ARIPIPRAZOLE TABLET

Canada - English - Health Canada

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Active ingredient:
ARIPIPRAZOLE
Available from:
SANIS HEALTH INC
ATC code:
N05AX12
INN (International Name):
ARIPIPRAZOLE
Dosage:
30MG
Pharmaceutical form:
TABLET
Composition:
ARIPIPRAZOLE 30MG
Administration route:
ORAL
Units in package:
100
Prescription type:
Prescription
Therapeutic area:
ATYPICAL ANTIPSYCHOTICS
Product summary:
Active ingredient group (AIG) number: 0152514005; AHFS: 28:16.08.04
Authorization status:
APPROVED
Authorization number:
02506785
Authorization date:
2020-10-19

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ARIPIPRAZOLE

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PRODUCT MONOGRAPH

Pr

ARIPIPRAZOLE

Aripiprazole Tablets

2 mg, 5 mg, 10 mg, 15 mg, 20 mg and 30 mg Aripiprazole

Antipsychotic agent

Sanis Health Inc.

1 President’s Choice Circle,

Brampton, Ontario

L6Y 5S5

Date of Revision:

October 15, 2020

Submission Control No.: 243590

ARIPIPRAZOLE

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Table of Contents

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

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

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

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

WARNINGS AND PRECAUTIONS ..................................................................................4

ADVERSE REACTIONS ..................................................................................................14

DRUG INTERACTIONS ..................................................................................................29

DOSAGE AND ADMINISTRATION ..............................................................................33

OVERDOSAGE ................................................................................................................35

ACTION AND CLINICAL PHARMACOLOGY ............................................................36

STORAGE AND STABILITY ..........................................................................................39

DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................39

PART II: SCIENTIFIC INFORMATION ...............................................................................41

PHARMACEUTICAL INFORMATION ..........................................................................41

CLINICAL TRIALS ..........................................................................................................42

DETAILED PHARMACOLOGY .....................................................................................45

TOXICOLOGY .................................................................................................................48

REFERENCES ..................................................................................................................56

PART III: CONSUMER INFORMATION

................................................................................57

ARIPIPRAZOLE

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Pr

ARIPIPRAZOLE

Aripiprazole Tablets USP

2 mg, 5 mg, 10 mg, 15 mg, 20 mg and 30 mg Aripiprazole

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form /

Strength

All Nonmedicinal Ingredients

oral

Tablet, 2 mg, 5 mg, 10

mg, 15 mg, 20 mg and

30 mg

Colloidal silicon dioxide, corn starch,

crospovidone, hydroxy propyl cellulose,

lactose monohydrate, magnesium stearate,

microcrystalline cellulose and coloring agents

2 mg tablet: FD&C Blue No. 2 / Indigo

Carmine AL and Iron oxide yellow

5mg tablet: FD&C Blue No. 2 / Indigo

Carmine AL

10 mg and 30 mg tablets: Iron oxide red

15 mg tablet: Iron oxide yellow

INDICATIONS AND CLINICAL USE

Adults

Schizophrenia

ARIPIPRAZOLE (aripiprazole) is indicated for the treatment of schizophrenia in adults. In

controlled clinical trials, Aripiprazole was found to improve both positive and negative

symptoms.

ARIPIPRAZOLE has been shown to be more effective than placebo in maintaining clinical

improvement for up to 26 weeks in adults.

Pediatrics (<18 years of age)

When prescribing to adolescents with schizophrenia (15-17 years of age) clinicians must

take into account the safety concerns associated with all antipsychotic drugs which include:

weight gain; hyperlipidemia; hyperglycemia; and, extrapyramidal effects which can be

more frequent or more severe in this patient population than in adults (see WARNINGS

AND PRECAUTIONS; ADVERSE REACTIONS). ARIPIPRAZOLE should only be

prescribed to adolescents with schizophrenia by clinicians who are experienced in the

ARIPIPRAZOLE

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diagnosis and treatment of adolescents with psychiatric illness and who are experienced in

the early detection and management of the above-mentioned safety issues associated with

this class of drugs.

Schizophrenia

ARIPIPRAZOLE is indicated for the treatment of schizophrenia in adolescents 15 – 17 years of

age.

Safety and efficacy were evaluated in one 6-week clinical trial in adolescents (13-17 years of

age) with schizophrenia. ARIPIPRAZOLE is not indicated for the treatment of schizophrenia in

adolescents less than 15 years of age due to insufficient safety and efficacy data (see ADVERSE

REACTIONS, CLINICAL TRIALS, Schizophrenia, Adolescents).

The safety and efficacy of ARIPIPRAZOLE during long term treatment have not been

systematically evaluated in adolescents with schizophrenia. The physician who elects to use

ARIPIPRAZOLE for extended periods in adolescents with schizophrenia should periodically re-

evaluate the long term usefulness of the drug for the individual patient.

Geriatrics (≥ 65years of age): ARIPIPRAZOLE is not indicated in elderly patients with

dementia. (See WARNINGS AND PRECAUTIONS – Serious Warnings and Precaution Box

and Special populations). The safety and efficacy of ARIPIPRAZOLE in patients 65 years of age

or older has not been established. Caution should be used when treating geriatric patients. (See

WARNINGS AND PRECAUTIONS, Special Populations and ACTIONS AND CLINICAL

PHARMACOLOGY).

CONTRAINDICATIONS

ARIPIPRAZOLE (aripiprazole) is contraindicated in those patients with a known

hypersensitivity to this drug or the excipients of the product. For a complete listing, see

DOSAGE FORMS, COMPOSITION AND PACKAGING.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Increased Mortality in Elderly Patients with Dementia

Elderly patients with dementia treated with atypical antipsychotic drugs are at an increased risk of death compared to placeb

controlled trials with various atypical antipsychotics (modal duration of 10 weeks) in these patients showed a mean 1.6

drug-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., he

infectious (e.g., pneumonia) in nature (see WARNINGS AND PRECAUTIONS - Special Populations, Use in Elderly Patients with Dementia).

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General

Body Temperature Regulation

Disruption of the body’s ability to reduce core body temperature has been attributed to

antipsychotic agents. Appropriate care is advised when prescribing ARIPIPRAZOLE for patients

who will be experiencing conditions which may contribute to an elevation in core body

temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant

medication with anticholinergic activity, or being subject to dehydration) (see ADVERSE

REACTIONS).

Carcinogenesis and Mutagenesis

For animal data, see Part II: TOXICOLOGY section.

Cardiovascular

Orthostatic Hypotension

Aripiprazole may be associated with orthostatic hypotension, perhaps due to its ɑ1-adrenergic

receptor antagonism. ARIPIPRAZOLE may induce orthostatic hypotension, tachycardia,

dizziness, and sometimes syncope, especially at the initiation of treatment. The incidence of

orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult

patients on oral aripiprazole (n=2643) included (aripiprazole incidence, placebo incidence):

orthostatic hypotension (1.0%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%,

0.3%); of adolescent patients (13-17 years of age) with schizophrenia on oral aripiprazole

(n=202) included (aripiprazole 10 mg/day incidence, aripiprazole 30 mg/day incidence, placebo

incidence): orthostatatic hypotension (0%, 2.9%, 0%), postural dizziness (0%, 2%, 0%), and

syncope (1%, 0%, 0%); The risk of orthostatic hypotension may be reduced by more gradual

titration to the target dose.

The incidence of a significant orthostatic change in blood pressure (defined as a decrease in

systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 bpm when

comparing standing to supine values) for oral aripiprazole was (aripiprazole incidence, placebo

incidence): 3.7%, 2.3% in adults; 0% (0/202), 0% (0/100) in adolescent patients (13-17 years of

age) with schizophrenia.

Aripiprazole should be used with caution in patients with known cardiovascular disease (e.g.,

history of myocardial infarction or ischemic heart disease, heart failure or conduction

abnormalities), cerebrovascular disease, or conditions which would predispose patients to

hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications).

Patients with a history of clinically significant cardiovascular disorders were excluded from

clinical trials.

QT Interval

In clinical trials with aripiprazole involving patients with schizophrenia, the incidence of QT

prolongation was comparable to placebo. In post-marketing experience, QT prolongation has

been reported very rarely with aripiprazole treatment. As with other antipsychotics, caution

should be exercised when ARIPIPRAZOLE is prescribed in patients with a history of cardiac

arrhythmias, in patients with congenital or family history of long QT syndrome, and in

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concomitant use with drugs known to prolong the QT interval (See ADVERSE REACTIONS -

ECG Changes; ADVERSE REACTIONS – Post-marketing Adverse Drug Reactions).

Dependence/Tolerance

Aripiprazole has not been systematically studied in humans for its potential for abuse, tolerance,

or physical dependence. In physical dependence studies in monkeys, withdrawal symptoms were

observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency

for any drug-seeking behavior, these observations were not systematic and it is not possible to

predict on the basis of this limited experience the extent to which a CNS-active drug will be

misused, diverted, or abused once marketed. Consequently, patients should be evaluated

carefully for a history of drug abuse, and such patients should be observed closely for signs of

aripiprazole misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking

behavior).

Pathological Gambling and Other Impulse-Control Disorders

Post-marketing reports of pathological gambling have been reported in patients treated with

aripiprazole. These reports suggest that patients can experience increased urges, particularly for

gambling, and the inability to control these urges while taking aripiprazole. With regards to

pathological gambling, patients with a prior history of gambling disorder may be at increased

risk and should be monitored carefully. Other urges, reported very rarely, include: increased

sexual urges, compulsive spending, binge or compulsive eating, and other impulsive and

compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is

important for prescribers to ask patients or their caregivers specifically about the development of

new or increased gambling urges, sexual urges, compulsive spending, binge or compulsive

eating, or other urges while being treated with aripiprazole. It should be noted that impulse-

control symptoms can be associated with the underlying disorder; however, in some cases,

although not all, urges were reported to have stopped when the dose was reduced or the

medication was discontinued. Although impulse-control disorders have been reported very

rarely, impulse-control disorders may result in harm to the patient and others if not recognized.

Consider dose reduction or stopping the medication if a patient develops such urges while taking

aripiprazole.

Endocrine and Metabolism

Hyperglycemia and Diabetes Mellitus

Diabetic ketoacidosis has occurred in patients with no reported history of hyperglycemia. As

with some other antipsychotics, exacerbation of pre-existing diabetes and hyperglycemia have

been reported rarely and diabetic ketoacidosis and diabetic coma including some fatal cases,

have been reported very rarely during the use of aripiprazole (see ADVERSE REACTIONS).

Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is

complicated by the possibility of an increased background risk of diabetes mellitus in patients

with schizophrenia and the increasing incidence of diabetes mellitus in the general population.

Given these confounders, the relationship between atypical antipsychotic use and

hyperglycemia-related adverse events is not completely understood. However, epidemiological

studies which did not include aripiprazole suggest an increased risk of treatment-emergent

hyperglycemia-related adverse events in patients treated with the atypical antipsychotics.

ARIPIPRAZOLE

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Because ARIPIPRAZOLE was not marketed at the time these studies were performed, it is not

known if ARIPIPRAZOLE is associated with this increased risk. Precise risk estimates for

hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not

available.

Patients should have baseline and periodic monitoring of blood glucose and body weight. Any

patient treated with atypical antipsychotics should also be monitored for symptoms of

hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop

symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo

fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical

antipsychotic was discontinued; however, some patients required continuation of anti-diabetic

treatment despite discontinuation of the suspect drug. Patients with risk factors for diabetes

mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical

antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and

periodically during treatment. Patients with an established diagnosis of diabetes mellitus who are

started on atypical antipsychotics should be monitored regularly for worsening of glucose

control.

Weight, glucose and lipid changes in adolescents with schizophrenia

There are limited data for ARIPIPRAZOLE in adolescents with schizophrenia (13-17 years of

age) from acute placebo controlled, fixed dose clinical trials 4 to 6 weeks, 10 mg/day and 30

mg/day) and from extension studies (up to 26 weeks of treatment) to assess the effects of

aripiprazole on weight, glucose, and lipid metabolism. Data for these parameters from the acute

placebo controlled clinical trials were from approximately 50 to 100 patients per treatment

group, and in the adolescent schizophrenia trial the majority of patients had received treatment

with other antipsychotic medications prior to inclusion in this study. Therefore, these data cannot

be considered entirely predictive of the effects of aripiprazole on weight, glucose and lipid

metabolism during use in adolescents with schizophrenia (see ADVERSE REACTIONS, Weight

Gain, Glucose, and Lipids). Published studies have demonstrated that the adverse effects of

atypical antipsychotic drugs on weight, glucose and lipid metabolism can be greater in

antipsychotic-naïve pediatric and adolescent patients than in patients who have been treated

previously with antipsychotic drugs.

Clinical monitoring of weight, glucose and lipids at baseline and at regular intervals is

recommended for adolescents with schizophrenia who are treated with antipsychotics including

aripiprazole.

Weight Gain

During acute placebo controlled and extension phase studies in pediatric and adolescent patients

with schizophrenia, the proportion of patients with potentially clinically significant weight gain

(≥ 7% increase from baseline weight) was greater among those treated with aripiprazole

compared to those that received placebo (see ADVERSE REACTIONS, Weight gain).

Glucose

See ADVERSE REACTIONS, Glucose.

ARIPIPRAZOLE

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Lipids

See ADVERSE REACTIONS, Lipids.

Genitourinary

Priapism

Rare cases of priapism have been reported with antipsychotic use such as aripiprazole. As with

other psychotropic drugs, this adverse reaction did not appear to be dose-dependent and did not

correlate with the duration of treatment.

Hematologic

In clinical trial and/or post-marketing experience, events of leukopenia/neutropenia have been

reported temporally related to antipsychotic agents, including aripiprazole. Agranulocytosis has

also been reported (see ADVERSE REACTIONS – Post-market Adverse Drug Reactions).

Therefore, it is recommended that patients have their complete blood count (CBC) tested prior to

starting ARIPIPRAZOLE and then periodically throughout treatment.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count

(WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a

clinically significant low WBC or drug-induced leukopenia/neutropenia should have their

complete blood count (CBC) monitored frequently during the first few months of therapy and

discontinuation of ARIPIPRAZOLE should be considered at the first sign of a clinically

significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other

symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients

with severe neutropenia (absolute neutrophil count <1000/mm

) should discontinue

ARIPIPRAZOLE and have their WBC followed until recovery.

Venous thromboembolism

Venous thromboembolism (VTE), including fatal pulmonary embolism, has been reported with

antipsychotic drugs, including aripiprazole in case reports and/or observational studies. When

prescribing ARIPIPRAZOLE all potential risk factors for VTE should be identified and

preventative measures undertaken.

Immune

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Post market cases of DRESS have been reported in association with similar atypical

antipshychotic drugs within the class.

Neurologic

Neuroleptic Malignant Syndrome (NMS)

Neuroleptic malignant syndrome is a potentially fatal symptom complex that has been reported

in association with antipsychotic drugs, including aripiprazole.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and

evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis,

ARIPIPRAZOLE

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and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase,

myoglobinuria (rhabdomyolysis), and acute renal failure.

In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes

both serious medical illness (e.g., pneumonia, systemic infection, etc.), and untreated or

inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations

in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and

primary central nervous system pathology.

The management of NMS should include 1) immediate discontinuation of all antipsychotic drugs

(including ARIPIPRAZOLE) and other drugs not essential to therapy; 2) intensive symptomatic

treatment and medical monitoring; and 3) treatment of any concomitant serious medical

problems for which specific treatments are available. There is no general agreement about

specific pharmacological treatment for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential re-

introduction of therapy should be very carefully considered. The patient should be carefully

monitored, since recurrence of NMS has been reported.

Falls

Antipsychotics, including aripiprazole, may cause somnolence, postural hypotension, motor and

sensory instability, which may lead to falls and, consequently, fractures or other injuries. For

patients with diseases, conditions, or medications that could exacerbate these effects, complete

fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-

term antipsychotic therapy.

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in

patients treated with antipsychotic drugs. Although the prevalence of the syndrome is highest

among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates

to predict, at the inception of antipsychotic treatment, which patients are likely to develop the

syndrome. Whether antipsychotic drug products differ in their potential to cause tardive

dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible

increase as the duration of treatment and the total cumulative dose of antipsychotic drugs

administered to the patient increase. However, the syndrome can develop, although much less

commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome

may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic

treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the

syndrome and, thereby, may possibly mask the underlying process. The effect that symptomatic

suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, ARIPIPRAZOLE should be prescribed in a manner that is most

ARIPIPRAZOLE

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likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should

generally be reserved for patients who suffer from a chronic illness that (1) is known to respond

to antipsychotic drugs and (2) for whom alternative, equally effective, but potentially less

harmful treatments are not available or appropriate. In patients who do require chronic treatment,

the smallest dose and the shortest duration of treatment producing a satisfactory clinical response

should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, drug

discontinuation should be considered. However, some patients may require treatment with

aripiprazole despite the presence of the syndrome.

Extrapyramidal Symptoms

The rate of extrapyramidal-related adverse events in adolescents (13- 17 years of age) with

schizophrenia was greater than the rate reported in adult patients (see ADVERSE REACTIONS,

Extrapyramidal Symptoms, Dose-Related Adverse Events, and Additional Findings Observed in

Clinical Trials).

Pediatric and adolescent patients are known to be at greater risk of experiencing certain adverse

events related to the use of atypical antipsychotics, including extrapyramidal symptoms (see

ADVERSE REACTIONS).

Seizure/Convulsion

In short-term, placebo-controlled trials of patients treated with oral aripiprazole,

seizures/convulsions occurred in 0.1% (3/2643) of adult patients; in 0% (0/202) of adolescent

(13-17 years of age) patients with schizophrenia. There were confounding factors that may have

contributed to the occurrence of seizures in some of these patients.

As with other antipsychotic drugs, aripiprazole should be used cautiously in patients with a

history of seizures or with conditions that lower the seizure threshold. Conditions that lower the

seizure threshold may be more prevalent in a population of 65 years or older.

Potential for Cognitive and Motor Impairment

Like other antipsychotics drugs, aripiprazole has the potential to impair judgment, thinking, or

motor skills. Somnolence was a commonly reported adverse event in patients treated with

aripiprazole in clinical trials. Somnolence (including sedation) adverse events were reported

more frequently in adolescents with schizophrenia (13 – 17 years of age) than in adult patients

(see ADVERSE REACTIONS, Somnolence).

Because aripiprazole may cause somnolence, and impair motor skills, patients should be

cautioned about performing activities requiring mental alertness, such as operating hazardous

machinery, including motor vehicles, until they are reasonably certain that aripiprazole therapy

does not affect them adversely.

Psychiatric

Suicide

The possibility of a suicide attempt is inherent in psychotic illnesses. Also, depression may be

ARIPIPRAZOLE

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co-morbid with schizophrenia. The risk of suicide-related events during a depressive episode

may persist until remission occurs. It is general clinical experience that the risk of suicide may

increase in the early stages of recovery. Close supervision and appropriate clinical management

of high-risk patients should accompany drug therapy. Prescriptions for ARIPIPRAZOLE should

be written for the smallest quantity of tablets consistent with good patient management, in order

to reduce the risk of overdose.

Special Populations

Pregnant Women

Teratogenic effects

There are no adequate and well-controlled studies in pregnant women. It is not known whether

aripiprazole can cause fetal harm when administered to a pregnant woman or can affect

reproductive capacity. In animal studies, aripiprazole demonstrated developmental toxicity,

including possible teratogenic effects in rats and rabbits (see TOXICOLOGY).

Non-teratogenic effects

Neonates exposed to antipsychotic drugs, including aripiprazole, during the third trimester of

pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There

have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress

and feeding disorder in these neonates. These complications have varied in severity; while in

some cases symptoms have been self-limited, in other cases neonates have required intensive

care unit support and prolonged hospitalization.

Aripiprazole should not be used during pregnancy unless the expected benefits to the mother

markedly outweigh the potential risks to the fetus.

Labor and Delivery

The effect of aripiprazole on labor and delivery in humans is unknown.

Nursing Women

Aripiprazole is excreted in human breast milk. It is recommended that women receiving

aripiprazole should not breast-feed.

Pediatrics (< 18 years of age)

When prescribing to adolescents with schizophrenia (15 – 17 years of age) clinicians must take

into account the safety concerns associated with all antipsychotic drugs which include: weight

gain; hyperlipidemia; hyperglycemia; and, extrapyramidal effects which can be more frequent or

more severe in this patient population than in adults (see ADVERSE REACTIONS).

ARIPIPRAZOLE should only be prescribed to adolescents with schizophrenia by clinicians who

are experienced in the diagnosis and treatment of adolescents with psychiatric illness and who

are experienced in the early detection and management of the above-mentioned safety issues

associated with this class of drugs.

Weight gain has been observed with atypical antipsychotic use in pediatric and adolescent

patient populations. Independent of any drug-specific effects, weight gain can be associated with

adverse changes in other metabolic parameters (e.g., glucose and lipid metabolism). Abnormal

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childhood weight and metabolic status can have adverse effects on cardiovascular outcomes in

adulthood. Weight gain and adverse effects on other metabolic parameters associated with

atypical antipsychotics can be more frequent or severe in pediatric and adolescent patients than

in the adult patients.

The long-term safety, including cardiometabolic effects and effects on growth, maturation and

behavioural development in patients under 18 years of age has not been systematically evaluated.

Safety and efficacy have been evaluated in one 6-week placebo-controlled clinical trial in

adolescents (13-17 years of age) with schizophrenia. ARIPIPRAZOLE is not indicated for the

treatment of schizophrenia in adolescents under 15 years of age due to insufficient safety and

efficacy data (see ADVERSE REACTIONS, CLINICAL TRIALS, Schizophrenia, Adolescents).

Geriatrics (≥ 65 years of age)

In formal single-dose pharmacokinetic studies (with aripiprazole given in a single dose of 15

mg), aripiprazole clearance was 20% lower in elderly (≥65 years) subjects compared to younger

adult subjects (18 to 64 years). There was no detectable age effect, however, in the population

pharmacokinetic analysis in schizophrenia patients. Also, the pharmacokinetics of aripiprazole

after multiple doses in elderly patients appeared similar to that observed in young, healthy

subjects (see WARNINGS AND PRECAUTIONS - Serious Warnings and Precautions Box and

DOSAGE AND ADMINISTRATION - Geriatrics).

Placebo-controlled studies of oral aripiprazole in schizophrenia, did not include sufficient

numbers of subjects aged 65 and over to determine whether they respond differently from

younger subjects.

Nevertheless, geriatric patients generally have decreased cardiac, hepatic and renal function, and

more frequent use of concomitant medication. The presence of multiple factors that might

increase the pharmacodynamic response to aripiprazole, or cause poorer tolerance or orthostasis,

should lead to consideration of a lower starting dose, slower titration, and careful monitoring

during the initial dosing period for elderly patients. The safety and efficacy of ARIPIPRAZOLE

in patients 65 years of age or older have not been established. Caution should be used when

treating geriatric patients.

Use in Elderly Patients with Dementia

Overall Mortality

Elderly patients with dementia treated with atypical antipsychotic drugs showed increased

mortality compared to placebo in a meta-analysis of 13 placebo-controlled trials of various

atypical antipsychotic drugs. In three placebo-controlled studies of aripiprazole in elderly

patients with Alzheimer’s disease (n=938; mean age: 82.4 years; range: 56-99 years), the

rate of death in aripiprazole-treated patients was 3.5%, compared to a rate of 1.7% in the

placebo group during or within 30 days after termination from the double-blind phase of

the studies. Although the causes of death were varied, most of the deaths appeared to be

either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in

nature. ARIPIPRAZOLE is not indicated for the treatment of patients with dementia (see

Serious Warnings and Precautions).

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Cerebrovascular Adverse Events, Including Stroke in Elderly Patients with Dementia

In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of elderly

patients with dementia, there was an increased incidence of cerebrovascular adverse events (e.g.,

stroke, transient ischemic attack), including fatalities, in aripiprazole-treated patients. In the

fixed-dose study, there was a statistically significant dose response relationship for

cerebrovascular adverse events in patients treated with aripiprazole. Aripiprazole is not indicated

for the treatment of patients with dementia (see WARNINGS AND PRECAUTIONS - Serious

Warnings and Precautions).

Frequent Treatment Emergent Adverse Events in Elderly Patients with Dementia

In the placebo-controlled studies of elderly patients with dementia (n=595 treated with

aripiprazole, n=343 treated with placebo), the following treatment-emergent adverse events were

reported at an incidence of ≥3% and aripiprazole incidence at least twice that for placebo:

lethargy [placebo 2%, aripiprazole 5%], somnolence (including sedation) [placebo 3%,

aripiprazole 8%], and incontinence (primarily, urinary incontinence) [placebo 1%, aripiprazole

5%], excessive salivation (placebo 0%, aripiprazole 4%), and lightheadedness (placebo 1%,

aripiprazole 4%).

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use,

including aripiprazole. Aspiration pneumonia is a common cause of morbidity and mortality in

elderly patients, in particular those with advanced Alzheimer’s dementia. Aripiprazole and other

antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia (see

ADVERSE REACTIONS).

The emergence of difficulty swallowing or excessive somnolence, could predispose patients to

accidental injury or aspiration (see WARNINGS AND PRECAUTIONS - Serious Warnings and

Precautions).

Use in Patients with Renal Impairment

No dosage adjustment is required in subjects with renal impairment (see ACTION AND

CLINICAL PHARMACOLOGY; Special populations – Renal Impairment).

Use in Patients with Hepatic Impairment

No dosage adjustment is required in subjects with hepatic impairment (see ACTION AND

CLINICAL PHARMACOLOGY; Special populations – Hepatic Impairment).

Use in Patients with Concomitant Illness

Clinical experience with aripiprazole tablet in patients with certain concomitant systemic

illnesses is limited. Aripiprazole tablet has not been evaluated or used to any appreciable extent

in patients with a recent history of myocardial infarction or unstable heart disease. Patients with

these diagnoses were excluded from pre-marketing clinical studies (see WARNINGS AND

PRECAUTIONS, Cardiovascular-Orthostatic Hypotension).

ARIPIPRAZOLE

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Gender

and AUC of aripiprazole and its active metabolite, dehydro-aripiprazole, are 30 to 40%

higher in women than in men, and correspondingly, the apparent oral clearance of aripiprazole is

lower in women. These differences, however, are largely explained by differences in body

weight (25%) between men and women. No dosage adjustment is recommended based on

gender.

Race

Although no specific pharmacokinetic study was conducted to investigate the effects of race on

the disposition of aripiprazole, population pharmacokinetic evaluation did not demonstrate

important race-related differences in the pharmacokinetics of aripiprazole. No dosage adjustment

is recommended based on race.

Lactose

ARIPIPRAZOLE tablets contain lactose monohydrate (46 mg, 43 mg, 40 mg, 58 mg, 81 mg and

118 mg for the 2 mg, 5 mg, 10 mg, 15 mg, 20 mg and 30 mg tablets respectively). Patients with

rare hereditary problems of galactose intolerance or glucose-galactose malabsorption should not

take ARIPIPRAZOLE.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Aripiprazole was evaluated for safety in 13,543 adult patients who participated in multiple-dose,

clinical trials including schizophrenia, dementia of the Alzheimer's type, Parkinson’s disease,

and alcoholism, and who had approximately 7619 patient-years of exposure to oral aripiprazole

and 749 patients with exposure to aripiprazole injection. A total of 3390 patients were treated

with oral aripiprazole for at least 180 days and 1933 patients treated with oral aripiprazole had at

least 1 year of exposure.

The conditions and duration of treatment with aripiprazole (monotherapy or adjunctive therapy

with antidepressants or mood stabilizers) included (in overlapping categories) double-blind,

comparative and noncomparative open-label studies, inpatient and outpatient studies, fixed- and

flexible-dose studies, and short- and longer-term exposure.

Aripiprazole was evaluated for safety in 202 adolescent patients (13 - 17 years of age) with

schizophrenia in a 6 week placebo controlled clinical trial. Adolescent patients from this study

were also treated with oral aripiprazole in uncontrolled, open label studies for more than 26

weeks (n=178) and more than 52 weeks (n=79). Treatment emergent adverse event frequencies

are reported for adolescent patients, 13 - 17 years of age, with schizophrenia that were included

in these studies, but the majority of patients were 15 - 17 years of age.

ARIPIPRAZOLE is not indicated for the treatment of schizophrenia in adolescent patients

under 15 years due to insufficient safety and efficacy data (see ADVERSE REACTIONS,

CLINICAL TRIALS, Schizophrenia, Adolescents.

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Adverse events during exposure were obtained by collecting volunteered adverse events, as well

as results of physical examinations, vital signs, weights, laboratory analyses, and ECG. Adverse

events were recorded by clinical investigators using terminology of their own choosing. In the

tables and tabulations that follow, MedDRA dictionary terminology has been used to classify

reported adverse events into a smaller number of standardized event categories, in order to

provide a meaningful estimate of the proportion of individuals reporting adverse events.

The stated frequencies of adverse events represent the proportion of individuals who reported at

least once, a treatment-emergent adverse event of the type listed. An event was considered

treatment emergent if it occurred for the first time or worsened while receiving therapy following

baseline evaluation. There was no attempt to use investigator causality assessments; i.e. all

events meeting the defined criteria, regardless of investigator causality are included.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction

rates observed in the clinical trials may not reflect the rates observed in practice and

should not be compared to the rates in the clinical trials of another drug. Adverse drug

reaction information from clinical trials is useful for identifying drug-related adverse

events and for approximating rates.

Short-Term, Placebo-Controlled Trials of Adult Patients with Schizophrenia

The following findings are based on a pool of five placebo-controlled trials (four 4-week and one

6-week) in which aripiprazole was administered orally in doses ranging from 2 to 30 mg/day.

Adverse Events Associated with Discontinuation of Treatment

Overall, there was little difference in the incidence of discontinuation due to adverse events

between aripiprazole-treated (7%) and placebo-treated (9%) patients. The types of adverse events

that led to discontinuation were similar between the aripiprazole and placebo-treated patients.

Commonly Reported Adverse Events

The only commonly observed adverse event associated with the use of aripiprazole in patients

with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for

placebo) was akathisia (placebo 4%; aripiprazole 8%).

Adverse Events Reported at an Incidence of 2% or More Among Adult Aripiprazole-Treated

Patients and Greater than Placebo in Short-Term, Schizophrenia Placebo-Controlled Trials

Table 1 enumerates the pooled incidence, rounded to the nearest percent, of treatment-emergent

adverse events that were reported during acute therapy (including up to 6 weeks in

schizophrenia), including only those events that were reported in 2% or more of patients treated

with aripiprazole (doses ≥2 mg/day) and for which the incidence in patients treated with

aripiprazole was greater than the incidence in patients treated with placebo in the combined

dataset.

Table 1:

Treatment-Emergent Adverse Events in Short-Term, Placebo-Controlled Trials in Adult

Patients with Schizophrenia

a

Treated with Oral Aripiprazole

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Percentage of Patients Reporting Event

b

System Organ Class

Aripiprazole

Placebo

Preferred Term

(n=1843)

(n=1166)

Eye Disorders

Blurred Vision

Gastrointestinal Disorders

Nausea

Constipation

Vomiting

Dyspepsia

Dry Mouth

Toothache

Abdominal Discomfort

Stomach Discomfort

General Disorders and Administration Site Conditions

Fatigue

Pain

Musculoskeletal and Connective Tissue Disorders

Musculoskeletal Stiffness

Pain in Extremity

Myalgia

Muscle Spasms

Nervous System Disorders

Headache

Dizziness

Akathisia

Sedation

Extrapyramidal Disorder

Tremor

Somnolence

Psychiatric Disorders

Agitation

Insomnia

Anxiety

Restlessness

Respiratory, Thoracic, and Mediastinal Disorders

Pharyngolaryngeal Pain

Cough

926 aripiprazole-treated patients and 413 placebo treated patients

Events reported by at least 2% of patients treated with oral aripiprazole, except events which had an

incidence equal to or less than placebo.

An examination of population subgroups did not demonstrate a difference in the incidence of

adverse events based on age, gender, or race.

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Patients should be advised of the risk of severe constipation during aripiprazole treatment and

that they should tell their doctor if constipation occurs or worsens as they may need laxatives.

Short-Term, Placebo-Controlled Trial of Adolescent Patients (13-17 years of age) with

Schizophrenia

The following findings are based on one 6-week placebo-controlled trial in which oral

aripiprazole was administered in doses ranging from 2 mg/day to 30 mg/day. Doses were titrated

to fixed doses of 10 mg/day or 30 mg/day aripiprazole.

Adverse Events Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse events was 7% for patients treated with 10

mg/day aripiprazole, 3.9% for patients treated with 30 mg/day aripiprazole and 2% for patients

treated with placebo.

Commonly Observed Adverse Events

Commonly observed adverse events associated with the use of aripiprazole in adolescent patients

with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for

placebo) were extrapyramidal disorder, somnolence, and tremor.

Adverse Events Reported at an Incidence of 1% or More Among Aripiprazole-Treated Patients

and Greater than Placebo in a Short-Term, Schizophrenia Placebo-Controlled Trial in

Adolescents (13-17 years of age)

Table 2 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse

events that were reported during acute therapy (up to 6 weeks in schizophrenia) with 10 mg/day

and 30 mg/day aripiprazole compared to placebo. Only adverse events that were reported in 1%

or more of adolescent patients treated with aripiprazole (doses ≥2 mg/day) and for which the

incidence in patients treated with aripiprazole was greater than the incidence in patients treated

with placebo are included in Table 2.

Table 2:

Treatment-Emergent Adverse Events in a 6-week, Placebo-Controlled Trial in Adolescent

Patients

a

with Schizophrenia Treated with Oral Aripiprazole

Percentage of Patients Reporting Event

b

System Organ Class

Aripiprazole

10

mg

Aripiprazole

30

mg

Placebo

Preferred Term

(n=100)

(n=102)

(n=100)

Cardiac Disorders

Tachycardia

Sinus bradycardia

Eye Disorders

Vision blurred

Gastrointestinal Disorders

Nausea

Constipation

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Percentage of Patients Reporting Event

b

System Organ Class

Aripiprazole

10

mg

Aripiprazole

30

mg

Placebo

Preferred Term

(n=100)

(n=102)

(n=100)

Diarrhea

Dry Mouth

Salivary Hypersecretion

Stomach discomfort

General Disorders and Administration Site Conditions

Fatigue

Pain

Infections and Infestations

Nasopharyngitis

Upper Respiratory Tract Infection

Influenza

Viral Infection

Investigations

Blood Glucose Increased

Blood insulin increased

Weight Increased

Metabolism and Nutrition Disorders

Increased Appetite

Musculoskeletal and Connective Tissue Disorders

Arthralgia

Muscle rigidity

Muscle weakness

Pain in Extremity

Nervous System Disorders

Extrapyramidal Disorder

Somnolence

Headache

Akathisia

Tremor

Dizziness

Dystonia

Dizziness postural

Drooling

Dysarthria

Dyskinesia

Psychiatric Disorders

Hallucination, auditory

Respiratory, Thoracic and Mediastinal Disorders

Hiccups

Skin and Subcutaneous Tissue Disorders

Rash

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Percentage of Patients Reporting Event

b

System Organ Class

Aripiprazole

10

mg

Aripiprazole

30

mg

Placebo

Preferred Term

(n=100)

(n=102)

(n=100)

Ecchymosis

Vascular Disorders

Orthostatic Hypotension

Treatment emergent adverse event incidences are based on the safety population that included patients

13 - 17 years of age, but 75% patients were 15 - 17 years of age. Aripiprazole is not indicated for patients

with schizophrenia < 15 years of age due to insufficient safety and efficacy data.

Events reported by at least 1% of 202 adolescent patients treated with oral aripiprazole, except events

which had an incidence equal to or less than placebo.

Incidence of somnolence does not include sedation. Sedation was reported in one patient receiving 10

mg/day aripiprazole.

Dose-Related Adverse Events

Schizophrenia

Dose response relationships for the incidence of treatment-emergent adverse events were

evaluated from four trials in adult patients with schizophrenia comparing various fixed oral doses

(2, 5, 10, 15, 20, or 30 mg/day) of aripiprazole to placebo. This analysis, stratified by study,

indicated that the only adverse event to have a possible dose response relationship, and then most

prominent only with 30 mg/day, was somnolence [including sedation]; (incidences were placebo,

7.4%; 10 mg/day, 8.5%; 15 mg/day, 8.7%; 20 mg/day, 7.5%; 30 mg/day, 12.6%).

In the study of adolescent patients with schizophrenia, four adverse events appeared to have a

possible dose response relationship: extrapyramidal disorder (incidences were placebo, 5.0%; 10

mg/day, 13.0%; 30 mg/day, 21.6%); somnolence (incidences were placebo, 6.0%; 10 mg/day,

11.0%; 30 mg/day, 21.6%); akathisia (incidences were placebo, 5.0%; 10 mg/day, 5.0%; 30

mg/day, 11.8%); and tremor (incidences were placebo, 2.0%; 10 mg/day, 2.0%; 30 mg/day,

11.8%). Orthostatic hypotension adverse events also appeared to have a possible dose response

relationship (see WARNINGS AND PRECAUTIONS, Cardiovascular).

Extrapyramidal Symptoms

Table 3 and Table 4 provide the percentage of patients reporting treatment-emergent

extrapyramidal symptoms in short-term placebo-controlled trials in adults and pediatrics,

respectively.

Table 3:

Percentage of Adult Patients Reporting Treatment-Emergent Extrapyramidal Symptoms in

Short-Term Placebo-Controlled Trials

Percentage of Patients Reporting Event

Schizophrenia

(dose range 2-30 mg/day)

Aripiprazole

Placebo

EPS-related AEs

(excluding akathisia)

Akathisia-related events

EPS-related AEs included Parkinsonism events, dystonic events, dyskinetic events and residual events such as

ARIPIPRAZOLE

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muscle twitching and myoclonus.

The incidence of reported EPS-related events in the placebo controlled trial in adolescent

patients with schizophrenia was greater than the incidence reported for adult schizophrenia

(Table 3 and Table 4).

Table 4:

Percentage of Children and Adolescent Patients Reporting Treatment-Emergent

Extrapyramidal Symptoms in Short-Term Placebo-Controlled Trials

Percentage of Patients Reporting Event

Schizophrenia

a

Aripiprazole

10 mg

30 mg

Placebo

EPS-related AEs

(excluding akathisia)

Akathisia-related events

Six-week schizophrenia trial of adolescent patients age 13-17

EPS-related AEs included Parkinsonism events, dystonic events, dyskinetic events and residual events such

as muscle twitching and myoclonus.

Commonly reported treatment emergent extrapyramidal symptoms in adolescent schizophrenia

patients were generally dose-related (see ADVERSE REACTIONS, Dose-Related Adverse

Events).

Table 5 and Table 6 provide the mean change from baseline to endpoint score on the Simpson

Angus Rating Scale (for EPS) (SAS), Barnes Akathisia Scale (for akathisia), and the

Assessments of Involuntary Movement Scales (for dyskinesia) (AIMS) from short-term,

placebo-controlled trials in adults and pediatrics, respectively.

Table 5:

Mean change from baseline to endpoint score on the SAS, Barnes Akathisia Scale, and

AIMS from short-term placebo-controlled trials in adults

Mean Change from Baseline to Endpoint Score

Schizophrenia

(dose range 2-30

mg/day)

Aripiprazole

Placebo

-0.06

-0.08

Barnes

0.08

-0.05

AIMS

-0.44

-0.02

A negative score indicates improvement.

p ≤ 0.01

Table 6:

Mean change from baseline to endpoint score on the SAS, Barnes Akathisia Scale, and

AIMS from short-term placebo-controlled trials in children and adolescents

Mean Change from Baseline to Endpoint Score

Schizophrenia

a

Aripiprazole

Placebo

10 mg

n=99

30 mg

n=97

n=98

-0.3

Barnes

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AIMS

-0.2

-0.1

-0.1

Six-week schizophrenia trial of adolescent patients age 13-17

A negative score indicates improvement.

p ≤ 0.01

p ≤ 0.05

In a long-term (26-week), placebo-controlled trial in adult patients with schizophrenia, data from

the Simpson Angus Rating Scale, the Barnes Akathisia Scale, and the Assessments of

Involuntary Movement Scales did not show a difference between aripiprazole and placebo.

Dystonia

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in

susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm

of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty,

difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low

doses, they occur more frequently and with greater severity with high potency and at higher

doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in

males and younger age groups.

Somnolence

Somnolence (including sedation) was a commonly reported adverse event in patients treated with

aripiprazole in clinical trials and was reported more frequently in children and adolescents than

in adults.

Table 7:

Percentage of Adult Patients Reporting Somnolence Adverse Events (including sedation) in

Short-Term Placebo-Controlled Trials

Percentage of Patients Reporting Event

Schizophrenia

(dose range 2-30

mg/day)

Aripiprazole

Placebo

Somnolence

(including sedation)

(89/926)

(32/413)

Somnolence (including sedation) led to discontinuation of treatment for (aripiprazole-treated,

placebo-treated) 0.1% and 0.2% of adult schizophrenia patients.

Table 8:

Percentage of Children and Adolescent Patients Reporting Somnolence Adverse Events

(including sedation) in Short-Term Placebo-Controlled Trials

Percentage of Patients Reporting Event

Schizophrenia

a

Aripiprazole

10 mg

30 mg

Placebo

Somnolence

(including sedation)

(12/100)

(22/102)

(6/100)

Six-week schizophrenia trial of adolescent patients age 13-17

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Somnolence (including sedation) led to discontinuation of treatment for (aripiprazole-treated,

placebo-treated) 0.5% and 0% of adolescent patients with schizophrenia.

Weight Gain

Adults

In 4- to 6- week trials in adults with schizophrenia, there was a slight difference in mean weight

gain between aripiprazole and placebo patients (+0.7 kg vs. -0.05 kg, respectively) and also a

statistically significant difference in the proportion of patients meeting a weight gain criterion of

≥7% of body weight [aripiprazole (8%) compared to placebo (3%)].

In a long-term (26-week) placebo-controlled study of aripiprazole in adults with schizophrenia, a

categorization of patients with schizophrenia at baseline on the basis of body mass index [BMI<

23 (“low”); 23-27 (“normal”); >27 (“high”)] revealed mean weight losses in patients treated with

aripiprazole and patients on placebo ( “low” BMI, -0.5 kg weight loss in both treatment groups;

“normal” BMI, mean weight loss of -1.3 kg in aripiprazole-treated patients and -0.6 kg in

placebo-treated patients; “high” BMI, mean weight loss of -2.1 kg in aripiprazole-treated patients

and -1.5 kg in placebo-treated patients).

In a long-term (52-week) study of aripiprazole and haloperidol in adults, a categorization of

patients with schizophrenia at baseline on the basis of BMI revealed the greatest mean weight

gain in patients with low BMI compared to normal or overweight patients in both groups

(patients with “low” BMI, mean weight gain 2.6 kg in aripiprazole-treated patients and 1.5 kg in

haloperidol-treated patients; “normal” BMI, a mean weight gain of 1.4 kg in aripiprazole-treated

patients and 0.2 kg in haloperidol-treated patients; “high” BMI, weight loss of -1.2 kg in

aripiprazole-treated patients and -0.8 kg in haloperidol-treated patients).

In both long-term schizophrenia studies, the highest incidence of clinically significant weight

gain (>7% of body weight) was in patients with a low BMI (<23) compared to normal (23-27) or

overweight patients (>27).

Adolescents

Changes in weight in the 6-week, placebo controlled clinical trial in adolescent patients with

schizophrenia are summarized in Table 9.

Table 9:

Change in weight (kg) and proportion of patients with ≥ 7% increase in body weight in acute

placebo controlled trials in children and adolescent patients

Schizophrenia

a

Placebo

Aripiprazole

10 mg

30 mg

N=100

n=98

N=100

n=99

N=102

n=97

Weight (kg)

Change from baseline to Last Visit

-0.8

Proportion of patients with ≥ 7% increase

from baseline weight at Last Visit

(1/98)

(4/99)

5.2%

(5/97)

Six-week schizophrenia trial of adolescent patients age 13-17

There was a mean increase in weight of +2.03 kg from baseline to Week 26 during an

uncontrolled, 26-week, flexible dose, open label extension study of adolescent patients with

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schizophrenia that completed the 6-week placebo controlled clinical trial. At Week 26, 26%

(47/181) of adolescent patients with schizophrenia had a >7% increase in weight from baseline,

not adjusted for normal growth (see WARNINGS AND PRECAUTIONS, Endocrine and

Metabolism, Weight, glucose and lipid changes in adolescent patients with schizophrenia).

Glucose

In the 6 –week placebo controlled clinical trials with adolescent schizophrenia patients there

were no patients with fasting serum glucose levels that shifted from normal baseline to clinically

significant high values (<5.55 mmol/L to ≥6.99 mmol/L) at end point in any treatment group. In

these studies fasting glucose data were from approximately 50 patients per treatment group.

Therefore, these data cannot be considered entirely predictive of the effects of aripiprazole on

glucose metabolism during use in adolescent patients with schizophrenia. . In a 26-week open

label extension trial that included adolescent patients with schizophrenia treated with

aripiprazole, a shift from normal to high fasting glucose at Week 26 was reported for 1.9%

(3/155) of the adolescent schizophrenia patients.

There was a mean increase of +0.12 mmol/L in fasting glucose at Week 26 during the 26-week

uncontrolled, open label extension study in adolescent schizophrenia patients (n=166, mean

baseline 4.87 mmol/L) (see WARNINGS AND PRECAUTIONS, Weight, glucose and lipid

changes in adolescent patients with schizophrenia).

Lipids

Table 10 shows the proportion of pediatric and adolescent patients with changes in total

cholesterol, fasting triglycerides and fasting HDL cholesterol in 6-week placebo-controlled trials

in adolescent patients (13-17 years) with schizophrenia, and the 26-week uncontrolled, open-

label extension trial for the patient population. In the 4- and 6-week placebo controlled clinical

trials lipid data were from approximately 30 to 50 patients of the treatment group. Therefore,

these data cannot be considered entirely predictive of the effects of aripiprazole on lipid

metabolism during use in adolescent patients with schizophrenia.

Table 10:

Changes in Blood Lipid Parameters in Pediatric and Adolescent Patients

a

Adolescent Patients with Schizophrenia

Category Change (at least once)

from Baseline

Trial Type and Duration

Treatment Arm

n/N

%

Total Cholesterol

Normal to High

(<4.40 mmol/L to ≥ 5.17 mmol/L)

6-week placebo-controlled

trial

10 mg Aripiprazole

2/52

30 mg Aripiprazole

1/52

Placebo

0/55

26-week open-label trial

Aripiprazole

4/139

Fasting Triglycerides

Normal to High

(<1.70 mmol/L to ≥ 2.26 mmol/L)

6-week placebo-controlled

trial

10 mg Aripiprazole

0/33

30 mg Aripiprazole

0/27

Placebo

0/28

26-week open-label trial

Aripiprazole

0/80

Fasting HDL

Normal to low

(>1.03 mmol/L ≤1.03 mmol/L)

6-week placebo-controlled

trial

10 mg Aripiprazole

5/34

14.7

30 mg Aripiprazole

2/28

Placebo

9/27

33.3

26-week open-label trial

Aripiprazole

5/69

Incidence rates are the number of patients with baseline values within the specified range and evaluated for

the given lab test at Week 6 for adolescent schizophrenia patients,.

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During the, 26-week, uncontrolled, open label extension study, there were mean decreases in

total cholesterol (fasting and nonfasting) at Week 26 in adolescent schizophrenia patients

(n=176, mean baseline 3.81 mmol/L; mean decrease -0.0013 mmol/L). There were mean

decreases in fasting triglycerides at Week 26 in adolescent schizophrenia patients (n=97, mean

baseline 1.19 mmol/L; mean decrease -0.12 mmol/L). There was a mean increase in fasting HDL

cholesterol at Week 26 in adolescent schizophrenia patients (n=97, mean baseline 1.23 mmol/L;

mean increase +0.015 mmol/L), (see WARNINGS AND PRECAUTIONS, Weight, Glucose and

Lipid changes in adolescent patients with schizophrenia).

ECG Changes

Between-group comparisons for a pooled analysis of placebo-controlled trials in adult patients

with schizophrenia, in the acute (4 - 6 week) placebo controlled trials in adolescent patients with

schizophrenia revealed no significant differences between oral aripiprazole and placebo in the

proportion of patients experiencing potentially important changes in ECG parameters. In adults

aripiprazole was associated with a median increase in heart rate of 2 beats per minute compared

to no increase among placebo patients.

Prolactin

In the 6-week placebo controlled clinical trial in adolescents (13 - 17 years of age) with

schizophrenia, there was a greater incidence of low serum prolactin levels in males (< 86.96

pmol/L) and females (< 130.434 pmol/L) treated with aripiprazole compared to placebo. Low

serum prolactin levels were reported for 38.6% (17/44), 31.7% (19/60) and 7% (4/57) of males

that received 10 mg/day aripiprazole, 30 mg/day aripiprazole or placebo, respectively. Low

serum prolactin levels were reported for 29.6% (16/54), 17.1% (6/35) and 10.3% (4/39) of

females that received 10 mg/day aripiprazole, 30 mg/day aripiprazole or placebo, respectively.

During a 26-week open label study of aripiprazole in adolescent schizophrenic, there was a mean

decrease in prolactin levels (-27.83 pmol/L) relative to baseline (274.78 pmol/L). The overall

incidence of low prolactin (as defined above) was 34.8%.

The clinical significance of low prolactin levels in adolescence is not known. However, animal

studies and case reports suggest a possible association between significantly low prolactin levels

and failure to lactate, menstrual cycle disruption, and pubertal development.

Additional Findings Observed in Clinical Trials

Adverse Events in Long-Term, Double-Blind, Placebo-Controlled Trials in Adults

The adverse events reported in a 26-week, double-blind trial comparing oral aripiprazole and

placebo in adult patients with schizophrenia were generally consistent with those reported in the

short-term, placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for

aripiprazole vs. 2% (3/153) for placebo]. In this study, the majority of the cases of tremor were

of mild intensity (8/12 mild and 4/12 moderate), occurred early in therapy (9/12 ≤49 days), and

were of limited duration (7/12 ≤10 days). Tremor infrequently led to discontinuation (<1%) of

aripiprazole. In addition, in a long-term (52-week), active-controlled study, the incidence of

tremor for aripiprazole was 5% (40/859).

Adverse Events in a 26-Week Open Label Extension Trial in Adolescent Patients with

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Schizophrenia

The safety profile in adolescent patients (13-17 years of age) with schizophrenia in a 26-week,

uncontrolled, open-label extension trial, which included patients that completed the 6-week

placebo controlled trial, was generally similar to that observed in the 6-week, placebo-controlled

trial.

Adverse events such as extrapyramidal disorder, somnolence, and tremor were reported at

similar frequencies in both the 6-week placebo-controlled trial and during the 26-week open

label extension trial (19.2% extrapyramidal disorder; 13.8% somnolence; 6.3% tremor). The

majority of these adverse events observed in the open-label 26-week study had a first onset

during that study.

Other Adverse Events Observed During the Pre-marketing Evaluation of Oral

Aripiprazole

Following is a list of MedDRA terms that reflect treatment-emergent adverse events as defined

in the introduction to the ADVERSE REACTIONS section reported by patients treated with oral

aripiprazole at multiple doses ≥2 mg/day during any phase of a trial within the database of

13,543 adult patients. All events assessed as possible adverse drug reactions have been included.

In addition, medically/clinically meaningful events particularly those that are likely to be useful

to the prescriber or that have pharmacologic plausibility, have been included. Events already

listed in Tables 1 to 2 or other parts of the ADVERSE REACTIONS section have been excluded.

Although the events reported occurred during treatment with aripiprazole, they were not

necessarily caused by it.

Events are further categorized by MedDRA system organ class and listed in order of decreasing

frequency according to the following definitions:

frequent adverse events are defined as those occurring on 1 or more occasions in at least 1/100

patients (only those not already listed in the tabulated results from placebo-controlled trials

appear in this listing); infrequent adverse events are those occurring in less than 1/100 but at least

1/1,000 patients; rare events are those occurring in less than 1/1,000.

Adults – Oral Administration

Blood and Lymphatic System Disorders:

Infrequent: leukopenia, neutropenia, thrombocytopenia

Cardiac Disorders:

Infrequent : bradycardia, palpitations, cardiopulmonary failure, myocardial infarction,

cardio-respiratory arrest, atrioventricular block, extrasystoles, sinus tachycardia, atrial

fibrillation, angina pectoris, myocardial ischemia;

Rare: atrial flutter, supraventricular tachycardia, ventricular tachycardia

Endocrine Disorders:

Infrequent: diabetes mellitus (including blood insulin increased, carbohydrate tolerance

decreased, diabetes mellitus non-insulin-dependent, glucose tolerance impaired,

glycosuria, glucose urine, glucose urine present), hyperglycemia, hypoglycemia,

polydipsia;

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Rare: - diabetic ketoacidosis, diabetic hyperosmolar coma

Eye Disorders:

Infrequent: photophobia, diplopia, eyelid edema, photopsia

Gastrointestinal Disorders:

Infrequent: gastroesophageal reflux disease, dysphagia, swollen tongue, esophagitis;

Rare: pancreatitis

General Disorders and Administration Site Conditions:

Frequent: asthenia, peripheral edema, irritability, chest pain;

Infrequent: feeling jittery, face edema, thirst, angioedema;

Rare: hypothermia

Hepatobiliary Disorders:

Rare: hepatitis, jaundice

Immune System Disorders:

Infrequent: hypersensitivity

Injury, Poisoning, and Procedural Complications:

Frequent: fall;

Infrequent: self-mutilation;

Rare: heat stroke

Investigations:

Frequent: weight decreased;

Infrequent: hepatic enzyme increased (increased ALT, increased AST), blood glucose

increased, blood prolactin increased, blood urea increased, electrocardiogram QT

prolonged, blood creatinine increased, blood bilirubin increased;

Rare: blood lactate dehydrogenase increased, glycosylated hemoglobin increased,

gamma-glutamyl transferase (GGT) increased

Metabolism and Nutrition Disorders:

Infrequent: hyperlipidemia, anorexia, hypokalemia, hyponatremia

Musculoskeletal and Connective Tissue Disorders:

Infrequent: muscle rigidity, muscular weakness, muscle tightness, mobility decreased;

Rare: rhabdomyolysis

Nervous System Disorders:

Frequent: coordination abnormal;

Infrequent: speech disorder, dyskinesia, parkinsonism, memory impairment, cogwheel

rigidity, cerebrovascular accident, convulsion, hypokinesia, tardive dyskinesia,

hypotonia, myoclonus, hypertonia, akinesia, bradykinesia;

Rare: Grand Mal convulsion, choreoathetosis, neuroleptic malignant syndrome

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Psychiatric Disorders:

Frequent: suicidal ideation;

Infrequent: aggression, loss of libido, suicide attempt, hostility, libido increased, anger,

anorgasmia, delirium, intentional self-injury, completed suicide, tic, homicidal ideation;

Rare: catatonia, sleep walking

Renal and Urinary Disorders:

Infrequent: urinary incontinence, urinary retention, polyuria, nocturia

Reproductive System and Breast Disorders:

Infrequent: menstruation irregular, erectile dysfunction, amenorrhea, breast pain;

Rare: gynaecomastia, priapism

Respiratory, Thoracic, and Mediastinal Disorders:

Frequent: nasal congestion, dyspnea, pneumonia aspiration

Skin and Subcutaneous Tissue Disorders:

Frequent: rash (including erythematous, exfoliative, generalized, macular,

maculopapular, papular rash; acneiform, allergic, contact, exfoliative, seborrheic

dermatitis, neurodermatitis, and drug eruption), hyperhydrosis;

Infrequent: pruritus, photosensitivity reaction, alopecia, urticaria

Vascular Disorders:

Frequent: hypertension;

Infrequent: hypotension, syncope

Adolescent schizophrenia patients (13-17 years of age) - Oral Administration

Most adverse reactions observed in the pooled database of 281 adolescent patients aged 13 - 17

years were also observed in the adult population (see Table 1 and Table 2; Other Adverse Events

Observed During the Pre-marketing Evaluation of Oral Aripiprazole-Adults, Oral

administration). Additional adverse reactions observed in the adolescent population are listed

below.

General Disorders and Administration Site Conditions:

Infrequent: feeling abnormal

Metabolism and Nutrition Disorders:

Infrequent: hypertriglyceridemia

Nervous System Disorders:

Infrequent: sleep talking

Respiratory, Thoracic, and Mediastinal Disorders:

Frequent: rhinorrhea

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Skin and Subcutaneous Tissue Disorders:

Infrequent: hirsutism

Abnormal Hematologic and Clinical Chemistry Findings

Between-group comparisons for 3- to 6-week, placebo-controlled trials in adult patients with

schizophrenia and a 6-week placebo-controlled trial in adolescent patients with schizophrenia

(13-17 years of age) revealed no differences between the aripiprazole and placebo groups in the

proportions of patients experiencing clinically important changes in most routine serum

chemistry, hematology, or urinalysis parameters (including changes in fasting glucose,

triglyceride, HDL, LDL and total cholesterol measurements) with the exception of prolactin.

Low prolactin levels were reported more frequently in adolescents treated with aripiprazole than

with placebo (see ADVERSE REACTIONS, Prolactin).

Similarly, there were no differences in the incidence of discontinuations for changes in serum

chemistry, hematology, or urinalysis.

In a long-term (26-week), placebo-controlled trial in adult patients with schizophrenia there were

no clinically important differences between the aripiprazole and placebo patients in the mean

change from baseline in prolactin, fasting glucose, triglyceride, HDL, LDL, and total cholesterol

measurements (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism;

ADVERSE REACTIONS, Prolactin).

Higher percentages of elevated creatine phosphokinase were observed in aripiprazole-treated

adult patients compared to placebo-treated patients in short-term and long-term clinical trials.

The most common AEs that were temporally associated with elevated CPK levels were

musculoskeletal stiffness, myalgia, chest pain, fall, and muscle rigidity.

Post-Market Adverse Drug Reactions

The adverse events presented in Table 11 were reported during the post-marketing use of

aripiprazole. Because these events are reported voluntarily from a population of uncertain size, it

is not always possible to reliably estimate their frequency or establish a causal relationship to

drug exposure.

Table 11- Post-Introduction Treatment-Emergent Adverse Events

Investigations:

Rare: Blood glucose fluctuation

Skin and Subcutaneous

Tissue Disorders:

Rare: Allergic reaction (e.g., anaphylactic reaction, angioedema,

laryngospasm, oropharyngeal spasm)

Psychiatric Disorders:

Unknown: Pathological gambling, Hypersexuality, Impulse Control disorders

Hepatobiliary Disorders:

Unknown: Hepatic failure

Eye Disorders:

Unknown: Oculogyric Crisis

Isolated cases of Serotonin Syndrome have been reported with the concomitant use of

aripiprazole and serotonergic drugs such as Serotonin-Norepinephrine Reuptake Inhibitor

(SNRI) and Selective Serotonin Reuptake Inhibitor (SSRI).

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As with other antipsychotics, sudden death, torsades de pointes, ventricular tachycardia,

arrhythmia, cardiopulmonary arrest and QT prolongation have been reported during treatment

with aripiprazole. These events during Aripiprazole treatment have been very rare or isolated.

Many of the patients had pre-existing cardiovascular disease, were on concomitant medications

known to prolong the QT interval, had risk factors for QT prolongation, took an overdose of

aripiprazole, and/or were morbidly obese. Very rarely, QT prolongation has been reported in the

absence of confounding factors.

Complex sleep-related behaviours such as somnambulism and sleep-related eating disorder have

been associated with the use of atypical antipsychotic drugs, including aripiprazole.

In clinical trial and/or post-marketing experience, events of leukopenia/neutropenia have been

reported temporally related to antipsychotic agents, including aripiprazole. Agranulocytosis has

also been reported. Therefore, it is recommended that patients have their complete blood count

(CBC) tested prior to starting aripiprazole and then periodically throughout treatment (see

WARNINGS AND PRECAUTIONS - Hematologic).

Atypical antipsychotic drugs, including aripiprazole, have been associated with cases of sleep

apnea, with or without concomitant weight gain. In patients who have a history of or are at risk

for sleep apnea, aripiprazole should be prescribed with caution.

DRUG INTERACTIONS

Overview

Drug-Drug Interactions

Potential for Other Drugs to Affect Aripiprazole

Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9,

CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation. This

suggests that an interaction of aripiprazole with inhibitors or inducers of these enzymes, or other

factors, like smoking, is unlikely.

Both CYP3A4 and CYP2D6 are responsible for aripiprazole metabolism (see ACTIONS AND

CLINICAL PHARMACOLOGY).

Agents that induce CYP3A4 (e.g., carbamazepine) could cause an increase in aripiprazole

clearance and lower blood levels. Inhibitors of CYP3A4 (e.g. ketoconazole) or CYP2D6 (e.g.

quinidine, fluoxetine, or paroxetine) can inhibit aripiprazole elimination and cause increased

blood levels.

Approximately 8% of Caucasians lack the capacity to metabolize CYP2D6 substrates and are

classified as poor metabolizers (PM), whereas the rest are extensive metabolizers (EM).

CYP2D6 metabolizing capacity should be considered when aripiprazole is co-administered with

drugs that inhibit CYP2D6.

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Ketoconazole and Other CYP3A4 Inhibitors

Co-administration of ketoconazole (200 mg/day for 14 days) with a 15-mg single dose of

aripiprazole increased the AUC of aripiprazole and its active metabolite by 63% and 77%,

respectively. The effect of a higher ketoconazole dose (400 mg/day) has not been studied. When

ketoconazole is administered concomitantly with aripiprazole, aripiprazole dose should be

reduced to one-half of its normal dose. Other strong inhibitors of CYP3A4 (itraconazole) would

be expected to have similar effects and require similar dose reductions; weaker inhibitors

(erythromycin, grapefruit juice) have not been studied. When the CYP3A4 inhibitor is

withdrawn from the combination therapy, the aripiprazole dose should be increased.

Quinidine and Other CYP2D6 Inhibitors

Co-administration of quinidine (166 mg/day for 13 days), a potent inhibitor of CYP2D6, with a

10-mg single dose of aripiprazole increased the AUC of aripiprazole by 107% but decreased the

AUC of its active metabolite, dehydro-aripiprazole, by 32%. The dose of aripiprazole should be

reduced to one-half of its normal dose when quinidine is administered concomitantly with

aripiprazole.

Concomitant administration of other significant inhibitors of CYP2D6, such as fluoxetine or

paroxetine, would be expected to have similar effects and, therefore, should be accompanied by

similar dose reductions. When the CYP2D6 inhibitor is withdrawn, from the combination

therapy, the aripiprazole dose should be increased. When adjunctive aripiprazole was

administered to patients, the maximum aripiprazole dose used with CYP2D6 inhibitors

paroxetine and fluoxetine was 15 mg/day.

Carbamazepine

Co-administration of carbamazepine (200 mg BID), a potent CYP3A4 inducer, with aripiprazole

(30 mg QD) resulted in an approximate 70% decrease in C

and AUC values of both

aripiprazole and its active metabolite, dehydro-aripiprazole. When carbamazepine is added to

aripiprazole therapy, the dose of aripiprazole should be doubled. Additional dose increases

should be based on clinical evaluation. When carbamazepine is withdrawn from the combination

therapy, the aripiprazole dose should be reduced.

Potential for Aripiprazole to Affect Other Drugs

Aripiprazole is unlikely to cause clinically important pharmacokinetic interactions with drugs

metabolized by cytochrome P450 enzymes. In in vivo studies, 10-mg/day to 30-mg/day doses of

aripiprazole had no significant effect on metabolism by CYP2D6 (dextromethorphan), CYP2C9

(warfarin), CYP2C19 (omeprazole, warfarin), and CYP3A4 (dextromethorphan) substrates.

Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-

mediated metabolism in vitro.

Due to its alpha-1 adrenergic receptor antagonist activity, aripiprazole has the potential to

enhance the effect of certain antihypertensive agents.

Drugs having no clinically important interactions with aripiprazole

Famotidine

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Co-administration of aripiprazole (given in a single dose of 15 mg) with a 40-mg single dose of

the H2 antagonist famotidine, a potent gastric acid blocker, decreased the solubility of

aripiprazole and, hence, its rate of absorption. The C

of aripiprazole and dehydro-aripiprazole,

was reduced by 37% and 21%, respectively. The extent of absorption (AUC) of aripiprazole and

dehydro-aripiprazole, was reduced by 13% and 15%, respectively. No dosage adjustment of

aripiprazole is required when administered concomitantly with famotidine.

Valproate

When valproate (500-1500 mg/day) and aripiprazole (30 mg/day) were co-administered, at

steady state the C

and AUC of aripiprazole were decreased by 25%. No dosage adjustment of

aripiprazole is required when administered concomitantly with valproate.

When aripiprazole (30 mg/day) and valproate (1000 mg/day) were co-administered, at steady

state there were no clinically important changes in the C

or AUC of valproate. No dosage

adjustment of valproate is required when administered concomitantly with aripiprazole.

Lithium

A pharmacokinetic interaction of aripiprazole with lithium is unlikely because lithium is not

bound to plasma proteins, is not metabolized, and is almost entirely excreted unchanged in urine.

Co-administration of therapeutic doses of lithium (1200-1800 mg/day) for 21 days with

aripiprazole (30 mg/day) did not result in clinically important changes in the pharmacokinetics of

aripiprazole or its active metabolite, dehydro-aripiprazole (C

and AUC increased by less than

20%). No dosage adjustment of aripiprazole is required when administered concomitantly with

lithium.

Co-administration of aripiprazole (30 mg/day) with lithium (900 mg/day) did not result in

clinically important changes in the pharmacokinetics of lithium. No dosage adjustment of lithium

is required when administered concomitantly with aripiprazole.

Lamotrigine

Co-administration of 10 to 30 mg daily oral doses of aripiprazole for 14 days to subjects had no

effect on the steady-state pharmacokinetics 100 to 400 mg once daily lamotrigine, a UDP-

glucuronosyltransferase 1A4 substrate. No dosage adjustment of lamotrigine is required if

aripiprazole and lamotrigine are administered concomitantly. Dosing recommendations for

lamotrigine should be followed closely if valproate is also to be administered.

Venlafaxine

Co-administration of 10 to 20 mg daily oral doses of aripiprazole for 14 days to healthy subjects

had no effect on the steady-state pharmacokinetics of venlafaxine and O-desmethylvenlafaxine

following 75 mg once daily venlafaxine XR, a CYP2D6 substrate. No dosage adjustment of

venlafaxine is required if aripiprazole is administered concomitantly with venlafaxine.

Escitalopram

Co-administration of 10 mg daily oral doses of aripiprazole for 14 days to healthy subjects had

no effect on the steady-state pharmacokinetics of 10 mg once daily escitalopram, a substrate of

CYP2C19 and CYP3A4. No dosage adjustment of escitalopram is required if aripiprazole and

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escitalopram are administered concomitantly.

Dextromethorphan

Aripiprazole at doses of 10 to 30 mg per day for 14 days had no effect on dextromethorphan’s O-

dealkylation to its major metabolite, dextrorphan, a pathway dependent on CYP2D6 activity.

Aripiprazole also had no effect on dextromethorphan’s N-demethylation to its metabolite 3-

methyoxymorphan, a pathway dependent on CYP3A4 activity. No dosage adjustment of

dextromethorphan is required when administered concomitantly with aripiprazole.

Warfarin

Aripiprazole 10 mg per day for 14 days had no effect on the pharmacokinetics of R- and S-

warfarin or on the pharmacodynamic end point of International Normalized Ratio, indicating the

lack of a clinically relevant effect of aripiprazole on CYP2C9 and CYP2C19 metabolism or the

binding of highly protein-bound warfarin. No dosage adjustment of warfarin is required when

administered concomitantly with aripiprazole.

Omeprazole

Co-administration of aripiprazole (10 mg per day for 15 days) and a single 20-mg dose of

omeprazole, a CYP2C19 substrate, had no effect on the pharmacokinetics of omeprazole in

healthy subjects. No dosage adjustment of omeprazole is required when administered

concomitantly with aripiprazole.

Lorazepam

Co-administration of oral lorazepam (2 mg) and oral aripiprazole (15 mg) to healthy subjects

(n=24 males; ages 18-43 years old) did not result in clinically important changes in the

pharmacokinetics of either drug. No dosage adjustment of either drug is required when they are

administered concomitantly. However, the intensity of sedation was greater with the combination

as compared to that observed with aripiprazole alone and the incidence of orthostatic

hypotension observed was greater with the combination as compared to that observed with

lorazepam alone (see WARNINGS AND PRECAUTIONS).

Fluoxetine, Paroxetine, and Sertraline

A population pharmacokinetic analysis in patients showed no substantial change in plasma

concentrations of fluoxetine (20 mg/day or 40 mg/day), paroxetine CR (37.5 mg/day or 50

mg/day), or sertraline (100 mg/day or 150 mg/day) dosed to steady-state. The steady-state

plasma concentrations of fluoxetine and norfluoxetine increased by about 18% and 36%,

respectively and concentrations of paroxetine decreased by about 27%. The steady- state plasma

concentrations of sertraline and desmethylsertraline were not substantially changed when these

antidepressant therapies were co-administered with aripiprazole. Aripiprazole dosing was 2

mg/day to 15 mg/day (when given with fluoxetine or paroxetine) or 2 mg/day to 20 mg/day

(when given with sertraline).

Drug-Food Interactions

ARIPIPRAZOLE can be administered with or without food (see ACTION AND CLINICAL

PHARMACOLOGY).

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Drug-Herb Interactions

Interactions with herbal products have not been studied.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been identified

Drug-Lifestyle Interactions

Alcohol/CNS Drugs

Given the primary CNS effects of aripiprazole, as with most psychoactive medications,

combination use of aripiprazole with alcohol or other CNS drugs with overlapping undesirable

effects such as sedation, should be avoided.

Smoking

Aripiprazole is metabolised by multiple pathways involving the CYP2D6 and CYP3A4 enzymes

but not CYP1A enzymes. Thus, no dosage adjustment is required for smokers.

DOSAGE AND ADMINISTRATION

Dosing Considerations

The efficacy and safety of ARIPIPRAZOLE, at doses greater than 30 mg/day, have not been

established.

Pediatric and adolescent patients are at greater risk of experiencing certain adverse events related

to the use of atypical antipsychotics including aripiprazole. Some of these adverse events appear

to be dose related (see WARNINGS AND PRECAUTIONS; ADVERSE REACTIONS).

ARIPIPRAZOLE can be taken without regard to meals. Tablets should not be crushed or cut;

they should be swallowed whole.

Refer to DRUG INTERACTION section for dosage adjustment in patients taking aripiprazole

concomitantly with strong CYP3A4 inhibitors (such as ketoconazole or clarithromycin), with

potential CYP2D6 inhibitors (such as quinidine, fluoxetine, or paroxetine) or with potential

CYP3A4 inducers (such as carbamazepine).

Schizophrenia

Adults

Usual Dose: The recommended starting and target dose for ARIPIPRAZOLE is 10 or 15 mg/day

administered on a once-a-day schedule. Doses in the range of 10 to 30 mg/day have been

established as effective in clinical trials. However, greater efficacy has not been demonstrated at

doses higher than 10 mg/day. Dosage increases, if needed, should only be made after 2 weeks,

the time needed to achieve steady state. The maximum daily dose should not exceed 30 mg/day.

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Patients should be maintained on the lowest effective dose that provides optimal clinical

response and tolerability and should be periodically reassessed to determine the need for

maintenance treatment.

Adolescents (15 -17 years of age)

Usual dose: The recommended target dose of ARIPIPRAZOLE is 10 mg/day administered on a

once-a-day schedule. The recommended starting daily dose is 2 mg/day, titrated to 5 mg/day

after 2 days and to the target dose of 10 mg/day after 2 additional days. Subsequent dose

increases should be administered, if needed and as tolerated, in 5 mg/day increments. Both the 10

mg/day and 30 mg/day doses have been shown to be effective in a double-blind, placebo-

controlled clinical trial; however, the 30 mg/day dose was not shown to be more efficacious than

the 10 mg/day dose.

The maximum daily dose should not exceed 30 mg/day. Patients should be maintained on the

lowest effective dose that provides optimal clinical response and tolerability.

The safety and efficacy of ARIPIPRAZOLE during long term treatment have not been

systematically evaluated in adolescent patients with schizophrenia. The physician who elects to

use ARIPIPRAZOLE for extended periods in adolescent patients with schizophrenia should

periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Switching from Other Antipsychotics

There are no systematically collected data to specifically address switching patients with

schizophrenia from other antipsychotics to ARIPIPRAZOLE or concerning concomitant

administration with other antipsychotics. While immediate discontinuation of the previous

antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual

discontinuation may be most appropriate for others. In all cases, the period of overlapping

antipsychotic administration should be minimized.

Dosing Considerations in Special Populations

Pediatrics (< 18 years of age): Safety and efficacy were evaluated in adolescent (13-17 years of

age) patients with schizophrenia in one 6-week clinical trial. ARIPIPRAZOLE is not indicated

for the treatment of schizophrenia in adolescent patients under 15 years of age due to insufficient

safety and efficacy data (see ADVERSE REACTIONS, CLINICAL TRIALS, Schizophrenia -

Adolescents).

Geriatric (≥ 65 years of age): Safety and efficacy of ARIPIPRAZOLE in the treatment of

schizophrenia in patients 65 years of age or older have not been established. Given the greater

sensitivity of this population, a lower starting dose may be considered when clinical factors

warrant (see WARNINGS AND PRECAUTIONS-Special Populations, Geriatrics).

ARIPIPRAZOLE is not indicated in elderly patients with dementia (see WARNINGS AND

PRECAUTIONS - Serious Warnings and Precautions).

Patients with hepatic impairment: No dosage adjustment is required for patients with hepatic

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impairment.

Patients with renal impairment: No dosage adjustment is required in patients with renal

impairment.

Gender: No dosage adjustment is required for female patients as compared to male patients.

Smoking status: No dosage adjustment is required for smokers (see DRUG INTERACTIONS –

Drug Lifestyle Interaction).

CYP2D6 poor metabolizers: Approximately 8% of Caucasians lack the capacity to metabolize

CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are extensive

metabolizers (EM). CYP2D6 metabolizing capacity should be considered when aripiprazole is

co-administered with drugs that inhibit CYP2D6 (see DRUG INTERACTIONS).

Missed Dose

If a patient misses a dose by a few hours, the patient should be advised to take their dose as soon

as he/she remembers. If most of the day has passed, he/she should be advised to wait until the

next scheduled dose. Patients should be advised to not take 2 doses of ARIPIPRAZOLE at once.

OVERDOSAGE

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

Immediately.

Human Experience

In clinical studies, no deaths were associated with accidental or intentional acute overdosage of

aripiprazole alone. In clinical trials, in the patient taking the largest confirmed amount of

aripiprazole, 1080 mg, ingested with alcohol, the only symptom reported was vomiting.

In post-marketing experience, there is a single case of death that was possibly associated with

accidental or intentional acute overdosage of aripiprazole alone. The patient ingested 900 mg of

aripiprazole, was hospitalized in the intensive care unit for 10 to 14 days and died. The patient’s

medical history included excessive alcohol use, although it is unclear whether alcohol was

present at the time of overdosage. In the patient taking the largest confirmed amount of

aripiprazole, 1680 mg, the only symptoms reported were vomiting, fatigue, and dizziness. In

addition, a report of non-fatal accidental overdose with aripiprazole alone (up to 195 mg) in a 2.5

year old child has been received. Vomiting, somnolence, lethargy, transient loss of consciousness

and CNS depression were reported for this patient. Other potentially medically important signs

and symptoms that have been observed during overdose included blood pressure increased and

tachycardia. In the patients who were evaluated in hospital settings, there were no reported

observations indicating clinically important adverse change in vital signs, laboratory

assessments, or electrocardiogram.

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Management of Overdosage

No specific information is available on the treatment of overdose with aripiprazole. Management

of overdose should concentrate on supportive therapy, maintaining an adequate airway,

oxygenation and ventilation, and management of symptoms. The possibility of multiple drug

involvement should be considered. Therefore, cardiovascular monitoring should commence

immediately and should include continuous electrocardiographic monitoring to detect possible

arrhythmias. Following any confirmed or suspected overdose with aripiprazole, close medical

supervision and monitoring should continue until the patient recovers.

Charcoal: In the event of an overdose of ARIPIPRAZOLE, an early charcoal administration may

be useful in partially preventing the absorption of aripiprazole. Administration of 50 g of

activated charcoal, one hour after a single 15-mg oral dose of aripiprazole, decreased the mean

AUC and C

of aripiprazole by 50%.

Hemodialysis: Although there is no information on the effect of hemodialysis in treating an

overdose with aripiprazole, hemodialysis is unlikely to be useful in overdose management since

aripiprazole is highly bound to plasma proteins.

For up-to-date information on the management of a suspected drug overdose, contact the

regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of aripiprazole, as with other drugs having efficacy in schizophrenia is

unknown. However, it has been proposed that the efficacy of aripiprazole may be mediated

through a combination of partial agonist activity at D

and 5-HT

receptors and antagonist

activity at 5-HT

receptors; however, the clinical relevance of these interactions has not been

established. Actions at receptors other than D

, 5-HT

, and 5-HT

may explain some of the

other clinical effects of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole

may be explained by its antagonist activity at adrenergic alpha1 receptors). The clinical

relevance of these receptor interactions with aripiprazole is unknown.

Pharmacodynamics

Aripiprazole exhibits high affinity for dopamine D

and D

, serotonin 5-HT

and 5-HT

receptors (Ki values of 0.34, 0.8, 1.7, and 3.4 nM, respectively), moderate affinity for dopamine

D4, serotonin 5-HT

and 5-HT

, alpha1-adrenergic and histamine H1 receptors (Ki values of 44,

15, 39, 57, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki=98

nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC50>1000

nM). Aripiprazole functions as a partial agonist at the dopamine D

and the

serotonin 5-HT

receptors, and as an antagonist at serotonin 5-HT

receptor. The clinical relevance of these

receptor interactions with aripiprazole is unknown.

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Pharmacokinetics

Aripiprazole activity is presumably primarily due to the parent drug, aripiprazole, and to a lesser

extent, to its major metabolite, dehydro-aripiprazole, which has affinities for D

receptors similar

to the parent drug and represents 40% of the parent drug exposure in plasma. The mean

elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole,

respectively. Steady-state concentrations are attained within 14 days of dosing for both active

moieties. Aripiprazole accumulation is predictable from single-dose pharmacokinetics. At steady

state, the pharmacokinetics of aripiprazole are dose-proportional. Elimination of aripiprazole is

mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4.

Absorption

Aripiprazole is well absorbed after oral administration of the tablet, with peak plasma

concentrations occurring within 3 to 5 hours; the absolute oral bioavailability of the tablet

formulation is 87%. ARIPIPRAZOLE can be administered with or without food. Administration

of a 15-mg Aripiprazole Tablet with a standard high-fat meal did not significantly affect the C

or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed T

by 3

hours for aripiprazole and 12 hours for dehydro-aripiprazole.

Distribution

The steady-state volume of distribution of aripiprazole following intravenous administration is

high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. At therapeutic

concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum

proteins, primarily to albumin. In healthy human volunteers administered 0.5 to 30 mg/day

aripiprazole for 14 days, there was dose-dependent D

receptor occupancy. The clinical

relevance of this receptor occupancy by aripiprazole is unknown.

Metabolism and Elimination

Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation,

hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes

are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is

catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in the systemic circulation.

At steady state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole

AUC in plasma.

Approximately 8% of Caucasians lack the capacity to metabolize CYP2D6 substrates and are

classified as poor metabolizers (PM), whereas the rest are extensive metabolizers (EM). PMs

have about an 80% increase in aripiprazole exposure and about a 30% decrease in exposure to

the active metabolite compared to EMs, resulting in about a 60% higher exposure to the total

active moieties from a given dose of aripiprazole compared to EMs. Co-administration of

aripiprazole with known inhibitors of CYP2D6, like quinidine in EMs, results in a 112% increase

in aripiprazole plasma exposure, and dose adjustment is needed (see DRUG INTERACTIONS).

The mean elimination half-life for aripiprazole is about 75 hours in EMs and 146 hours in PMs.

Aripiprazole does not inhibit or induce the CYP2D6 pathway.

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Following a single oral dose of [

C]-labeled aripiprazole, approximately 25% and 55% of the

administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of

unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was

recovered unchanged in the feces.

Special Populations and Conditions

Geriatrics

In formal single-dose pharmacokinetic studies (with aripiprazole given in a single dose of 15

mg), clearance of aripiprazole was 20% lower in elderly (≥65 years) subjects compared to

younger adult subjects (18 to 64 years). However, there was no effect of age in the population

pharmacokinetic analysis in schizophrenia patients. Also, the pharmacokinetics of aripiprazole

after multiple doses in elderly patients appeared similar to that observed in young, healthy

subjects. (see WARNINGS AND PRECAUTIONS - Special Populations, Geriatrics and

DOSAGE AND ADMINISTRATION).

Gender

and AUC of aripiprazole and its active metabolite, dehydro-aripiprazole, are 30 to 40%

higher in women than in men, and correspondingly, the apparent oral clearance of aripiprazole is

lower in women. However, these differences are largely explained by differences in body weight

(25%) between men and women. No dosage adjustment is recommended based on gender.

Race

Although no specific pharmacokinetic study was conducted to investigate the effects of race on

the disposition of aripiprazole, population pharmacokinetic evaluation did not demonstrate

clinically important race-related differences in the pharmacokinetics of aripiprazole. No dosage

adjustment is recommended based on race.

Renal Impairment

In patients with severe renal impairment (creatinine clearance <30 mL/min), C

of aripiprazole

(given in a single dose of 15 mg) and dehydro-aripiprazole increased by 36% and 53%,

respectively, but AUC was 15% lower for aripiprazole and 7% higher for dehydro-aripiprazole.

Renal excretion of both unchanged aripiprazole and dehydro-aripiprazole is less than 1% of the

dose. No dosage adjustment is required in subjects with renal impairment.

Hepatic Impairment

In a single-dose study (15 mg of aripiprazole) in subjects with varying degrees of liver cirrhosis

(Child-Pugh Classes A, B, and C), the AUC of aripiprazole, compared to healthy subjects,

increased 31% in mild HI, increased 8% in moderate HI, and decreased 20% in severe HI. None

of these differences would require dose adjustment.

Smoking

Based on studies utilizing human liver enzymes in vitro, aripiprazole is not a substrate for

CYP1A2 and also does not undergo direct glucuronidation. Smoking should, therefore, not have

an effect on the pharmacokinetics of aripiprazole. Consistent with these in vitro results,

population pharmacokinetic evaluation did not demonstrate any significant pharmacokinetic

ARIPIPRAZOLE

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differences between smokers and non-smokers. No dosage adjustment is recommended based on

smoking status.

STORAGE AND STABILITY

Store tablets at 15º C to 30º C.

DOSAGE FORMS, COMPOSITION AND PACKAGING

2 mg

Green color, modified rectangular shaped, uncoated tablets debossed with ‘251’ on one side and

plain on other side. Each tablet contains: aripiprazole 2 mg. Non-medicinal ingredients: colloidal

silicon dioxide, corn starch, crospovidone, hydroxy propyl cellulose, lactose monohydrate,

magnesium stearate, microcrystalline cellulose. Coloring agents: FD&C Blue No. 2 / Indigo

Carmine AL and Iron oxide yellow. Bottles of 30 and 100 tablets and blister packs of 100 tablets.

5 mg

Blue color, modified rectangular shaped, uncoated tablets debossed with ‘250’ on one side and

plain on other side. Each tablet contains: aripiprazole 5 mg. Non-medicinal ingredients: colloidal

silicon dioxide, corn starch, crospovidone, hydroxy propyl cellulose, lactose monohydrate,

magnesium stearate, microcrystalline cellulose. Coloring agents: FD&C Blue No. 2 / Indigo

Carmine AL. Bottles of 30 and 100 tablets and blister packs of 100 tablets.

10 mg

Pink color, modified rectangular shaped, uncoated tablets debossed with ‘252’ on one side and

plain on other side. Each table contains: aripiprazole 10 mg. Non-medicinal ingredients:

colloidal silicon dioxide, corn starch, crospovidone, hydroxy propyl cellulose, lactose

monohydrate, magnesium stearate, microcrystalline cellulose. Coloring agents: Iron oxide red.

Bottles of 30 and 100 tablets and blister packs of 100 tablets.

15 mg

Yellow color, round shaped, beveled edge, uncoated tablets debossed with ‘253’ on one side and

plain on other side. Each tablet contains: aripiprazole 15 mg. Non-medicinal ingredients:

colloidal silicon dioxide, corn starch, crospovidone, hydroxy propyl cellulose, lactose

monohydrate, magnesium stearate, microcrystalline cellulose. Coloring agents: Iron oxide

yellow. Bottles of 30 and 100 tablets and blister packs of 100 tablets.

20 mg

White to off white, round shaped, beveled edge, uncoated tablets debossed with ‘L254’ on one

side and plain on other side. Each tablet contains: aripiprazole 20 mg. Non-medicinal

ingredients: colloidal silicon dioxide, corn starch, crospovidone, hydroxy propyl cellulose,

lactose monohydrate, magnesium stearate, microcrystalline cellulose. Bottles of 30 and 100

tablets and blister packs of 100 tablets.

ARIPIPRAZOLE

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30 mg

Pink color, round shaped, beveled edge, uncoated tablets debossed with ‘L255’ on one side and

plain on other side. Each tablet contains: aripiprazole 30 mg. Non-medicinal ingredients:

colloidal silicon dioxide, corn starch, crospovidone, hydroxy propyl cellulose, lactose

monohydrate, magnesium stearate, microcrystalline cellulose. Coloring agents: Iron oxide red.

Bottles of 30 and 100 tablets and blister packs of 100 tablets.

ARIPIPRAZOLE

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PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

aripiprazole

Chemical name:

7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy] -3,4-

dihydrocarbostyril

Molecular formula:

Molecular mass:

448.38 g/mol

Structural formula:

Physicochemical properties: A white to off-white crystalline powder is practically

insoluble in water. The pKa was determined to be 7.6 (in

20% ethanol solution).

ARIPIPRAZOLE

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CLINICAL TRIALS

Comparative Bioavailability Studies

A single-dose, two-treatment, two-period, crossover comparative bioavailability study of

ARIPIPRAZOLE (aripiprazole, Sanis Health Inc.) 5 mg tablet and ABILIFY (aripiprazole,

Bristol-Myers Squibb Canada Inc.) 5 mg tablet was conducted in 41 (forty-one) healthy Asian

male volunteers under fasting conditions. Bioavailability data were measured and the results are

summarized in the following table.

Summary Table of the Comparative Bioavailability Data for Aripiprazole (5 mg)

Aripiprazole

(1×5 mg)

From measured data

uncorrected for potency

Geometric Mean

Arithmetic Mean (CV %)

Parameter

Test

*

Reference

% Ratio of

Geometric Means

90% Confidence

Interval

0-72

(ng.h/mL)

859.97

878.63 (21.7)

824.75

849.21 (24.3)

104.2

99.9 - 108.8

(ng/mL)

21.07

21.69 (24.3)

20.52

21.24 (25.6)

102.5

96.6 - 108.8

4.50

(1.000 – 10.000)

4.00

(2.000 – 20.000)

Aripiprazole (as aripiprazole) 5 mg tablet; Manufactured for Sanis Health Inc.

† Pr

ABILIFY

(as Aripiprazole) 5 mg tablet; Manufactured by Bristol-Myers Squibb Canada Inc. and purchased in

Canada

Expressed as the median (range)

ARIPIPRAZOLE

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A single-dose, two-treatment, two-period, crossover comparative bioavailability study of

ARIPIPRAZOLE (aripiprazole, Sanis Health Inc.) 10 mg tablet and ABILIFY (aripiprazole,

Bristol-Myers Squibb Canada Inc.) 10 mg tablet was conducted in 39 (thirty-nine) healthy Asian

male volunteers under fasting conditions. Bioavailability data were measured and the results are

summarized in the following table.

Summary Table of the Comparative Bioavailability Data for Aripiprazole (10 mg)

Aripiprazole

(1×10 mg)

From measured data

uncorrected for potency

Geometric Mean

Arithmetic Mean (CV %)

Parameter

Test

*

Reference

% Ratio of

Geometric Means

90% Confidence

Interval

0-72

(ng.h/mL)

2052.49

2104.05 (23.6)

1858.94

1915.16 (25.4)

110.3

107.3 - 113.5

(ng/mL)

49.45

50.85 (24.6)

44.03

45.05 (22.2)

112.2

107.5 - 117.1

4.00

(1.00 - 10.000)

4.50

(1.000 - 10.000)

Aripiprazole (as aripiprazole) 10 mg tablet; Manufactured for Sanis Health Inc.

† Pr

ABILIFY

(as aripiprazole) 10 mg tablet; Manufactured by Bristol-Myers Squibb Canada Inc. and purchased in

Canada

Expressed as the median (range)

ARIPIPRAZOLE

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Schizophrenia

Adults

The efficacy of Aripiprazole tablets (aripiprazole) in the treatment of schizophrenia was

evaluated in five short-term (4- and 6-week), placebo-controlled trials of acutely relapsed

inpatients who predominantly met DSM-III/IV criteria for schizophrenia. Four of the five trials

were able to distinguish aripiprazole from placebo, but one study, the smallest, did not. Three of

these studies also included an active control group consisting of either risperidone (one trial) or

haloperidol (two trials), but they were not designed to allow for a comparison of aripiprazole and

the active comparators.

In the four positive trials for Aripiprazole tablets, four primary measures were used for assessing

psychiatric signs and symptoms. The Positive and Negative Syndrome Scale (PANSS) is a multi-

item inventory of general psychopathology used to evaluate the effects of drug treatment in

schizophrenia. The PANSS positive subscale is a subset of items in the PANSS that rates seven

positive symptoms of schizophrenia (delusions, conceptual disorganization, hallucinatory

behavior, excitement, grandiosity, suspiciousness/persecution, and hostility). The PANSS

negative subscale is a subset of items in the PANSS that rates seven negative symptoms of

schizophrenia (blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal,

difficulty in abstract thinking, lack of spontaneity/flow of conversation, stereotyped thinking).

The Clinical Global Impression (CGI) assessment reflects the impression of a skilled observer,

fully familiar with the manifestations of schizophrenia, about the overall clinical state of the

patient.

In a 4-week trial (n=414) comparing two fixed doses of aripiprazole (15 or 30 mg/day)

and haloperidol (10 mg/day) to placebo, both doses of aripiprazole were superior to

placebo in the PANSS total score, PANSS positive subscale, and CGI-severity score. In

addition, the 15-mg dose was superior to placebo in the PANSS negative subscale.

In a 4-week trial (n=404) comparing two fixed doses of aripiprazole (20 or 30 mg/day)

and risperidone (6 mg/day) to placebo, both doses of aripiprazole were superior to

placebo in the PANSS total score, PANSS positive subscale, PANSS negative subscale,

and CGI-severity score.

In a 6-week trial (n=420) comparing three fixed doses of aripiprazole (10, 15, or 20

mg/day) to placebo, all three doses of aripiprazole were superior to placebo in the

PANSS total score, PANSS positive subscale, and the PANSS negative subscale.

In a 6-week trial (n=367) comparing three fixed doses of aripiprazole (2, 5, or 10 mg/day)

to placebo, the 10-mg dose of aripiprazole was superior to placebo in the PANSS total

score, the primary outcome measure of the study. The 2-mg and 5-mg doses did not

demonstrate superiority to placebo on the primary outcome measure.

In a fifth study, a 4-week trial (n=103) comparing aripiprazole in a range of 5 to 30

mg/day or haloperidol 5 to 20 mg/day to placebo, haloperidol was superior to placebo, in

the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general

ARIPIPRAZOLE

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psychopathology traditionally used to evaluate the effects of drug treatment in psychosis,

and in a responder analysis based on the CGI-severity score, the primary outcomes for

that trial. Aripiprazole was only significantly different compared to placebo in a

responder analysis based on the CGI-severity score.

Thus, the efficacy of 10-mg, 15-mg, 20-mg, and 30-mg daily doses was established in two

studies for each dose. Among these doses, there was no evidence that the higher dose groups

offered any advantage over the lowest dose group of these studies.

An examination of population subgroups did not demonstrate any clear evidence of differential

responsiveness on the basis of age, gender, or race.

A longer-term trial enrolled 310 inpatients or outpatients meeting DSM-IV criteria for

schizophrenia who were, by history, symptomatically stable on other antipsychotic medications

for periods of 3 months or longer. These patients were discontinued from their antipsychotic

medications and randomized to aripiprazole 15 mg/day or placebo for up to 26 weeks of

observation for relapse. Relapse during the double-blind phase was defined as CGI-Improvement

score of ≥5 (minimally worse), scores ≥5 (moderately severe) on the hostility or

uncooperativeness items of the PANSS, or ≥20% increase in the PANSS total score. Patients

receiving aripiprazole 15 mg/day experienced a significantly longer time to relapse over the

subsequent 26 weeks compared to those receiving placebo.

Adolescents (13-17 years of age)

The efficacy of Aripiprazole tablets (aripiprazole) in the treatment of schizophrenia was

evaluated in one 6-week, placebo-controlled trial that included outpatients, 13 - 17 years of age,

who met DSM-IV criteria for schizophrenia and had a PANSS score ≥ 70 at baseline. The

majority of patients included in this trial (75%) were 15 - 17 years of age. Seventy-four percent

of patients had received antipsychotic treatment for previous episodes. In this trial comparing

two fixed doses of aripiprazole (10 mg/day, n=100 or 30 mg/day, n=102) to placebo (n=100),

aripiprazole was titrated starting from 2 mg/day to the target dose in 5 days in the 10 mg/day

treatment arm and in 11 days in the 30 mg/day treatment arm.

Both doses of aripiprazole were superior to placebo in the PANSS total score, the primary

outcome measure of the study. The 30 mg/day dose was not shown to be more efficacious than

the 10 mg/day dose. Maintenance of efficacy has not been systematically evaluated in adolescent

patients.

ARIPIPRAZOLE is not indicated for the treatment of schizophrenia in adolescents less than 15

years of age due to insufficient safety and efficacy data (see INDICATIONS, WARNINGS AND

PRECAUTIONS, Special Populations, and ADVERSE REACTIONS).

DETAILED PHARMACOLOGY

Nonclinical pharmacodynamics

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Extensive in vitro and in vivo studies demonstrated that aripiprazole is a potent partial agonist at

dopamine D

and serotonin 5-HT

receptors and an antagonist at serotonin 5-HT

receptors.

Aripiprazole binds with high affinity to dopamine D

and D

and serotonin 5-HT

and 5-HT

receptors; with moderate affinity to dopamine D

, serotonin 5-HT

and 5-HT

, alpha1-

adrenergic and histamine H

receptors and the serotonin transporter and with low affinity to

muscarinic receptors. As a D

partial agonist, aripiprazole blocks postsynaptic D

receptors at a

dose comparable to that at which it acts as agonist at presynaptic dopamine receptors.

Aripiprazole exhibits the properties of an agonist in animal models of dopaminergic hypoactivity

and the properties of an antagonist in animal models of dopaminergic hyperactivity. In multiple

behavioral models, aripiprazole exhibits an antipsychotic profile and is several fold less potent

than atypical antipsychotics in animal models predictive of extrapyramidal side effect liability.

Cardiorespiratory System

Aripiprazole and OPC-14857 inhibited the HERG/IKr current at 140- and 461-fold multiples of

the maximum steady-state plasma free-drug concentration, respectively, and there were no

effects on action potential duration (APD) in the rabbit Purkinje fiber assay. OPC-3373

demonstrated no in vitro inhibition of HERG/IKr current or prolongation of APD at

concentrations up to 10 mcM. Neither aripiprazole nor the main human metabolites (OPC-14857,

OPC-3373) accumulate in rat cardiac tissue following single or repeat (13 days) dosing. Potential

cardiovascular effects were also assessed in in vitro and in vivo safety pharmacology

(anesthetized dogs) and toxicology studies (39-week treatment in monkeys) in which no

significant changes were observed.

Central and Peripheral Nervous Systems

In animals, aripiprazole was less potent than chlorpromazine and haloperidol in producing

behavioral signs consistent with CNS depression, in inducing catalepsy, and in suppressing

spontaneous motor activity and, unlike these comparators, did not cause convulsions.

Additionally, it reduced motor coordination and prolonged the duration of hexobarbital-induced

hypnosis with a potency comparable to chlorpromazine. In contrast, aripiprazole demonstrated

less potential than chlorpromazine or haloperidol to induce muscular relaxation and analgesia.

Other Systems and Tissues

In vitro and in vivo safety pharmacology studies were conducted to assess the potential of

aripiprazole to alter gastric secretion, gastrointestinal motility, smooth muscle contractility, and

urine volume and electrolyte excretion. These studies indicated that aripiprazole has little

potential to cause gastrointestinal or renal side effects or affect smooth muscle contractility.

Nonclinical Pharmacokinetics

The absorption, distribution, metabolism and excretion properties of aripiprazole were evaluated

in a series of in vitro and in vivo studies in mice, rats, rabbits, dogs, minipigs, and monkeys.

Aripiprazole had only moderate intrinsic membrane permeability in vitro, but was well absorbed

following oral administration in animals and humans.

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Following intravenous administration of aripiprazole, its elimination half-life (1 to 5 hours) was

shorter and its plasma clearance (14 to 110 mL/min/kg) was more rapid in animals than in

humans (75 hours and 0.7 mL/min/kg, respectively). As in humans, the steady-state volumes of

distribution in animals suggest extensive extravascular distribution.

The exposure of mice, rats, and monkeys to aripiprazole after oral dosing was dose-related. In

rats, possibly due to saturation of presystemic metabolism and/or clearance, the increase in

exposure was greater than the dose increment; however, in mice and monkeys, exposure

increased in a generally dose-proportional manner. After repeated daily doses, exposures to

aripiprazole and its pharmacologically-active metabolite, dehydro-aripiprazole, were slightly

higher in female rats than in male rats; there were no gender-related differences in mice or

monkeys. Systemic accumulation of aripiprazole and its metabolites was seen at toxicologically-

relevant doses after once-daily chronic administration in both rats and monkeys.

In rats, concentrations of unchanged aripiprazole in the brain were up to 5-times higher than

plasma concentrations. Following [

C]-aripiprazole administration to pregnant rats, radioactivity

in the fetus was low and only a trace amount was detected in the amniotic fluid. After [

aripiprazole administration to lactating rats, milk vs blood concentration ratios were greater than

one for up to 24 hours. In vitro, aripiprazole bound extensively (99.4 to 99.8%) to proteins in

mouse, rat, rabbit, dog, monkey, and human sera.

Parent drug was undetectable in rat and monkey urine, indicating that renal clearance is not an

important mechanism of elimination. Aripiprazole was mainly eliminated via metabolic

clearance and aripiprazole metabolites were eliminated by both renal and biliary routes in

monkeys and predominantly by the biliary route in rats. After oral administration of [

aripiprazole to rats and monkeys, drug-derived radioactivity was recovered primarily in the feces

(~90 and 62% of dose, respectively). The metabolism of aripiprazole in rats and monkeys was

qualitatively similar to that in humans, though the rate of elimination through metabolism in

humans was slower compared to animals. The metabolism of aripiprazole was primarily by

dehydrogenation, hydroxylation, and N-dealkylation. Formation of the pharmacologically-active

dehydro-aripiprazole was a major route metabolism. This and other Phase 1 metabolites were

subject to further metabolism, including conjugation reactions. In rats, as in humans, unchanged

drug was the major drug-related component in plasma, while in monkeys, aripiprazole accounted

for only 13% of the drug-related material in plasma. All of the major metabolites in human

plasma were present in the plasma rats and monkeys, the principle species used for nonclinical

toxicity testing, indicating that these species were appropriate for safety assessment of

aripiprazole and its metabolites.

In vitro studies indicated that cytochrome P450 (CYP) isoforms, CYP3A4 and CYP2D6 were

responsible for the dehydrogenation and hydroxylation of aripiprazole, while its N-dealkylation

was catalyzed by CYP3A4 only. Clinical studies were conducted to evaluate the potential for

drug-drug interactions in vivo. While co-administration of CYP3A4 or CYP2D6 inhibitors

decreased the oral clearance of aripiprazole by approximately 40-50% and co-administration of

an inducer of CYP3A4 increased the oral clearance of aripiprazole, these changes were not

regarded as clinically meaningful. In vitro studies also indicated that neither aripiprazole nor it’s

ARIPIPRAZOLE

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dehydro metabolite should meaningfully inhibit the in vivo activity of CYP isozymes at

clinically-relevant concentrations. This was confirmed in clinical studies in which no clinically-

meaningful effect of aripiprazole on the clearance of substrates for CYP3A4, CYP2D6,

CYP2C9, and CYP2C19 was found.

TOXICOLOGY

Acute Toxicity

The acute oral toxicity of aripiprazole was determined in rats and monkeys. The estimated

median lethal oral dose in male and female rats was 953 and 705 mg/kg, respectively, and in

monkeys was greater than 2000 mg/kg for both sexes. Clinical signs consistent with

pharmacologically mediated central nervous (CNS) depression and extrapyramidal side effects

were noted in both species. In rats, clinical signs included decreased spontaneous motor activity,

crouching, prone position, ataxia, tremors, convulsions, straub tail, catalepsy, ptosis, and

coldness to touch. In monkeys, principal drug-related effects included impaired motor activity,

hyporeactivity to external stimuli, tremors, catalepsy, closed eyes, crouching, and prone and/or

lateral position.

Short- and Long-Term Toxicity

The short- and long-term toxicity of aripiprazole was determined in 4- to 52-week oral toxicity

studies in rats and monkeys. The results from these studies are summarized in the following

table.

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Short- and Long-Term Toxicity

Species/ Strain

Route of

Administration

Duration of

Dosing

Dose (mg/kg)

Number/ Sex

Noteworthy Findings

Rat/SD

Oral gavage

4 weeks

0, 60, 100

10 or 15 M

10 or 15 F

60 and 100 mg/kg/day: Sedation (primarily in Week 1) and dose-related decreases in

body weight, body weight gain, and food consumption; dose-related minimal or mild

increases in serum glutamic pyruvic transaminase, glutamic oxaloacetic transaminase,

and ɤ-glutamyltranspeptidase; and microscopically, dose-related minimal to moderate

adrenocortical hypertrophy, mild atrophy of the pars intermedia in the pituitary gland,

minimal to mild bone marrow hypocellularity, increased incidence and severity of

pulmonary alveolar foam cell accumulation in the lung, minimal salivary gland acinar

cell hypertrophy, minimal mammary gland lobular hyperplasia with minimal to mild

milk secretion, minimally decreased numbers of ovarian corpora lutea, and low

incidences of minimal uterine atrophy.

100 mg/kg/day: Emaciation, transient hypothermia, lacrimation, tremors, and unkempt

appearance and microscopically, minimal mucification of the vaginal epithelium.

All mammary gland and reproductive tract changes in females were considered to be

secondary to aripiprazole-related increases in serum prolactin. Additionally, all

changes were reversible or partially reversible after a 4-week post-dose period for the

100 mg/kg/day animals.

Rat/SD

Oral gavage

13 weeks

0, 2, 6, 20

10 or 16 M

10 or 16 F

2 and 6 (M) mg/kg/day: No drug-related changes.

6 (F) and 20 mg/kg/day: In females, minimal increases in body weight gain and food

consumption (6 mg/kg/day only) and microscopically, mucification of vaginal

epithelium and lobular hyperplasia of the mammary glands.

20 mg/kg/day: Minimal decreases in body weight gain and food consumption in males;

decreased liver and uterus weights; and microscopically, mammary milk secretion in

females. Anatomic changes in the mammary gland and reproductive tract of females

were considered to be secondary to aripiprazole-related increases in serum prolactin.

At the end of the 4-week post-dose period, all findings were reversible except for

minimal decreases in body weight gain and food consumption.

Rat/SD

Oral gavage

26 weeks

0, 10, 30, 60

20 or 25 M

20 or 25 F

10 mg/kg/day: Minimal or mild increases in body weight and food consumption in

females.

10, 30, and 60 mg/kg/day: Dose-related minimal to moderate decreases in body weight

(10 mg/kg/day only in males), including initial weight loss at 60 mg/kg/day; minimal

or mild decreases in serum total protein and albumin; pale discoloration of the lungs;

and microscopically, dose-related minimal to moderate atrophy of pituitary pars

intermedia, increased incidence of minimal to moderate pulmonary histiocytosis, and

changes in the mammary gland (atrophy in males ≥ 30 mg/kg/day; hyperplasia in

females) and female reproductive tract (i.e., persistent diestrus) that were considered

secondary to drug-related hyperprolactinemia.

30 and 60 mg/kg/day: Dose-related increased incidences of transient post-dose

hypoactivity and ptosis and predose hyperactivity; minimal to moderate decreases in

food consumption; and microscopically, minimally increased adrenocortical lipofuscin

pigment and minimal to mild adrenocortical hypertrophy in females.

60 mg/kg/day: Minimal decreases in hematocrit, reticulocytes, and hemoglobin

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Species/ Strain

Route of

Administration

Duration of

Dosing

Dose (mg/kg)

Number/ Sex

Noteworthy Findings

(females); increased adrenal (females) and lung weights; decreased testicular size and

weight; dark discoloration of the adrenals and ovaries; and, microscopically, minimal

to moderate bilateral testicular atrophy and minimally increased ovarian lipofuscin

pigment.

Except for remnants of the adrenal and ovarian pigment, all aripiprazole-related effects

were reversible or partially reversible (hyperactivity and pulmonary histiocytosis with

associated increases in lung weight) after a 13-week post-dose period.

Rat/SD

Oral gavage

52 weeks

0, 1, 3, 10

20 M

20 F

1, 3, and 10 mg/kg/day: Mild to moderate uterine atrophy and slight increase in

corpora lutea.

3 and 10 mg/kg/day: Minimal to mild increases (transient at 10 mg/kg/day) in body

weights; minimal, sporadic increases in food consumption; decreases in adrenal, liver,

kidney, and uterus weights and increases in ovarian weights; and microscopically,

increased severity of lobular hyperplasia of mammary gland and increased incidence

and severity of vaginal epithelial mucification in females (changes considered

secondary to aripiprazole-related increases in prolactin).

10 mg/kg/day: Decreased liver weight; macroscopic evidence of mammary gland

development in females; and microscopically, karyomegaly of hepatocytes, renal

proximal tubular epithelium, and Harderian gland acinar cells.

Monkey/

Cynomolgus

Oral gavage

4 weeks

1, 5, 25, 125

1, 5, 25, and 125 mg/kg/day: Impairment of motor activity characterized by ataxic gait,

reduced motor activity, and/or absence of motion (1 mg/kg/day only in Week 1).

5, 25, and 125 mg/kg/day: Closed eyes, catalepsy, tremors, and slight decreases in food

consumption (Weeks 1 and 2).

25 and 125 mg/kg/day: Abnormal posture (crouching, lateral, or prone position) and

hyporeactivity; minimal dose-related body weight loss (Weeks 1 and 2); and at

necropsy, retention of gallsand (granular material) in the gallbladder.

125 mg/kg/day: At necropsy, a stone (calculus) in the gallbladder of 1 animal.

Monkey/

Cynomolgus

Oral gavage

13 weeks

0, 0.5, 1, 5, 25

3 to 5 M

3 to 5 F

0.5 and 1 mg/kg/day: No drug-related findings.

5 and 25 mg/kg/day: Dose-related impairment of motor activity, hyporeactivity,

tremors, catalepsy, and abnormal posture. These clinical signs generally were mild at 5

mg/kg/day and severe at 25 mg/kg/day early in the study, but improved with continued

dosing at 25 mg/kg/day.

25 mg/kg/day: Minimal decreases in body weight, moderate decreases in food

consumption, and sporadic absence of feces in Weeks 1 and 2 and moderate to severe

muddy substance in the bile at necropsy.

All drug-related alterations disappeared or improved during the 4-week post-dose

period.

Monkey/

Cynomolgus

Oral gavage

39 weeks

0, 25, 50,

75/100

Due to pronounced clinical signs at 100 mg/kg/day on Day 1, high-dose animals were

not treated on Days 2 to 4. Starting on Day 5 through remainder of the study, high-dose

animals were treated at 75 mg/kg/day.

25 mg/kg/day: Low incidence of impaired motor activity in 1 male.

25, 50, and 75 mg/kg/day: Dose-related tremors and mild to moderate hypoactivity

(transient at 25 mg/kg/day), vomitus (emesis), qualitatively reduced food consumption,

ARIPIPRAZOLE

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Species/ Strain

Route of

Administration

Duration of

Dosing

Dose (mg/kg)

Number/ Sex

Noteworthy Findings

low incidences of hunched or unusual posture, and mucus-like and granular (gallsand)

materials in the gallbladder.

50 and 75 mg/kg/day: Low incidences of excessive salivation, sternal recumbency, and

gallbladder calculi (gallstones); and, microscopically, low incidence of generally

minimal liver alterations consistent with hepatolithiasis in the subcapsular parenchyma

of the right median lobe proximal to the gallbladder.

75 mg/kg/day: One female euthanatized moribund in Week 3 due to severe clinical

toxicity characterized by mild to severe hypoactivity, tremors, excessive salivation,

lateral or sternal recumbency, hunched or unusual posture, impaired motor activity,

and reduced food consumption (low or none). This female was the only high-dose

animal that had not recovered when dosing resumed at 75 mg/kg/day on Day 5.

Minimal decreases in body weight in males and low incidence of ataxia in 1 female.

Analyses of gallsand and gallstones indicated that sulfate conjugates of hydroxy

metabolites of aripiprazole were the major drug-related constituents; and bile acids,

principally taurodeoxycholic acid, were the primary nondrug-related constituents.

Analyses of intrahepatic concretions (hepatoliths) demonstrated morphologic features

and elemental composition that were similar to gallsand and gallstones.

Monkey/

Cynomolgus

Oral gavage

52 weeks

0, 0.5, 5, 25

0.5 mg/kg/day: No drug-related changes.

5 and 25 mg/kg/day: Dose-related incidences and/or severity of impaired motor

activity, hyporeactivity, tremors, catalepsy, and abnormal posture (crouching, lateral,

and/or prone position) that were most evident during Weeks 1 and 2. At 25 mg/kg/day,

impaired motor activity was severe in Week 1 and generally mild during the remainder

of the study. Hyporeactivity disappeared by Week 3 and catalepsy and abnormal

posture were observed sporadically throughout the dosing period.

25 mg/kg/day: Minimal decreases in body weight and mild to moderate decreases in

food consumption during Weeks 1 and 2. At necropsy, slight to generally moderate

gallsand in 3 animals and gallstones in 1 animal. In comparison, slight gallsand noted

in 2 controls.

ARIPIPRAZOLE

Page 52 of 61

Juvenile Toxicity

In repeat-dose studies in juvenile rats and dogs, the toxicity profile of aripiprazole was

comparable to that observed in adult animals, and there was no evidence of neurotoxicity or

adverse effects on development.

Mutagenesis

The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation

assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse

lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells,

the in vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay in rats.

Aripiprazole was clastogenic in the in vitro chromosomal aberration assay in CHL cells with and

without metabolic activation. A positive response was obtained in the in vivo micronucleus assay

in mice; however, the response was due to a mechanism considered not relevant to humans.

Reproductive Toxicity

In animal studies, aripiprazole demonstrated developmental toxicity, including possible

teratogenic effects in rats and rabbits.

Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 10 times the

maximum recommended human dose [MRHD] on a mg/m

basis) of aripiprazole during the

period of organogenesis. Gestation was slightly prolonged at 30 mg/kg. Treatment caused a

slight delay in fetal development, as evidenced by decreased fetal weight (30 mg/kg),

undescended testes (30 mg/kg), and delayed skeletal ossification (10 and 30 mg/kg). There were

no adverse effects on embryofetal or pup survival. Delivered offspring had decreased

bodyweights (10 and 30 mg/kg), and increased incidences of hepatodiaphragmatic nodules and

diaphragmatic hernia at 30 mg/kg (the other dose groups were not examined for these findings).

A low incidence of diaphragmatic hernia was also seen in the fetuses exposed to 30 mg/kg.

Postnatally, delayed vaginal opening was seen at 10 and 30 mg/kg and impaired reproductive

performance (decreased fertility rate, corpora lutea, implants, and live fetuses and increased post-

implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg.

Some maternal toxicity was seen at 30 mg/kg; however, there was no evidence to suggest that

these developmental effects were secondary to maternal toxicity.

In pregnant rats receiving aripiprazole injection intravenously (3, 9, and 27 mg/kg/day) during

the period of organogenesis, decreased fetal weight and delayed skeletal ossification were seen at

the highest dose, which also caused maternal toxicity.

Pregnant rabbits were treated with oral doses of 10, 30, and 100 mg/kg/day (2, 3, and 11 times

human exposure at MRHD based on AUC) of aripiprazole during the period of organogenesis.

Decreased maternal food consumption and increased abortions were seen at 100 mg/kg.

Treatment caused increased fetal mortality (100 mg/kg), decreased fetal weight (30 and 100

mg/kg), increased incidence of a skeletal abnormality (fused sternebrae at 30 and 100 mg/kg),

and minor skeletal variations (100 mg/kg).

In pregnant rabbits receiving aripiprazole injection intravenously (3, 10, and 30 mg/kg/day)

during the period of organogenesis, the highest dose, which caused pronounced maternal

ARIPIPRAZOLE

Page 53 of 61

toxicity, resulted in decreased fetal weight, increased fetal abnormalities (primarily skeletal), and

decreased fetal skeletal ossification. The fetal no-effect dose was 10 mg/kg, which produced 5

times the human exposure at the MRHD based on AUC.

In a study in which rats were treated with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 10

times the MRHD on a mg/m

basis) of aripiprazole perinatally and postnatally (from day 17 of

gestation through day 21 postpartum), slight maternal toxicity and slightly prolonged gestation

were seen at 30 mg/kg. An increase in stillbirths and decreases in pup weight (persisting into

adulthood) and survival were seen at this dose.

In rats receiving aripiprazole injection intravenously (3, 8, and 20 mg/kg/day) from day 6 of

gestation through day 20 postpartum, an increase in stillbirths was seen at 8 and 20 mg/kg, and

decreases in early postnatal pup weights and survival were seen at 20 mg/kg. These doses

produced some maternal toxicity. There were no effects on postnatal behavioral and reproductive

development.

Impairment of fertility

Female rats were treated with oral doses of 2, 6, and 20 mg/kg/day (0.6, 2, and 6 times the

MRHD on a mg/m

basis) of aripiprazole from 2 weeks prior to mating through day 7 of

gestation. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no

impairment of fertility was seen. Increased pre-implantation loss was seen at 6 and 20 mg/kg and

decreased fetal weight was seen at 20 mg/kg.

Male rats were treated with oral doses of 20, 40, and 60 mg/kg/day (6, 13, and 19 times the

MRHD on a mg/m

basis) of aripiprazole from 9 weeks prior to mating through mating.

Disturbances in spermatogenesis were seen at 60 mg/kg and prostate atrophy was seen at 40 and

60 mg/kg, but no impairment of fertility was seen.

Carcinogenicity

Lifetime carcinogenicity studies were conducted in ICR mice and in Sprague-Dawley (SD) and

F344 rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30

mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2 to 5 and 0.3 to 3 times the

MRHD based on mg/m

, respectively). In addition, SD rats were dosed orally for 2 years at 10,

20, 40, and 60 mg/kg/day (3 to 19 times the MRHD based on mg/m

). Aripiprazole did not

induce tumors in male mice or rats. In female mice, the incidences of pituitary gland adenomas

and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3

to 30 mg/kg/day (0.1 to 0.9 times human exposure at MRHD based on AUC and 0.5 to 5 times

the MRHD based on mg/m

). In female rats, the incidence of mammary gland fibroadenomas

was increased at a dietary dose of 10 mg/kg/day (0.1 times human exposure at MRHD based on

AUC); and the incidences of adrenocortical carcinomas and combined adrenocortical

adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (10 times human exposure

at MRHD based on AUC).

Proliferative changes in the pituitary and mammary gland of rodents have been observed

following chronic administration of other antipsychotic agents and are considered prolactin-

mediated. Serum prolactin was not measured in the aripiprazole carcinogenicity studies.

ARIPIPRAZOLE

Page 54 of 61

However, increases in serum prolactin levels were observed in female mice in a 13-week dietary

study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not

increased in female rats in 4- and 13-week dietary studies at the dose associated with mammary

gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine

tumors in rodents is unknown.

Other Toxicity Studies

Adrenocortical Changes in Rats

A series of investigative studies were conducted in rats to determine the mechanism for the

aripiprazole-related adrenocortical changes after subchronic and chronic dosing. The data from

these studies supported the conclusion that the female rat-specific adrenocortical tumorigenic

response at 60 mg/kg/day in the oral carcinogenicity study was secondary to aripiprazole-related

adrenocortical cytotoxicity and consequent increased cell proliferation. The female specificity of

the adrenocortical tumorigenic response was considered a consequence of the earlier onset and

greater severity of the adrenocortical cytotoxic changes. The adrenocortical cytotoxic and

tumorigenic effects have no established clinical relevance since they occurred at a dose 10 times

human exposure at the MRHD based on AUC.

Retinal Degeneration in Rats

Aripiprazole produced retinal degeneration in albino Sprague-Dawley (SD) rats in a 26-week

chronic toxicity study at a dose of 60 mg/kg and in a 2-year carcinogenicity study at doses of 40

and 60 mg/kg. The 40 and 60 mg/kg doses are 7 to 10 times human exposure at the MRHD based

on AUC. In a subsequent 18-month investigative study in albino SD and pigmented Long-Evans

(LE) rats administered 60 mg/kg/day aripiprazole, pharmacologically mediated hyperactivity

occurred in both rat strains early in the study predisposing the animals to increased light

exposure. Time-dependent retinal degeneration with electroretinographic and morphologic

features consistent with spontaneous light-induced retinal degeneration was observed in albino

SD rats, whereas there was no evidence of light-induced retinal injury in pigmented LE rats at

any time point despite comparable systemic exposures to aripiprazole. This was due to the

photoprotective effect of ocular melanin pigment in LE rats. Therefore, the retinal degeneration

observed in albino SD rats after chronic dosing at high doses of aripiprazole was considered to

be a consequence of drug-related, pharmacologically mediated hyperactivity during the animal

room light phase, resulting in increased light exposure rather than a direct drug effect on the

retina. Light-induced retinal degeneration in albino SD rats has no established clinical relevance.

Dermal Sensitization and Dermal and Ocular Irritation

Aripiprazole was not a dermal sensitizer in mice and was nonirritating to rabbit skin and eye.

Phototoxicity

Aripiprazole was nonphototoxic in Balb/c 3T3 mouse fibroblast cultures.

ARIPIPRAZOLE

Page 55 of 61

Antigenicity

Aripiprazole produced no evidence of active systemic anaphylaxis or passive cutaneous reactions

in guinea pigs.

Immunotoxicity

Aripiprazole did not adversely affect the T-cell-dependent humoral immune response to sheep

red blood cells in rats.

Dependence

In a battery of studies conducted to evaluate physical dependence and abuse potential,

aripiprazole demonstrated no abuse liability in rats; mild, transient physical dependence in

monkeys (rebound arousal) considered to be of little clinical significance; and no positive

reinforcing effects in monkeys. Overall, the results support that aripiprazole has no abuse

liability.

Metabolites

In single-dose intravenous studies in rats, OPC-14857 produced clinical effects similar to those

observed at high single oral doses of parent drug, whereas OPC-3373 produced no drug-related

toxicity. In a 28-day oral toxicity study in rats, 2,3-DCPP produced CNS-related clinical signs

with deaths at the high dose (30 mg/kg/day) but no evidence of target organ toxicity. All 3

metabolites were not mutagenic in bacterial reverse-mutation tests. In an in vitro cytogenetics

assay in CHL cells, 2,3-DCPP increased chromosome aberrations in the presence and absence of

metabolic activation; however, the increases were considered secondary to excessive cytotoxicity

rather than direct DNA reactivity.

ARIPIPRAZOLE

Page 56 of 61

REFERENCES

Cutler et al. The Efficacy and Safety of Lower Doses of Aripiprazole for the Treatment of

Patients with Acute Exacerbation of Schizophrenia (2006) CNS Spectr. 2006;11(9):691-

Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL, Ali MW.

Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with

schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763-771

McEvoy, et al. A randomized, double-blind, placebo-controlled study of the efficacy and

safety of aripiprazole 10, 15 or 20 mg/day for the treatment of patients with acute

exacerbations of schizophrenia. J Psychiatr Res. 2007 Dec;41(11):895-905.

Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E, Stringfellow J, Ingenito

G, Marder SR. Aripiprazole, an antipsychotic with a novel mechanism of action, and

risperidone vs. placebo in patients with schizophrenia and schizoaffective disorder. Arch

Gen Psychiatry 2003;60(7):681-690

Otsuka Canada Pharmaceutical Inc., Product Monograph,

ABILIFY

Control

No.:234620, Date of Revision: April 15, 2020.

IMPORTANT: PLEASE READ

ARIPIPRAZOLE

Page 57 of 61

PART III: CONSUMER INFORMATION

Pr

ARIPIPRAZOLE

Aripiprazole Tablets USP

2 mg, 5 mg, 10 mg, 15 mg, 20 mg and 30 mg

This leaflet is part III of a three-part "Product

Monograph" published when ARIPIPRAZOLE was

approved for sale in Canada and is designed

specifically for Consumers. This leaflet is a

summary and will not tell you everything about

ARIPIPRAZOLE. Contact your doctor or pharmacist

if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

ARIPIPRAZOLE is used to treat symptoms of

schizophrenia in adults and in adolescents (15-17

years of age). Schizophrenia is characterised by

symptoms such as:

hearing, seeing or sensing things that are not

there

suspiciousness, mistaken beliefs

incoherent speech and behaviour and

emotional flatness

People with this condition may also feel depressed,

guilty, anxious or tense.

ARIPIPRAZOLE is not a cure for your condition, but it

can help manage your symptoms and in adult patients

may reduce the risk of relapse.

Your doctor may have prescribed ARIPIPRAZOLE for

another reason. Ask your doctor if you have any

questions about why ARIPIPRAZOLE has been

prescribed for you.

What it does:

ARIPIPRAZOLE belongs to a group of medicines

called atypical antipsychotic drugs.

Antipsychotic medications affect the chemicals that

allow communication between nerve cells

(neurotransmitters). Illnesses that affect the brain may

be due to certain chemicals in the brain being out of

balance. These imbalances may cause some of the

symptoms you may be experiencing. Doctors and

scientists are not sure what causes these imbalances

to occur. Exactly how ARIPIPRAZOLE works is

unknown. However, it seems to adjust the balance of

chemicals called dopamine and serotonin.

When it should not be used:

Do not take ARIPIPRAZOLE if you have had an

allergic reaction to ARIPIPRAZOLE or any of the

ingredients listed in the “What the nonmedicinal

ingredients are” section of this leaflet. Signs of allergic

reaction may include a rash, itching, shortness of

breath or swelling of the face, lips or tongue.

What the medicinal ingredient is:

Aripiprazole

What the nonmedicinal ingredients are:

Colloidal silicon dioxide, corn starch, crospovidone,

hydroxy propyl cellulose, lactose monohydrate,

magnesium stearate, microcrystalline cellulose.

ARIPIPRAZOLE tablets also contain coloring agents

listed below for each strength:

2 mg Tablet: FD&C Blue No. 2 / Indigo Carmine AL

and Iron oxide yellow.

5 mg Tablet: FD&C Blue No. 2 / Indigo Carmine AL.

10 mg Tablet: Iron oxide red.

15 mg Tablet: Iron oxide yellow.

20 mg Tablet: None

30 mg Tablet: Iron oxide red.

What dosage forms it comes in:

Tablets of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg and 30

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Various medicines of the group to which

ARIPIPRAZOLE belongs, including ARIPIPRAZOLE,

have been associated with an increased rate of death

when used in elderly patients with dementia.

ARIPIPRAZOLE is not indicated in elderly patients

with dementia.

ARIPIPRAZOLE is not for use in children with

schizophrenia under the age of 15.

BEFORE you use ARIPIPRAZOLE talk to your

doctor or pharmacist if you:

IMPORTANT: PLEASE READ

ARIPIPRAZOLE

Page 58 of 61

are taking any other medicines (prescriptions

or over the counter medicines).

are pregnant, think you are pregnant or plan to

become pregnant. You should not take

ARIPIPRAZOLE if you are pregnant unless

you have discussed this with your doctor.

are breast-feeding or plan to breast-feed.

Breast-feeding mothers should not take

ARIPIPRAZOLE.

have high blood sugar or a family history of

diabetes.

have a low white blood cell count.

have ever had blackouts or seizures.

have involuntary, irregular muscle movements,

especially in the face.

suffer from heart disease or have a family

history of heart disease, stroke or "mini" stroke.

have a history of any problems with the way

your heart beats or if you are taking any

medicines that may have an impact on the way

your heart beats.

suffer from abnormal (high) blood pressure or

have rapid heartbeat and a drop in blood

pressure when getting up.

are an elderly patient suffering from dementia

(loss of memory and other mental abilities),

you or your carer/relative should tell your

doctor if you have ever had a stroke or "mini"

stroke.

have risk factors for developing blood clots

such as: a family history of blood clots, age

over 65, smoking, obesity, recent major

surgery (such as hip or knee replacement),

immobility due to air travel or other reason,

take oral contraceptives ("The Pill").

exercise vigorously or work in hot, sunny

places.

drink alcoholic beverages or use recreational

drugs.

have ever abused drugs.

have a history of gambling or impulse control

disorders (urge to gamble, spend money, eat

or other urges).

have a history of or are at risk of sleep apnea

(a sleep disorder where your breathing is

interrupted during sleep)

suffer from lactose intolerance or have

hereditary galactose intolerance or glucose-

galactose malabsorption, because

ARIPIPRAZOLE tablets contain lactose.

Thoughts of suicide and worsening of your mental

illnesses:

If you are depressed and/or have other mental

illnesses you may sometimes have thoughts of

harming or killing yourself. These may be increased

when first starting treatment, since these medicines all

take time to work, usually about two weeks but

sometimes longer.

If you have thoughts of harming or killing yourself at

any time, contact your doctor or go to a hospital

straight away.

You may find it helpful to tell a relative or close friend

that you have other mental illnesses, and ask them to

read this leaflet. You might ask them to tell you if they

think your mental illness is getting worse, or if they are

worried about changes in your behaviour.

Effects on newborns

In some cases, babies born to a mother taking

ARIPIPRAZOLE during pregnancy have experienced

symptoms that are severe and require the newborn to

be hospitalized. Sometimes, the symptoms may

resolve on their own. Be prepared to seek emergency

medical attention for your newborn, if he/she has

difficulty breathing, is overly sleepy, has muscle

stiffness or floppy muscles (like a rag doll), is shaking

or is having difficulty feeding.

Falls: Feeling sleepy, a fall in blood pressure when you

stand up from sitting or lying down, vision and speech

problems have been reported with the use of

antipsychotic drugs. This can lead to falls that may

cause fractures or other fall related-injuries. Certain

medications, diseases or conditions can make this

worse.

Serious allergic reaction

Taking ARIPIPRAZOLE may affect your skin or other

parts of your body such as your

liver,

kidneys,

heart,

or blood cells.

These allergic reactions can be life-threatening and

can cause death.

Get immediate medical attention if you have:

fever

severe rash, hives

swollen lymph glands

swelling of your face

flu-like feeling

yellow skin or eyes

shortness of breath

swelling of the legs

IMPORTANT: PLEASE READ

ARIPIPRAZOLE

Page 59 of 61

INTERACTIONS WITH THIS MEDICATION

Tell all doctors, dentists and pharmacists who are

treating you that you are taking ARIPIPRAZOLE.

Please tell your doctor or pharmacist if you are taking

or have recently taken any other medicines, including

medicines obtained without a prescription.

If you are taking other medicines, your doctor

may need to change your dose of

ARIPIPRAZOLE. You should tell your doctor if

you are taking ketoconazole (antifungal),

quinidine (antiarrythmic),

paroxetine

(antidepressant) or fluoxetine (antidepressant).

These medicines may lead to higher

concentrations of aripiprazole in your blood.

You should also tell your doctor if you are

taking carbamazepine as it may lead to lower

concentrations of aripiprazole in your blood,

making ARIPIPRAZOLE less effective.

ARIPIPRAZOLE may increase the effect of medicines

used to lower the blood pressure. Be sure to tell your

doctor if you take a medicine to keep your blood

pressure under control.

The effects of alcohol could be made worse while

taking ARIPIPRAZOLE. It is recommended that you do

not drink alcohol while taking ARIPIPRAZOLE.

Only take other medicines while you are on

ARIPIPRAZOLE if your doctor tells you to.

PROPER USE OF THIS MEDICATION

The most important thing about taking ARIPIPRAZOLE

is to take it exactly the way your doctor has prescribed

it, every day. You should check with your doctor or

pharmacist if you are not sure. Your doctor has

decided on the best dosage for you based on your

individual situation. Your doctor may increase or

decrease your dose depending on your response.

Schizophrenia

Usual adult dose: The usual dose is 10 mg or 15 mg

once a day, without regard to meals. However, your

doctor may prescribe a lower or higher dose to a

maximum of 30 mg once a day.

Usual adolescent (15 -17 years of age) dose: The

usual dose is 10 mg once a day, without regard to

meals. At the start of treatment, your doctor will

prescribe a lower daily dose (2 mg) and will increase

the dose to 5 mg once a day after 2 days and to the

target dose of 10 mg once a day after 2 additional

days. Depending on how well you respond and tolerate

the 10 mg dose, your doctor may prescribe a lower or

higher dose, to a maximum of 30 mg once a day.

Try to take ARIPIPRAZOLE at the same time each

day. It does not matter whether you take it with or

without food. Always take the tablet with water and

swallow it whole.

If you have the impression that the effect of

ARIPIPRAZOLE is too strong or too weak, talk to your

doctor or pharmacist.

Even if you feel better, do not change or discontinue

the daily dose of ARIPIPRAZOLE without first

consulting your doctor. Although ARIPIPRAZOLE

cannot cure your condition, it can help relieve your

symptoms. If your symptoms improve or disappear, it is

probably because your treatment is working.

ARIPIPRAZOLE should be taken for as long as you

and your doctor believe it is helping you.

Do not give ARIPIPRAZOLE to anyone else. Your

doctor has prescribed it for you and your condition.

ARIPIPRAZOLE is not for use in children under the

age of 15 years for the treatment of schizophrenia.

Overdose:

If you have taken more ARIPIPRAZOLE tablets than

your doctor has prescribed (or if someone else has

taken some of your ARIPIPRAZOLE tablets), contact

your regional Poison Control Centre and talk to your

doctor right away or go to your nearest hospital

emergency department. Take the medication package

with you.

Missed Dose:

If you miss a dose, take the missed dose as soon as

you remember but do not take two doses in one day.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like other medicines, ARIPIPRAZOLE can cause

some side effects. These side effects are most likely to

be minor and temporary. However, some may be

serious and need medical attention.

IMPORTANT: PLEASE READ

ARIPIPRAZOLE

Page 60 of 61

Certain side effects occur more frequently in

adolescent compared to adult patients, including

abnormal movements, drowsiness and weight gain.

The most common side effects of ARIPIPRAZOLE are:

feeling of restlessness (akathisia)

drowsiness

shaking (tremors)

abnormal movements

nausea, vomiting, upset stomach

dizziness

constipation

headaches

insomnia

anxiety

sleep apnea (a sleep disorder where your

breathing is interrupted during sleep)

sleep walking and eating while asleep (sleep-

related eating disorders)

The following other side effects may also happen in

some people who take

ARIPIPRAZOLE:

weight gain

increase in the amount of sugar (glucose) in

the blood (hyperglycemia). Symptoms of high

blood sugar can include feeling very thirsty

and/or hungry, needing to urinate more than

usual, feeling weak or tired, feeling sick to your

stomach, feeling confused, fruity smelling

breath.

decrease in the amount of white blood cells.

difficulty swallowing, which may lead to

aspiration and choking.

decreased blood pressure. Symptoms of

decreased blood pressure can include

lightheadedness or fainting when rising too

quickly from a sitting or lying position.

hypersexuality (uncontrollable and/or

inappropriate sexual behaviour of severity or

duration that causes distress).

an urge to gamble,

to spend money, to eat

(binge eating) or other urges (development of a

new or increased urge).

Because some people experience sleepiness, you

should avoid driving a car or operating machinery until

you know how ARIPIPRAZOLE affects you.

Your doctor should check your body weight before

starting ARIPIPRAZOLE and continue to monitor it for

as long as you are being treated.

Your doctor should take blood tests before starting

ARIPIPRAZOLE. These tests will monitor blood sugar,

cholesterol, triglycerides and the number of infection

fighting white blood cells. Your doctor should continue

to monitor your blood for as long as you are being

treated.

You should tell your doctor if you notice any symptoms

that worry you, even if you think the problems are not

connected with the medicine or are not listed here.

SERIOUS SIDE EFFECTS AND WHAT TO DO ABOUT

THEM

Symptom / effect

Talk to your

healthcare

professional

Stop taking

drug and

seek

immediate

emergency

help

Only if

severe

In all

cases

Common

Skin Rash on its own

Constipation

Uncommon

Tardive Dyskinesia:

Muscle twitching or

abnormal movement of

your face or tongue

Stroke and Transient

Ischemic Attacks:

Sudden weakness or

numbness of the face,

arms, or legs and

speech or vision

problems

Allergic Reaction:

Symptoms include

swelling in the mouth,

tongue, face and throat,

itching, rash.

Seizure: Loss of

consciousness with

uncontrollable shaking

Neuroleptic Malignant

Syndrome:

Pronounced muscle

stiffness or inflexibility

with high fever, rapid or

irregular heartbeat,

sweating, state of

confusion or reduced

consciousness

IMPORTANT: PLEASE READ

ARIPIPRAZOLE

Page 61 of 61

SERIOUS SIDE EFFECTS AND WHAT TO DO ABOUT

THEM

Symptom / effect

Talk to your

healthcare

professional

Stop taking

drug and

seek

immediate

emergency

help

Only if

severe

In all

cases

Priapism: Long-lasting

(greater than 4 hours in

duration) and painful

erection of the penis

Blood Clots: Swelling,

pain and redness in an

arm or leg that is warm

to touch. You may

develop sudden chest

pain, difficulty breathing

and heart palpitations

Allergic Reactions

known as Drug

Reaction with

Eosinophilia and

Systemic Symptoms

(DRESS) (serious skin

reaction that may

affect more than one

or more organs):

fever, severe rash,

hives, swollen lymph

glands, swelling of your

face, flu-like feeling,

yellow skin or eyes,

shortness of breath,

swelling of the legs, dry

cough, chest pain or

discomfort, urinating

less often, less urine or

dark urine.

This is not a complete list of side effects. For any

unexpected effects while taking ARIPIPRAZOLE,

contact your doctor or pharmacist.

HOW TO STORE IT

ARIPIPRAZOLE should be stored at room temperature

(15ºC to 30ºC). Do not use ARIPIPRAZOLE after the

expiry date which is stated on the label or carton as

EXP.

Keep 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 the Web page on Adverse Reaction

Reporting (https://www.canada.ca/en/health-

canada/services/drugs-health-

products/medeffect-canada/adverse-reaction-

reporting.html) for 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

ARIPIPRAZOLE:

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/services/drugs-health-products/drug-

products/drug-product-database.html); Sanis

Health Inc.’s website www.sanis.com, or by

contacting Sanis Health Inc. at:

1-866-236-4076

or quality@sanis.com

This leaflet was prepared by:

Sanis Health Inc.

1 President's Choice Circle,

Brampton, Ontario

L6Y 5S5

Last revised: October 15, 2020

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