Abilify

Name: Abilify

Abilify Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability of conventional tablets is 87%.1

Peak plasma concentrations achieved within 3–5 hours after oral administration of conventional tablets; steady-state concentrations of aripiprazole and dehydro-aripiprazole achieved within 14 days.1

Orally disintegrating tablets and conventional tablets are bioequivalent.1

Well absorbed when administered as oral solution; plasma aripiprazole concentrations are higher after administration of oral solution than conventional tablets at equivalent doses.1 (See Dosage under Dosage and Administration.)

Oral solution-to-tablet ratios of geometric mean maximum plasma concentrations and AUCs were 122 and 114%, respectively.1

Immediate-release IM aripiprazole (Abilify): Peak plasma concentrations following IM administration achieved within 1–3 hours and are 19% higher than those achieved following oral administration of conventional tablets.1 Absolute IM bioavailability of a 5-mg dose is 100%.1 Systemic exposure over 24 hours is similar following IM and oral administration; however, AUC was 90% higher within first 2 hours after IM than after oral tablet administration.1

Extended-release IM aripiprazole (Abilify Maintena): Peak plasma concentrations following multiple IM doses achieved within a median of 4 days with deltoid administration and 5–7 days with gluteal administration.118 Although single-dose IM administration into the deltoid results in 31% higher peak plasma concentrations compared with the gluteal site, extent of absorption similar for both injection sites.118 At steady state, AUCs and peak plasma concentrations similar for both deltoid and gluteal injection sites.118

Extended-release IM aripiprazole lauroxil (Aristada): Following IM administration, aripiprazole appears in systemic circulation in 5–6 days and is continually released for an additional 36 days.119 Plasma concentrations of aripiprazole increase with consecutive doses and reach steady-state concentrations following the fourth monthly injection.119 When administered with oral aripiprazole for 21 days following the first injection, therapeutic plasma concentrations of aripiprazole achieved within 4 days.119 IM injection into the deltoid and gluteal areas results in similar systemic exposures; these injection sites are interchangeable.119

Food

Administration of conventional tablets with a high-fat meal delayed rate but not extent of absorption.1

Distribution

Extent

Large volume of distribution following IV administration indicates extensive extravascular distribution.1

Distributed into milk.1 111 118 119

Plasma Protein Binding

Aripiprazole and its major metabolite, dehydro-aripiprazole, are >99% bound, principally to albumin.1

Elimination

Metabolism

Extensively metabolized in the liver principally via dehydrogenation, hydroxylation, and N-dealkylation by CYP2D6 and CYP3A4.1

Extended-release IM aripiprazole lauroxil (Aristada): Aripiprazole lauroxil is a prodrug of aripiprazole and is probably converted by enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole, which is then hydrolyzed to aripiprazole.119

Elimination Route

Following oral administration, approximately 18% and <1% excreted unchanged in feces and urine, respectively; IM administration is not expected to alter metabolic pathways.1

Half-life

Oral aripiprazole: 75 hours.1

Dehydro-aripiprazole: 94 hours.1

Extended-release aripiprazole (Abilify Maintena): Following multiple, once-monthly IM administration, about 30 days for the 300-mg dosage and 47 days for the 400-mg dosage.118

Extended-release aripiprazole lauroxil (Aristada) 441, 662, and 882 mg administered IM every 4 weeks: About 29–35 days.119

Special Populations

Pediatric patients 10–17 years of age: Pharmacokinetics similar to those in adults after correcting for body weight differences.1

Actions

  • Exact mechanism of action in schizophrenia, bipolar disorder, major depressive disorder, irritability associated with autistic disorder, Tourette's syndrome, and agitation associated with schizophrenia or bipolar mania has not been fully elucidated; may involve the drug’s activity at dopamine D2 and serotonin type 1 (5-HT1A) and type 2 (5-HT2A) receptors.1 2 3 4 5 6 7

  • Demonstrates partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors.1 2 3 4 5 6 7 89 The major active metabolite, dehydro-aripiprazole, exhibits affinity for D2 receptors similar to that of the parent compound.1

  • Antagonism at other receptors (e.g., α1-adrenergic receptors, histamine H1 receptors) may contribute to other therapeutic and adverse effects (e.g., orthostatic hypotension, somnolence).1 89

Precautions While Using Abilify

It is very important that your doctor check your progress at regular visits to allow for changes in your dose and to make sure this medicine is working properly. Blood and urine tests may be needed to check for any unwanted effects.

For some patients, this medicine can increase thoughts of suicide. Tell your doctor right away if you start to feel more depressed and have thoughts about hurting yourself. Report any unusual thoughts or behaviors that trouble you, especially if they are new or are getting worse quickly. Make sure the doctor knows if you have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. Also tell the doctor if you have sudden or strong feelings, such as feeling nervous, angry, restless, violent, or scared. Let the doctor know if you or anyone in your family has bipolar disorder (manic-depressive illness) or has tried to commit suicide.

This medicine may add to the effects of alcohol and other central nervous system (CNS) depressants (medicines that make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicines for hay fever, other allergies, or colds, sedatives, tranquilizers, or sleeping medicines, prescription pain medicines or narcotics, medicines for seizures or barbiturates, muscle relaxants, or anesthetics, including some dental anesthetics. Check with your doctor before taking any CNS depressants while you are taking this medicine.

Aripiprazole may cause drowsiness, trouble with thinking, or trouble with controlling movements, which may lead to falls, fractures or other injuries. Make sure you know how you react to this medicine before you drive, use machines, or do other jobs that require you to be alert, well-coordinated, or able to think well.

Check with your doctor right away if you have any of the following symptoms while using this medicine: convulsions (seizures), difficulty with breathing, a fast heartbeat, a high fever, high or low blood pressure, increased sweating, loss of bladder control, severe muscle stiffness, unusually pale skin, or tiredness. These could be symptoms of a serious condition called neuroleptic malignant syndrome (NMS).

This medicine may cause tardive dyskinesia (a movement disorder) especially in elderly women. Check with your doctor right away if you have any of the following symptoms while taking this medicine: lip smacking or puckering, puffing of the cheeks, rapid or worm-like movements of the tongue, uncontrolled chewing movements, or uncontrolled movements of the arms and legs.

Some people who have used this medicine had unusual changes in their behavior. Talk with your doctor right away if you start having unusual urges, such as gambling urges, binge or compulsive eating, compulsive shopping, or sexual urges while using this medicine.

Dizziness, lightheadedness, or fainting may occur, especially when you get up from a lying or sitting position. Getting up slowly may help. If this problem continues or gets worse, check with your doctor.

This medicine may make it more difficult for your body to cool down. It might reduce how much you sweat. Your body could get too hot if you do not sweat enough. If your body gets too hot, you might feel dizzy, weak, tired, or confused. You might have an upset stomach or vomit. Call your doctor if drinking cool water and moving away from the heat does not cool you down.

This medicine may increase the amount of sugar in your blood. Also, the oral liquid form contains sugar. Check with your doctor right away if you have increased thirst or increased urination. If you have diabetes, you may notice a change in the results of your urine or blood sugar tests. If you have any questions, check with your doctor.

This medicine can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.

This medicine may increase your weight. Your doctor may need to check your weight on a regular basis while you are using this medicine.

Do not change the dose or stop taking this medicine without checking first with your doctor.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines) and herbal or vitamin supplements.

Abilify Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common
  • Difficulty with speaking
  • drooling
  • loss of balance control
  • muscle trembling, jerking, or stiffness
  • restlessness
  • shuffling walk
  • stiffness of the limbs
  • twisting movements of the body
  • uncontrolled movements, especially of the face, neck, and back
Less common
  • Blurred vision
  • dizziness
  • headache
  • inability to move the eyes
  • increased blinking or spasms of the eyelid
  • nervousness
  • pounding in the ears
  • slow or fast heartbeat
  • sticking out the tongue
  • trouble with breathing or swallowing
  • unusual facial expressions
Rare
  • Convulsions
  • fast heartbeat
  • high fever
  • high or low blood pressure
  • increased sweating
  • lip smacking or puckering
  • loss of bladder control
  • muscle spasm or jerking of all extremities
  • puffing of the cheeks
  • rapid or worm-like movements of the tongue
  • severe muscle stiffness
  • sudden loss of consciousness
  • tiredness
  • uncontrolled chewing movements
  • uncontrolled movements of the arms and legs
  • unusually pale skin
Incidence not known
  • Hives or welts, itching, or skin rash
  • itching, puffiness, or swelling of the eyelids or around the eyes, face, lips, or tongue
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
  • redness of the skin
  • tightness in the chest
  • unusual tiredness or weakness

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose
  • Bigger, dilated, or enlarged pupils (black part of the eye)
  • diarrhea
  • fast, pounding, or irregular heartbeat or pulse
  • increased sensitivity of the eyes to light
  • lack or loss of strength
  • nausea
  • sleepiness or unusual drowsiness
  • vomiting

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Acid or sour stomach
  • anxiety
  • belching
  • blurred vision
  • difficulty having a bowel movement (stool)
  • dry mouth
  • fear
  • fever
  • headache
  • heartburn
  • hyperventilation
  • inability to sit still
  • indigestion
  • irritability
  • lightheadedness
  • need to keep moving
  • nervousness
  • rash
  • runny nose
  • shaking
  • sore throat
  • stomach discomfort, upset, or pain
  • trouble sleeping
  • weight gain
Less common
  • Accidental injury
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • body aches or pain
  • congestion
  • coughing
  • difficulty with moving
  • dryness or soreness of the throat
  • hoarseness
  • increased appetite
  • increased salivation
  • joint pain
  • muscle aching or cramping
  • muscle pains or stiffness
  • rapid weight gain
  • sneezing
  • stuffy nose
  • swollen joints
  • tender, swollen glands in the neck
  • tingling of the hands or feet
  • tremor
  • unusual weight gain or loss
  • voice changes

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Dosage Forms and Strengths

Abilify® (aripiprazole) Tablets are available as described in Table 3.

Table 3: Abilify Tablet Presentations

Tablet

Strength

Tablet

Color/Shape

Tablet

Markings

2 mg

green

modified rectangle

“A-006”

and “2”

5 mg

blue

modified rectangle

“A-007”

and “5”

10 mg

pink

modified rectangle

“A-008”

and “10”

15 mg

yellow

round

“A-009”

and “15”

20 mg

white

round

“A-010”

and “20”

30 mg

pink

round

“A-011”

and “30”

Abilify DISCMELT® (aripiprazole) Orally Disintegrating Tablets are available as described in Table 4.

Table 4: Abilify DISCMELT Orally Disintegrating Tablet Presentations

Tablet

Strength

Tablet

Color/Shape

Tablet

Markings

10 mg

pink (with scattered specks)

round

“A” and “640”

“10”

15 mg

yellow (with scattered specks)

round

“A” and “641”

“15”

Abilify® (aripiprazole) Oral Solution (1 mg/mL) is a clear, colorless to light-yellow solution, supplied in child-resistant bottles along with a calibrated oral dosing cup.

Abilify® (aripiprazole) Injection for Intramuscular Use is a clear, colorless solution available as a ready-to-use, 9.75 mg/1.3 mL (7.5 mg/mL) solution in clear, Type 1 glass vials.

Adverse Reactions

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)] • Cerebrovascular Adverse Events, Including Stroke [see WARNINGS AND PRECAUTIONS (5.2)] • Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.3)] • Neuroleptic Malignant Syndrome (NMS) [see WARNINGS AND PRECAUTIONS (5.4)] • Tardive Dyskinesia [see WARNINGS AND PRECAUTIONS (5.5)] • Metabolic Changes [see WARNINGS AND PRECAUTIONS (5.6)] • Pathological Gambling and Other Compulsive Behaviors [see WARNINGS AND PRECAUTIONS (5.7)] • Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS (5.8)] • Falls [see WARNINGS AND PRECAUTIONS (5.9)] • Leukopenia, Neutropenia, and Agranulocytosis [see WARNINGS AND PRECAUTIONS (5.10)] • Seizures/Convulsions [see WARNINGS AND PRECAUTIONS (5.11)] • Potential for Cognitive and Motor Impairment [see WARNINGS AND PRECAUTIONS (5.12)] • Body Temperature Regulation [see WARNINGS AND PRECAUTIONS (5.13)] • Suicide [see WARNINGS AND PRECAUTIONS (5.14)] • Dysphagia [see WARNINGS AND PRECAUTIONS (5.15)]

The most common adverse reactions in adult patients in clinical trials (≥10%) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness.

The most common adverse reactions in the pediatric clinical trials (≥10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased.

Abilify has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in schizophrenia, bipolar disorder, major depressive disorder, Dementia of the Alzheimer’s type, Parkinson’s disease, and alcoholism, and who had approximately 7619 patient-years of exposure to oral Abilify and 749 patients with exposure to Abilify injection. A total of 3390 patients were treated with oral Abilify for at least 180 days and 1933 patients treated with oral Abilify had at least 1 year of exposure.

Abilify has been evaluated for safety in 1,686 patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar mania, autistic disorder, or Tourette’s disorder and who had approximately 1,342 patient-years of exposure to oral Abilify. A total of 959 pediatric patients were treated with oral Abilify for at least 180 days and 556 pediatric patients treated with oral Abilify had at least 1 year of exposure.

The conditions and duration of treatment with Abilify (monotherapy and 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.

Clinical Trials Experience

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 oral Abilify was administered in doses ranging from 2 to 30 mg/day.

Commonly Observed Adverse Reactions

The only commonly observed adverse reaction associated with the use of Abilify in patients with schizophrenia (incidence of 5% or greater and Abilify incidence at least twice that for placebo) was akathisia (Abilify 8%; placebo 4%).

Adult Patients with Bipolar Mania

Monotherapy

The following findings are based on a pool of 3-week, placebo-controlled, bipolar mania trials in which oral Abilify was administered at doses of 15 or 30 mg/day.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of Abilify in patients with bipolar mania (incidence of 5% or greater and Abilify incidence at least twice that for placebo) are shown in Table 16.

Table 16: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Adult Patients with Bipolar Mania Treated with Oral Abilify Monotherapy

Percentage of Patients Reporting Reaction

Abilify

Placebo

Preferred Term

(n=917)

(n=753)

Akathisia

13

4

Sedation

8

3

Restlessness

6

3

Tremor

6

3

Extrapyramidal Disorder

5

2

Less Common Adverse Reactions in Adults

Table 17 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania), including only those reactions that occurred in 2% or more of patients treated with Abilify (doses ≥2 mg/day) and for which the incidence in patients treated with Abilify was greater than the incidence in patients treated with placebo in the combined dataset.

Table 17: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral Abilify

Percentage of Patients Reporting Reactiona

System Organ Class

Abilify

Placebo

Preferred Term

(n=1843)

(n=1166)

Eye Disorders

Blurred Vision

3

1

Gastrointestinal Disorders

Nausea

15

11

Constipation

11

7

Vomiting

11

6

Dyspepsia

9

7

Dry Mouth

5

4

Toothache

4

3

Abdominal Discomfort

3

2

Stomach Discomfort

3

2

General Disorders and Administration Site Conditions

Fatigue

6

4

Pain

3

2

Musculoskeletal and Connective Tissue Disorders

Musculoskeletal Stiffness

4

3

Pain in Extremity

4

2

Myalgia

2

1

Muscle Spasms

2

1

Nervous System Disorders

Headache

27

23

Dizziness

10

7

Akathisia

10

4

Sedation

7

4

Extrapyramidal Disorder

5

3

Tremor

5

3

Somnolence

5

3

Psychiatric Disorders

Agitation

19

17

Insomnia

18

13

Anxiety

17

13

Restlessness

5

3

Respiratory, Thoracic, and Mediastinal Disorders

Pharyngolaryngeal Pain

3

2

Cough

3

2

a Adverse reactions reported by at least 2% of patients treated with oral Abilify, except adverse reactions which had an incidence equal to or less than placebo.

An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race.

Adult Patients with Adjunctive Therapy with Bipolar Mania

The following findings are based on a placebo-controlled trial of adult patients with bipolar disorder in which Abilify was administered at doses of 15 or 30 mg/day as adjunctive therapy with lithium or valproate.

Adverse Reactions Associated with Discontinuation of Treatment

In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 12% for patients treated with adjunctive Abilify compared to 6% for patients treated with adjunctive placebo. The most common adverse drug reactions associated with discontinuation in the adjunctive Abilify-treated compared to placebo-treated patients were akathisia (5% and 1%, respectively) and tremor (2% and 1%, respectively).

Commonly Observed Adverse Reactions

The commonly observed adverse reactions associated with adjunctive Abilify and lithium or valproate in patients with bipolar mania (incidence of 5% or greater and incidence at least twice that for adjunctive placebo) were: akathisia, insomnia, and extrapyramidal disorder.

Less Common Adverse Reactions in Adult Patients with Adjunctive Therapy in Bipolar Mania

Table 18 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute treatment (up to 6 weeks), including only those reactions that occurred in 2% or more of patients treated with adjunctive Abilify (doses of 15 or 30 mg/day) and lithium or valproate and for which the incidence in patients treated with this combination was greater than the incidence in patients treated with placebo plus lithium or valproate.

Table 18: Adverse Reactions in a Short-Term, Placebo-Controlled Trial of Adjunctive Therapy in Patients with Bipolar Disorder

Percentage of Patients Reporting Reactiona

System Organ Class

Abilify +

Li or Val*

Placebo +

Li or Val*

Preferred Term

(n=253)

(n=130)

Gastrointestinal Disorders

Nausea

8

5

Vomiting

4

0

Salivary Hypersecretion

4

2

Dry Mouth

2

1

Infections and Infestations

Nasopharyngitis

3

2

Investigations

Weight Increased

2

1

Nervous System Disorders

Akathisia

19

5

Tremor

9

6

Extrapyramidal Disorder

5

1

Dizziness

4

1

Sedation

4

2

Psychiatric Disorders

Insomnia

8

4

Anxiety

4

1

Restlessness

2

1

  aAdverse reactions reported by at least 2% of patients treated with oral Abilify, except adverse reactions which had an incidence equal to or less than placebo.   * Lithium or Valproate
Pediatric Patients (13 to 17 years) with Schizophrenia

The following findings are based on one 6-week, placebo-controlled trial in which oral Abilify was administered in doses ranging from 2 to 30 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between Abilify-treated and placebo-treated pediatric patients (13 to 17 years) was 5% and 2%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of Abilify in adolescent patients with schizophrenia (incidence of 5% or greater and Abilify incidence at least twice that for placebo) were extrapyramidal disorder, somnolence, and tremor.

Pediatric Patients (10 to 17 years) with Bipolar Mania

The following findings are based on one 4-week, placebo-controlled trial in which oral Abilify was administered in doses of 10 or 30 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between Abilify-treated and placebo-treated pediatric patients (10 to 17 years) was 7% and 2%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of Abilify in pediatric patients with bipolar mania (incidence of 5% or greater and Abilify incidence at least twice that for placebo) are shown in Table 19.

Table 19: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (10 to 17 years) with Bipolar Mania Treated with Oral Abilify

Percentage of Patients Reporting Reaction

Abilify

Placebo

Preferred Term

(n=197)

(n=97)

Somnolence

23

3

Extrapyramidal Disorder

20

3

Fatigue

11

4

Nausea

11

4

Akathisia

10

2

Blurred Vision

8

0

Salivary Hypersecretion

6

0

Dizziness

5

1

Pediatric Patients (6 to 17 years) with Autistic Disorder

The following findings are based on two 8-week, placebo-controlled trials in which oral Abilify was administered in doses of 2 to 15 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between Abilify-treated and placebo-treated pediatric patients (6 to 17 years) was 10% and 8%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of Abilify in pediatric patients with autistic disorder (incidence of 5% or greater and Abilify incidence at least twice that for placebo) are shown in Table 20.

Table 20: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 17 years) with Autistic Disorder Treated with Oral Abilify

Percentage of Patients Reporting Reaction

Abilify

Placebo

Preferred Term

(n=212)

(n=101)

Sedation

21

4

Fatigue

17

2

Vomiting

14

7

Somnolence

10

4

Tremor

10

0

Pyrexia

9

1

Drooling

9

0

Decreased Appetite

7

2

Salivary Hypersecretion

6

1

Extrapyramidal Disorder

6

0

Lethargy

5

0

Pediatric Patients (6 to 18 years) with Tourette's Disorder

The following findings are based on one 8-week and one 10-week, placebo-controlled trials in which oral Abilify was administered in doses of 2 to 20 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between Abilify-treated and placebo-treated pediatric patients (6 to 18 years) was 7% and 1%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of Abilify in pediatric patients with Tourette's disorder (incidence of 5% or greater and Abilify incidence at least twice that for placebo) are shown in Table 21.

Table 21: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) with Tourette's Disorder Treated with Oral Abilify

Percentage of Patients Reporting Reaction

Abilify

Placebo

Preferred Term

(n=121)

(n=72)

Sedation

13

6

Somnolence

13

1

Nausea

11

4

Headache

10

3

Nasopharyngitis

9

0

Fatigue

8

0

Increased Appetite

7

1

Less Common Adverse Reactions in Pediatric Patients (6 to 18 years) with Schizophrenia, Bipolar Mania, Autistic Disorder, or Tourette’s Disorder

Table 22 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia, up to 4 weeks in bipolar mania, up to 8 weeks in autistic disorder, and up to 10 weeks in Tourette’s disorder), including only those reactions that occurred in 2% or more of pediatric patients treated with Abilify (doses ≥2 mg/day) and for which the incidence in patients treated with Abilify was greater than the incidence in patients treated with placebo.

Table 22: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) Treated with Oral Abilify

Percentage of Patients Reporting Reactiona

System Organ Class

Abilify

Placebo

Preferred Term

(n=732)

(n=370)

Eye Disorders

Blurred Vision

3

0

Gastrointestinal Disorders

Abdominal Discomfort

2

1

Vomiting

8

7

Nausea

8

4

Diarrhea

4

3

Salivary Hypersecretion

4

1

Abdominal Pain Upper

3

2

Constipation

2

2

General Disorders and Administration Site Conditions

Fatigue

10

2

Pyrexia

4

1

Irritability

2

1

Asthenia

2

1

Infections and Infestations

Nasopharyngitis

6

3

Investigations

Weight Increased

3

1

Metabolism and Nutrition Disorders

Increased Appetite

7

3

Decreased Appetite

5

4

Musculoskeletal and Connective Tissue Disorders

Musculoskeletal Stiffness

2

1

Muscle Rigidity

2

1

Nervous System Disorders

Somnolence

16

4

Headache

12

10

Sedation

9

2

Tremor

9

1

Extrapyramidal Disorder

6

1

Akathisia

6

4

Drooling

3

0

Lethargy

3

0

Dizziness

3

2

Dystonia

2

1

Respiratory, Thoracic, and Mediastinal Disorders

Epistaxis

2

1

Skin and Subcutaneous Tissue Disorders

Rash

2

1

  aAdverse reactions reported by at least 2% of pediatric patients treated with oral Abilify, except
adverse reactions which had an incidence equal to or less than placebo.
Adult Patients Receiving Abilify as Adjunctive Treatment of Major Depressive Disorder

The following findings are based on a pool of two placebo-controlled trials of patients with major depressive disorder in which Abilify was administered at doses of 2 mg to 20 mg as adjunctive treatment to continued antidepressant therapy.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions was 6% for adjunctive Abilify-treated patients and 2% for adjunctive placebo-treated patients.

Commonly Observed Adverse Reactions

The commonly observed adverse reactions associated with the use of adjunctive Abilify in patients with major depressive disorder (incidence of 5% or greater and Abilify incidence at least twice that for placebo) were: akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision.

Less Common Adverse Reactions in Adult Patients with Major Depressive Disorder

Table 23 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks), including only those adverse reactions that occurred in 2% or more of patients treated with adjunctive Abilify (doses ≥2 mg/day) and for which the incidence in patients treated with adjunctive Abilify was greater than the incidence in patients treated with adjunctive placebo in the combined dataset.

Table 23: Adverse Reactions in Short-Term, Placebo-Controlled Adjunctive Trials in Patients with Major Depressive Disorder

Percentage of Patients Reporting Reactiona

System Organ Class

Abilify + ADT*

Placebo + ADT*

Preferred Term

(n=371)

(n=366)

Eye Disorders

Blurred Vision

6

1

Gastrointestinal Disorders

Constipation

5

2

General Disorders and Administration Site Conditions

Fatigue

8

4

Feeling Jittery

3

1

Infections and Infestations

Upper Respiratory Tract Infection

6

4

Investigations

Weight Increased

3

2

Metabolism and Nutrition Disorders

Increased Appetite

3

2

Musculoskeletal and Connective Tissue Disorders

Arthralgia

4

3

Myalgia

3

1

Nervous System Disorders

Akathisia

25

4

Somnolence

6

4

Tremor

5

4

Sedation

4

2

Dizziness

4

2

Disturbance in Attention

3

1

Extrapyramidal Disorder

2

0

Psychiatric Disorders

Restlessness

12

2

Insomnia

8

2

  aAdverse reactions reported by at least 2% of patients treated with adjunctive Abilify, except adverse reactions which had an incidence equal to or less than placebo.   * Antidepressant Therapy
Patients with Agitation Associated with Schizophrenia or Bipolar Mania (Intramuscular Injection)

The following findings are based on a pool of three placebo-controlled trials of patients with agitation associated with schizophrenia or bipolar mania in which Abilify injection was administered at doses of 5.25 mg to 15 mg.

Commonly Observed Adverse Reactions

There was one commonly observed adverse reaction (nausea) associated with the use of Abilify injection in patients with agitation associated with schizophrenia and bipolar mania (incidence of 5% or greater and Abilify incidence at least twice that for placebo).

Less Common Adverse Reactions in Patients with Agitation Associated with Schizophrenia or Bipolar Mania

Table 24 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (24-hour), including only those adverse reactions that occurred in 2% or more of patients treated with Abilify injection (doses ≥5.25 mg/day) and for which the incidence in patients treated with Abilify injection was greater than the incidence in patients treated with placebo in the combined dataset.

Table 24: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Patients Treated with Abilify Injection

Percentage of Patients Reporting Reactiona

System Organ Class

Abilify

Placebo

Preferred Term

(n=501)

(n=220)

Cardiac Disorders

Tachycardia

2

<1

Gastrointestinal Disorders

Nausea

9

3

Vomiting

3

1

General Disorders and Administration Site Conditions

Fatigue

2

1

Nervous System Disorders

Headache

12

7

Dizziness

8

5

Somnolence

7

4

Sedation

3

2

Akathisia

2

0

  aAdverse reactions reported by at least 2% of patients treated with Abilify injection, except adverse reactions which had an incidence equal to or less than placebo.
Dose-Related Adverse Reactions

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 doses (2, 5, 10, 15, 20, and 30 mg/day) of oral Abilify to placebo. This analysis, stratified by study, indicated that the only adverse reaction to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [including sedation]; (incidences were placebo, 7.1%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%).

In the study of pediatric patients (13 to 17 years of age) with schizophrenia, three common adverse reactions appeared to have a possible dose response relationship: extrapyramidal disorder (incidences were placebo, 5.0%; 10 mg, 13.0%; 30 mg, 21.6%); somnolence (incidences were placebo, 6.0%; 10 mg, 11.0%; 30 mg, 21.6%); and tremor (incidences were placebo, 2.0%; 10 mg, 2.0%; 30 mg, 11.8%).

Bipolar Mania

In the study of pediatric patients (10 to 17 years of age) with bipolar mania, four common adverse reactions had a possible dose response relationship at 4 weeks; extrapyramidal disorder (incidences were placebo, 3.1%; 10 mg, 12.2%; 30 mg, 27.3%); somnolence (incidences were placebo, 3.1%; 10 mg, 19.4%; 30 mg, 26.3%); akathisia (incidences were placebo, 2.1%; 10 mg, 8.2%; 30 mg, 11.1%); and salivary hypersecretion (incidences were placebo, 0%; 10 mg, 3.1%; 30 mg, 8.1%).

Autistic Disorder

In a study of pediatric patients (6 to 17 years of age) with autistic disorder, one common adverse reaction had a possible dose response relationship: fatigue (incidences were placebo, 0%; 5 mg, 3.8%; 10 mg, 22.0%; 15 mg, 18.5%).

Tourette’s Disorder

In a study of pediatric patients (7 to 17 years of age) with Tourette’s disorder, no common adverse reaction(s) had a dose response relationship.

Extrapyramidal Symptoms

Schizophrenia

In short-term, placebo-controlled trials in schizophrenia in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for Abilify-treated patients was 13% vs. 12% for placebo; and the incidence of akathisia-related events for Abilify-treated patients was 8% vs. 4% for placebo. In the short-term, placebo-controlled trial of schizophrenia in pediatric patients (13 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for Abilify-treated patients was 25% vs. 7% for placebo; and the incidence of akathisia-related events for Abilify-treated patients was 9% vs. 6% for placebo.

Objectively collected data from those trials was collected on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias). In the adult schizophrenia trials, the objectively collected data did not show a difference between Abilify and placebo, with the exception of the Barnes Akathisia Scale (Abilify, 0.08; placebo, –0.05). In the pediatric (13 to 17 years) schizophrenia trial, the objectively collected data did not show a difference between Abilify and placebo, with the exception of the Simpson Angus Rating Scale (Abilify, 0.24; placebo, –0.29).

Similarly, in a long-term (26-week), placebo-controlled trial of schizophrenia in adults, objectively collected data on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias) did not show a difference between Abilify and placebo.

Bipolar Mania

In the short-term, placebo-controlled trials in bipolar mania in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for monotherapy Abilify-treated patients was 16% vs. 8% for placebo and the incidence of akathisia-related events for monotherapy Abilify-treated patients was 13% vs. 4% for placebo. In the 6-week, placebo-controlled trial in bipolar mania for adjunctive therapy with lithium or valproate, the incidence of reported EPS-related events, excluding events related to akathisia for adjunctive Abilify-treated patients was 15% vs. 8% for adjunctive placebo and the incidence of akathisia-related events for adjunctive Abilify-treated patients was 19% vs. 5% for adjunctive placebo. In the short-term, placebo-controlled trial in bipolar mania in pediatric (10 to 17 years) patients, the incidence of reported EPS-related events, excluding events related to akathisia, for Abilify-treated patients was 26% vs. 5% for placebo and the incidence of akathisia-related events for Abilify-treated patients was 10% vs. 2% for placebo.

In the adult bipolar mania trials with monotherapy Abilify, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between Abilify and placebo (Abilify, 0.50; placebo, –0.01 and Abilify, 0.21; placebo, –0.05). Changes in the Assessments of Involuntary Movement Scales were similar for the Abilify and placebo groups. In the bipolar mania trials with Abilify as adjunctive therapy with either lithium or valproate, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive Abilify and adjunctive placebo (Abilify, 0.73; placebo, 0.07 and Abilify, 0.30; placebo, 0.11). Changes in the Assessments of Involuntary Movement Scales were similar for adjunctive Abilify and adjunctive placebo. In the pediatric (10 to 17 years), short-term, bipolar mania trial, the Simpson Angus Rating Scale showed a significant difference between Abilify and placebo (Abilify, 0.90; placebo, −0.05). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the Abilify and placebo groups.

Major Depressive Disorder

In the short-term, placebo-controlled trials in major depressive disorder, the incidence of reported EPS-related events, excluding events related to akathisia, for adjunctive Abilify-treated patients was 8% vs. 5% for adjunctive placebo-treated patients; and the incidence of akathisia-related events for adjunctive Abilify-treated patients was 25% vs. 4% for adjunctive placebo-treated patients.

In the major depressive disorder trials, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive Abilify and adjunctive placebo (Abilify, 0.31; placebo, 0.03 and Abilify, 0.22; placebo, 0.02). Changes in the Assessments of Involuntary Movement Scales were similar for the adjunctive Abilify and adjunctive placebo groups.

Autistic Disorder

In the short-term, placebo-controlled trials in autistic disorder in pediatric patients (6 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for Abilify-treated patients was 18% vs. 2% for placebo and the incidence of akathisia-related events for Abilify-treated patients was 3% vs. 9% for placebo.

In the pediatric (6 to 17 years) short-term autistic disorder trials, the Simpson Angus Rating Scale showed a significant difference between Abilify and placebo (Abilify, 0.1; placebo, –0.4). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the Abilify and placebo groups.

Tourette’s Disorder

In the short-term, placebo-controlled trials in Tourette’s disorder in pediatric patients (6 to 18 years), the incidence of reported EPS-related events, excluding events related to akathisia, for Abilify-treated patients was 7% vs. 6% for placebo and the incidence of akathisia-related events for Abilify-treated patients was 4% vs. 6% for placebo.

In the pediatric (6 to 18 years) short-term Tourette’s disorder trials, changes in the Simpson Angus Rating Scale, Barnes Akathisia Scale and Assessments of Involuntary Movement Scale were not clinically meaningfully different for Abilify and placebo.

Agitation Associated with Schizophrenia or Bipolar Mania

In the placebo-controlled trials in patients with agitation associated with schizophrenia or bipolar mania, the incidence of reported EPS-related events excluding events related to akathisia for Abilify-treated patients was 2% vs. 2% for placebo and the incidence of akathisia-related events for Abilify-treated patients was 2% vs. 0% for placebo. Objectively collected data on the Simpson Angus Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) for all treatment groups did not show a difference between Abilify 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.

Additional Findings Observed in Clinical Trials

Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials

The adverse reactions reported in a 26-week, double-blind trial comparing oral Abilify and placebo in 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 Abilify 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 Abilify. In addition, in a long-term (52 week), active-controlled study, the incidence of tremor was 5% (40/859) for Abilify. A similar profile was observed in a long-term monotherapy study and a long-term adjunctive study with lithium and valproate in bipolar disorder.

Other Adverse Reactions Observed During the Premarketing Evaluation of Abilify

The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.

Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients:

Adults - Oral Administration

Blood and Lymphatic System Disorders:

  rare - thrombocytopenia

Cardiac Disorders:

  infrequent – bradycardia, palpitations, rare – atrial flutter, cardio-respiratory arrest, atrioventricular block, atrial fibrillation, angina pectoris, myocardial ischemia, myocardial infarction, cardiopulmonary failure

Eye Disorders:

  infrequent – photophobia; rare - diplopia

Gastrointestinal Disorders:

  infrequent - gastroesophageal reflux disease

General Disorders and Administration Site Conditions:

  frequent - asthenia; infrequent – peripheral edema, chest pain; rare – face edema

Hepatobiliary Disorders:

  rare - hepatitis, jaundice

Immune System Disorders:

  rare - hypersensitivity

Injury, Poisoning, and Procedural Complications:

  infrequent – fall; rare – heat stroke

Investigations:

  frequent - weight decreased, infrequent - hepatic enzyme increased, blood glucose increased, blood lactate dehydrogenase increased, gamma glutamyl transferase increased; rare – blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased, electrocardiogram QT prolonged, glycosylated hemoglobin increased

Metabolism and Nutrition Disorders:

  frequent – anorexia; rare - hypokalemia, hyponatremia, hypoglycemia

Musculoskeletal and Connective Tissue Disorders:

  infrequent - muscular weakness, muscle tightness; rare – rhabdomyolysis, mobility decreased

Nervous System Disorders:

  infrequent - parkinsonism, memory impairment, cogwheel rigidity, hypokinesia, bradykinesia; rare – akinesia, myoclonus, coordination abnormal, speech disorder, Grand Mal convulsion; <1/10,000 patients - choreoathetosis

Psychiatric Disorders:

  infrequent – aggression, loss of libido, delirium; rare – libido increased, anorgasmia, tic, homicidal ideation, catatonia, sleep walking

Renal and Urinary Disorders:

  rare - urinary retention, nocturia

Reproductive System and Breast Disorders:

  infrequent - erectile dysfunction; rare – gynaecomastia, menstruation irregular, amenorrhea, breast pain, priapism

Respiratory, Thoracic, and Mediastinal Disorders:

  infrequent - nasal congestion, dyspnea

Skin and Subcutaneous Tissue Disorders:

  infrequent - rash, hyperhidrosis, pruritus, photosensitivity reaction, alopecia; rare - urticaria

Vascular Disorders:

  infrequent – hypotension, hypertension Pediatric Patients - Oral Administration

Most adverse events observed in the pooled database of 1,686 pediatric patients, aged 6 to 18 years, were also observed in the adult population. Additional adverse reactions observed in the pediatric population are listed below.

Eye Disorders

  infrequent - oculogyric crisis

Gastrointestinal Disorders:

  infrequent -tongue dry, tongue spasm

Investigations:

  frequent - blood insulin increased

Nervous System Disorders:

  infrequent - sleep talking

Renal and Urinary Disorders

  frequent – enuresis

Skin and Subcutaneous Tissue Disorders:

  infrequent - hirsutism Adults - Intramuscular Injection

Most adverse reactions observed in the pooled database of 749 adult patients treated with Abilify injection, were also observed in the adult population treated with oral Abilify. Additional adverse reactions observed in the Abilify injection population are listed below.

General Disorders and Administration Site Conditions:

  ≥1/100 patients - injection site reaction; ≥1/1000 patients and <1/100 patients - venipuncture site bruise

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Abilify. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), pathological gambling, hiccups and blood glucose fluctuation.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lifetime carcinogenicity studies were conducted in ICR mice, Sprague-Dawley (SD) rats, 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 times and 0.3 to 3 times the maximum recommended human dose [MRHD] based on mg/m2, 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/m2). Aripiprazole did not induce tumors in male mice or male 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/m2). 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 3 times the MRHD based on mg/m2); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (14 times human exposure at MRHD based on AUC and 19 times the MRHD based on mg/m2).

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. 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-week 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.

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 and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation. The metabolite, 2,3-DCPP, produced increases in numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans.

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 maximum recommended human dose [MRHD] on a mg/m2 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/day and decreased fetal weight was seen at 20 mg/kg/day.

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/m2 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.

Animal Toxicology and/or Pharmacology

Aripiprazole produced retinal degeneration in albino 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/day doses are 13 and 19 times the maximum recommended human dose (MRHD) based on mg/m2 and 7 to 14 times human exposure at MRHD based on AUC. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.

Clinical Studies

Efficacy of the oral formulations of Abilify (aripiprazole) was established in the following adequate and well-controlled trials:

• Four short-term trials and one maintenance trial in adult patients and one short-term trial in adolescents (ages 13-17) with schizophrenia [see CLINICAL STUDIES (14.1)] • Four short-term monotherapy trials and one 6-week adjunctive trial in adult patients and one short-term monotherapy trial in pediatric patients (ages 10-17) with manic or mixed episodes [see CLINICAL STUDIES (14.2)] • One maintenance monotherapy trial and in one maintenance adjunctive trial in adult patients with bipolar I disorder [see CLINICAL STUDIES (14.2)] • Two short-term trials in adult patients with MDD who had an inadequate response to antidepressant therapy during the current episode [see CLINICAL STUDIES (14.3)] • Two short-term trials in pediatric patients (ages 6-17 years) for the treatment of irritability associated with autistic disorder [see CLINICAL STUDIES (14.4)] • Two short-term trials in pediatric patients (ages 6-18 years) with Tourette’s disorder [see CLINICAL STUDIES (14.5)]

Efficacy of the injectable formulation of Abilify (aripiprazole) was established in the following adequate and well-controlled trials:

• Three 24-hour trials in agitated adult patients with schizophrenia or manic/mixed episodes of bipolar I disorder [see CLINICAL STUDIES (14.6)]

Schizophrenia

Adults

The efficacy of Abilify in the treatment of schizophrenia was evaluated in five short-term (4-week 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 Abilify 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 Abilify and the active comparators.

In the four positive trials for Abilify, four primary measures were used for assessing psychiatric signs and symptoms. Efficacy was evaluated using the total score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210. 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 Abilify (15 or 30 mg/day) to placebo, both doses of Abilify were superior to placebo in the PANSS total score (Study 1 in Table 26), 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 Abilify (20 or 30 mg/day) to placebo, both doses of Abilify were superior to placebo in the PANSS total score (Study 2 in Table 26), PANSS positive subscale, PANSS negative subscale, and CGI-severity score.   In a 6-week trial (n=420) comparing three fixed doses of Abilify (10, 15, or 20 mg/day) to placebo, all three doses of Abilify were superior to placebo in the PANSS total score (Study 3 in Table 26), PANSS positive subscale, and the PANSS negative subscale.   In a 6-week trial (n=367) comparing three fixed doses of Abilify (2, 5, or 10 mg/day) to placebo, the 10 mg dose of Abilify was superior to placebo in the PANSS total score (Study 4 in Table 26), the primary outcome measure of the study. The 2 and 5 mg doses did not demonstrate superiority to placebo on the primary outcome measure.

Thus, the efficacy of 10, 15, 20, 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 reveal 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 Abilify 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 Abilify 15 mg/day experienced a significantly longer time to relapse over the subsequent 26 weeks compared to those receiving placebo (Study 5 in Figure 6).

Pediatric Patients

The efficacy of Abilify (aripiprazole) in the treatment of schizophrenia in pediatric patients (13 to 17 years of age) was evaluated in one 6-week, placebo-controlled trial of outpatients who met DSM-IV criteria for schizophrenia and had a PANSS score ≥70 at baseline. In this trial (n=302) comparing two fixed doses of Abilify (10 or 30 mg/day) to placebo, Abilify 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 Abilify were superior to placebo in the PANSS total score (Study 6 in Table 26), the primary outcome measure of the study. The 30 mg/day dosage was not shown to be more efficacious than the 10 mg/day dose. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.

Table 26: Schizophrenia Studies

Study Number

Treatment Group

Primary Efficacy Measure: PANSS

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

Study 1

Abilify (15 mg/day)*

98.5 (17.2)

-15.5 (2.40)

-12.6 (-18.9, -6.2)

Abilify (30 mg/day)*

99.0 (19.2)

-11.4 (2.39)

-8.5 (-14.8, -2.1)

Placebo

100.2 (16.5)

-2.9 (2.36)

--

Study 2

Abilify (20 mg/day)*

92.6 (19.5)

-14.5 (2.23)

-9.6 (-15.4, -3.8)

Abilify (30 mg/day)*

94.2 (18.5)

-13.9 (2.24)

-9.0 (-14.8, -3.1)

Placebo

94.3 (18.5)

-5.0 (2.17)

--

Study 3

Abilify (10 mg/day)*

92.7 (19.5)

-15.0 (2.38)

-12.7 (-19.00, -6.41)

Abilify (15 mg/day)*

93.2 (21.6)

-11.7 (2.38)

-9.4 (-15.71, -3.08)

Abilify (20 mg/day)*

92.5 (20.9)

-14.4 (2.45)

-12.1 (-18.53, -5.68)

Placebo

92.3 (21.8)

-2.3 (2.35)

--

Study 4

Abilify (2 mg/day)

90.7 (14.5)

-8.2 (1.90)

-2.9 (-8.29, 2.47)

Abilify (5 mg/day)

92.0 (12.6)

-10.6 (1.93)

-5.2 (-10.7, 0.19)

Abilify (10 mg/day)*

90.0 (11.9)

-11.3 (1.88)

-5.9 (-11.3, -0.58)

Placebo

90.8 (13.3)

-5.3 (1.97)

--

Study 6 (Pediatric, 13-17 years)

Abilify (10 mg/day)*

93.6 (15.7)

-26.7 (1.91)

-5.5 (-10.7, -0.21)

Abilify (30 mg/day)*

94.0 (16.1)

-28.6 (1.92)

-7.4 (-12.7, -2.13)

Placebo

94.6 (15.6)

-21.2 (1.93)

--

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

a Difference (drug minus placebo) in least-squares mean change from baseline.

* Doses statistically significantly superior to placebo.

Figure 6: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Schizophrenia Study 5)

Bipolar Disorder

Acute Treatment of Manic and Mixed Episodes

Adults

Monotherapy

The efficacy of Abilify as monotherapy in the acute treatment of manic episodes was established in four 3-week, placebo-controlled trials in hospitalized patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These studies included patients with or without psychotic features and two of the studies also included patients with or without a rapid-cycling course.

The primary instrument used for assessing manic symptoms was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score). A key secondary instrument included the Clinical Global Impression-Bipolar (CGI-BP) Scale.

In the four positive, 3-week, placebo-controlled trials (n=268; n=248; n=480; n=485) which evaluated Abilify in a range of 15 mg to 30 mg, once daily (with a starting dose of 30 mg/day in two studies and 15 mg/day in two studies), Abilify was superior to placebo in the reduction of Y-MRS total score (Studies 1-4 in Table 27) and CGI-BP Severity of Illness score (mania). In the two studies with a starting dose of 15 mg/day, 48% and 44% of patients were on 15 mg/day at endpoint. In the two studies with a starting dose of 30 mg/day, 86% and 85% of patients were on 30 mg/day at endpoint.

Adjunctive Therapy

The efficacy of adjunctive Abilify with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in a 6-week, placebo-controlled study (n=384) with a 2-week lead-in mood stabilizer monotherapy phase in adult patients who met DSM-IV criteria for bipolar I disorder. This study included patients with manic or mixed episodes and with or without psychotic features.

Patients were initiated on open-label lithium (0.6 to 1.0 mEq/L) or valproate (50 to 125 μg/mL) at therapeutic serum levels, and remained on stable doses for 2 weeks. At the end of 2 weeks, patients demonstrating inadequate response (Y-MRS total score ≥16 and ≤25% improvement on the Y-MRS total score) to lithium or valproate were randomized to receive either Abilify (15 mg/day or an increase to 30 mg/day as early as day 7) or placebo as adjunctive therapy with open-label lithium or valproate. In the 6-week, placebo-controlled phase, adjunctive Abilify starting at 15 mg/day with concomitant lithium or valproate (in a therapeutic range of 0.6 to 1.0 mEq/L or 50 to 125 μg/mL, respectively) was superior to lithium or valproate with adjunctive placebo in the reduction of the Y-MRS total score (Study 5 in Table 27) and CGI-BP Severity of Illness score (mania). Seventy-one percent of the patients coadministered valproate and 62% of the patients coadministered lithium were on 15 mg/day at 6-week endpoint.

Pediatric Patients

The efficacy of Abilify in the treatment of bipolar I disorder in pediatric patients (10 to 17 years of age) was evaluated in one 4-week, placebo-controlled trial (n=296) of outpatients who met DSM-IV criteria for bipolar I disorder manic or mixed episodes with or without psychotic features and had a Y-MRS score ≥20 at baseline. This double-blind, placebo-controlled trial compared two fixed doses of Abilify (10 or 30 mg/day) to placebo. The Abilify dose was started at 2 mg/day, which was titrated to 5 mg/day after 2 days, and to the target dose in 5 days in the 10 mg/day treatment arm, and in 13 days in the 30 mg/day treatment arm. Both doses of Abilify were superior to placebo in change from baseline to week 4 on the Y-MRS total score (Study 6 in Table 27).

Table 27: Bipolar Studies

Study Number

Treatment Group

Primary Efficacy Measure: Y-MRS

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

Study 1

Abilify (30 / 15 mg/day)*

29.0 (5.9)

-12.52 (1.05)

-5.33 (-7.90, -2.76)

Placebo

28.5 (4.6)

-7.19 (1.07)

--

Study 2

Abilify (30 / 15 mg/day)*

27.8 (5.7)

-8.15 (1.23)

-4.80 (-7.80, -1.80)

Placebo

29.1 (6.9)

-3.35 (1.22)

--

Study 3

Abilify (15 - 30 mg/day)*

28.5 (5.6)

-12.64 (0.84)

-3.63 (-5.75 , -1.51)

Placebo

28.9 (5.9)

9.01 (0.81)

--

Study 4

Abilify (15 -30 mg/day)*

28.0 (5.8)

-11.98 (0.80)

-2.28 (-4.44 , -0.11)

Placebo

28.3 (5.8)

-9.70 (0.83)

--

Study 5

Abilify (15 or 30 mg/day)* + Lithium/Valproate

23.2 (5.7)

-13.31 (0.50)

-2.62 (-4.29 , -0.95)

Placebo + Lithium/Valproate

23.0 (4.9)

-10.70 (0.69)

--

Study 6

(Pediatric, 10-17 years)

Abilify (10 mg/day)*

29.8 (6.5)

-14.2 (0.89)

-5.99 (-8.49, -3.50)

Abilify (30 mg/day)*

29.5 (6.3)

-16.5 (0.87)

-8.26 (-10.7, -5.77)

Placebo

30.7 (6.8)

-8.2 (0.91)

--

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

a Difference (drug minus placebo) in least-squares mean change from baseline.

* Doses statistically significantly superior to placebo.

Maintenance Treatment of Bipolar I Disorder

Monotherapy Maintenance Therapy

A maintenance trial was conducted in adult patients meeting DSM-IV criteria for bipolar I disorder with a recent manic or mixed episode who had been stabilized on open-label Abilify and who had maintained a clinical response for at least 6 weeks. The first phase of this trial was an open-label stabilization period in which inpatients and outpatients were clinically stabilized and then maintained on open-label Abilify (15 or 30 mg/day, with a starting dose of 30 mg/day) for at least 6 consecutive weeks. One hundred sixty-one outpatients were then randomized in a double-blind fashion, to either the same dose of Abilify they were on at the end of the stabilization and maintenance period or placebo and were then monitored for manic or depressive relapse. During the randomization phase, Abilify was superior to placebo on time to the number of combined affective relapses (manic plus depressive), the primary outcome measure for this study (Study 7 in Figure 7). A total of 55 mood events were observed during the double-blind treatment phase. Nineteen were from the Abilify group and 36 were from the placebo group. The number of observed manic episodes in the Abilify group (6) were fewer than that in the placebo group (19), while the number of depressive episodes in the Abilify group (9) was similar to that in the placebo group (11).

An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age and gender; however, there were insufficient numbers of patients in each of the ethnic groups to adequately assess inter-group differences.

Figure 7: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Bipolar Study 7)

Adjunctive Maintenance Therapy

An adjunctive maintenance trial was conducted in adult patients meeting DSM-IV criteria for bipolar I disorder with a recent manic or mixed episode. Patients were initiated on open-label lithium (0.6 to 1.0 mEq/L) or valproate (50 to 125 μg/mL) at therapeutic serum levels, and remained on stable doses for 2 weeks. At the end of 2 weeks, patients demonstrating inadequate response (Y-MRS total score ≥16 and ≤35% improvement on the Y-MRS total score) to lithium or valproate received Abilify with a starting dose of 15 mg/day with the option to increase to 30 mg or reduce to 10 mg as early as day 4, as adjunctive therapy with open-label lithium or valproate. Prior to randomization, patients on the combination of single-blind Abilify and lithium or valproate were required to maintain stability (Y-MRS and MADRS total scores ≤12) for 12 consecutive weeks. Three hundred thirty-seven patients were then randomized in a double-blind fashion, to either the same dose of Abilify they were on at the end of the stabilization period or placebo plus lithium or valproate and were then monitored for manic, mixed, or depressive relapse for a maximum of 52 weeks. Abilify was superior to placebo on the primary endpoint, time from randomization to relapse to any mood event (Study 8 in Figure 8). A mood event was defined as hospitalization for a manic, mixed, or depressive episode, study discontinuation due to lack of efficacy accompanied by Y-MRS score >16 and/or a MADRS >16, or an SAE of worsening disease accompanied by Y-MRS score >16 and/or a MADRS >16. A total of 68 mood events were observed during the double-blind treatment phase. Twenty-five were from the Abilify group and 43 were from the placebo group. The number of observed manic episodes in the Abilify group (7) were fewer than that in the placebo group (19), while the number of depressive episodes in the Abilify group (14) was similar to that in the placebo group (18). The Kaplan-Meier curves of the time from randomization to relapse to any mood event during the 52-week, double-blind treatment phase for Abilify and placebo groups are shown in Figure 8.

Figure 8: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse to Any Mood Event (Bipolar Study 8)

An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age and gender; however, there were insufficient numbers of patients in each of the ethnic groups to adequately assess inter-group differences.

Adjunctive Treatment of Major Depressive Disorder

Adults

The efficacy of Abilify in the adjunctive treatment of major depressive disorder (MDD) was demonstrated in two short-term (6-week), placebo-controlled trials of adult patients meeting DSM-IV criteria for MDD who had had an inadequate response to prior antidepressant therapy (1 to 3 courses) in the current episode and who had also demonstrated an inadequate response to 8 weeks of prospective antidepressant therapy (paroxetine controlled-release, venlafaxine extended-release, fluoxetine, escitalopram, or sertraline). Inadequate response for prospective treatment was defined as less than 50% improvement on the 17-item version of the Hamilton Depression Rating Scale (HAMD17), minimal HAMD17 score of 14, and a Clinical Global Impressions Improvement rating of no better than minimal improvement. Inadequate response to prior treatment was defined as less than 50% improvement as perceived by the patient after a minimum of 6 weeks of antidepressant therapy at or above the minimal effective dose.

The primary instrument used for assessing depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale used to assess the degree of depressive symptomatology. The key secondary instrument was the Sheehan Disability Scale (SDS), a 3-item self-rated instrument used to assess the impact of depression on three domains of functioning with each item scored from 0 (not at all) to 10 (extreme).

In the two trials (n=381, n=362), Abilify was superior to placebo in reducing mean MADRS total scores (Studies 1, 2 in Table 28). In one study, Abilify was also superior to placebo in reducing the mean SDS score.

In both trials, patients received Abilify adjunctive to antidepressants at a dose of 5 mg/day. Based on tolerability and efficacy, doses could be adjusted by 5 mg increments, one week apart. Allowable doses were: 2, 5, 10, 15 mg/day, and for patients who were not on potent CYP2D6 inhibitors fluoxetine and paroxetine, 20 mg/day. The mean final dose at the end point for the two trials was 10.7 and 11.4 mg/day.

An examination of population subgroups did not reveal evidence of differential response based on age, choice of prospective antidepressant, or race. With regard to gender, a smaller mean reduction on the MADRS total score was seen in males than in females.

Table 28: Adjunctive Treatment of Major Depressive Disorder Studies

Study Number

Treatment Group

Primary Efficacy Measure: MADRS

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

Study 1

Abilify (5-20 mg/day)* + Antidepressant

25.2 (6.2)

-8.49 (0.66)

-2.84 (-4.53, -1.15)

Placebo + Antidepressant

27.0 (5.5)

-5.65 (0.64)

--

Study 2

Abilify (5-20 mg/day)* + Antidepressant

26.0 (6.0)

-8.78 (0.63)

-3.01 (-4.66, -1.37)

Placebo + Antidepressant

26.0 (6.5)

-5.77 (0.67)

--

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

a Difference (drug minus placebo) in least-squares mean change from baseline.

* Doses statistically significantly superior to placebo.

Irritability Associated with Autistic Disorder

Pediatric Patients

The efficacy of Abilify (aripiprazole) in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in pediatric patients (6 to 17 years of age) who met the DSM-IV criteria for autistic disorder and demonstrated behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these problems. Over 75% of these subjects were under 13 years of age.

Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Improvement (CGI-I) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured symptoms of irritability in autistic disorder.

The results of these trials are as follows:

In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=98), aged 6 to 17 years, received daily doses of placebo or Abilify 2 to 15 mg/day. Abilify, starting at 2 mg/day with increases allowed up to 15 mg/day based on clinical response, significantly improved scores on the ABC-I subscale and on the CGI-I scale compared with placebo. The mean daily dose of Abilify at the end of 8-week treatment was 8.6 mg/day (Study 1 in Table 29).

In the other 8-week, placebo-controlled trial in children and adolescents with autistic disorder (n=218), aged 6 to 17 years, three fixed doses of Abilify (5 mg/day, 10 mg/day, or 15 mg/day) were compared to placebo. Abilify dosing started at 2 mg/day and was increased to 5 mg/day after one week. After a second week, it was increased to 10 mg/day for patients in the 10 and 15 mg dose arms, and after a third week, it was increased to 15 mg/day in the 15 mg/day treatment arm (Study 2 in Table 29). All three doses of Abilify significantly improved scores on the ABC-I subscale compared with placebo.

Table 29: Irritability Associated with Autistic Disorder Studies (Pediatric)

Study Number

Treatment Group

Primary Efficacy Measure: ABC-I

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

Study 1

Abilify (2-15 mg/day)*

29.6 (6.37)

-12.9 (1.44)

-7.9 (-11.7, -4.1)

Placebo

30.2 (6.52)

-5.0 (1.43)

--

Study 2

Abilify (5 mg/day)*

28.6 (7.56)

-12.4 (1.36)

-4.0 (-7.7, -0.4)

Abilify (10 mg/day)*

28.2 (7.36)

-13.2 (1.25)

-4.8 (-8.4, -1.3)

Abilify (15 mg/day)*

28.9 (6.41)

-14.4 (1.31)

-6.0 (-9.6, -2.3)

Placebo

28.0 (6.89)

-8.4 (1.39)

--

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

a Difference (drug minus placebo) in least-squares mean change from baseline.

* Doses statistically significantly superior to placebo.

Tourette’s Disorder

Pediatric Patients

The efficacy of Abilify (aripiprazole) in the treatment of Tourette’s disorder was established in one 8-week (7 to 17 years of age) and one 10-week (6 to 18 years of age), placebo-controlled trials in pediatric patients (6 to 18 years of age) who met the DSM-IV criteria for Tourette’s disorder and had a Total Tic score (TTS) ≥ 20 - 22 on the Yale Global Tic Severity Scale (YGTSS). The YGTSS is a fully validated scale designed to measure current tic severity. Efficacy was evaluated using two assessment scales: 1) the Total Tic score (TTS) of the YGTSS and 2) the Clinical Global Impressions Scale for Tourette’s Syndrome (CGI-TS), a clinician-determined summary measure that takes into account all available patient information. Over 65% of these patients were under 13 years of age.

The primary outcome measure in both trials was the change from baseline to endpoint in the TTS of the YGTSS. Ratings for the TTS are made along 5 different dimensions on a scale of 0 to 5 for motor and vocal tics each. Summation of these 10 scores provides a TTS (i.e., 0-50).

The results of these trials are as follows:

In the 8-week, placebo-controlled, fixed-dose trial, children and adolescents with Tourette’s disorder (n=133), aged 7 to 17 years, were randomized 1:1:1 to low dose Abilify, high dose Abilify, or placebo. The target doses for the low and high dose Abilify groups were based on weight. Patients < 50 kg in the low dose Abilify group started at 2 mg per day with a target dose of 5 mg per day after 2 days. Patients ≥ 50 kg in the low dose Abilify group, started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a target dose of 10 mg per day at day 7. Patients <50 kg in the high dose Abilify group started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a target dose of 10 mg per day at day 7. Patients ≥ 50 kg in the high dose Abilify group, started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a dose of 10 mg per day at day 7 and were allowed weekly increases of 5 mg per day up to a target dose 20 mg per day at Day 21. Abilify (both high and low dose groups) demonstrated statistically significantly improved scores on the YGTSS TTS (Study 1 in Table 30) and on the CGI-TS scale compared with placebo. The estimated improvements on the YGTSS TTS over the course of the study are displayed in Figure 9.

Figure 9: Least Square Means of Change from Baseline in YGTSS TTS by Week (Tourette’s Disorder Study 1)

In the 10-week, placebo-controlled, flexible-dose trial in children and adolescents with Tourette’s disorder (n=61), aged 6 to 18 years, patients received daily doses of placebo or Abilify, starting at 2 mg/day with increases allowed up to 20 mg/day based on clinical response. Abilify demonstrated statistically significantly improved scores on the YGTSS TTS scale compared with placebo (Study 2 in Table 30). The mean daily dose of Abilify at the end of 10-week treatment was 6.54 mg/day.

Table 30: Tourette’s Disorder Studies (Pediatric)

Study Number

Treatment Group

Primary Efficacy Measure: YGTSS TTS

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

Study 1

Abilify (low dose)*

29.2 (5.63)

-13.4 (1.59)

-6.3 (-10.2, -2.3)

Abilify (high dose)*

31.2 (6.40)

-16.9 (1.61)

-9.9 (-13.8, -5.9)

Placebo

30.7 (5.95)

-7.1 (1.55)

--

Study 2

Abilify (2-20 mg/day)*

28.3 (5.51)

-15.0 (1.51)

-5.3 (-9.8, -0.9)

Placebo

29.5 (5.60)

-9.6 (1.64)

--

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

a Difference (drug minus placebo) in least-squares mean change from baseline.

* Doses statistically significantly superior to placebo.

Agitation Associated with Schizophrenia or Bipolar Mania

The efficacy of intramuscular Abilify for injection for the treatment of agitation was established in three short-term (24-hour), placebo-controlled trials in agitated inpatients from two diagnostic groups: schizophrenia and bipolar I disorder (manic or mixed episodes, with or without psychotic features). Each of the trials included a single active comparator treatment arm of either haloperidol injection (schizophrenia studies) or lorazepam injection (bipolar mania study). Patients could receive up to three injections during the 24-hour treatment periods; however, patients could not receive the second injection until after the initial 2-hour period when the primary efficacy measure was assessed. Patients enrolled in the trials needed to be: (1) judged by the clinical investigators as clinically agitated and clinically appropriate candidates for treatment with intramuscular medication, and (2) exhibiting a level of agitation that met or exceeded a threshold score of ≥15 on the five items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness, and excitement items) with at least two individual item scores ≥4 using a 1-7 scoring system (1 = absent, 4 = moderate, 7 = extreme). In the studies, the mean baseline PANSS Excited Component score was 19, with scores ranging from 15 to 34 (out of a maximum score of 35), thus suggesting predominantly moderate levels of agitation with some patients experiencing mild or severe levels of agitation. The primary efficacy measure used for assessing agitation signs and symptoms in these trials was the change from baseline in the PANSS Excited Component at 2 hours post-injection. A key secondary measure was the Clinical Global Impression of Improvement (CGI-I) Scale. The results of the trials follow:

In a placebo-controlled trial in agitated inpatients predominantly meeting DSM-IV criteria for schizophrenia (n=350), four fixed Abilify injection doses of 1 mg, 5.25 mg, 9.75 mg, and 15 mg were evaluated. At 2 hours post-injection, the 5.25 mg, 9.75 mg, and 15 mg doses were statistically superior to placebo in the PANSS Excited Component (Study 1 in Table 31) and on the CGI-I Scale.

In a second placebo-controlled trial in agitated inpatients predominantly meeting DSM-IV criteria for schizophrenia (n=445), one fixed Abilify injection dose of 9.75 mg was evaluated. At 2 hours post-injection, Abilify for injection was statistically superior to placebo in the PANSS Excited Component (Study 2 in Table 31) and on the CGI-I Scale.

In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for bipolar I disorder (manic or mixed) (n=291), two fixed Abilify injection doses of 9.75 mg and 15 mg were evaluated. At 2 hours post-injection, both doses were statistically superior to placebo in the PANSS Excited Component (Study 3 in Table 31).

Examination of population subsets (age, race, and gender) did not reveal any differential responsiveness on the basis of these subgroupings.

Table 31: Agitation Associated with Schizophrenia or Bipolar Mania Studies

Study Number

Treatment Group

Primary Efficacy Measure: PANSS Excited Component

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

Agitation Associated with Schizophrenia

Study 1

Abilify (1 mg)

19.16 (3.26)

-4.47 (0.72)

-1.19 (-2.96 , 0.59)

Abilify (5.25 mg)*

19.41 (3.31)

-5.65 (0.68)

-2.37 (-4.10 , -0.63)

Abilify (9.75 mg)*

19.42 (2.80)

-6.69 (0.72)

-3.40 (-5.18 , -1.62)

Abilify (15 mg)*

19.34 (2.38)

-5.72 (0.72)

-2.44 (-4.21 , -0.68)

Placebo

19.18 (2.95)

-3.28 (0.70)

--

Study 2

Abilify (9.75 mg)*

18.82 (2.67)

-7.27 (0.59)

-2.48 (-3.77, -1.19)

Placebo

18.74 (2.71)

-4.78 (0.69)

--

  Agitation Associated with Bipolar Mania

Study 3

Abilify (9.75 mg)*

18.77 (2.45)

-8.74 (0.57)

-2.99 (-4.53, -1.44)

Abilify (15 mg)*

18.29 (2.49)

-8.67 (0.57)

-2.91 (-4.44, -1.38)

Placebo

17.95 (2.63)

-5.76 (0.58)

--

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

a Difference (drug minus placebo) in least-squares mean change from baseline.

* Doses statistically significantly superior to placebo.

Medication guide

Abilify® (a BIL ĭ fī)

(aripiprazole)

Tablets

Abilify® (a BIL ĭ fī)

(aripiprazole)

Orally Disintegrating Tablets

Abilify® (a BIL ĭ fī)

(aripiprazole)

Oral Solution

Abilify® (a BIL ĭ fī)

(aripiprazole)

Injection, for intramuscular use

What is the most important information I should know about Abilify?

(For other side effects, also see “What are the possible side effects of Abilify?”).

Serious side effects may happen when you take Abilify, including:

• Increased risk of death in elderly patients with dementia-related psychosis: Medicines like Abilify can raise the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). Abilify is not approved for the treatment of patients with dementia-related psychosis. • Risk of suicidal thoughts or actions: Antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions: 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions.Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling very agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood

What else do I need to know about antidepressant medicines?

• Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information.

What is Abilify?

• Abilify Oral Tablets, Orally-Disintegrating Tablets, and Oral Solution are prescription medicines used to treat: o Schizophrenia o manic or mixed episodes that happen with bipolar I disorder o major depressive disorder (MDD) when Abilify is used with antidepressant medicines o irritability associated with autistic disorder o Tourette’s disorder • Abilify Injection is a prescription medicine used to treat: o agitation associated with schizophrenia or bipolar mania

It is not known if Abilify is safe or effective in children:

• under 13 years of age with schizophrenia • under 10 years of age with bipolar I disorder • under 6 years of age with irritability associated with autistic disorder • under 6 years of age with Tourette’s disorder

Do not take Abilify if you are allergic to aripiprazole or any of the ingredients in Abilify. See the end of this Medication Guide for a complete list of ingredients in Abilify.

Before taking Abilify, tell your healthcare provider about all your medical conditions, including if you have or had:

• diabetes or high blood sugar in you or your family; your healthcare provider should check your blood sugar before you start Abilify and also during therapy. • seizures (convulsions). • low or high blood pressure. • heart problems or stroke. • pregnancy or plans to become pregnant. It is not known if Abilify will harm your unborn baby. • breast-feeding or plans to breast-feed. Abilify can pass into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you receive Abilify. • low white blood cell count. • phenylketonuria. Abilify DISCMELT Orally Disintegrating Tablets contain phenylalanine.

Tell your healthcare provider about all the medicines that you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Abilify and other medicines may affect each other causing possible serious side effects. Abilify may affect the way other medicines work, and other medicines may affect how Abilify works.

Your healthcare provider can tell you if it is safe to take Abilify with your other medicines. Do not start or stop any medicines while taking Abilify without talking to your healthcare provider first. Know the medicines you take. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.

How should I take Abilify?

• Take Abilify exactly as your healthcare provider tells you to take it. Do not change the dose or stop taking Abilify yourself. • Abilify can be taken with or without food. • Abilify tablets should be swallowed whole. • If you miss a dose of Abilify, take the missed dose as soon as you remember. If it is almost time for the next dose, just skip the missed dose and take your next dose at the regular time. Do not take two doses of Abilify at the same time. • If you have been prescribed Abilify DISCMELT, take it as follows: o Do not open the blister until ready to take the DISCMELT tablet. o To remove one DISCMELT tablet, open the package and peel back the foil on the blister to expose the tablet. o Do not push the tablet through the foil because this could damage the tablet. o Immediately upon opening the blister, using dry hands, remove the tablet and place the entire Abilify DISCMELT Orally Disintegrating Tablet on the tongue. o Tablet disintegration occurs rapidly in saliva. It is recommended that Abilify DISCMELT be taken without liquid. However, if needed, it can be taken with liquid. o Do not attempt to split the DISCMELT tablet. • If you take too much Abilify, call your healthcare provider or poison control center at 1-800-222-1222 right away, or go to the nearest hospital emergency room.

What should I avoid while taking Abilify?

• Do not drive, operate heavy machinery, or do other dangerous activities until you know how Abilify affects you. Abilify may make you drowsy. • Avoid getting over-heated or dehydrated. o Do not over-exercise. o In hot weather, stay inside in a cool place if possible. o Stay out of the sun. Do not wear too much or heavy clothing. o Drink plenty of water.

What are the possible side effects of Abilify?

Abilify may cause serious side effects, including:

• See “ What is the most important information I should know about Abilify?” • Stroke in elderly people (cerebrovascular problems) that can lead to death • Neuroleptic malignant syndrome (NMS). Tell your healthcare provider right away if you have some or all of the following symptoms: high fever, stiff muscles, confusion, sweating, changes in pulse, heart rate, and blood pressure. These may be symptoms of a rare and serious condition that can lead to death. Call your healthcare provider right away if you have any of these symptoms. • Uncontrolled body movements (tardive dyskinesia). Abilify may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop receiving Abilify. Tardive dyskinesia may also start after you stop receiving Abilify. • Problems with your metabolism such as: ▪ High blood sugar (hyperglycemia) and diabetes. Increases in blood sugar can happen in some people who take Abilify. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or a family history of diabetes), your healthcare provider should check your blood sugar before you start Abilify and during your treatment.   Call your healthcare provider if you have any of these symptoms of high blood sugar while receiving Abilify: ➢ feel very thirsty ➢ need to urinate more than usual ➢ feel very hungry ➢ feel weak or tired ➢ feel sick to your stomach ➢ feel confused, or your breath smells fruity o Increased fat levels (cholesterol and triglycerides) in your blood. o Weight gain. You and your healthcare provider should check your weight regularly. • Unusual urges. Some people taking Abilify have had unusual urges, such as gambling, binge eating or eating that you cannot control (compulsive), compulsive shopping and sexual urges.   If you or your family members notice that you are having unusual urges or behaviors, talk to your healthcare provider. • Orthostatic hypotension (decreased blood pressure). Lightheadedness or fainting may happen when rising too quickly from a sitting or lying position. • Low white blood cell count • Seizures (convulsions) • Problems with control of your body temperature especially when you exercise a lot or are in an area that is very hot. It is important for you to drink water to avoid dehydration. See “What should I avoid while receiving Abilify?” • Difficulty swallowing that can cause food or liquid to get into your lungs.

The most common side effects of Abilify in adults include:

• nausea • dizziness
• vomiting • anxiety
• constipation • insomnia
• headache • restlessness
• blurred vision • inner sense of
• upper respiratory illness   restlessness/need to move
(akathisia)

The most common side effects of Abilify in children include:

• feeling sleepy • insomnia
• headache • nausea
• vomiting • stuffy nose
• fatigue • weight gain
• increased or decreased appetite • uncontrolled movement such as restlessness, tremor
• increased saliva or drooling • muscle stiffness

These are not all the possible side effects of Abilify.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Abilify?

Store Abilify at room temperature, between 68°F to 77°F (20°C to 25°C).

Opened bottles of Abilify Oral Solution can be used for up to 6 months after opening, but not beyond the expiration date on the bottle.

Keep Abilify and all medicines out of the reach of children.

General information about the safe and effective use of Abilify

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Abilify for a condition for which it was not prescribed. Do not give Abilify to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about Abilify that was written for healthcare professionals.

What are the ingredients in Abilify?

Active ingredient: aripiprazole

Inactive ingredients:

Tablets: cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Colorants include ferric oxide (yellow or red) and FD&C Blue No. 2 Aluminum Lake

Abilify DISCMELT Orally Disintegrating Tablets: acesulfame potassium, aspartame (which contains phenylalanine), calcium silicate, croscarmellose sodium, crospovidone, crème de vanilla (natural and artificial flavors), magnesium stearate, microcrystalline cellulose, silicon dioxide, tartaric acid, and xylitol. Colorants include ferric oxide (yellow or red) and FD&C Blue No. 2 Aluminum Lake

Abilify Oral Solution: disodium edetate, fructose (200 mg per mL), glycerin, dl-lactic acid, methylparaben, propylene glycol, propylparaben, sodium hydroxide, sucrose (400 mg per mL), and purified water. The oral solution is flavored with natural orange cream and other natural flavors

For more information about Abilify go to www.Abilify.com or call 1-800-438-6055.

Tablets manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

Orally Disintegrating Tablets, Oral Solution, and Injection manufactured by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA

Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA

Abilify is a trademark of Otsuka Pharmaceutical Company.

© 2016, Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

  This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: August 2016

Package/label principal display panel

30 Tablets NDC 59148-006-13
Abilify®
(aripiprazole)
TABLETS
2 mg
DISPENSE WITH MEDICATION GUIDE
Rx only
Otsuka America Pharmaceutical, Inc.

Do I need a prescription for this medication?

Yes, you need a doctor or other medical health professional to write a prescription for it.

About aripiprazole

Type of medicineAn antipsychotic medicine
Used forSchizophrenia; mania
Also calledAbilify®
Available asTablets, melt-in-the-mouth (orodispersible) tablets, oral liquid medicine, and injection

Aripiprazole belongs to a group of medicines called antipsychotics. It will have been prescribed for one of two different mood disorders. You may have been prescribed it to relieve the symptoms of schizophrenia. Alternatively, it will have been prescribed for the treatment and/or prevention of high mood swings, a condition called mania. In both of these conditions, aripiprazole works on the balance of chemical substances in your brain.

Maintenance doses of aripiprazole can also be given to people with schizophrenia by depot injection. There is a separate medicine leaflet providing more information about this, called Aripiprazole long-acting injection.

Abilify Overview

Abilify is a prescription medication used in treatment of such conditions as schizophrenia, bipolar disorder, and autism. It can also be used in combination with an antidepressant to treat depression. Abilify belongs to a group of drugs called atypical antipsychotics. These medications work by altering the activity of certain natural substances in the brain.

This medication comes in tablet and oral solution form and is usually taken once a day, with or without food.

This medication is also available in immediate injectable form to be given directly into the muscle (IM) by a healthcare professional.

Common side effects of Abilify include insomnia, fatigue, and an inner sense of restlessness or need to move.

Abilify and Pregnancy

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Abilify and Lactation

Tell your doctor if you are breastfeeding or plan to breastfeed.

Abilify has been detected in human breast milk. Because of the possibility for adverse reactions in nursing infants from Abilify, a choice should be made whether to stop nursing or to stop use of this medication. The importance of the drug to the mother should be considered.

Other Requirements

  • Store Abilify at room temperature.
  • Opened bottles of Abilify oral solution can be used for up to 6 months after opening, but not beyond the expiration date on the bottle.
  • Keep Abilify and all medicines out of the reach of children.

What should i discuss with my healthcare provider before taking aripiprazole (abilify, abilify discmelt)?

Aripiprazole is not for use in psychotic conditions that are related to dementia. Aripiprazole may cause heart failure, sudden death, or pneumonia in older adults with dementia-related conditions.

You should not take aripiprazole if you are allergic to it.

To make sure you can safely take aripiprazole, tell your doctor if you have any of these other conditions:

  • liver or kidney disease;
  • heart disease, high blood pressure, heart rhythm problems;
  • high cholesterol or triglycerides (a type of fat in the blood);
  • a history of low white blood cell (WBC) counts;
  • a history of heart attack or stroke;
  • a history of breast cancer;
  • seizures or epilepsy;
  • a personal or family history of diabetes; or
  • trouble swallowing.

The liquid form (oral solution) of this medication may contain up to 15 grams of sugar per dose. Before taking aripiprazole oral solution, tell your doctor if you have diabetes.

The orally disintegrating tablet form of this medication may contain over 3 milligrams of phenylalanine per tablet. Before taking Abilify Discmelt, tell your doctor if you have phenylketonuria.

Aripiprazole may cause you to have high blood sugar (hyperglycemia). Talk to your doctor if you have any signs of hyperglycemia such as increased thirst or urination, excessive hunger, or weakness. If you are diabetic, check your blood sugar levels on a regular basis while you are taking aripiprazole.

FDA pregnancy category C. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

Taking antipsychotic medication during the last 3 months of pregnancy may cause problems in the newborn, such as withdrawal symptoms, breathing problems, feeding problems, fussiness, tremors, and limp or stiff muscles. However, you may have withdrawal symptoms or other problems if you stop taking your medicine during pregnancy. If you become pregnant while taking aripiprazole, do not stop taking it without your doctor's advice.

Aripiprazole can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Before taking this medicine

You should not take Abilify if you are allergic to aripiprazole.

Abilify is not approved for use in psychotic conditions related to dementia. Aripiprazole may increase the risk of death in older adults with dementia-related conditions.

To make sure Abilify is safe for you, tell your doctor if you have:

  • liver or kidney disease;

  • heart disease, high or low blood pressure, heart rhythm problems;

  • high cholesterol or triglycerides (a type of fat in the blood);

  • a history of low white blood cell (WBC) counts;

  • a history of heart attack or stroke;

  • seizures or epilepsy;

  • trouble swallowing;

  • a personal or family history of diabetes; or

  • a history of obsessive-compulsive disorder, impulse-control disorder, or addictive behaviors.

Some young people have thoughts about suicide when taking medicine for a major depressive disorder and other psychiatric disorders. Your doctor should check your progress at regular visits. Your family or other caregivers should also be alert to changes in your mood or symptoms.

The liquid form (oral solution) of this medication may contain up to 15 grams of sugar per dose. Before taking Abilify oral solution, tell your doctor if you have diabetes.

Abilify may cause you to have high blood sugar (hyperglycemia). If you are diabetic, check your blood sugar levels on a regular basis while you are taking this medicine.

The orally disintegrating tablet form of this medication may contain over 3 milligrams of phenylalanine per tablet. Before taking Abilify Discmelt, tell your doctor if you have phenylketonuria.

Taking antipsychotic medicine in the last 3 months of pregnancy may cause problems in the newborn, such as withdrawal symptoms, breathing problems, feeding problems, fussiness, tremors, and limp or stiff muscles. However, you may have withdrawal symptoms or other problems if you stop taking your medicine during pregnancy. If you become pregnant, do not stop taking Abilify without your doctor's advice.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of aripiprazole on the baby.

Aripiprazole can pass into breast milk and may harm a nursing baby. You should not breast-feed while using this medicine.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

How it works

  • Abilify is a brand (trade) name for aripiprazole.
  • Experts aren't sure exactly how aripiprazole works to relieve the symptoms of schizophrenia but suggest it may partially activate dopamine 2 and serotonin 1A receptors and block serotonin 2A receptors. It does appear to have some activity at other receptors, which may account for its side effects (for example its tendency to cause low blood pressure on standing may be due to its blocking effect on adrenergic alpha1 receptors).
  • Aripiprazole belongs to the class of medicines known as atypical antipsychotics (atypical means it is less likely than older antipsychotics to cause side effects, and more likely to be effective in the treatment of symptoms such as lack of motivation and social withdrawal).

Downsides

If you are between the ages of 18 and 60, take no other medication or have no other medical conditions, side effects you are more likely to experience include:

  • Akathisia (an inner restlessness), sedation, headache, insomnia, agitation, anxiety, nausea, tremor. Other reasonably common side effects include constipation, vomiting, dry mouth, stomach upsets and extrapyramidal symptoms (such as restlessness, tremor, uncontrolled muscle contractions). May also cause difficulty swallowing.
  • Should not be used for the treatment of dementia-related psychosis in elderly people as associated with a higher risk of death.
  • If being used as an adjunct therapy in the treatment of depression, monitor for worsening depression, agitation or mood changes.
  • May cause a drop in blood pressure on standing, particularly during the initial dose titration period; dosage may need reducing. May not be suitable for people with cardiovascular disease (history of a heart attack, angina, heart failure, or arrhythmia), stroke, seizure disorders, and people at risk of dehydration.
  • Blood levels may need monitoring as Abilify can cause numbers of white blood cells to decrease.
  • May increase blood sugar levels. People with a history of diabetes or at risk of diabetes should be monitored closely. Less likely than some other antipsychotics to cause undesirable changes in blood cholesterol and lipid levels or to cause weight gain.
  • Potentially irreversible tardive dyskinesia can develop, even with low dosages used short-term. Symptoms include facial grimacing, repetitive chewing, and tongue thrusting.
  • Rarely, may cause Neuroleptic Malignant Syndrome; symptoms include high body temperature, muscle rigidity, and mental disturbances; discontinue immediately and seek urgent medical advice.
  • May interact with a number of drugs, including benzodiazepines, carbamazepine, fluoxetine, and itraconazole. See prescribing information for a full list of interactions.

Notes: In general, seniors or children, people with certain medical conditions (such as liver or kidney problems, heart disease, diabetes, seizures) or people who take other medications are more at risk of developing a wider range of side effects. For a complete list of all side effects, click here.

Bottom Line

Abilify is an antipsychotic used in the treatment of schizophrenia and several other disorders. Abilify is less likely than some other antipsychotics to cause weight gain.

Aripiprazole Pregnancy Warnings

There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in neonates exposed to antipsychotic drugs during the third trimester of pregnancy. 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. Animal studies have revealed evidence of developmental toxicity, including possible teratogenic effects. Congenital anomalies have been reported; however, a causal relationship has not been established. There are no controlled data in human pregnancy. AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. AU TGA pregnancy category: C US FDA pregnancy category: C Comments: -Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. -Patients should be advised to notify their physician if they are pregnant or plan to become pregnant during treatment. -U.S. National Pregnancy Registry for Atypical Antipsychotics monitors pregnancy outcomes in women exposed to atypical antipsychotics during pregnancy; for information call 1-866-961-2388 or visit https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

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