volume of

distribution was similar across the patient

weight

range after normalising

for body weight.

therapeutic concentrations,

98% of

atomoxetine in plasma is bound to

protein, primarily albumin.

Metabolism

Atomoxetine undergoes

biotransformation primarily

through the cytochrome P450 2D6

(CYP2D6)

enzymatic

pathway.

major

oxidative

metabolite

formed

hydroxyatomoxetine, which is rapidly glucuronidated. 4-Hydroxyatomoxetine is equipotent to

atomoxetine

circulates

plasma

much

lower

concentrations.

Although

hydroxyatomoxetine is primarily formed by CYP2D6, in individuals that lack CYP2D6 activity,

4-hydroxyatomoxetine can be formed by several

other cytochrome P450 enzymes,

slower rate. Atomoxetine does not inhibit or induce the CYP2D6 pathway.

There are two major

phenotypes associated with CYP2D6:

extensive metabolisers that

comprise greater

than 90% of

the population and poor

metabolisers.

Co-administration of

APO-ATOMOXETINE with known inhibitors of

CYP2D6 does not

result

in an increased

sensitivity to APO-ATOMOXETINE,

although it

may result

in higher

atomoxetine plasma

exposure.

Adjustment

dosing regimens based on metabolism through the CYP2D6

pathway is not necessary.

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

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Page 18 of 19

Elimination

Mean apparent plasma clearance of

atomoxetine after oral

administration in adult extensive

metabolisers is 0.35L/hr/kg and the mean half-life is 3.6 hours. Following oral

administration

in CYP2D6 poor metabolisers, mean apparent plasma clearance is 0.034 L/hr/kg and mean

half-life is 21 hours. At steady state, the AUC of atomoxetine is approximately 10-fold higher

and the maximum plasma concentration at

steady state (C

ss,max

is about

5-fold higher

CYP2D6 poor

metabolisers

than in extensive metabolisers.

No statistically

significant

differences in adverse events or mean efficacious dose were observed between extensive

and poor

metabolisers,

although variability was observed in drug clearance across the

population

studied.

Atomoxetine

excreted

primarily

4-hydroxyatomoxetine-O-

glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the

faeces (less than 17% of the dose). Only a small

fraction of

the APO-ATOMOXETINE dose

was excreted as unchanged atomoxetine (less than 3% of

the dose),

indicating extensive

biotransformation.

Chemical Structure

List of excipients

Each capsule contains 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg or 100 mg atomoxetine

(as the hydrochloride).

In addition to atomoxetine hydrochloride,

each APO-Atomoxetine

capsule contains starch - pregelatinised (maize).

The capsule shell

consists of gelatin, titanium dioxide, iron oxide yellow CI 77492 (18 mg, 25

40 mg,

60 mg,

80 mg,

100 mg),

iron oxide red CI

77491 (80 mg,

100 mg),

indigo

carmine CI

73015 (25 mg,

40 mg,

60 mg).

The capsules are printed with edible black ink

(TekPrint SW-9008/SW-9009).

Gluten free. Lactose free.

Pharmaceutical Precautions

Instructions for Handling

APO-ATOMOXETINE capsules are not

intended to be opened.

Atomoxetine is an ocular

irritant.

In the event

capsule 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.

APO-ATOMOXETINE

Atomoxetine Hydrochloride 10mg, 18mg, 25mg, 40mg, 60mg,

80mg and 100mg Immediate Release Capsules

Please refer to Medsafe website (www.medsafe.govt.nz) for the most recent datasheet

Page 19 of 19

Incompatibilities

Shelf-Life

Shelf life: 2 years from the date of manufacture.

Special Precautions for Storage

Store at or below 25°C

Package Quantities

Blister packs of 28 capsules: 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, 100 mg

Bottles of 1000 capsules for all strengths

Not all strengths, pack types and/or pack sizes may be available

Medicine Schedule

Prescription Medicine

Sponsor Details

Apotex NZ Ltd

32 Hillside Road

Glenfield

Private Bag 102-995

North Shore Mail Centre

Auckland

Telephone:

(09) 444 2073

Fax:

(09) 444 2951

Date of Preparation

22 August 2014

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