JAMP ATOMOXETINE CAPSULE

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Active ingredient:
ATOMOXETINE (ATOMOXETINE HYDROCHLORIDE)
Available from:
JAMP PHARMA CORPORATION
ATC code:
N06BA09
INN (International Name):
ATOMOXETINE
Dosage:
60MG
Pharmaceutical form:
CAPSULE
Composition:
ATOMOXETINE (ATOMOXETINE HYDROCHLORIDE) 60MG
Administration route:
ORAL
Units in package:
100
Prescription type:
Prescription
Therapeutic area:
MISCELLANEOUS CENTRAL NERVOUS SYSTEM AGENTS
Product summary:
Active ingredient group (AIG) number: 0150434005; AHFS: 28:92.00
Authorization status:
APPROVED
Authorization number:
02506858
Authorization date:
2020-10-20

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JAMP ATOMOXETINE

Product Monograph

Page 1

PRODUCT MONOGRAPH

Pr

JAMP Atomoxetine

Atomoxetine Capsules

10, 18, 25, 40, 60, 80 and 100 mg atomoxetine (as atomoxetine hydrochloride)

House standard

Selective Norepinephrine Reuptake Inhibitor

for Attention-Deficit/Hyperactivity Disorder (ADHD)

JAMP Pharma Corporation

1310, rue Nobel

Boucherville, Québec

J4B 5H3

Date of Approval:

October 19, 2020

Submission Control No 235031

JAMP ATOMOXETINE

Product Monograph

Page 2

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ................................................... 3

SUMMARY PRODUCT INFORMATION ....................................................................... 3

INDICATIONS AND CLINICAL USE .......................................................................... 3

CONTRAINDICATIONS ............................................................................................... 4

WARNINGS AND PRECAUTIONS ............................................................................. 5

ADVERSE REACTIONS ............................................................................................. 12

DRUG ABUSE AND DEPENDENCE ......................................................................... 22

DRUG INTERACTIONS .............................................................................................. 23

DOSAGE AND ADMINISTRATION .......................................................................... 24

OVERDOSAGE ............................................................................................................ 27

ACTION AND CLINICAL PHARMACOLOGY ........................................................ 28

STORAGE AND STABILITY ..................................................................................... 32

DOSAGE FORMS, COMPOSITION AND PACKAGING ......................................... 33

PART II: SCIENTIFIC INFORMATION ......................................................................... 34

PHARMACEUTICAL INFORMATION ..................................................................... 34

CLINICAL TRIALS...................................................................................................... 34

DETAILED PHARMACOLOGY ................................................................................. 40

TOXICOLOGY ............................................................................................................. 43

REFERENCES .............................................................................................................. 46

PART III: CONSUMER INFORMATION ....................................................................... 49

JAMP ATOMOXETINE

Product Monograph

Page 3

Pr

JAMP Atomoxetine

Atomoxetine Capsules

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of Administration

Dosage Form / Strength

All Nonmedicinal Ingredients

Oral

10, 18, 25, 40, 60, 80 or

100 mg capsules

The capsules also contain pregelatinized starch and

colloidal silicon Dioxide. The capsule shells contain

gelatin,

sodium lauryl sulfate, and other inactive

ingredients.

The capsule shells also contain one or

more of the

following: FD&C Blue No. 2, synthetic

yellow iron

oxide, red iron oxide, titanium dioxide.

INDICATIONS AND CLINICAL USE

JAMP Atomoxetine (atomoxetine hydrochloride) is indicated for the treatment of Attention-

Deficit/Hyperactivity Disorder (ADHD) in children 6 years of age and over, adolescents, and

adults.

A diagnosis of ADHD (DSM-IV) implies the presence of hyperactive-impulsive or inattentive

symptoms that cause impairment and that were present before age 7 years. The symptoms must

be persistent, must be more severe than is typically observed in individuals at a comparable level

of development, must cause clinically significant impairment, e.g., in social, academic, or

occupational functioning, and must be present in 2 or more settings, e.g., school (or work) and at

home. The symptoms must not be better accounted for by another mental disorder. For the

Inattentive type, at least 6 of the following symptoms must have persisted for at least 6 months:

lack of attention to details/careless mistakes, lack of sustained attention, poor listener, failure to

follow through on tasks, poor organization, avoids tasks requiring sustained mental effort, loses

things, easily distracted, forgetful. For the Hyperactive-Impulsive type, at least 6 of the following

symptoms must have persisted for at least 6 months: fidgeting/squirming, leaving seat,

inappropriate running/climbing, difficulty with quiet activities, “on the go,” excessive talking,

blurting answers, can’t wait turn, intrusive. For a Combined Type diagnosis, both inattentive and

hyperactive-impulsive criteria must be met.

Special Diagnostic Considerations

The specific etiology of ADHD is unknown, and there is no single diagnostic test. Adequate

diagnosis requires the use not only of medical but also of special psychological, educational, and

social resources. Learning may or may not be impaired. The diagnosis must be based upon a

complete history and evaluation of the patient and not solely on the presence of the required

number of DSM-IV characteristics.

JAMP ATOMOXETINE

Product Monograph

Page 4

Need for Comprehensive Treatment Program

JAMP Atomoxetine is indicated as an integral part of a total treatment program for ADHD that

may include other measures (psychological, educational, and social) for patients with this

syndrome.

Drug treatment may not be indicated for all patients with this syndrome. Drug

treatment is not

intended for use in the patient who exhibits symptoms secondary to

environmental factors and/or

other primary psychiatric disorders, including psychosis.

Appropriate educational placement is

essential in children and adolescents with this diagnosis

and psychosocial intervention is often

helpful. When remedial measures alone are insufficient,

the decision to prescribe drug treatment

medication will depend upon the physician’s assessment

of the chronicity and severity of the

patient’s symptoms.

Pediatrics (<6 years of age)

The safety and efficacy of atomoxetine capsules in pediatric patients less than 6 years of age have

been established.

CONTRAINDICATIONS

Hypersensitivity: JAMP Atomoxetine (atomoxetine hydrochloride) is contraindicated in

patients

known to be hypersensitive to atomoxetine or other constituents of the product

(see

WARNINGS).

Monoamine Oxidase Inhibitors: JAMP Atomoxetine should not be taken with monoamine

oxidase inhibitors (MAOI), or within 2 weeks after discontinuing MAOI. Treatment with

MAOI should not be initiated within 2 weeks after discontinuing JAMP Atomoxetine. With

other

drugs that affect brain monoamine concentrations, there have been reports of serious,

sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability

with possible rapid fluctuations of vital signs, and mental status changes that include

extreme agitation progressing to delirium and coma) when taken in combination with

MAOI. Some cases presented with features resembling neuroleptic malignant syndrome.

Such reactions may occur when these drugs are given concurrently or in close proximity.

Pheochromocytoma: JAMP Atomoxetine should not be used in patients with

pheochromocytoma

or a history of pheochromocytoma. Serious reactions, including

elevated blood pressure and

tachyarrhythmia, have been reported in patients with

pheochromocytoma or a history of pheochromocytoma who received atomoxetine capsules.

Narrow Angle Glaucoma: In clinical trials, atomoxetine capsules use was associated with

increased risk of mydriasis and therefore its use is not recommended in patients with

narrow angle glaucoma.

Symptomatic cardiovascular disease.

Severe Cardiovascular Disorders: JAMP 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.

JAMP ATOMOXETINE

Product Monograph

Page 5

Moderate to severe hypertension.

Advanced arteriosclerosis.

Uncontrolled hyperthyroidism.

WARNINGS AND PRECAUTIONS

POTENTIAL ASSOCIATION WITH THE OCCURRENCE OF BEHAVIOURAL AND

EMOTIONAL CHANGES, INCLUDING SELF-HARM

Pediatric Placebo-Controlled Clinical Trial Data: An increased risk over placebo for

suicide-related events in children and adolescents taking atomoxetine capsules, was

identified in a

pooled analysis of placebo-controlled trials of 6-18 weeks duration. Of

1357 patients who received atomoxetine capsules, 5 (0.37%) had reports of suicidal

ideation compared to 0% of 851 patients who received placebo. In addition, one suicide

attempt (overdose) was identified, which occurred in a atomoxetine capsules patient. No

completed suicides occurred

during these trials. (See also WARNINGS AND

PRECAUTIONS, Special Populations, Pediatrics, 6-18 years of age).

Post-Marketing Data: There have been very rare reports of suicidal ideation, suicidal

attempts, suicidal depression and completed suicides in children, adolescents and adults (see

ADVERSE REACTIONS, Post-Market Adverse Drug Reactions, Tables 8 and 9).

ADHD and its related co-morbidities may be associated with increased risk of suicidal

ideation and/or behaviour. Rigorous clinical monitoring for suicidal ideation or other

indicators of potential for suicidal behaviour is advised in patients of all ages. This includes

monitoring for agitation-type of emotional and behavioural changes, and clinical worsening.

Families and caregivers of pediatric patients being treated with JAMP Atomoxetine should be

alerted about the need to monitor patients for the emergence of agitation, anxiety, panic

attacks, hostility, irritability, hypomania or mania, unusual changes in behaviour, and other

symptoms, as well as the emergence of suicidality particularly after starting treatment or

changing the dose. Such symptoms should be reported immediately to healthcare providers.

Such monitoring should include daily observation by families and caregivers.

Screening Patients for Bipolar Disorder

Particular care should be taken in treating ADHD in patients with comorbid bipolar disorder

because of concern for possible induction of a mixed/manic episode in patients at risk for bipolar

disorder. Prior to initiating treatment with JAMP Atomoxetine, patients with comorbid

depressive

symptoms should be adequately screened to determine if they are at risk for bipolar

disorder;

such screening should include a detailed psychiatric history, including a family history

of suicide,

bipolar disorder, and depression.

JAMP ATOMOXETINE

Product Monograph

Page 6

Emergence of New Psychotic or Manic Symptoms

Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or

mania in children and adolescents without a prior history of psychotic illness or mania can occur

with atomoxetine use 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. In a

pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in

about 0.2% (4 patients with events out of 1939 exposed to atomoxetine for several weeks at usual

doses) of atomoxetine-treated patients compared to 0 out of 1056 placebo-treated patients.

Pre-Existing Psychosis:

Administration of medications for ADHD may also exacerbate symptoms of behaviour

disturbance

and thought disorder in patients with a pre-existing psychotic disorder.

Severe Liver Injury

Post-marketing reports indicate that atomoxetine capsules can cause severe liver injury in

rare

cases, including acute liver failure. Although no evidence of liver injury was detected in

clinical

trials of about 6000 patients, there have been rare cases in postmarketing experience of

clinically significant liver injury that were considered probably or possibly related to

atomoxetine capsules. In one patient, liver injury, manifested by elevated hepatic enzymes (up to

40 X upper limit of normal [ULN]) and jaundice (bilirubin up to 12 X ULN), recurred upon

rechallenge and was followed by recovery upon drug discontinuation, providing evidence that

atomoxetine capsules likely caused the liver injury. This patient recovered from his liver injury,

and did

not require a liver transplant. Such reactions may occur several months after therapy is

started,

but laboratory abnormalities may continue to worsen for several weeks after drug is

stopped.

One case of hepatic failure leading to a liver transplant has been reported in a child taking

atomoxetine. Because of probable under-reporting, it is impossible to provide an accurate

estimate of the true incidence of these events. Severe liver injury due to any drug may potentially

progress to acute liver failure resulting in death or the need for a liver transplant.

JAMP 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 done upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark

urine,

jaundice, right upper quadrant tenderness, or unexplained "flu-like" symptoms). (See also

CONSUMER INFORMATION).

Allergic Events

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

edema, and urticaria, have been reported in patients taking atomoxetine capsules.

Effects on Growth

Growth and development should be monitored during treatment with atomoxetine. Patients

requiring long-term therapy should be monitored and consideration should be given to dose

reduction or interrupting therapy in patients who are not growing or gaining weight satisfactorily.

JAMP ATOMOXETINE

Product Monograph

Page 7

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.

In general, the weight and height gain of pediatric patients treated with atomoxetine capsules

lags behind that predicted by normative population data for about the first 9 - 12 months of

treatment.

Subsequently, weight gain rebounds and at about 3 years of treatment, patients

treated with

atomoxetine capsules gained 17.9 kg on average, 0.5 kg more than predicted by

their baseline data.

After about 12 months, gain in height stabilizes, and at 3 years, patients treated with

atomoxetine capsules gained 19.4 cm on average, 0.4 cm less than predicted by their baseline

data.

Cardiovascular

Pre existing Cardiovascular Conditions

JAMP Atomoxetine can increase heart rate and blood pressure. It is recommended that heart

rate and blood pressure be measured before treatment is started, after the dose is increased or

decreased,

and periodically during treatment to detect possible clinically important increases,

particularly during the first few months of therapy.

JAMP 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, or cardiovascular or cerebrovascular disease (see

CONTRAINDICATIONS and ADVERSE REACTIONS).

In addition, JAMP Atomoxetine should be used with caution in patients with congenital long QT

syndrome, acquired long QT syndrome (for example, due to concomitant use of a drug that may

prolong the QT), or a family history of QT prolongation. Patients should be screened for pre-

existing or underlying cardiovascular or cerebrovascular conditions before initiation of treatment

with JAMP Atomoxetine and monitored for new conditions of the heart or brain during the course

of treatment.

Orthostatic hypotension has been reported in subjects taking atomoxetine capsules. In short-term

child- and adolescent-controlled trials, 5.2% (34/657) of atomoxetine capsules-treated subjects

experienced

symptoms of postural hypotension compared with 2.0% (8/408) of placebo-treated

subjects.

JAMP 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.

The increase in blood pressure and heart rate observed during treatment with atomoxetine

capsules

during placebo-controlled clinical trials for pediatric patients and adults with ADHD are

shown in

Tables 1 and 2, respectively.

JAMP ATOMOXETINE

Product Monograph

Page 8

Table 1.

Proportion of pediatric ADHD patients treated with atomoxetine capsules (any

dose) or placebo, in whom a given increase in diastolic and systolic blood

pressure and heart rate was observed during acute placebo-controlled trials.

Parameter

(unit)

Change from

baseline

(limit of interest)

Percent of ADHD pediatric patients (%)

Time observed

Maximum

(change at any post-baseline visit)

Endpoint

(change at the last visit)

atomoxetine

capsules

N = 2287

Placebo

N = 1334

atomoxetine

capsules

N = 2287

Placebo

N = 1334

Diastolic BP

(mm Hg)

Systolic BP

(mm Hg)

Heart rate

(beats/min)

Table 2.

Proportion of adult ADHD patients treated with atomoxetine capsules (any dose)

or placebo, in whom a given increase in diastolic and systolic blood pressure and

heart rate was observed during long-term placebo-controlled trials.

Parameter

(unit)

Change from

baseline

(limit of interest)

Percent of ADHD adult patients (%)

Time observed

Maximum

(change at any post-baseline visit)

Endpoint

(change at the last visit)

atomoxetine

capsules

N = 499

Placebo

N = 1334

atomoxetine

capsules

N = 499

Placebo

N = 1334

Diastolic BP

(mm Hg)

Systolic BP

(mm Hg)

Heart rate

(beats/min)

The overall increase in blood pressure and heart rate observed during treatment with

atomoxetine

capsules during controlled and uncontrolled clinical trials for pediatric patients with ADHD are

shown in Table 3.

JAMP ATOMOXETINE

Product Monograph

Page 9

Table 3.

Proportion of overall pediatric ADHD patients treated with atomoxetine capsules

(any dose), in whom a given increase in diastolic and systolic blood pressure and

heart rate was observed during controlled and uncontrolled clinical trials.

Parameter

(unit)

Change from

baseline

(limit of interest)

atomoxetine capsules N = 8417

Percent of ADHD pediatric patients (%)

Time observed

Maximum

(change at any post-baseline visit)

Endpoint

(change at the last visit)

Diastolic BP

(mm Hg)

Systolic BP

(mm Hg)

Heart rate

(beats/min)

Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart

Problems

Children and Adolescents: Sudden death has been reported in association with atomoxetine

treatment at usual doses in children and adolescents with structural cardiac abnormalities or other

serious heart problems as well as in some patients without structural heart problems. Although

some serious heart problems alone carry an increased risk of sudden death, atomoxetine

generally should not be used in children or adolescents with known serious structural cardiac

abnormalities,

cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac

problems that may

place them at increased vulnerability to the noradrenergic effects of

atomoxetine.

Adults: Sudden deaths, stroke, and myocardial infarction have been reported in adults taking

atomoxetine at usual doses for ADHD. Although the role of atomoxetine in these adult cases is

also unknown, adults have a greater likelihood than children of having serious structural cardiac

abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or

other serious cardiac problems. Consideration should be given to not treating adults with

clinically significant cardiac abnormalities.

General

Children: Theoretically there exists a pharmacological potential for all ADHD drugs to increase

the risk of sudden/cardiac death. Although confirmation of an incremental risk for adverse

cardiac events arising from treatment with ADHD medications is lacking, prescribers should

consider this potential risk.

All drugs with sympathomimetic effects prescribed in the management of ADHD should be used

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

stimulants, or c) have a family history of sudden/cardiac death. Prior to the initiation of

JAMP ATOMOXETINE

Product Monograph

Page 10

treatment with sympathomimetic medications, a personal and family history (including

assessment for a family

history of sudden death or ventricular arrhythmia) and physical exam

should be obtained to

assess for the presence of cardiac disease. In patients with relevant risk

factors and based on the

clinician’s judgment, further cardiovascular evaluation may be

considered (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such

as exertional

chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease

during ADHD treatment should undergo a prompt cardiac evaluation. Patients who are

considered to need

extended treatment with JAMP Atomoxetine should undergo periodic

evaluation of their

cardiovascular status (see DOSAGE AND ADMINISTRATION).

Genitourinary

Effects on urine outflow from the bladder: In adult ADHD controlled trials, the rates of urinary

retention and urinary hesitation were increased among atomoxetine subjects compared with

placebo subjects. A complaint of urinary retention or urinary hesitancy should be considered

potentially related to atomoxetine.

Priapism: Rare postmarketing cases of priapism, defined as painful and non-painful penile

erection lasting more than 4 hours, have been reported for pediatric and adult patients treated

with atomoxetine capsules. The erections resolved in cases in which follow-up information was

available, some following discontinuation of atomoxetine capsules. Prompt medical attention is

required in the event of suspected priapism

Vascular

Periph eral Vasculopath y, Inclu din g Raynaud’s Phenom enon

Medications used to treat ADHD, including stimulants and non-stimulant (JAMP Atomoxetine),

associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and

symptoms

are usually intermittent and mild; however, very rare sequelae include digital

ulceration and/or

soft tissue breakdown. Effects of peripheral vasculopathy, including

Raynaud’s phenomenon,

were observed in post-marketing reports at different times and at

therapeutic doses in all age

groups throughout the course of treatment. Signs and symptoms

generally improve after reduction in dose or discontinuation of drug. Careful observation for

digital changes is necessary during treatment with ADHD medications. Further clinical

evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

Special Populations

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

women. JAMP Atomoxetine should not be used during pregnancy unless the potential benefit

justifies the potential risk to the fetus. The effect of atomoxetine capsules on labour and delivery

in humans is unknown.

The extent of exposure in pregnancy during clinical trials was very limited.

JAMP ATOMOXETINE

Product Monograph

Page 11

Nursing Mothers: Atomoxetine and/or its metabolites were excreted in the milk of rats. It is not

known if atomoxetine is excreted in human milk. Caution should be exercised if JAMP

Atomoxetine is administered to a nursing woman.

Pediatrics (< 6 years of age): The safety and efficacy of atomoxetine capsules in pediatric

patients less than 6 years of age have not been established.

Pediatrics (6–18 years of age):

Risk of Suicide-Related Behaviours and Ideation in Children (see also WARNINGS AND

PRECAUTIONS – POTENTIAL ASSOCIATION WITH THE OCCURRENCE OF

BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).

Pediatric Placebo-Controlled Clinical Trial Data: An increased risk over placebo, for suicide-

related events in children and adolescents taking atomoxetine capsules was identified in a

combined analysis of 12 short-term (6 – 18 weeks) placebo-controlled trials (11 in ADHD and 1

enuresis). Of 1357 patients who received atomoxetine capsules, 5 (0.37%) had reports of

suicidal

ideation compared to 0% of 851 patients who received placebo. In addition, one

suicide

attempt (overdose) was identified which occurred in a atomoxetine capsules patient.

These 6 events

occurred in atomoxetine capsules patients 7 to 12 years of age who were male.

There were no events in older adolescents, who comprised about 25 percent of the study

population. Time to onset

ranged from 9 to 32 days, and doses ranged from 0.48 to 1.40

mg/kg/day. A similar analysis in

adult patients treated with atomoxetine capsules for either

ADHD or major depressive disorder (MDD) found no increased risk over placebo of suicidal

ideation or behaviour with the use of atomoxetine capsules.

Not included in these numerators were 6 cases (3 in the atomoxetine capsules arms and 3 in the

placebo arms) of non-fatal potentially self-injurious actions where the intent is unknown, including

burns

and taking more than one dose of medication at a time.

Post Marketing Data: There have been very rare reports of suicidal ideation, suicidal attempts,

suicidal depression and completed suicides in children and adolescents (see ADVERSE

REACTIONS, Post-Market Adverse Drug Reactions, Tables 8 and 9).

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal

behaviour is advised in patients of all ages. This includes monitoring for agitation-type of

emotional and behavioural changes, and clinical worsening.

Irritability and Mood Swings: Clinical Trial Data

Clinical trial data in children and adolescents show higher rates than placebo for irritability, mood

swings, aggression, crying and tearfulness (see ADVERSE REACTIONS, Tables 4 and 5). The

relationship, if any, between these events and suicide-related behaviours in children and

adolescents with ADHD is unclear.

Aggressive Behaviour or Hostility

Patients beginning treatment for ADHD should be monitored for the appearance of, or worsening

of, aggressive behaviour or hostility.

JAMP ATOMOXETINE

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Caregivers/patients should be instructed to call their doctor as soon as possible should they notice

an increase in aggression or hostility.

Aggressive behaviour or hostility has been observed in patients with ADHD, and has been

reported with some medications indicated for the treatment of ADHD.

Although there is no conclusive evidence that atomoxetine causes aggressive behaviour or

hostility, this was observed more frequently in clinical trials among children, adolescents and

adults treated with atomoxetine compared to placebo (risk ratios varying from 1.03 in children

and adolescents to 1.38 in adults – not statistically significant).

Geriatrics (> 65 years of age): The safety and efficacy of atomoxetine capsules in geriatric

patients

have not been established.

Monitoring and Laboratory Tests

Routine laboratory tests are not required

CYP2D6 metabolism: Poor metabolizers (PMs) of CYP2D6 have a 10-fold higher AUC and a

5-fold higher peak concentration to a given dose of atomoxetine capsules compared with

extensive

metabolizers (EMs). Approximately 7% of a Caucasian population are PMs.

Laboratory tests

are available to identify CYP2D6 PMs. The blood levels in PMs are similar to

those attained by taking strong inhibitors of CYP2D6. The higher blood levels in PMs lead to a

higher rate of some adverse effects of atomoxetine capsules (see ADVERSE REACTIONS).

ADVERSE REACTIONS

Atomoxetine capsules was administered to 3262 children or adolescent patients with

ADHD and 471 adults with ADHD in clinical studies. During the ADHD clinical trials,

1409 patients

(1236 pediatric and 173 adults) were treated for longer than 1 year and 1940

patients (1704 pediatric and 236 adults) were treated for over 6 months.

The data in the following tables and text cannot be used to predict the incidence of side effects in

the course of usual medical practice where patient characteristics and other factors differ from

those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with

data obtained from other clinical investigations involving different treatments, uses, or

investigators. The cited data provide the prescribing physician with some basis for estimating the

relative contribution of drug and non-drug factors to the adverse event incidence in the population

studied.

Child and Adolescent Clinical Trials

Reasons for discontinuation of treatment due to adverse events in child and adolescent clinical

trials: In acute child and adolescent placebo-controlled trials, 4.1% (27/661) of atomoxetine

subjects and 1.2% (5/410) placebo subjects discontinued for adverse events. For all studies,

(including open-label and long-term studies), 5.8% of extensive metabolizer (EM) patients and

8.9% of poor metabolizer (PM) patients discontinued because of an adverse event. Among

atomoxetine capsules-treated patients, somnolence (0.8%, N = 5); aggression (0.5%, N = 3);

irritability (0.5%, N = 3); vomiting (0.5%, N = 3) and abdominal pain (0.3%, N = 2) were the

reasons for discontinuation reported by more than 1 patient.

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Commonly observed adverse events in acute child and adolescent, placebo-controlled trials:

Commonly observed adverse events associated with the use of atomoxetine capsules (incidence

of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients

(atomoxetine capsules incidence greater than placebo) are listed in Table 4 for all acute

placebo-controlled trials. Results were similar in the BID trials and QD trials except as shown in

Table 5, which shows both BID and QD results for selected adverse events. The most commonly

observed adverse events in patients treated with atomoxetine capsules (incidence of 5% or greater

and at

least twice the incidence in placebo patients, for either BID or QD dosing) were: appetite

decreased, dizziness, dyspepsia, fatigue and/or lethargy, irritability, nausea, somnolence, and

vomiting (see Table 4). Additional data on blood pressure and heart rate from ADHD clinical

trials is shown in Tables 1 - 3.

Table 4:

Common Treatment-Emergent Adverse Events Reported in atomoxetine capsules

Placebo- Controlled Clinical Trials in Children and Adolescents with ADHD

a

Adverse Event

Percentage of Patients Reporting Events

Atomoxetine capsules

(N = 657)

Placebo

(N = 408)

Gastrointestinal Disorders

Abdominal pain upper

Dyspepsia

Nausea

Vomiting

General Disorders

Fatigue and/or Lethargy

Investigations

Weight decreased

Metabolism and Nutritional Disorders

Anorexia

<1

Appetite decreased

Nervous System Disorders

Dizziness

Headache

Somnolence

Psychiatric Disorders

Irritability

Mood swings

<1

Respiratory Disorders

Rhinorrhea

Skin and Subcutaneous Tissue Disorders

Rash

a

Events reported by at least 2% of patients treated with atomoxetine, and greater than placebo. 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: aggression, blood pressure increased, early morning

awakening, flushing, mydriasis, sinus tachycardia, crying, tearfulness, suicidal ideation. The following events

were reported by at least 2% of patients treated with atomoxetine, and equal to or less than placebo: cough,

diarrhea, insomnia, nasal congestion, nasopharyngitis, pharyngitis, pyrexia, upper respiratory tract infection.

JAMP ATOMOXETINE

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Table 5:

Common Treatment-Emergent Adverse Events Associated with the Use of atomoxetine

capsules in Acute (up to 9 weeks) Child and Adolescent Trials

a

Adverse Event

Percentage of Patients Reporting

Events from BID Trials

Percentage of Patients Reporting

Events from QD Trials

Atomoxetine

Capsules

Placebo

Atomoxetine

Capsules

Placebo

(N = 201)

(N = 340)

(N = 207)

(N = 317)

Gastrointestinal Disorders

Abdominal pain

<1

<1

Abdominal pain upper

Constipation

<1

Dyspepsia

<1

Nausea

Vomiting

General Disorders

Fatigue and/or Lethargy

Pyrexia

Infections and Infestations

Ear infection

<1

Influenza

<1

Pharyngitis streptococcal

<1

<1

<1

Investigations

Weight decreased

Metabolism and Nutritional Disorders

Anorexia

<1

<1

Appetite decreased

Nervous System Disorders

Dizziness

<1

Headache

Sedation

Somnolence

Psychiatric Disorders

Aggression

<1

Crying

Mood swings

Irritability

Respiratory Disorders

Cough

Rhinorrhoea

Skin and Subcutaneous Tissue Disorders

Rash

a

Events reported by at least 2% of patients treated with atomoxetine, and greater than placebo in either BID

or QD trials.

The following adverse events occurred in child and adolescent patients, and were obtained from

ongoing clinical trials:

JAMP ATOMOXETINE

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Common: depression (including major depression, depressive symptoms, depressed mood, and

dysphoria), insomnia (including initial insomnia, middle insomnia, and terminal insomnia), and

pruritus.

Uncommon: asthenia, palpitations, sinus tachycardia, syncope (includes syncope vasovagal), and

tremor.

The following adverse events occurred in at least 2% of child and adolescent CYP2D6 PM

patients and were statistically significantly more frequent in PM patients compared with CYP2D6

EM patients: appetite decreased (24% of PMs, 17% of EMs); insomnia and middle

insomnia (14% of PMs, 7% of EMs); weight decreased (7% of PMs, 4% of EMs); constipation

(7% of PMs, 4% of EMs); sedation (4% of PMs, 2% of EMs); depression and/or depressed

mood (5% of PMs, 3% of EMs); abrasion (4% of PMs, 2% of EMs); tremor (5% of PMs, 1% of

EMs); early morning awakening (2% of PMs, 1% of EMs); enuresis (3% of PMs, 1% of EMs);

pruritus (3% of PMs, 1% of EMs); mydriasis (2% of PMs, 1% of EMs); conjunctivitis (3% of

PMs, 1% of EMs); syncope (2% of PMs, 1% of EMs); animal bite (2% of PMs, 1% of EMs).

Adult Clinical Trials

Reasons for discontinuation of treatment due to adverse events in acute adult placebo-controlled

trials: In the acute adult placebo-controlled trials, 8.5% (23/270) atomoxetine subjects and

3.4% (9/266) placebo subjects discontinued for adverse events. Among atomoxetine capsules-

treated

patients, insomnia (1.1%, N = 3); chest pain (0.7%, N = 2); palpitations (0.7%, N = 2);

urinary retention (0.7%, N = 2) were the reasons for discontinuation reported by more than

1 patient.

Commonly observed adverse events in acute adult placebo-controlled trials: Commonly

observed adverse events associated with the use of atomoxetine capsules (incidence of 2% or

greater) and not observed at an equivalent incidence among placebo-treated patients

(atomoxetine capsules

incidence greater than placebo) are listed in Table 6.

The most commonly observed adverse events in patients treated with atomoxetine capsules

(incidence of 5% or greater and at least twice the incidence in placebo patients) were:

constipation, dry mouth, nausea, appetite decreased, dizziness, insomnia, decreased libido,

ejaculatory problems, erectile

disturbance, urinary hesitation and/or urinary retention and/or

difficulty in micturition, and

dysmenorrhea (see Table 6). Additional data on blood pressure and

heart rate from ADHD clinical trials is shown in Tables 1 - 3.

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Table 6:

Common Treatment-Emergent Adverse Events Associated with the Use of

atomoxetine capsules in Acute (up to 10 weeks) Adult Trials

Percentage of Patients Reporting Event

Adverse Event

a

Atomoxetine

Capsules

(N = 269)

Placebo

(N = 263)

Cardiac Disorders

Palpitations

Gastrointestinal Disorders

Constipation

Dry mouth

Dyspepsia

Flatulence

Nausea

General Disorders

Fatigue and/or Lethargy

Pyrexia

Chills

Infections

Sinusitis

Investigations

Weight decreased

Metabolism and Nutritional Disorders

Appetite decreased

Musculoskeletal Disorders

Myalgia

Nervous System Disorders

Dizziness

Headache

Insomnia and/or middle insomnia

Paraesthesia

Sinus headache

Psychiatric Disorders

Abnormal dreams

Libido decreased

Sleep disorder

Renal and Urinary Disorders

Urinary hesitation and/or urinary retention

and dysuria

Reproductive System and Breast Disorders

Dysmenorrhea

Ejaculation failure

and/or

ejaculation disorder

Erectile dysfunction

Impotence

Menses delayed

Menstrual disorder

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Menstruation irregular

Orgasm abnormal

Prostatitis

Skin and Subcutaneous Tissue Disorders

Rash

Sweating increased

Vascular Disorders

Hot flushes

Events reported by at least 2% of patients treated with atomoxetine, and greater than placebo. 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: early morning awakening, peripheral coldness, tachycardia. The following events were reported by at

least 2% of patients treated with atomoxetine, and equal to or less than placebo: abdominal pain upper, arthralgia, back pain,

cough, diarrhea, influenza, irritability, nasopharyngitis, sore throat, upper respiratory tract infection, vomiting.

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

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

The following adverse events occurred in adult patients, and were obtained from ongoing clinical

trials:

Common: agitation, asthenia, dysgeusia, feeling jittery, flushing, hyperhidrosis, pollakiuria,

somnolence (including sedation), testicular pain, thirst, and tremor.

Uncommon: feeling cold, muscle spasms, pruritus, restlessness, urticaria, and vision blurred.

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% EMs); feeling jittery (4.9%

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% of EMs); hyperhidrosis (14.8% of PMs, 6.8%

of EMs); peripheral coldness (3.0% of PMs, 0.5% or EMs).

Male and female sexual dysfunction: Atomoxetine appears to impair sexual function in some

patients. Changes in sexual desire, sexual performance, and sexual satisfaction are not well

assessed in most clinical trials because they need special attention and because patients and

physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of

untoward sexual experience and performance cited in product labelling are likely to

underestimate the actual incidence. The table below displays the incidence of sexual side effects

reported by at least 2% of adult patients taking atomoxetine capsules in placebo-controlled trials.

Table 7

Atomoxetine

Capsules

Placebo

Erectile dysfunction

Libido decreased

Ejaculation failure

and/or ejaculation disorder

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Impotence

Orgasm abnormal

Males only.

There are no adequate and well-controlled studies examining sexual dysfunction with

atomoxetine capsules treatment. While it is difficult to know the precise risk of sexual

dysfunction associated with the use of atomoxetine capsules, physicians should routinely inquire

about such possible

side effects.

Post-Market Adverse Drug Reactions

During the first 5 years of post-market experience, it is estimated that over 5 million patients have

been treated with atomoxetine capsules, for 1,715,000 patient-years of therapy.

Tables 8 and 9 are based on post-market spontaneous adverse event reports. The percentages

shown are calculated by dividing the number of adverse events reported to the company by the

estimated number of patients exposed to the drug during the same time period. The causal

relationship between atomoxetine capsules and the emergence of these events has not been

established.

Table 8:

Atomoxetine capsules Post-Market Spontaneous Adverse Event Reports in

Children and Adolescents with ADHD.

Adverse Event

Frequency

1%

<1% and

0.1%

<0.1% and

0.01%

<0.01%

Cardiac Disorders

Palpitations

Sinus tachycardia

Electrocardiogram QT prolonged

Eye Disorders

Mydriasis

Gastrointestinal Disorders

Abdominal pain

Dyspepsia

Hepatobiliary effects

Liver Function Tests abnormal

Nausea

Vomiting

General Disorders

Lethargy

Sudden death

Injury

Overdose

Investigations

Weight decreased

Metabolism and Nutritional Disorders

Anorexia

Appetite decreased

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Adverse Event

Frequency

1%

<1% and

0.1%

<0.1% and

0.01%

<0.01%

Nervous System Disorders

Dizziness

Hypoaesthesia

Paraesthesia

Seizure

Somnolence

Syncope

Tics

Psychiatric Disorders

Aggression/Hostility

Anxiety

Depression and depressed mood

Early morning awakening

Irritability

Mood swings

Sensory disturbances including

hallucinations

Suicidality

Skin and Subcutaneous Tissue Disorders

Hyperhidrosis

Pruritis

Rash

Urogenital Disorders

Male genital pain

Painful or prolonged penile erection

Urinary hesitation

Urinary retention

Vascular Disorders

Peripheral vascular instability, e.g.,

Raynaud’s phenomenon

Potential to exacerbate pre-existing

Raynaud’s phenomenon

a

These spontaneously reported cases are not well documented, and the method of correction is unknown.

Frequency of seizures reported = 0.01%

Includes reports of ‘loss of consciousness’.

Includes reports of completed suicide, suicidal ideation, suicide attempt and suicidal depression.

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Table 9:

Atomoxetine capsules Post-Market Spontaneous Adverse Event Reports in Adult

Patients with

ADHD.

Adverse Event

Frequency

1%

<1% and

0.1%

<0.1% and

0.01%

<0.01%

Cardiac Disorders

Palpitations

Tachycardia

Electrocardiogram QT prolonged

a

Gastrointestinal Disorders

Abdominal pain

Constipation

Dry mouth

Dyspepsia

Flatulence

Hepatobiliary effects

Liver Function Tests abnormal

Nausea

General Disorders

Fatigue

Lethargy

Chills

Sudden death

Injury

Overdose

Investigations

Weight decreased

Metabolism and Nutritional Disorders

Appetite decreased

Nervous System Disorders

Dizziness

Hypoaesthesia

Insomnia

Middle insomnia

Seizure

Sinus headache

Syncope

Tics

Psychiatric Disorders

Anxiety

Depression and depressed mood

Early morning awakening

Libido decreased

Sleep disorder

Suicidality

Renal and Urinary Disorders

Difficulty in micturition

Urinary hesitation

JAMP ATOMOXETINE

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Adverse Event

Frequency

1%

<1% and

0.1%

<0.1% and

0.01%

<0.01%

Urinary retention

Reproductive System and Breast Disorders

Dysmenorrhea

Ejaculation disorder

Ejaculation failure

Erectile dysfunction

Male genital pain

Menstruation irregular

Orgasm abnormal

Prostatitis

Skin and Subcutaneous Tissue Disorders

Dermatitis

Hyperhidrosis

Urogenital Disorders

Male genital pain

Painful or prolonged penile erection

Vascular Disorders

Hot flushes

Peripheral coldness

Peripheral vascular instability, e.g.,

Raynaud’s phenomenon

Potential to exacerbate pre-existing

Raynaud’s phenomenon

These spontaneously reported cases are not well documented, and the method of correction is unknown.

Frequency of seizures reported = 0.0035%

Includes reports of ‘loss of consciousness’.

Includes reports of completed suicide, suicidal ideation, suicide attempt, and suicidal depression.

In post-market experience, serious skin reactions, hepatic failure and severe hepatic injury were

reported at a spontaneous reporting rate less than 0.001%.

DRUG ABUSE AND DEPENDENCE

JAMP Atomoxetine is not a controlled substance.

JAMP Atomoxetine is not a stimulant drug.

In a randomized, double-blind, placebo-controlled,

abuse-

potential

study in

adults

comparing effects

atomoxetine

capsules

placebo,

atomoxetine capsules was not

associated with a pattern of response that suggested stimulant or

euphoriant properties.

Clinical trials data in over 4000 children, adolescents, and adults with ADHD showed only

isolated incidents of drug diversion or inappropriate self-administration associated with

atomoxetine capsules. There was no evidence of symptom rebound or adverse events suggesting

a drug- discontinuation or withdrawal syndrome.

In preclinical studies, atomoxetine did not show a behavioural profile or stimulant properties

associated with drugs that have abuse liability.

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DRUG INTERACTIONS

Overview

Atomoxetine hydrochloride is primarily metabolized by the CYP2D6 pathway to

hydroxyatomoxetine. In extensive metabolizers (EMs), inhibitors of CYP2D6 (e.g., paroxetine,

fluoxetine, quinidine) increase atomoxetine steady-state plasma concentrations to

exposures

similar to those observed in poor metabolizers (PMs). Dosage adjustment of

JAMP Atomoxetine

may be necessary when coadministered with CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and

quinidine (see DOSAGE AND ADMINISTRATION). In EM individuals treated

with paroxetine

or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and C

ss,max

about 3- to 4-

fold greater than atomoxetine alone.

JAMP Atomoxetine should be used with caution if used concomitantly with other drugs that

increase QT interval or disturb electrolyte balance or inhibit CYP2D6.

In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not

further increase the plasma concentration of atomoxetine.

Atomoxetine did not cause clinically significant inhibition or induction of cytochrome P450

enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9.

Drugs that affect norepinephrine should be used cautiously when co-administered with

JAMP

Atomoxetine because of the potential for additive or synergistic pharmacological effects.

Drug-Drug Interactions

Table 10.

Established or Potential Drug-Drug Interactions with atomoxetine capsules

Drug

Ref

Effect

Clinical comment

MAO Inhibitors

There have been reports of serious,

sometimes fatal, reactions when MAO

Inhibitors are given concurrently or in close

proximity to other drugs that affect brain

monoamine concentrations.

See CONTRAINDICATIONS

Desipramine

Coadministration of atomoxetine

capsules with desipramine did not alter

pharmacokinetics of desipramine.

Because desipramine has noradrenergic effects,

it should not be used in combination with

JAMP Atomoxetine.

Fluoxetine,

Paroxetine

Coadministration of selective inhibitors of

CYP2D6 may increase atomoxetine steady-

state plasma concentrations to exposures

similar to those observed in CYP2D6 poor

metabolizer patients.

Slower titration of JAMP Atomoxetine may be

necessary in those patients who are also taking

fluoxetine, paroxetine or other CYP2D6

inhibitor drugs (see Dosage and

Administration, Special Populations).

Salbutamol or other

-adrenergic

receptor agonists

There was no significant interaction

between salbutamol and atomoxetine

JAMP Atomoxetine may be used in

combination with inhaled β2 agonists, e.g.,

salbutamol, but should be used with caution in

patients being treated with systemically

administered (oral or intravenous)

2 agonists,

including salbutamol.

JAMP ATOMOXETINE

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Drug

Ref

Effect

Clinical comment

Anti-hypertensive

drugs and Pressor

Agents

Possible effects on blood pressure.

JAMP Atomoxetine should be used with

caution in patients being treated with anti-

hypertensive

drugs and pressor agents, or

other drugs that

increase blood pressure.

Methylphenidate

Co-administration of methylphenidate with

atomoxetine capsules did not increase

cardiovascular effects beyond those seen

with methylphenidate administration alone.

Midazolam

Co-administration

atomoxetine

capsules

with

midazolam

resulted

small

increases

midazolam plasma

concentrations.

No dosage adjustment required.

Drugs highly bound

to plasma protein

vitro

Atomoxetine did not affect the binding of

warfarin, acetylsalicylic acid, phenytoin, or

diazepam to human albumin in-vitro.

Similarly, these compounds did not affect

the binding of atomoxetine to human

albumin.

No dosage adjustment required.

Drugs affecting

gastric pH

Drugs that elevate gastric pH (magnesium

hydroxide/aluminum hydroxide,

omeprazole) had no effect on

atomoxetine capsules bioavailability.

No dosage adjustment required.

Legend: CT = Clinical Trial; T = Theoretical

Drug-Food Interactions

JAMP Atomoxetine may be taken with or without food.

Drug-Lifestyle Interactions

Alcohol: Consumption of ethanol with atomoxetine capsules did not change the intoxicating

effects of ethanol.

DOSAGE AND ADMINISTRATION

Dosing Considerations

JAMP Atomoxetine should be administered starting at the lowest possible dose. Dosage should

then be individually and slowly adjusted to the lowest effective dose, since individual patient

response to JAMP Atomoxetine varies widely.

JAMP Atomoxetine should not be used in patients with symptomatic cardiovascular disease and

should not generally be used in patients with known structural cardiac abnormalities (see

CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS).

Children: Theoretically there exists a pharmacological potential for all ADHD drugs to increase

the risk of sudden/cardiac death. Although confirmation of an incremental risk for adverse

JAMP ATOMOXETINE

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cardiac events arising from treatment with ADHD medications is lacking, prescribers should

consider this potential risk.

All drugs with sympathomimetic effects prescribed in the management of ADHD should be used

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

or c) have a family history of sudden/cardiac death. Prior to the initiation of treatment with

sympathomimetic medications, a personal and family history (including assessment for a family

history of sudden death or ventricular arrhythmia) and physical exam should be obtained to

assess for the presence of cardiac disease. In patients with relevant risk factors and based on the

clinician’s judgment, further cardiovascular evaluation may be considered (e.g.,

electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional

chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during ADHD

treatment should undergo a prompt cardiac evaluation. Patients who are considered to need

extended treatment with JAMP Atomoxetine should undergo periodic evaluation of their

cardiovascular status. (See WARNINGS AND PRECAUTIONS).

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for

suicidal behaviour is advised in patients of all ages. This includes monitoring of agitation-

type emotional and behavioural changes, and clinical worsening (see WARNINGS AND

PRECAUTIONS – POTENTIAL ASSOCIATION WITH THE OCCURRENCE OF

BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).

JAMP Atomoxetine (atomoxetine hydrochloride) is intended for oral administration and may be

taken with or without food, either as a single daily dose in the morning or as divided doses in the

morning and late afternoon/early evening.

Initial improvement of ADHD symptoms is generally observed within 1 to 4 weeks of initiating

therapy.

Atomoxetine capsules did not worsen tics in pediatric patients, and may be used in patients with

ADHD and comorbid motor tics or diagnosis of Tourette's Disorder. Atomoxetine capsules did

not worsen anxiety in either pediatric or adult patients, and may be used in patients with ADHD

and comorbid anxiety disorders. (See ACTION AND CLINICAL PHARMACOLOGY, Special

Populations and Conditions, Patients with Concomitant Illness).

If patients miss a dose, they should take it as soon as possible; however, they should not take

more than the prescribed total daily amount of JAMP Atomoxetine in any 24-hour period.

JAMP Atomoxetine may be discontinued without tapering the dose.

Recommended Dose and Dosage Adjustment

Children (6 years and over) and Adolescents up to 70 kg Body Weight:

Do not exceed the recommended initial dose and subsequent dose escalations of JAMP

Atomoxetine. More rapid dose escalation may be associated with increased rates of

somnolence and digestive system complaints. Do not exceed the recommended maximum

total daily dose of 1.4 mg/kg or 100 mg, whichever is less. No additional benefit has been

JAMP ATOMOXETINE

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demonstrated at doses greater than 1.2 mg/kg/day (see Clinical Trials). The safety of single

doses over 1.8 mg/kg/day and total daily doses above 1.8 mg/kg have not been systematically

evaluated, and therefore should not be administered because of potential side-effects (see

ACTION AND CLINICAL PHARMACOLOGY – Cardiovascular Safety, OVERDOSAGE

and DETAILED PHARMACOLOGY [Safety Pharmacology, Cardiac Function and

Pharmacokinetics]).

JAMP Atomoxetine should be initiated at a total daily dose of approximately 0.5 mg/kg (Step 1)

for 7 to 14 days. Based on tolerability, the dose should be successively increased to

approximately 0.8 mg/kg/day (Step 2) for 7 to 14 days, and then to approximately 1.2

mg/kg/day (Step 3). Table 11 below provides for each titration step the corresponding daily

JAMP Atomoxetine dose according to body weight. After a minimum of 30 days, the

maintenance dose should be

reassessed and adjusted according to clinical response.

The total daily dose in children and adolescents up to 70 kg should not exceed 1.4 mg/kg or

100 mg, whichever is less.

As the lowest available capsule strength is 10 mg, the child should weigh at least 20 kg at the

time of initiation of therapy. Only whole capsules should be administered.

Table 11.

Daily JAMP Atomoxetine Dose for Each Titration Step as per Body Weight, in Children

and Adolescents up to 70 kg Body Weight

Body Weight

Step 1

(approx. 0.5 mg/kg/day)

Step 2

(approx. 0.8 mg/kg/day)

Step 3

(approx. 1.2 mg/kg/day)

Maximum Dose

20-29 kg

10 mg/day

18 mg/day

25 mg/day

1.4 mg/kg/day

or 100 mg/day

(whichever is less)

30-44 kg

18 mg/day

25 mg/day

40 mg/day

45-64 kg

25 mg/day

40 mg/day

60 mg/day

65-70 kg

40 mg/day

60 mg/day

80 mg/day

Children and Adolescents over 70 kg Body Weight, and Adults

Do not exceed the recommended initial dose and subsequent dose escalations of JAMP

Atomoxetine. Do not exceed the recommended maximum total daily dose of 100 mg. The

safety of single doses over 120 mg and total daily doses above 150 mg have not been

systematically evaluated and therefore should not be administered because of potential side

effects (see ACTION AND CLINICAL PHARMACOLOGY – Cardiovascular Safety,

OVERDOSAGE and DETAILED PHARMACOLOGY [Safety Pharmacology, Cardiac Function

and Pharmacokinetics]).

JAMP Atomoxetine should be initiated at a total daily dose of 40 mg/day (Step 1) for 7 to 14

days. Based on tolerability, the dose should be successively increased to 60 mg/day (Step 2) for

7 to

14 days, and then to 80 mg/day (Step 3). After 2 to 4 additional weeks, the total daily dose

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

response.

The maximum recommended total daily dose in children and adolescents over 70 kg and

adults is 100 mg.

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Dosage Adjustment for Special Populations

Hepatic Impaired

Atomoxetine clearance may be reduced in ADHD patients with hepatic impairment. For patients

with moderate hepatic impairment (Child-Pugh Class B), initial and target doses should be

reduced to 50% of the normal dose. For patients with severe hepatic impairment (Child-Pugh

Class C), initial dose and target doses should be reduced to 25% of the normal dose.

Renal Impaired

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. JAMP Atomoxetine 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.

Dosing adjustment for use with a strong CYP2D6 inhibitor

In children (

6 years old) and adolescents up to 70 kg body weight administered strong

CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, JAMP Atomoxetine should be

initiated at

0.5 mg/kg/day and only increased to the next dose level if symptoms fail to improve after 14

days and the previous dose is well tolerated.

In children (

6 years old) and adolescents over 70 kg body weight and adults administered

strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, JAMP Atomoxetine

should be

initiated at 40 mg/day and only increased to the next dose level if symptoms fail to

improve after 14 days and the previous dose is well tolerated.

Maintenance/Extended Treatment

Pharmacological treatment of ADHD may be needed for extended periods. The efficacy of

atomoxetine capsules in maintaining symptom response during long-term treatment in children

and adolescents was studied in an 18-month trial (3 months of acute open-label treatment

followed by

up to 15 months of placebo-controlled maintenance treatment). The results from

this study

suggest that atomoxetine may be beneficial in the long-term treatment of ADHD. Too

few patients completed the study to permit an adequate assessment of the long-term safety

profile of atomoxetine capsules in this study. The long-term safety of atomoxetine capsules has

been demonstrated in

double-blind and open-label clinical trials of at least 24 months. The

physician who elects to use

JAMP Atomoxetine for extended periods should periodically

reevaluate the long-term usefulness of the drug for the individual patient (see INDICATIONS

AND CLINICAL USE).

OVERDOSAGE

During post-marketing, there have been reports of non-fatal, acute and chronic overdoses of

For management of a suspected drug overdose, contact your regional Poison Control Centre.

JAMP ATOMOXETINE

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atomoxetine capsules alone. The most commonly reported symptoms accompanying acute and

chronic

overdoses were somnolence, dizziness, tremor, abnormal behaviour, and gastrointestinal

symptoms. Hyperactivity and agitation have also been reported. Signs and symptoms consistent

with mild to moderate sympathetic nervous system activation (e.g., mydriasis, tachycardia, dry

mouth, blood pressure increased) have also been observed. Most events were mild to moderate.

In some cases of overdose with atomoxetine capsules, seizures have also been reported, including

myoclonus of the extremities. Less commonly, there have been reports of QT prolongation and

mental changes, including disorientation and hallucinations.

There were no deaths involving overdose of atomoxetine capsules alone. There have also been

reports of fatal, acute overdoses involving a mixed ingestion of atomoxetine capsules and at

least one other drug.

In the first 18 months of market availability in the US, among the mixed overdose reports

involving atomoxetine capsules where at least one other drug was taken in overdose amounts,

there were

3 deaths reported, all in adults. The largest quantity of atomoxetine capsules alone in a

single overdose was 1400 mg, taken by a 17 year old patient. He experienced chest pain and

drowsiness and was treated with activated charcoal about 2 hours after the ingestion and

recovered fully after an

overnight hospital stay for observation.

Management of Overdose: There is no established antidote for atomoxetine capsules overdose.

Treatment has been supportive, including establishing an airway when necessary, monitoring of

cardiac and vital signs, 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 in the treatment of overdose.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Atomoxetine hydrochloride is a selective norepinephrine reuptake inhibitor. Its

therapeutic effect

in ADHD is thought to be related to its potent inhibition of the pre-synaptic

norepinephrine

transporter, with minimal affinity for other noradrenergic receptors or for other neurotransmitter

transporters or receptors.

Pharmacodynamics

In ex vivo uptake and neurotransmitter depletion studies, atomoxetine was found to selectively

inhibit the pre-synaptic norepinephrine transporter without directly affecting the serotonin or

dopamine transporters. Atomoxetine has minimal affinity for other receptor systems.

Atomoxetine is primarily oxidized to 4-hydroxyatomoxetine, which is also a potent inhibitor of

the pre-synaptic norepinephrine transporter.

Cardiovascular Safety

The safety and tolerability of gradually increasing multiple-dose regimes of atomoxetine 60 to

150 mg/day was studied in 16 healthy adults (10 EM subjects and 6 PM subjects). None of the

JAMP ATOMOXETINE

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Page 28

mean or individual QT

c(F)

intervals exceeded the upper limits of normal for each gender. The

EM group had no statistically significant changes in mean QT

c(F)

interval compared to the

placebo treatment. No statistically significant changes in QT

c(F)

were noted 1 hour post dose

(during peak plasma concentrations) in the PM group. The PM group had a statistically

significant increase in the mean QT

c(F)

interval measured at time 0 (during trough plasma

concentrations) on the last day of the 60- and 75-mg atomoxetine twice-daily dosing regimens

compared to the placebo. The greatest mean prolongation was about 17 msec at the 60-mg BID

dose level, with the mean interval length of 417.2 msec. At the 75-mg BID atomoxetine dose

level, the greatest mean prolongation was 15 msec, and the mean interval length was 414.9 msec.

The 60 mg BID and 75 mg BID doses correspond to 1.4 - 2.24 mg/kg/day and

1.75 - 2.8 mg/kg/day, respectively. Baseline ECGs obtained during screening of pediatric

patients for atomoxetine clinical trials were reviewed for cases of QTc prolongation. Using a

correction method based on data from baseline ECGs, there were 32/3902 cases (0.8%) with

QTc(

) > 450 msec and 5/3902 cases (0.1%) with QTc(

) > 500 msec. In a meta-analysis of

ECG data from patients who received atomoxetine in pediatric clinical trials, no relationship was

observed between changes from baseline to final QTc(

) and prescribed atomoxetine dose, or

between changes from baseline to QTc(

) at time of expected peak exposure and prescribed

atomoxetine dose.

Overall,

data

suggest

meaningful

relationship

between

atomoxetine

plasma

concentrations and the length of the QT interval corrected for heart rate in the recommended

dosage range. However, since there is no requirement for a priori screening of ADHD patients

for CYP2D6 metabolizer status before initiating treatment with atomoxetine, it is important that

the lowest effective dose be used, so as to minimize potential cardiac side effects.

Pharmacokinetics

Atomoxetine is well-absorbed after oral administration and is minimally affected by food. It is

eliminated primarily by oxidative metabolism through the cytochrome P450 2D6 (CYP2D6)

enzymatic pathway and subsequent glucuronidation. Atomoxetine has a half-life of about

5 hours. A fraction of the population (about 7% of Caucasians and 2% of African Americans) are

poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced

activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma

concentrations, and slower elimination (plasma half-life of 21.6 hours) of atomoxetine compared

with people with normal activity [extensive metabolizers (EMs)]. Drugs that inhibit CYP2D6,

such as fluoxetine, paroxetine, and quinidine, cause similar increases in exposure.

The pharmacokinetics of atomoxetine have been evaluated in more than 400 children and

adolescents in selected clinical trials using a population approach. Single-dose and steady-state

individual pharmacokinetic data were also obtained in children, adolescents, and adults. When

doses were normalized to a mg/kg basis, similar half-life, C

, and AUC values were observed

in children, adolescents, and adults. Clearance and volume of distribution after adjustment for

body weight were also similar.

Atomoxetine pharmacokinetics are dose proportional within the therapeutic range; hence,

administration of atomoxetine capsules once- or twice-daily is expected to result in the same

systemic

exposure (AUC) over a 24-hour period. Results of efficacy analysis show that once-

daily (QD) dosing with atomoxetine capsules is efficacious in the treatment of ADHD.

JAMP ATOMOXETINE

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JAMP Atomoxetine 80 mg capsules are bioequivalent to 2 x 40 mg capsules. JAMP Atomoxetine

100 mg

capsules are bioequivalent to a combination of one 40 mg and one 60 mg capsule.

Absorption: Atomoxetine is rapidly absorbed after oral administration, with absolute

bioavailability of about 63% in extensive metabolizers (EMs) and 94% in poor metabolizers

(PMs). Mean maximal plasma concentrations (C

) are reached approximately 1 to 2 hours after

dosing.

JAMP Atomoxetine can be administered with or without food. In clinical trials with children and

adolescents, administration of atomoxetine capsules with food resulted in a 9% lower C

Administration of atomoxetine capsules with a standard high-fat meal in adults did not affect the

extent

of oral absorption of atomoxetine (AUC), but did decrease the rate of absorption,

resulting in a

37% lower C

and delayed T

by 3 hours.

Distribution: The steady-state volume of distribution after intravenous administration was

approximately 0.85 L/kg indicating that 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 is similar across the patient weight range after normalizing

for body weight.

At 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. People with reduced activity in the CYP2D6 pathway

(PMs) have higher plasma concentrations of atomoxetine compared with people with normal

activity (EMs). For PMs, AUC of atomoxetine at steady-state is approximately 10-fold higher

and C

ss,max

is about 5-fold greater than for EMs.

Coadministration of atomoxetine capsules with potent inhibitors of CYP2D6, such as fluoxetine,

paroxetine, or quinidine, results in a substantial increase in atomoxetine plasma exposure, and

dosing adjustment may be necessary (see Drug-Drug Interactions). In EM patients treated with

potent CYP2D6 inhibitors such as fluoxetine, and paroxetine, the AUC of atomoxetine is

approximately 6- to 8-fold and C

ss,max

is about 3- to 4-fold greater than with atomoxetine alone.

In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not

increase the plasma concentration of atomoxetine.

Atomoxetine did not inhibit or induce the CYP2D6 pathway.

The major oxidative metabolite formed regardless of CYP2D6 status is 4-hydroxy-atomoxetine,

which is rapidly glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an

inhibitor of the norepinephrine transporter, but circulates in plasma at much lower concentrations

(1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentration in PMs).

4-Hydroxyatomoxetine is primarily formed by CYP2D6. In individuals that lack CYP2D6

activity (poor metabolizers), 4-hydroxyatomoxetine is formed by several other cytochrome P450

enzymes, but at a slower rate. N-Desmethyl-atomoxetine is formed by CYP2C19 and other

cytochrome P450 enzymes, but has much less pharmacological activity than atomoxetine, and

JAMP ATOMOXETINE

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plasma concentrations are lower (5% of atomoxetine concentration in EMs and 45% of

atomoxetine concentration in PMs).

Elimination: The mean elimination half-life of atomoxetine after oral administration is 5.2 hours

and 21.6 hours in EM and PM subjects, respectively. The elimination half-life of

4-hydroxyatomoxetine is similar to that of N-desmethylatomoxetine (6 to 8 hours) in EM

subjects, while the half-life of N-desmethylatomoxetine is much longer in PM subjects (34 to 40

hours).

Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine

(greater than 80% of the dose) and to a lesser extent in the feces (less than 17% of the dose).

Only a small fraction (less than 3%) of the atomoxetine capsules dose is excreted as unchanged

atomoxetine, indicating extensive biotransformation.

Special Populations and Conditions

Pediatrics: 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.

Geriatrics: The pharmacokinetics of atomoxetine have not been systematically evaluated in the

geriatric population.

Gender: Gender did not influence atomoxetine disposition.

Race: Ethnic origin did not influence atomoxetine disposition.

Hepatic Insufficiency: Single doses of atomoxetine capsules administered to EM subjects with

moderate to severe hepatic insufficiency (Child-Pugh Class B and C) resulted in increased

atomoxetine exposure, reduced atomoxetine clearance, and prolonged half-life of parent drug

compared with healthy subjects. Dosage adjustment is recommended for patients with moderate

or severe hepatic impairment (see DOSAGE AND ADMINISTRATION).

Renal Insufficiency: Single doses of atomoxetine capsules administered to EM subjects with

end stage

renal disease resulted in higher atomoxetine exposure (AUC) than in healthy subjects

(about a

65% increase), but there was no difference when exposure was corrected for mg/kg

dose.

JAMP Atomoxetine can therefore be administered to ADHD patients with end stage renal disease

or lesser degrees of renal insufficiency using the normal dosing regimen.

Genetic Polymorphism: There are two major phenotypes associated with CYP2D6: extensive

metabolizers that comprise > 90% of the population, and poor metabolizers. Approximately 7%

of the Caucasian population and 2% of Black population are poor metabolizers of CYP2D6.

Patients with Concomitant Illness

JAMP ATOMOXETINE

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Pediatric Patients with ADHD and Comorbid Tics:

Study LYAS enrolled patients meeting DSM-IV criteria for ADHD and comorbid Tourette’s

Disorder or chronic motor tics. Atomoxetine capsules met the primary study objective of non-

inferiority to placebo with respect to worsening of tics and had a beneficial effect in reducing tic

severity.

Atomoxetine capsules was also markedly superior to placebo in reducing symptoms of ADHD

as assessed by the ADHDRS-IV-Parent:Inv Total score (p = 0.002).

Patients with ADHD and Comorbid Anxiety Disorder

Study LYBP: Pediatric patients (n = 176, age 8 - 17), who met DSM-IV criteria for ADHD and

at least one of the anxiety disorders of separation anxiety disorder, generalized anxiety disorder

or social phobia were randomized 1:1 into a 12-week double-blind, placebo-controlled trial. The

statistical analysis plan specified that patients responding (i.e., > 25% reduction in Pediatric

Anxiety Rating Scale (PARS) total scores) during a blinded placebo lead-in period be excluded

from the primary efficacy analyses. However, all of the enrolled patients with a baseline and at

least one post-baseline score were included in the remaining efficacy analyses. Initial

atomoxetine capsules dose was 0.8 mg/kg/day, with increase to a target dose of 1.2 mg/kg/day

(median dose 1.3 mg/kg/day ± 0.3 mg/kg/day). Atomoxetine capsules was markedly superior to

placebo in

reducing symptoms of ADHD as assessed by the ADHDRS-IV-Parent: Inv Total

score (p < 0.001) and mean PARS total score improved significantly for atomoxetine capsules

relative to

placebo (p = 0.011). Worsening of anxiety was defined post-hoc as a 25% increase

in PARS, or patient-reported anxiety as an adverse event. Based on these criteria, patients on

atomoxetine capsules

did not have worsening of anxiety relative to the placebo group. Of the

158 patients who completed the double-blind placebo lead-in, 26 (16%) discontinued the study.

Study LYDQ: Adult patients (n = 442, age 18 - 65) , who met DSM-IV criteria for adult ADHD

and social anxiety disorder (23% of whom also had Generalized Anxiety Disorder) were

randomized into a 16-week double-blind, placebo-controlled trial. The statistical analysis plan

specified that patients responding (i.e., > 25% decrease in social anxiety symptoms as measured

by the Liebowitz Social Anxiety Scale) during a blinded placebo lead-in period be excluded from

the primary efficacy analyses. However, all of the enrolled patients with a baseline and at least

one post-baseline score were included in the remaining efficacy analyses. Atomoxetine capsules

was initiated at 40 mg/day to a maximum dose of 100 mg/day (mean daily dose 83 mg/day ±19.5

mg/day). Atomoxetine capsules was markedly superior to placebo in reducing symptoms of

ADHD as assessed by the Conners’ Adult ADHD Rating Scale (p < 0.001) and mean LSAS total

score

improved significantly for atomoxetine capsules relative to placebo (p ≤ 0.01). Worsening

of anxiety

was defined post-hoc as a 25% increase in LSAS, or patient-reported anxiety as an

adverse event.

Based on these criteria, patients on atomoxetine capsules did not have worsening

of anxiety relative to

the placebo group. Of the 436 patients who completed the double-blind

placebo lead-in, 172 (39%) discontinued the study.

STORAGE AND STABILITY

Store at controlled room temperature, 15 to 30°C.

JAMP Atomoxetine capsules are not intended to be opened, they should be taken whole.

JAMP ATOMOXETINE

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Page 32

DOSAGE FORMS, COMPOSITION AND PACKAGING

JAMP Atomoxetine (atomoxetine hydrochloride) capsules are supplied in 10, 18, 25, 40 60, 80

and 100 mg strengths, as atomoxetine base equivalent.

JAMP Atomoxetine Capsules

10 mg

Opaque white cap/ opaque white body size “3” capsules containing white to off white powder,

with ‘JP’ on cap and ‘A10’ on body imprinted with black ink.

18 mg

Gold cap/ opaque white body size “3” capsules containing white to off white powder, with ‘JP’

on cap and ‘A18’ on body imprinted with black ink.

25 mg

Opaque blue cap/ opaque white body size “3” capsules containing white to off white powder,

with ‘JP’ on cap and ‘A25’ on body imprinted with black ink.

40 mg

Opaque blue cap/ opaque blue body size “3” capsules containing white to off white powder, with

‘JP’ on cap and ‘A40’ on body imprinted with black ink.

60 mg

Opaque blue cap/ gold body size “2” capsules containing white to off white powder, with ‘JP’ on

cap and ‘A60’ on body imprinted with black ink.

80 mg

Opaque brown cap/ opaque white body size “2” capsules containing white to off white powder,

with ‘JP’ on cap and ‘A80’ on body imprinted with black ink.

100 mg

Opaque brown cap/ opaque brown body size “1” capsules containing white to off white powder,

with ‘JP’ on cap and ‘A100’ on body imprinted with black ink.

JAMP Atomoxetine 80 mg capsules are bioequivalent to 2 x 40 mg capsules. JAMP Atomoxetine 100

capsules are bioequivalent to a combination of one 40 mg and one 60 mg capsule.

Supplied as: Bottles of 30 capsules and blisters packages of 28 capsules.

Composition

Each capsule contains atomoxetine hydrochloride equivalent to 10 mg, 18 mg, 25 mg, 40 mg,

60 mg, 80 mg or 100 mg of atomoxetine. The capsules also contain pregelatinized starch and

colloidal

silicon dioxide. The capsule shells contain gelatin, sodium lauryl sulfate, and other

inactive ingredients. The capsule shells also contain one or more of the following: FD&C Blue

No. 2, synthetic yellow iron oxide, red iron oxide, titanium dioxide.

JAMP ATOMOXETINE

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PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name:

Atomoxetine Hydrochloride

Chemical Name:

Benzenepropanamine N-methyl-gamma(2-methylphenoxy)

hydrochloride,(-)

Molecular Formula:

NO·HCl

Molecular Weight:

291.82 g/mol

Structural Formula:

Physicochemical Properties: Atomoxetine hydrochloride is a white to practically white solid,

which has a solubility of 27.8 mg/mL in water. Atomoxetine

hydrochloride is the R(-) isomer, as determined by x-ray

diffraction.

pH:

4.80 (1% aqueous solution)

pKa:

10.13

Melting Point:

Onset temperature 168-169

JAMP ATOMOXETINE

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CLINICAL TRIALS

Comparative Bioavailability Study

A double blind, randomized, two-treatment, two-period, two-sequence, single-dose, crossover, oral

comparative

bioavailability

study

JAMP

Atomoxetine

capsules

(JAMP

Pharma

Corporation, Canada) and Strattera

60 mg capsules (ELI LILLY CANADA INC.) was conducted

in 26 healthy, adult, male human subjects under fasting conditions. A summary of the bioavailability

data from the 25 subjects who completed the study is presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

Atomoxetine

(1 × 60 mg)

Geometric Mean

Arithmetic Mean (CV %)

Parameter

Test

Reference

% Ratio of

Geometric

Means

90% Confidence

Interval

(ng.h/mL)

3713.59

5001.18 (121.8)

3666.55

4889.62 (113.5)

101.3

96.8 - 106.0

(ng.h/mL)

3829.51

5947.61 (173.9)

3757.88

5405.00 (140.2)

101.9

97.1 - 107.0

(ng/mL)

641.10

691.61 (42.2)

640.59

681.74 (36.2)

100.1

88.7 - 112.9

0.83

(0.33 - 6.00)

0.83

(0.33 - 1.75)

5.13

(93.1)

4.95

(62.4)

JAMP Atomoxetine (atomoxetine as atomoxetine hydrochloride) 60 mg capsules (JAMP Pharma Corporation, Canada)

Strattera

(atomoxetine as atomoxetine hydrochloride) 60 mg capsules (ELI LILLY CANADA INC.)

Expressed as the median (range) only

Expressed as the Arithmetic mean (%CV) only

The efficacy and safety of atomoxetine capsules for the treatment of ADHD in children,

adolescents and

adults (Table 12) who met the Diagnostic and Statistical Manual 4th edition

(DSM-IV) criteria

were established in 6 acute, randomized, double-blind, placebo-controlled

studies. Examination of population subsets (gender, age) did not reveal any differential

responsiveness on the basis of these subgroupings.

Four additional double-blind, placebo-controlled studies were also conducted with children

and adolescents in the school setting, and in adults (Table 12). Efficacy and safety were

assessed in patients with comorbid tic disorder (pediatrics), and comorbid anxiety disorders

(pediatrics and adults). As well, evening efficacy was assessed with once daily dosing

(pediatrics and adults).

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Long-term efficacy of atomoxetine capsules was established in an 18 month, randomized,

double-blind, placebo-controlled relapse-prevention study. Too few patients completed to allow

an adequate

assessment of long-term safety from this study.

The long-term safety of atomoxetine capsules has been demonstrated in double-blind and open-

label

clinical trials involving 5382 children or adolescent patients and 525 adult patients with

ADHD.

During the ADHD clinical trials, 1625 children and adolescent patients were treated

for longer than 1 year and 2529 children and adolescent patients were treated for over 6

months.

In both pediatric and adult studies, atomoxetine capsules showed efficacy in patients who had

been previously treated with stimulants, as well as in stimulant-naïve patients. Atomoxetine

capsules has a

different mechanism of action from stimulant therapies. Data on evening efficacy

suggest that

atomoxetine capsules is not associated with the ‘on/off’ phenomena characteristic of

stimulants.

Study Demographics and Trial Design

Table 12.

Summary of Patient Demographics for Controlled Clinical Trials in ADHD Patients

Study No.

Trial design

Atomoxetine

Dose/Duration

No. of

Subjects

Mean Age

(range)

Gender

Randomized, Double-Blind Studies in Children and Adolescents

HFBD

Acute, placebo-controlled, parallel

groups.

BID dosing,

max 2.0 mg/kg/day;

9 weeks.

n = 147

9.7 years

(7 – 13)

M = 119

F = 28

HFBK

Acute, placebo-controlled, parallel

groups.

BID dosing,

max 2.0 mg/kg/day;

9 weeks.

n = 144

9.9 years

(7 – 13)

M = 117

F = 27

LYAC

Acute, dose-ranging, placebo-

controlled, parallel groups.

Fixed BID doses 0.5,

1.2, and 1.8 mg/kg/day;

8 weeks.

n = 297

11.2 years

(8 – 18)

M = 212

F = 85

LYAT

Once-daily dosing, acute, placebo-

controlled, parallel groups.

QD dosing,

max 1.5 mg/kg/day;

6 weeks.

n = 171

10.3 years

(6 - 16)

M = 120

F = 51

LYBG

Once-daily dosing, acute, placebo-

controlled, parallel groups, and

assessment of evening efficacy.

QD dosing,

max 1.8 mg/kg/day;

8 weeks.

n = 197

9.5 years

(6 – 13)

M = 139

F = 58

LYAW

Once- daily dosing, acute, placebo-

controlled, parallel groups, and

assessment of efficacy in the school

setting.

QD dosing,

max 1.8 mg/kg/day;

7 weeks.

n = 153

9.9 years

(7 - 13)

M = 123

F = 30

LYAS

1

Acute, placebo-controlled, parallel

groups, patients with ADHD and

comorbid tic disorder.

BID dosing,

max 1.5 mg/kg/day;

up to 18 weeks

n = 148

11.2 years

(7 – 17)

M = 131

F = 17

LYBI

Parallel-group comparison of

atomoxetine, extended-release

methylphenidate and placebo.

BID dosing

max 1.8 mg/kg/day;

approx. 6 weeks.

n = 516

10.2 years

(6 – 17)

M = 383

F = 133

JAMP ATOMOXETINE

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Study No.

Trial design

Atomoxetine

Dose/Duration

No. of

Subjects

Mean Age

(range)

Gender

LYAF

Long-term relapse prevention,

placebo-controlled, parallel groups.

BID dosing,

max 1.8 mg/kg/day;

52 weeks double-blind.

n = 416

10.4 years

(6 – 16)

M = 373

F = 43

LYBP

2

Placebo-controlled, parallel group

study in patients with ADHD and

comorbid anxiety.

BID dosing

max 1.8 mg/kg/day;

approx. 12 weeks.

n = 176

12.0 years

(8 – 18)

M = 114

F = 62

Randomized, Double-Blind Studies in Adults

LYAA

Acute, placebo-controlled, parallel

groups.

BID dosing,

max 120 mg/day

10 weeks

n = 280

40.3 years

(18 – 67)

M = 178

F = 102

LYAO

Acute, placebo-controlled, parallel

groups.

BID dosing

max 120 mg/day

10 weeks

n = 256

42.1 years

(19 – 77)

M = 170

F = 86

LYDQ

3

Placebo-controlled, parallel group

study in adult patients with ADHD

and comorbid social anxiety.

BID dosing

max 100 mg/day;

approx. 16 weeks.

n = 442

38.0 years

(18 – 65)

M = 237

F = 205

1, 2, and 3

:

See Action and Clinical Pharmacology, Special Populations, Patients with concomitant illness.

Children and Adolescents: Improvement on signs and symptoms of ADHD were evaluated by a

comparison of mean change from baseline to endpoint for atomoxetine capsules- and placebo-

treated

patients. The primary efficacy measure in all studies was the ADHD Rating Scale-IV-

Parent

Version (ADHDRS), with the exception of Study LYAW which used the ADHD Rating

Scale-IV- Teacher Version. Both scales have been well-validated and contain 18 items

corresponding exactly to the DSM-IV symptom criteria, thus providing strong content validity.

Both scales

were administered and scored by an investigator following interviews with a parent or

teacher.

Doses ranged from 0.5 to 2.0 mg/kg/day. In clinical trials, the mean weight of children 6 to

12 years of age was 35 kg, and their mean final dose was 45 mg/day. Atomoxetine capsules was

dosed

twice daily, morning and late afternoon/early evening in Studies HFBD, HFBK, and

LYAC, or once daily in the morning in Studies LYAT, LYAW, and LYBG.

Adults: The primary outcome measure in the adult studies was the validated Conners’ Adult

ADHD Rating scale (CAARS), which contains 18 items that correspond exactly to the DSM-IV

symptom criteria. This instrument is investigator-administered and scored, with ratings based on

patient self-report. Adult patients with current diagnoses of depression and anxiety were

excluded, which ensured that improvements related to atomoxetine capsules were attributable to

improvements in ADHD. Doses ranged from 30 to 60 mg twice daily, which correspond, on a

weight-adjusted basis for a 70 kg adult, to the dosing used in children.

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Study Results

Children and Adolescents

Acute, Double-Blind, Placebo-Controlled Studies: The effectiveness of atomoxetine capsules in

treatment of ADHD was established in 6 randomized, double-blind, placebo-controlled

studies of

pediatric patients, ages 6 to 18 (Studies HFBD, HFBK, LYAC, LYAT, LYAW,

LYBG).

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. In all studies,

atomoxetine capsules demonstrated a statistically significantly (p < 0.001) greater mean

reduction in

core ADHD symptoms compared with placebo on the primary efficacy measure

(Figure 1).

Mean Change from Baseline to Endpoint in ADHDRS Total Score

Placebo

Atomoxetine*

Atomoxetine

1.8 mg/kg/day.8 mg/kg/day

HFBD

HFBK

LYAC

LYAT

LYAW

LYBG

* In LYAC ATX 1.2 mg/kg/day. Across other studies the ATX mean

final dose was 1.2 to 1.6 mg/kg/day

.001 in all studies

Figure 1.

Mean change from baseline to endpoint on the ADHDRS-IV-Parent:Inv Total

score in the acute, double-blind, placebo-controlled pediatric studies.

The effect size in the atomoxetine capsules treatment group was similar across studies,

providing evidence of a consistent treatment effect regardless of dosing regimen (once

or twice daily) or which observer (teacher or parent) was providing information for the

primary outcome measure. The efficacy of atomoxetine capsules in children and

adolescents

was demonstrated in both Hyperactive-Impulsive and Inattentive symptom

domains, in

ADHD patients with or without comorbidity (e.g., Oppositional Defiant

Disorder, depression), and in patients with or without prior stimulant use.

Improvements in the primary outcome measure were consistently accompanied by improvements

in broader measures of quality of life and functioning, including behaviour at school, self-esteem

and family functioning.

Decrease

ADHDRS

Total

Score

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The results of the fixed dose study (LYAC) provided evidence of dose response (onset of effect

at 0.5 mg/kg/day, with maximal effect at 1.2 mg/kg/day). For the overall group, no further

benefit was demonstrated at 1.8 mg/kg/day.

Study LYAT demonstrated the effectiveness of atomoxetine capsules when administered once

daily in

the morning (Figure 2). Clinical improvement was typically seen within 1 week of

starting

treatment, and at 2 to 4 weeks, mean reductions in symptom severity scores were

approaching maximal reductions. Study LYBG further demonstrated that the efficacy of

atomoxetine capsules persisted from morning until late evening following a once-daily morning

dose.

Figure 2.

Once-Daily Administration of atomoxetine capsules.

Long-Term Placebo-Controlled Study: The effectiveness of atomoxetine capsules in maintaining

symptom response was investigated in Study LYAF, an 18-month study of children and

adolescents aged 6 to 15 who met DSM-IV criteria for ADHD. A total of 604 patients were

enrolled in this study. Patients who responded to atomoxetine capsules during approximately 3-

months open-label treatment (n = 416) were randomized to double-blind, placebo-controlled

continuation

at their current doses of atomoxetine (n = 292) or on placebo (n = 124) for

approximately 9 months to observe for relapse. Patients who were still on atomoxetine capsules

(n = 163) at the end of 12 months of treatment were further randomized to an additional 6 months

double-blind, placebo-

controlled continuation at their current doses of atomoxetine (n = 81) or

on placebo (n = 82). The

results from this study suggest that atomoxetine may be beneficial in

the long-term treatment of ADHD. Too few patients completed to allow an adequate assessment

of long-term safety from this study.

Children and adolescents enrolled in acute double-blind, placebo-controlled clinical trials,

as well as those enrolled in open-label trials, were followed prospectively to assess safety,

tolerability, and effects on growth. The long-term safety of atomoxetine capsules has

been demonstrated in double-blind and open-label clinical trials involving 5382 children

or adolescent patients. During the ADHD clinical trials, 1625 children and adolescent

patients

were treated for longer than 1 year and 2529 children and adolescent patients

were treated for over 6 months. In these trials, atomoxetine capsules was safe and well

JAMP ATOMOXETINE

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tolerated, and there

were minimal, if any, long-term effects on weight and height

compared to normal growth

curves.

Active Comparator Study: Study LYBI was a randomized, double-blind, parallel group, 6

week pediatric study to test the non-inferiority of atomoxetine to a standard extended-release

stimulant

comparator. The comparator was shown to be associated with superior response

rates compared to atomoxetine (p = 0.016). However, this study excluded patients who were

stimulant

nonresponders, so it is possible that the results were biased favouring the stimulant

comparator.

For patients not previously treated with a stimulant, there was no significant

difference in

response rates between stimulant comparator and atomoxetine (p = 0.423). Both

atomoxetine

and the comparator were statistically superior to placebo. Both atomoxetine and

comparator

were safe and well-tolerated. Neither medication produced statistically significant

prolongation compared to placebo.

Studies in Adult ADHD Patients

The results of 2 large placebo-controlled studies in adult patients with ADHD (N = 536) have

demonstrated the efficacy and safety of atomoxetine capsules in this population. Atomoxetine

capsules statistically significantly superior to placebo at reducing ADHD symptoms as measured

on the

CAARS Total ADHD symptom score (Figure 3, LYAA p = 0.004, LYAO p = 0.002).

Efficacy was observed for overall ADHD symptoms as well as in the individual

domains of

Predominately Inattentive and Predominately Hyperactive-Impulsive symptoms.

LYAA

LYAO

Figure 3.

CAARS Total Scores

Mean change from baseline to endpoint in randomized,

double-blind, placebo-controlled adult studies

Decrease

CAARS:

Total

Score

JAMP ATOMOXETINE

Product Monograph

Page 40

DETAILED PHARMACOLOGY

Efficacy Pharmacology

Atomoxetine hydrochloride was designed to be a potent and selective inhibitor of the

norepinephrine transporter. In vitro, atomoxetine was found to have highly selective potency for

the norepinephrine transporter over the dopamine and serotonin transporters, and was highly

selective for inhibiting the uptake of radiolabelled norepinephrine into hypothalamic

synaptosomes. Of the two primary phase I metabolites, 4-hydroxyatomoxetine was found to have

similar in vitro potency for the norepinephrine transporter and inhibition of norepinephrine uptake

compared to atomoxetine, while N-desmethylatomoxetine had lower affinity than

atomoxetine for all three monoamine transporters. Further, atomoxetine and these metabolites

were found to have relatively low affinities for neurotransmitter receptors and ion channels. In

vivo evaluation of atomoxetine also demonstrated high potency and selectivity of atomoxetine for

the norepinephrine transporter. In the prefrontal cortex, a site believed to be important for

attention in humans, dose-dependent increases in the extracellular concentrations of

norepinephrine and dopamine occurred when atomoxetine was given intraperitoneally or when

atomoxetine was delivered directly through a microdialysis probe, suggesting that the increases

in prefrontal cortex norepinephrine and dopamine were produced by local inhibition of the

norepinephrine transporter. Atomoxetine did not produce a significant increase in the

extracellular concentrations of dopamine in the nucleus accumbens, an area believed to mediate

the rewarding effects of dopamine transporter inhibitors, and the striatum, an area believed to

mediate the effects of dopamine transporter inhibitors on locomotor activity.

Safety Pharmacology

Atomoxetine was evaluated in animals or in vitro for potential effects on the central nervous

system and behaviour, including abuse potential, and for effects on cardiovascular, respiratory,

renal, gastrointestinal, and immune function.

In contrast to the high affinity of atomoxetine for the norepinephrine transporter site,

atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine, have relatively low binding

affinities for adrenergic, muscarinic, histaminergic, GABAergic, serotonergic, and dopaminergic

receptors, as well as many other receptor sites and ion channels. Atomoxetine exhibited no

agonist effects on isolated smooth and cardiac tissues and did not inhibit acetylcholine- or

isoproterenol-induced contractions of these respective tissues. Therefore, atomoxetine would not

be expected to interfere with the physiologic function mediated by these receptor systems or

produce toxicity associated with muscarinic or adrenergic receptors. Importantly, clinical signs

observed in rodents and dogs were consistent only with effects on the central nervous system (for

example, reduced motor activity, leg weakness, jerky gait, tremors, and convulsions).

Atomoxetine is not associated with abuse potential, based upon its receptor binding profile and

nonclinical behavioural pharmacology, as well as animal drug discrimination studies conducted

with atomoxetine.

Atomoxetine produced no important changes in respiratory or renal function, gastrointestinal

motility, or immune function in animals.

JAMP ATOMOXETINE

Product Monograph

Page 41

Cardiac Function

Atomoxetine was evaluated for effects on cardiac function in vitro and in dogs. In vitro blockade

of the cloned human cardiac I

(HERG) channel by atomoxetine occurred with an IC

0.869 µM. Studies with canine Purkinje tissue and in dogs given atomoxetine orally did not

produce effects predictive or consistent with a compound-related QT interval prolongation.

Concomitant inhibition of sodium and calcium inward currents in vitro helps explain the lack of

in vivo findings. These observations, together with the clinical experience with atomoxetine,

indicate that the in vitro HERG blockade observation is not likely predictive of an increased

cardiovascular risk for atomoxetine.

Cardiovascular Safety Study:

The safety and tolerability of gradually increasing multiple-dose regimes of atomoxetine was

studied during a 20 day period in a clinical pharmacology study involving 16 healthy adults

(10 EM subjects and 6 PM subjects). Placebo or atomoxetine 60 to 150 mg/day, was given as

twice daily doses of 30 mg, 45 mg, 60 mg, and 75 mg. None of the mean or individual QT

c(F)

intervals (QT interval corrected by the Fridericia method) exceeded the upper limits of normal for

each gender.

The EM group had no statistically significant changes in mean QT

c(F)

interval following any dose

of atomoxetine compared to the placebo treatment. No statistically significant changes in QT

c(F)

were noted 1 hour post dose (during peak plasma concentrations) in the PM group. The PM

group had a statistically significant increase in the mean QT

c(F)

interval measured at time 0

(during trough plasma concentrations) on the last day of the 60- and 75-mg atomoxetine twice-

daily dosing regimens compared to the placebo. The greatest mean prolongation was about

17 msec at the 60-mg BID dose level, with the mean interval length of 417.2 msec. At the 75-mg

BID atomoxetine dose level, the greatest mean prolongation was 15 msec, and the mean interval

length was 414.9 msec. The 60 mg BID and 75 mg BID doses correspond to 1.4-2.24 mg/kg/day

and 1.75-2.8 mg/kg/day, respectively.

Baseline ECGs obtained during screening of pediatric patients for atomoxetine clinical trials were

reviewed for cases of QTc prolongation. Using Bazett’s method for correcting QT (the usual

method for automated QTc intervals), there were 131/3902 cases (3.4%) with QTc(B) > 450

msec and 5/3902 cases (0.1%) with QTc(B) > 500 msec. Using a correction method based on

data from baseline ECGs (the method preferred by most regulatory agencies), there were 32/3902

cases (0.8%) with QTc(D) > 450 msec and 5/3902 cases (0.1%) with QTc(D) > 500 msec. In a

meta-analysis of ECG data from patients who received atomoxetine in pediatric clinical trials, no

relationship was observed between changes from baseline to final QTc(

) and prescribed

atomoxetine dose (n = 3127 patients), or between changes from baseline to QTc(

) at time of

expected peak exposure and prescribed atomoxetine dose (n = 2084 all patients, n = 151 PM

patients). For clinical trial patients where plasma concentrations were available, no relationship

was observed between changes from baseline QTc(

) and atomoxetine plasma concentration

during peak atomoxetine exposure (n = 728 all patients, n = 83 PM patients).

JAMP ATOMOXETINE

Product Monograph

Page 42

Overall,

data

suggest

meaningful

relationship

between

atomoxetine

plasma

concentrations and the length of the QT interval corrected for heart rate in the recommended

dosage range. However, since there is no requirement for a priori screening of ADHD patients

for CYP2D6 metabolizer status before initiating treatment with atomoxetine, it is important that

the lowest effective dose be used, so as to minimize potential cardiac side effects.

Pharmacokinetics

Atomoxetine was well absorbed following oral administration to adult mice, rats, and dogs.

The primary oxidative (phase I) metabolite of atomoxetine was identified as

4-hydroxyatomoxetine, and its major ultimate metabolite is 4-hydroxyatomoxetine-O-

glucuronide, in all species evaluated. The major routes of metabolism are aromatic ring-

hydroxylation, benzylic/aliphatic hydroxylation, and N-demethylation. Subsequent

O-glucuronidation and O-sulfation of the hydroxylated metabolites are the only phase II

metabolic pathways to participate in the conjugation of the oxidized atomoxetine metabolites.

Plasma concentrations of atomoxetine and its primary phase I metabolites,

N-desmethylatomoxetine and 4-hydroxyatomoxetine, increased with dose in each species. There

was generally minimal accumulation with repeated dosing, which appeared to be due to the

relatively rapid clearance of atomoxetine in each of the species evaluated. The half-life of

atomoxetine following a single intravenous dose was 1.2 hr, 1.4 hr and 3.4 hr in the mouse, rat

and dog, respectively. The most profound difference observed among species was the low

bioavailability in rodents (approximately 4%) compared to the high bioavailability in dog

(approximately 74%). These differences appear to be almost purely mediated by the efficient

first-pass hepatic clearance of atomoxetine in rodents, resulting in poor systemic exposure to

atomoxetine but high exposure to its metabolites. In the dog, atomoxetine does not undergo

extensive first-pass metabolism.

Increases in hepatic cytochrome P450 activity were observed in mice and rats after large oral

doses of atomoxetine. Slight increases in total cytochrome P450 content were observed at the

highest dose tested (16 mg/kg/day) in male dogs. However, no evidence of such changes in

cytochrome P450 activity have been observed in clinical studies.

Binding of atomoxetine and N-desmethylatomoxetine to plasma protein was high in each species

evaluated including humans (82% to 99%), while the binding of 4-hydroxyatomoxetine to plasma

protein was substantially lower (55% to 67%).

In the rat, atomoxetine and its metabolites were rapidly and widely distributed in tissues, with the

highest levels being observed in the gastrointestinal tract and the liver. Milk excretion is not a

major route of elimination for atomoxetine and/or its metabolites. Atomoxetine and/or its

metabolites crossed the placenta resulting in relatively low fetal exposure compared to exposure

in maternal tissues.

The major route of excretion of atomoxetine-derived radioequivalents was via the urine in each

of the species evaluated. A low amount of fecal excretion appears to be due to biliary

elimination. Very little atomoxetine was excreted intact, indicating that direct renal or biliary

elimination of atomoxetine are minor routes of systemic clearance.

JAMP ATOMOXETINE

Product Monograph

Page 43

TOXICOLOGY

Acute Toxicity

The median lethal oral dose of atomoxetine hydrochloride in animals was estimated to be

25 mg/kg for cats, >37.5 mg/kg for dogs, and

190 mg/kg in rats and mice. Premonitory signs of

toxicity following single oral doses of atomoxetine in animals included mydriasis and reduced

pupillary light reflex, mucoid stools, salivation, vomiting, ataxia, tremors, myoclonic jerking, and

convulsions.

Long-Term Toxicity

Toxicity studies of up to 1 year were conducted in adult rats and dogs to evaluate the potential

chronic toxicity of atomoxetine. There was no major target organ toxicity observed in dogs given

oral doses up to 16 mg/kg/day or in rats given atomoxetine in the diet at time-weighted average

doses up to 47 mg/kg/day. These doses are approximately 6 - 7 times the maximum

recommended daily oral dose in children, and approximately 4 - 5 times the maximum

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

basis. Mild hepatic effects, characterized by

mottling and pallor of the liver, increased relative liver weights, hepatocellular vacuolation, and

slightly increased serum ALT values, occurred in male rats given time-weighted average doses

14 mg/kg/day. No hepatic effects were observed in dogs. Clinical signs of mydriasis, reduced

pupillary light reflex, emesis, and tremors were observed in dogs, and these effects were minimal

in adult dogs given

8 mg/kg/day. Similar clinical signs were observed in young dogs (8 weeks

of age) given atomoxetine orally for 1 month.

Toxicity studies were conducted to evaluate potential effects of atomoxetine on growth,

neurobehavioural, and sexual development as well as reproductive performance in rats dosed

from the early postnatal period to early adulthood. No important effects on bone growth, brain

morphology, neurobehavioral or reproductive performance were observed in rats administered

atomoxetine hydrochloride from 10 days of age through adulthood, at oral doses up to 50 mg/kg,

approximately 7 times the maximum recommended daily oral dose in children on a mg/m

basis.

There were no effects on the anatomy or morphology of either male or female reproductive

organs. There was a minor, dose-related increase in time-to-onset of vaginal patency and

preputial separation (1 to 3 days compared with controls), but all animals reached sexual maturity

and no malformations of the vagina or prepuce/glans penis were observed. In male rats,

spermatogenesis was normal. There were slight decreases in the number of sperm held in the

epididymis but no effects on fertility. For both male and female rats, there were no effects on

mating or fertility indices, no effects on embryo implantation or embryo viability, and no effects

on learning and memory tests. The significance of these findings to humans is not known.

JAMP ATOMOXETINE

Product Monograph

Page 44

Carcinogenicity

Atomoxetine hydrochloride was not carcinogenic in rats and mice when given in the diet for 2

years at time-weighted average doses up to 47 and 458 mg/kg/day, respectively. The highest

dose used in rats is approximately 8 and 5 times the maximum human dose in children and adults,

respectively, on a mg/m

basis. Plasma levels (AUC) of atomoxetine at this dose in rats are

estimated to be 1.8 times (extensive metabolizers) or 0.2 times (poor metabolizers) those in

humans receiving the maximum human dose. The highest dose used in mice is approximately 39

and 26 times the maximum human dose in children and adults, respectively, on a mg/m

basis.

Mutagenicity

Atomoxetine hydrochloride was negative in a battery of genotoxicity studies that included a

reverse point mutation assay (Ames Test), an in vitro mouse lymphoma assay, a chromosomal

aberration test in Chinese hamster ovary cells, an unscheduled DNA synthesis test in rat

hepatocytes and an in vivo micronucleus test in mice. However, there was a slight increase in the

percentage of Chinese hamster ovary cells with diplochromosomes, suggesting endoreduplication

(numerical aberration).

The metabolite N-desmethylatomoxetine hydrochloride was negative in the Ames Test, mouse

lymphoma assay, and unscheduled DNA synthesis test.

Teratogenicity

No evidence of drug-associated teratogenicity or retarded fetal development was produced in

rabbits or rats administered atomoxetine hydrochloride throughout organogenesis at oral doses up

to 100 mg/kg/day and 150 mg/kg/day (at least 20 times the 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.

Atomoxetine hydrochloride did not impair fertility when administered to rats from 10 days of age

through adulthood at oral doses up to 50 mg/kg/day (up to 7 times the maximum recommended

daily oral dose in children and 4 times the maximum recommended daily oral dose in adults, on a

mg/m

basis). In addition, no evidence of impaired fertility was observed in either of two fertility

studies in adult rats provided atomoxetine HCl in the diet at 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).

Parturition in rats was not affected by atomoxetine.

Impairment of fertility

Atomoxetine HCl did not impair fertility in rats when given in the diet at doses of up to

57 mg/kg/day, which is approximately 6 times the maximum human dose on a mg/m

basis.

JAMP ATOMOXETINE

Product Monograph

Page 45

Growth and Neurobehavioural/Sexual development in rats

A study was conducted in young rats to evaluate the effects of atomoxetine on growth and

neurobehavioral and sexual development. Rats were treated with 1, 10, or 50 mg/kg/day

(approximately 0.2, 2, and 8 times, respectively, the maximum human dose on a mg/m

basis) of

atomoxetine given by gavage from the early postnatal period (Day 10 of age) through adulthood.

Slight delays in onset of vaginal patency (all doses) and preputial separation (10 and 50 mg/kg),

slight decreases in epididymal weight and sperm number (10 and 50 mg/kg), and a slight decrease

in corpora lutea (50 mg/kg) were seen, but there were no effects on fertility or reproductive

performance. A slight delay in onset of incisor eruption was seen at 50 mg/kg. A

slight increase

in motor activity was seen on Day 15 (males at 10 and 50 mg/kg and females at

50 mg/kg) and on

Day 30 (females at 50 mg/kg) but not on Day 60 of age. There were no effects

on learning and

memory tests. The significance of these findings to humans is unknown.

JAMP ATOMOXETINE

Product Monograph

Page 46

REFERENCES

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efficacy of atomoxetine in adults with attention-deficit/hyperactivity disorder: An interim

Analysis. J Clin Psychiatry 2005;66:294-299.

Adler L, Sutton V, Moore R, et al. Quality of life assessment in adult patients with

attention-deficit/hyperactivity disorder treated with atomoxetine. J Clin Psychopharmacol

2006;26:648-652.

Adler L, Liebowitz M, Kronenberger W, et al. Atomoxetine treatment in adults with

Attention-Deficit/Hyperactivity Disorder and comorbid Social Anxiety Disorder.

Depression and Anxiety 2009;0:1–11.

Adler L, Spencer T, Brown T, et al. Once-daily atomoxetine for adult Attention-

Deficit/Hyperactivity Disorder: A 6-month, double-blind trial. J Clin Psychopharmacol

2009;29:44-50.

Allen AJ, Kurlan R, Gilbert D, et al. Atomoxetine treatment in children and adolescents

with ADHD and comorbid tic disorders. Neurology 2005;65:1941–1949.

American Academy of Pediatrics (2001), Clinical Practice Guideline: Treatment of the

School-Aged Child with Attention-Deficit/Hyperactivity Disorder. Pediatrics

108:1033-1044.

American Psychiatric Association (2000), Diagnostic and Statistical Manual of Mental

Disorders: DSM-IV-TR. American Psychiatric Association, Washington, DC.

Buitelaar J, Michelson D, Danckaerts M, et al. A randomized, double-blind study of

continuation treatment for Attention-Deficit/Hyperactivity Disorder after 1 year. Biol

Psychiatry 2007;61:694–699.

Canadian ADHD Resource Alliance (www.CADDRA.ca): Canadian ADHD Practice

Guidelines:

Medications for Attention Deficit/Hyperactivity Disorder, 2006 (1

Ed);

Chapter 10 (App 17), 1-14.

Chalon S, Desager J, Desante K, et al. Effect of hepatic impairment on the

pharmacokinetics of atomoxetine and its metabolites. Clin Pharmacol Therap 2003;

73:178-191.

Dell'Agnello G, Maschietto D, Bravaccio C, et al. Atomoxetine hydrochloride in the

treatment of children and adolescents with Attention-Deficit/Hyperactivity Disorder and

Comorbid Oppositional Defiant disorder: A placebo-controlled Italian study. European

Neuropsychopharmacol (2009);19:822–834.

Faries D, Yalcin I, Harder D, et al. Validation of the ADHD Rating Scale as a clinician

administered and scored instrument. J Attn Disorders 2001;5(2):107-115.

Geller D, Donnelly C, Lopez F, et al. Atomoxetine treatment for pediatric patients with

attention-deficit/hyperactivity disorder with comorbid anxiety disorder. J Amer Acad Child

& Adolesc Psych 2007;46:1119-1127

Hesdorffer DC, Ludvigsson P, Olafsson E, et al. ADHD as a risk factor for incident

unprovoked seizures and epilepsy in children. Arch Gen Psychiatry 2004;61:731-736.

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Heil S, Holmes H, Bickel W, et al. Comparison of the subjective, physiological, and

psychomotor effects of atomoxetine and methylphenidate in light drug users. Drug and

Alcohol Dependence 2002;67:149-156.

Kelsey D, Sumner C, Casat C, Allen AJ, et al. Once-daily atomoxetine treatment for

children with Attention-Deficit/Hyperactivity Disorder, including an assessment of evening

and morning behavior: a double-blind, placebo-controlled trial. Pediatrics 2004;

114(1)e1-e8.

Kratochvil C, Heiligenstein J, Dittmann R, et al. Atomoxetine and methylphenidate

treatment in children with ADHD: A prospective, randomized, open-label trial. J Amer

Acad Child Adolesc Psych 2002;41:776-784.

Kratochvil C, Newcorn J, Arnold LE, et al. Atomoxetine alone or combined with

fluoxetine for treating ADHD with comorbid depressive or anxiety symptoms. J Am Acad

Child Adolesc Psychiatry 2005;44(9):915–924.

19.

Kratochvil C, Wilens T, Greenhill L, et al. Effects of long-term atomoxetine treatment for

young children with attention-deficit/hyperactivity disorder. J Amer Acad Child & Adolesc

Psych 2006;45:919-927.

Lowe S, Lim M, Smith B, et al. Haemodynamic effects of IV salbutamol and oral

atomoxetine, alone and in combination. J Clin Pharmacol 2001;41(9):1025.

Maziade M, Rouleau N, Lee B, et al. Atomoxetine and neuropsychological function in

children with Attention-Deficit/Hyperactivity Disorder: Results of a pilot study. J Child

Adolesc Psychopharmacol 2009;19(6):709-718.

Michelson D, Faries D, Wernicke J. Atomoxetine in the Treatment of Children and

Adolescents with ADHD: A Randomized, Placebo-Controlled, Dose-Response Study.

Pediatrics 2001;108(5):1-9.

Michelson D, Allen A, Busner J, et al. Once-daily atomoxetine treatment for children and

adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled

study. Amer J Psychiatry 2002;159:1896-1901.

Michelson D, Adler L, Spencer T, et al. Atomoxetine in adults with ADHD: Two

randomized, placebo-controlled studies. Biol Psychiatry 2003;53:112–120.

Michelson D, Buitelaar J, Danckaerts M, et al. Relapse prevention in pediatric patients

with ADHD treated with atomoxetine: A randomized, double-blind, placebo-controlled

study. J. Am. Acad. Child Adolesc. Psychiatry 2004;43:896–904.

Montoya A, Hervas A, Cardo E, et al. Evaluation of atomoxetine for first-line treatment of

newly diagnosed, treatment-naïve children and adolescents with attention deficit/

hyperactivity disorder. Curr Med Research & Opinion 2009;25(11):2745–2754.

Newcorn J, Spencer T, Biederman J, et al. Atomoxetine treatment in children and

adolescents with Attention-Deficit/Hyperactivity Disorder and comorbid Oppositional

Defiant Disorder. J Am Acad Child Adolesc Psychiatry 2005;44(3):240–248.

Perwien A, Kratochvil C, Faries DE, et al. Atomoxetine treatment in children and

adolescents with attention-deficit hyperactivity disorder: What are the long-term health-

related quality-of-life outcomes? J Child & Adolesc Psychopharmacol 2006;16:713-724.

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Quintana H, Cherlin E, et al. Transitioning from methylphenidate or amphetamine to

atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder- a

preliminary tolerability and efficacy study. Clinical Therapeutics, June 2007.

Sangal R, Owens J, Allen AJ, et al. Effects of atomoxetine and methylphenidate on sleep

in children with ADHD. Sleep 2006;29:1573-1585.

Sauer JM, Ring B, Witcher J. Clinical pharmacokinetics of atomoxetine. Clin

Pharmacokinet 2005;44(6):571-590.

Simpson D, Plosker G. Atomoxetine: A review of its use in adults with Attention Deficit

Hyperactivity Disorder. Drugs 2004;64:205-222.

Smith B, Soon D, Teng C, et. al. Hemodynamic effects of atomoxetine are less

pronounced than methylphenidate, and not additive in combination. J Clin Pharmacol

2001;41:1014-1033.

Spiller HA, Lintner CP, Winter ML: Atomoxetine ingestions in children: A report from

Poison Centers. Ann Pharmacother 2005;39:1045-1048.

Svanborg P, Thernlund G, Gustafsson P, et al. Efficacy and safety of atomoxetine as

add-on to psychoeducation in the treatment of attention deficit/hyperactivity disorder:

A randomized, double-blind, placebo-controlled study in Swedish children and adolescents.

Eur Child Adolesc Psychiatry 2009;18:240–249.

Svanborg P, Thernlund G, Gustafsson P, et al. Atomoxetine improves patient and family

coping in attention deficit/hyperactivity disorder: A randomized, double-blind, placebo-

controlled study in Swedish children and adolescents. Eur Child Adolesc Psychiatry 2009;

Published On-line May 23, 2009.

Weiss M, Tannock R, Kratochvil C, et al. A randomized, placebo-controlled study of

once-daily atomoxetine in the school setting in children with ADHD. J Am Acad Child

Adolesc Psychiatry 2005;44(7):647–655.

Wernicke J, Adler L, Spencer T, et al. Changes in symptoms and adverse events after

discontinuation of atomoxetine in children and adults with Attention Deficit/Hyperactivity

Disorder: A Prospective, Placebo-Controlled Assessment. J Clin Psychopharmacol 2004;

24:30-35.

Wernicke J, Faries D, Girod D et al. Cardiovascular effects of atomoxetine in children,

adolescents, and adults. Drug Safety 2003;26:729-40.

Wernicke JF, Holdridge KC, Jin L, et al. Seizure Risk in Patients with ADHD Treated

with Atomoxetine. Dev Med Child Neur 2007;49:498-502.

Wilens T. Drug therapy for adults with Attention-Deficit Hyperactivity Disorder. Drugs

2003;63:2395-2411.

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(atomoxetine capsules) Control #

184870, Date of Revision: October 1, 2015.

JAMP ATOMOXETINE

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Page 52

IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

Pr

JAMP Atomoxetine

Atomoxetine Capsules

This leaflet is part III of a three-part "Product Monograph"

published when JAMP Atomoxetine was approved for sale in

Canada and is designed specifically for adults and parents of

children/adolescents who will be prescribed this medication.

This leaflet is a summary and will not tell you everything

about JAMP Atomoxetine. Contact your doctor or

pharmacist if

you have any questions about this drug.

What JAMP Atomoxetine is used for:

JAMP Atomoxetine is a medicine for the treatment of

Attention-

Deficit/Hyperactivity Disorder (ADHD) in

children 6 years of

age and over, adolescents, and adults.

JAMP Atomoxetine should

not be used in children under 6

years of age.

JAMP Atomoxetine is a part of your overall treatment

program for

ADHD that may include other measures

(psychological,

educational, and social). Your doctor may

also recommend

other therapy.

What it does:

JAMP Atomoxetine is a selective norepinephrine reuptake

inhibitor

medicine that increases the amount of

noradrenaline, a natural

chemical in the brain. JAMP

Atomoxetine may help increase

attention and decrease

impulsiveness and hyperactivity in

patients with ADHD.

JAMP Atomoxetine works differently from other medicines

used

for the treatment of ADHD. JAMP Atomoxetine is not

a stimulant

and is not addictive.

What is ADHD:

ADHD has 3 main types of symptoms: inattention,

hyperactivity, and impulsiveness. Symptoms of inattention

include not paying attention, making careless mistakes, not

listening, not finishing tasks, not following directions, and

being easily distracted. Symptoms of hyperactivity and

impulsiveness include fidgeting, talking excessively, running

around at inappropriate times, and interrupting others. Some

patients have more symptoms of hyperactivity and

impulsiveness while others have more symptoms of

inattentiveness. Some patients have all 3 types of symptoms.

Symptoms of ADHD in adults may include a lack of

organization, problems starting tasks, impulsive actions,

daydreaming, daytime drowsiness, slow processing of

information, difficulty learning new things, irritability, lack of

motivation, sensitivity to criticism, forgetfulness, low self-

esteem, and excessive effort to maintain some organization.

The symptoms shown by adults who primarily have attention

problems but not hyperactivity have been commonly

described as Attention-Deficit Disorder (ADD).

Many people have these symptoms from time to time.

However, people with ADHD have these symptoms most

the time. Symptoms must be present for at least 6

months to

be certain of the diagnosis. In addition, the

symptoms cause

problems in more than one area of life

(home, school, work,

or social situations).

When it should not be used:

Do not take JAMP Atomoxetine if you:

are taking, or have recently taken, an

antidepressant

medicine known as a monoamine

oxidase inhibitor

(MAOI). Some names of

MAOI medicines are

phenelzine and

tranylcypromine.

have narrow angle glaucoma, an eye disease.

are allergic to atomoxetine or any other ingredient

JAMP Atomoxetine.

have symptomatic cardiovascular disease.

have moderate to severe high blood pressure.

have advanced arteriosclerosis (hardened arteries).

have uncontrolled hyperthyroidism (an overactive

thyroid

gland).

have a tumour of the adrenal gland (phaeochromocytoma).

What the medicinal ingredient is:

Atomoxetine

What the nonmedicinal ingredients are:

The capsules contain pregelatinized starch and colloidal

silicon dioxide.

The capsule shells contain gelatin,

sodium lauryl sulfate, and

one or more of the following:

FD&C Blue No. 2, iron oxide red, synthetic

yellow iron

oxide, titanium dioxide.

What dosage forms it comes in:

Capsules of JAMP Atomoxetine contain 10 mg, 18

mg, 25 mg,

40 mg, 60 mg, 80 mg, or 100 mg of

atomoxetine.

WARNINGS AND PRECAUTIONS

The following have been reported with use of atomoxetine

capsules

and also with stimulant medications:

1.

Suicidal thoughts and actions in children

and

teenagers

Some children and teenagers may have a higher

chance of

having suicidal thoughts or actions. Tell

your child or

teenager’s doctor if your child or teenager

(or there is a

family history of):

has bipolar illness (manic-depressive illness)

had suicidal thoughts or actions before starting

JAMP

Atomoxetine.

The chance for suicidal thoughts and actions are higher:

ABOUT THIS MEDICATION

JAMP ATOMOXETINE

Product Monograph

Page 53

IMPORTANT: PLEASE READ

early during JAMP Atomoxetine treatment

during dose adjustments.

Prevent suicidal thoughts and action in your child or

teenager by:

paying close attention to your child or teenager’s moods,

behaviours,

thoughts,

feelings

during

JAMP

Atomoxetine

treatment

keeping all follow-up visits with your child or teenager’s

doctor as scheduled.

Watch for the following signs in your child or teenager

during JAMP Atomoxetine treatment:

anxiety

agitation

panic attacks

trouble sleeping

irritability

hostility

aggressiveness

impulsivity

restlessness

mania

depression

suicidal thoughts.

Call your child or teenager’s doctor right away if they

have any of the above signs, especially if they are new,

sudden, or severe. Your child or teenager may need to be

closely watched for suicidal thoughts and actions or need a

change in medicine.

Should any of the above signs also happen to you while

taking JAMP Atomoxetine, it is important that you talk to

your

doctor about how you are feeling.

2.

Severe liver damage

Call your doctor right away if you or your child have the

following signs of liver problems:

itching

right upper belly pain

dark urine

yellow skin or eyes

unexplained flu-like symptoms

3.

Heart-related problems:

sudden death in patients who have heart problems or

heart defects as well as in patients without pre-existing

cardiac disease.

stroke and heart attack in adults

increased blood pressure and heart rate

Tell your doctor if you or your child have any heart problems,

heart defects, high blood pressure, or a family history of these

problems.

Your doctor may wish to check you or your child

carefully

heart

problems

before

starting

JAMP

Atomoxetine.

Your doctor may wish to check you or your child’s blood

pressure and heart rate regularly during treatment with

JAMP Atomoxetine.

Call your doctor right away if you or your child has any

signs

of heart problems such as chest pain, irregular heart

rate,

palpitations, shortness of breath, dizziness or fainting

while

taking JAMP Atomoxetine.

4.

New mental (psychiatric) problems in children

and

teenagers:

new psychotic symptoms (such as hearing voices,

believing things that are not true, are suspicious) or

manic symptoms.

Call your child or teenager’s doctor right away about

any

new mental symptoms. JAMP Atomoxetine

treatment may be

stopped.

BEFORE you use JAMP Atomoxetine, talk to your

doctor or

pharmacist if you or your child:

have or had suicidal thoughts or actions

have structural heart abnormalities,

inborn, acquired or family history of long QT interval

have mental problems, including psychosis,

mania,

bipolar illness, or depression;

have had seizures (convulsions, epilepsy) or

abnormal

EEGs (electroencephalograms);

have or had any disorder of the blood vessels in the

brain

(e.g. aneurysm, stroke, vasculitis);

have a family history of sudden death or death related

heart problems;

do strenuous exercise;

take other drugs for ADHD;

have or had liver problems. You may need a lower dose;

have mild high blood pressure. JAMP

Atomoxetine can

increase blood pressure;

have problems with your heart or an irregular

heartbeat.

JAMP Atomoxetine can increase heart

rate (pulse);

have low blood pressure. JAMP Atomoxetine can

cause

dizziness or fainting in people with low

blood pressure

are nursing, pregnant, or thinking of becoming pregnant;

have circulation problems in fingers and toes, including

numbness; feeling cold or pain (Raynaud’s

Phenomenon).

Do not drive a car or operate hazardous machinery

until

you know how JAMP Atomoxetine affects you.

This medicine was prescribed for your use only. Do not

anyone else take your JAMP Atomoxetine.

INTERACTIONS WITH THIS MEDICATIONS

JAMP ATOMOXETINE

Product Monograph

Page 54

IMPORTANT: PLEASE READ

Tell your doctor about all the medicines you/your child take

or plan to take, including prescription and non-prescription

medicines, dietary supplements, and herbal remedies. Your

doctor will decide if you can take JAMP Atomoxetine with

your

other medicines. Also tell your doctor if there have

been any

changes in dosing with your other medicines.

Certain medicines may change the way your body reacts to

JAMP Atomoxetine.

Drugs that may interact with JAMP Atomoxetine include:

Anti-depression medicines: Your doctor may need to

change your dose of JAMP Atomoxetine if you are

taking

paroxetine,

fluoxetine,

certain

other

medicines like

quinidine.

You should not take JAMP Atomoxetine if you are

taking

desipramine.

Asthma medicines: JAMP Atomoxetine may change

the way

your body reacts to oral, intravenous, or

nebulized

salbutamol (or drugs with similar actions),

but the

effectiveness of these drugs will not be

changed.

Blood pressure medicines: JAMP Atomoxetine should

be used

with caution if you are being treated with drugs

for high

blood pressure.

PROPER USE OF THIS MEDICATION

Usual dose:

Take JAMP Atomoxetine exactly as directed by your doctor.

It is

very important that you do not take a larger dose of

JAMP Atomoxetine than prescribed by your doctor.

Your doctor may tell you to take JAMP Atomoxetine once a

day or

twice a day (morning and late afternoon/early

evening). To

help you remember to take JAMP

Atomoxetine, you may want to

take it at the same time

every day.

Improvement of your ADHD symptoms is generally observed

within 1 to 4 weeks of starting JAMP Atomoxetine.

JAMP Atomoxetine may be taken with or without food.

You should not open JAMP Atomoxetine capsules, but if

they are

accidentally opened or broken, avoid contact with

the powder

and wash away any loose powder as soon as

possible with

water. If any of the powder gets in your eyes

you should rinse

them with water immediately and contact

your doctor.

Overdose:

If you think you have taken too much JAMP

Atomoxetine contact your healthcare professional,

hospital emergency department or regional poison

control centre immediately, even if there are no

symptoms.

Missed Dose:

If you miss a dose, take it as soon as possible, but do not take

more than your total daily dose in any 24-hour period.

SIDE EFFECTS AND WHAT TO DO ABOUT

THEM

All prescription medicines may cause side effects in some

patients. If you have some side-effects such as upset

stomach, nausea, sleepiness or tiredness, your doctor may

you to take JAMP Atomoxetine twice a day with

meals, or in the

evening. Most side effects will disappear

after the first few

weeks.

The following common side effects were reported in clinical

trials with atomoxetine capsules:

In teenagers and children over 6:

upset stomach

decreased appetite

nausea or vomiting

dizziness

tiredness

constipation

low blood pressure

weight loss may occur especially in the first few weeks.

In Adults:

constipation

dry mouth

nausea

decreased appetite

dizziness

problems sleeping

sexual side effects

problems urinating

menstrual cramps

rapid or irregular heartbeat

tiredness

SERIOUS SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Symptom / effect

Talk with

your doctor

or

pharmacist

Stop taking

drug and

seek

immediate

emergency

help

Only

if

sever

In

all

case

Very

common

Heart-related

problems: Blood

pressure increased,

heart rate increased.

(see Warnings and

Precautions)

JAMP ATOMOXETINE

Product Monograph

Page 55

IMPORTANT: PLEASE READ

SERIOUS SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Symptom / effect

Talk with

your doctor

or

pharmacist

Stop taking

drug and

seek

immediate

emergency

help

Only

if

sever

In

all

case

Common

Rare (in

children)

Urinary retention:

problem passing

urine

emptying bladder

Uncommon

Allergic Reaction:

Swelling, hives, or

difficulty breathing

Suicidal Behavior:

Thoughts or

actions about

hurting or killing

yourself.

(see Warnings

and Precautions)

New psychotic

symptoms:

Paranoia,

delusions-

hallucinations

(seeing, feeling or

hearing things that

are not real)

Aggressive

Behavior

or

Hostility

Rare

Liver Injury: Dark

urine, yellow skin/

eyes, upper right-

sided abdominal

tenderness, or flu-

like

symptoms

Priapism: Long-

lasting (greater

than 4 hours in

duration) and

painful erection

of the penis

Raynaud’s

Phenomenon:

discoloration of the

fingers and toes,

pain, sensations of

cold and/or

numbness

Unknown

Slowing of growth

in

children (height

and weight)

SERIOUS SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Symptom / effect

Talk with

your doctor

or

pharmacist

Stop taking

drug and

seek

immediate

emergency

help

Only

if

sever

In

all

case

New manic

symptoms: Mania

(feeling unusually

excited, overactive,

or un-inhibited)

This is not a complete list of side effects. For any unexpected effects

while taking JAMP Atomoxetine, contact your doctor or pharmacist.

HOW TO STORE IT

JAMP Atomoxetine should be stored at room temperature

(15 to

30°C).

Keep all medicines, including JAMP Atomoxetine, out of the

reach and sight

of children.

REPORTING SIDE EFFECTS

You can report any suspected side effects associated with

the use of health products to

Health Canada by:

Visiting

page

Adverse

Reaction

Reporting

(https://www.canada.ca/en/health-

canada/services/drugs-health-products/medeffect-

canada/adverse-reaction-reporting.html)

information

on how to report online, by mail or by

fax; or

Calling toll-free at 1-866-234-2345.

NOTE:

Contact

your

health

professional

if

you

need

information about how to manage your side effects. The

Canada

Vigilance

Program

does

not

provide

medical

advice.

MORE INFORMATION

If you want more information about JAMP Atomoxetine:

Talk to your healthcare professional

Find the full Product Monograph that is prepared for

healthcare professionals and includes this Consumer

Information by visiting the Health Canada website

(https://www.canada.ca/en/health-canada.html); or by

contacting the sponsor, JAMP Pharma Corporation, at:

1-866-399-9091.

JAMP ATOMOXETINE

Product Monograph

Page 56

IMPORTANT: PLEASE READ

This leaflet was prepared by JAMP Pharma Corporation.

1310, rue Nobel

Boucherville, Qu

J4B 5H3

Last Approved: October 19, 2020

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