HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use ABILIFY
`safely and effectively. See full prescribing information for ABILIFY.
`
`ABILIFY® (aripiprazole) Tablets
`ABILIFY® DISCMELT™ (aripiprazole) Orally Disintegrating Tablets
`ABILIFY® (aripiprazole) Oral Solution
`ABILIFY® (aripiprazole) Injection FOR INTRAMUSCULAR USE ONLY
`Initial U.S. Approval: 2002
`
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA-RELATED PSYCHOSIS
`See full prescribing information for complete boxed warning.
`Elderly patients with dementia-related psychosis treated with atypical
`antipsychotic drugs are at an increased risk of death compared to
`placebo. ABILIFY is not approved for the treatment of patients with
`dementia-related psychosis. (5.1)
`---------------------------RECENT MAJOR CHANGES---------------------------
`Indications and Usage, Pediatric (13 to 17 yrs) Schizophrenia (1.1) 10/2007
`Dosage and Administration, Pediatric Schizophrenia (2.1) 10/2007
`
`---------------------------INDICATIONS AND USAGE----------------------------
`ABILIFY is an atypical antipsychotic indicated
` as oral formulations for:
`• Treatment of Schizophrenia in adults and adolescents aged 13-17 years (1.1)
`• Treatment of acute manic or mixed episodes associated with Bipolar I
`Disorder in adults (1.2)
` as an injection for:
`• Treatment of adults with agitation associated with Schizophrenia or Bipolar I
`Disorder, manic or mixed (1.3)
`
`
`------------------------DOSAGE AND ADMINISTRATION----------------------
`Recommended Dose Maximum
`
`Initial Dose
`Dose
`30 mg /day
`
`Schizophrenia-
`adults (2.1)
`Schizophrenia –
`adolescents
`(2.1)
`Bipolar Mania–
`adults (2.2)
`
`Agitation
`associated with
`Schizophrenia or
`Bipolar Mania–
`adults (2.5)
`
`10-15 mg
`/day
`2 mg
`/day
`
` 10-15 mg /day
`
`10 mg
`/day
`
`15-30 mg
`/day
`
` 15-30 mg
`/day
`
`9.75 mg /1.3
`mL injected
`IM
`
`
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`•
`Tablets: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg (3)
`•
`Orally Disintegrating Tablets: 10 mg and 15 mg (3)
`•
`Oral Solution: 1 mg/mL (3)
`•
`Injection: 9.75 mg/1.3 mL single-dose vial (3)
`
`------------------------------CONTRAINDICATIONS-------------------------------
`Known hypersensitivity to ABILIFY (4)
`
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`•
`Elderly patients with dementia-related psychosis: Increased incidence of
`cerebrovascular adverse events (eg, stroke, transient ischemic attack,
`including fatalities) (5.1)
`Neuroleptic Malignant Syndrome: Manage with immediate discontinuation
`and close monitoring (5.2)
`Tardive Dyskinesia: Discontinue if clinically appropriate (5.3)
`Hyperglycemia and Diabetes Mellitus: Monitor glucose regularly in
`patients with and at risk for diabetes (5.4)
`Orthostatic Hypotension: Use with caution in patients with known
`cardiovascular or cerebrovascular disease (5.5)
`Seizures/Convulsions: Use cautiously in patients with a history of seizures
`or with conditions that lower the seizure threshold (5.6)
`Potential for Cognitive and Motor Impairment: Use caution when
`operating machinery (5.7)
`Suicide: Closely supervise high-risk patients (5.10)
`
`•
`
`•
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`-------------------------------ADVERSE REACTIONS------------------------------
`Commonly observed adverse reactions (incidence > 5%and at least twice that for
`placebo) were (6.2):
`•
`Adult patients with Schizophrenia: akathisia
`•
`Pediatric patients (13 to 17 yrs) with Schizophrenia: extrapyramidal
`disorder, somnolence, and tremor
`Adult patients with Bipolar Mania: constipation, akathisia, sedation,
`tremor, restlessness, and extrapyramidal disorder
`Adult patients with agitation associated with Schizophrenia or Bipolar
`Mania: nausea .
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
`Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch
`
`--------------------------------DRUG INTERACTIONS-----------------------------
`•
`Strong CYP3A4 or CYP2D6 inhibitors will increase ABILIFY drug
`concentrations;
`reduce ABILIFY dose by one-half when used
`concomitantly (2.1, 7.1)
`CYP3A4 inducers will decrease ABILIFY drug concentrations; double
`ABILIFY dose when used concomitantly (2.1, 7.1)
`
`30 mg /day
`
`30 mg /day
`
`30 mg /day
`injected IM
`
`•
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`Revised: 10/2007
`
`
`
`
`ABILIFY oral formulations: Administer once daily without regard to meals
`(2)
`ABILIFY injection: Wait at least 2 hours between doses. Maximum daily
`dose 30 mg (2.3)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 1 of 53
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`•
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`
`
`
`
`
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`

`
`8
`
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Labor and Delivery
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Renal Impairment
`8.7
`Hepatic Impairment
`8.8
`Gender
`8.9
`Race
`8.10 Smoking
`DRUG ABUSE AND DEPENDENCE
`9.1
`Controlled Substance
`9.2
`Abuse and Dependence
`OVERDOSAGE
`10.1 Human Experience
`10.2 Management of Overdosage
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`CLINICAL STUDIES
`14.1 Schizophrenia
`14.2 Bipolar Disorder
`14.3 Agitation Associated with Schizophrenia or Bipolar Mania
`HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage
`PATIENT COUNSELING INFORMATION
`17
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`11
`12
`
`9
`
`10
`
`13
`
`14
`
`16
`
`2
`
`3
`4
`5
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING:INCREASED MORTALITY IN ELDERLY PATIENTS WITH
`DEMENTIA-RELATED PSYCHOSIS
`1
`INDICATIONS AND USAGE
`1.1
`Schizophrenia
`1.2
`Bipolar Disorder
`1.3
`Agitation Associated with Schizophrenia or Bipolar Mania
`DOSAGE AND ADMINISTRATION
`2.1
`Schizophrenia
`2.2
`Bipolar Disorder
`2.3
`Agitation Associated with Schizophrenia or Bipolar
`Disorder
`2.4
`Dosing of Oral Solution
`Dosing of Orally Disintegrating Tablets
`2.5
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Use in Elderly Patients with Dementia-Related Psychosis
`5.2
`Neuroleptic Malignant Syndrome (NMS)
`5.3
`Tardive Dyskinesia
`5.4
`Hyperglycemia and Diabetes Mellitus
`5.5
`Orthostatic Hypotension
`5.6
`Seizures/Convulsions
`5.7
`Potential for Cognitive and Motor Impairment
`5.8
`Body Temperature Regulation
`5.9
`Dysphagia
`5.10 Suicide
`5.11 Use in Patients with Concomitant Illness
`ADVERSE REACTIONS
`6.1
`Overall Adverse Reactions Profile
`6.2
`Clinical Studies Experience
`6.3
`Postmarketing Experience
`DRUG INTERACTIONS
`7.1
`Potential for Other Drugs to Affect ABILIFY
`7.2
`Potential for ABILIFY to Affect Other Drugs
`7.3
`Drugs having No Clinically Important Interactions with
`ABILIFY
`
`6
`
`7
`
`2
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA-RELATED PSYCHOSIS
`
`Elderly patients with dementia-related psychosis treated with atypical antipsychotic
`drugs are at an increased risk of death compared to placebo. Analyses of seventeen
`placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a
`risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in
`placebo-treated patients. Over the course of a typical 10-week controlled trial, the
`rate of death in drug-treated patients was about 4.5%, compared to a rate of about
`2.6% in the placebo group. Although the causes of death were varied, most of the
`deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or
`infectious (eg, pneumonia) in nature. ABILIFY (aripiprazole) is not approved for
`the treatment of patients with dementia-related psychosis. [see WARNINGS AND
`PRECAUTIONS (5.1)].
`
`1
`
`INDICATIONS AND USAGE
`
`1.1 Schizophrenia
`
`Adults
`
`ABILIFY is indicated for acute and maintenance treatment of Schizophrenia [see
`CLINICAL STUDIES (14.1)].
`
`Adolescents
`
`ABILIFY is indicated for the treatment of Schizophrenia in adolescents 13 to 17 years of
`age [see CLINICAL STUDIES (14.1)].
`
`1.2 Bipolar Disorder
`
`Adults
`
`ABILIFY is indicated for acute and maintenance treatment of manic and mixed episodes
`associated with Bipolar I Disorder with or without psychotic features [see CLINICAL
`STUDIES (14.2)].
`
`3
`
`

`

`
`
`1.3 Agitation Associated with Schizophrenia or Bipolar Mania
`
`Adults
`
`ABILIFY Injection is indicated for the treatment of agitation associated with
`Schizophrenia or Bipolar Disorder, manic or mixed. "Psychomotor agitation" is defined
`in DSM-IV as "excessive motor activity associated with a feeling of inner tension."
`Patients experiencing agitation often manifest behaviors that interfere with their diagnosis
`and care (eg, threatening behaviors, escalating or urgently distressing behavior, or self-
`exhausting behavior), leading clinicians to the use of intramuscular antipsychotic
`medications to achieve immediate control of the agitation [see CLINICAL STUDIES
`(14.3)].
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Schizophrenia
`
`Usual Dose
`
`Adults
`
`The recommended starting and target dose for ABILIFY is 10 mg/day or 15 mg/day
`administered on a once-a-day schedule without regard to meals. ABILIFY has been
`systematically evaluated and shown to be effective in a dose range of 10 mg/day to 30
`mg/day, when administered as the tablet formulation; however, doses higher than 10
`mg/day or 15 mg/day were not more effective than 10 mg/day or 15 mg/day. Dosage
`increases should not be made before 2 weeks, the time needed to achieve steady state.
`[See CLINICAL STUDIES (14.1)].
`
`Adolescents
`
` The recommended target dose of ABILIFY is 10 mg/day. Aripiprazole was studied in
`pediatric patients 13 to 17 years of age with Schizophrenia at daily doses of 10 mg and 30
`mg. The starting daily dose of the tablet formulation in these patients was 2 mg, which
`was titrated to 5 mg after 2 days and to the target dose of 10 mg after 2 additional days.
`Subsequent dose increases should be administered in 5 mg increments. The 30 mg/day
`dose was not shown to be more efficacious than the 10 mg/day dose. ABILIFY can be
`administered without regard to meals. [See CLINICAL STUDIES (14.1)].
`
`4
`
`

`

`
`
`Dosage in Special Populations
`
`Dosage adjustments are not routinely indicated on the basis of age, gender, race, or renal
`or hepatic impairment status [see USE IN SPECIFIC POPULATIONS (8.4-8.10)].
`
`Dosage adjustment for patients taking aripiprazole concomitantly with strong
`CYP3A4 inhibitors: When concomitant administration of aripiprazole with
`strong CYP3A4 inhibitors such as ketoconazole or clarithromycin is indicated,
`the aripiprazole dose should be reduced to one-half the usual dose. When the
`CYP3A4 inhibitor is withdrawn from the combination therapy, the aripiprazole
`dose should then be increased [see DRUG INTERACTIONS (7.1)].
`
`Dosage adjustment for patients taking aripiprazole concomitantly with potential
`CYP2D6 inhibitors: When concomitant administration of potential CYP2D6
`inhibitors such as quinidine, fluoxetine, or paroxetine with aripiprazole occurs,
`aripiprazole dose should be reduced at least to one-half of its normal dose. When
`the CYP2D6 inhibitor is withdrawn from the combination therapy, the
`aripiprazole dose should then be increased [see DRUG INTERACTIONS (7.1)].
`
`Dosage adjustment for patients taking potential CYP3A4 inducers: When a
`potential CYP3A4 inducer such as carbamazepine is added to aripiprazole
`therapy, the aripiprazole dose should be doubled. Additional dose increases
`should be based on clinical evaluation. When the CYP3A4 inducer is withdrawn
`from the combination therapy, the aripiprazole dose should be reduced to 10 mg
`to 15 mg [see DRUG INTERACTIONS (7.1)].
`
`Maintenance Therapy
`
`Adults
`
`While there is no body of evidence available to answer the question of how long a patient
`treated with aripiprazole should remain on it, systematic evaluation of patients with
`Schizophrenia who had been symptomatically stable on other antipsychotic medications
`for periods of 3 months or longer, were discontinued from those medications, and were
`then administered ABILIFY 15 mg/day and observed for relapse during a period of up to
`26 weeks, has demonstrated a benefit of such maintenance treatment [see CLINICAL
`STUDIES (14.1)]. Patients should be periodically reassessed to determine the need for
`maintenance treatment.
`
`5
`
`

`

`
`
`Pediatric Patients
`
`The efficacy of ABILIFY for the maintenance treatment of Schizophrenia in the pediatric
`population has not been evaluated.
`
`Switching from Other Antipsychotics
`
`There are no systematically collected data to specifically address switching patients with
`Schizophrenia from other antipsychotics to ABILIFY or concerning concomitant
`administration with other antipsychotics. While immediate discontinuation of the
`previous antipsychotic
`treatment may be acceptable
`for some patients with
`Schizophrenia, more gradual discontinuation may be most appropriate for others. In all
`cases, the period of overlapping antipsychotic administration should be minimized.
`
`2.2 Bipolar Disorder
`
`Usual Dose
`
`Adults
`
`In clinical trials, the starting dose was 30 mg given once a day, without regard to meals.
`A dose of 30 mg/day was found to be effective when administered as the tablet
`formulation. Approximately 15% of patients had their dose decreased to 15 mg based on
`assessment of tolerability. The safety of doses above 30 mg/day has not been evaluated in
`clinical trials.
`
`Dosage in Special Populations
`
`See DOSAGE AND ADMINISTRATION (2.1).
`
`Maintenance Therapy
`
`While there is no body of evidence available to answer the question of how long a patient
`treated with aripiprazole should remain on it, adult patients with Bipolar I Disorder who
`had been symptomatically stable on ABILIFY Tablets (15 mg/day or 30 mg/day with a
`starting dose of 30 mg/day) for at least 6 consecutive weeks and then randomized to
`ABILIFY Tablets (15 mg/day or 30 mg/day) or placebo and monitored for relapse,
`demonstrated a benefit of such maintenance treatment [see CLINICAL STUDIES (14.2)].
`While it is generally agreed that pharmacological treatment beyond an acute response in
`Mania is desirable, both for maintenance of the initial response and for prevention of new
`
`6
`
`

`

`
`
`manic episodes, there are no systematically obtained data to support the use of
`aripiprazole in such longer-term treatment (beyond 6 weeks). Physicians who elect to use
`ABILIFY for extended periods, that is, longer than 6 weeks, should periodically re-
`evaluate the long-term usefulness of the drug for the individual.
`
`2.3 Agitation Associated with Schizophrenia or Bipolar Mania
`(Intramuscular Injection)
`
`Usual Dose
`
`Adults
`
`The recommended dose in these patients is 9.75 mg. The effectiveness of aripiprazole
`injection in controlling agitation in Schizophrenia and Bipolar Mania was demonstrated
`over a dose range of 5.25 mg to 15 mg. No additional benefit was demonstrated for 15
`mg compared to 9.75 mg. A lower dose of 5.25 mg may be considered when clinical
`factors warrant. If agitation warranting a second dose persists following the initial dose,
`cumulative doses up to a total of 30 mg/day may be given. However, the efficacy of
`repeated doses of aripiprazole injection in agitated patients has not been systematically
`evaluated in controlled clinical trials. The safety of total daily doses greater than 30 mg
`or injections given more frequently than every 2 hours have not been adequately
`evaluated in clinical trials [see CLINICAL STUDIES (14.3)].
`
`If ongoing aripiprazole therapy is clinically indicated, oral aripiprazole in a range of
`10 mg/day to 30 mg/day should replace aripiprazole injection as soon as possible [see
`DOSAGE AND ADMINISTRATION (2.1 and 2.2)].
`
`Administration of ABILIFY Injection
`
`To administer ABILIFY Injection, draw up the required volume of solution into the
`syringe as shown in Table 1. Discard any unused portion.
`
`Table 1: ABILIFY Injection Dosing Recommendations
`
`Required Volume of Solution
`Single-Dose
`0.7 mL
`5.25 mg
`1.3 mL
`9.75 mg
`2 mL
`15 mg
`ABILIFY Injection is intended for intramuscular use only. Do not administer
`intravenously or subcutaneously. Inject slowly, deep into the muscle mass.
`
`7
`
`

`

`
`
`Parenteral drug products should be inspected visually for particulate matter and
`discoloration prior to administration, whenever solution and container permit.
`
`Dosage in Special Populations
`
`See DOSAGE AND ADMINISTRATION (2.1).
`
`2.4 Dosing of Oral Solution
`
`The oral solution can be substituted for tablets on a mg-per-mg basis up to the 25 mg
`dose level. Patients receiving 30 mg tablets should receive 25 mg of the solution [see
`CLINICAL PHARMACOLOGY (12.3)].
`
`2.5 Dosing of Orally Disintegrating Tablets
`
`The dosing for ABILIFY Orally Disintegrating Tablets is the same as for the oral tablets
`[see DOSING AND ADMINISTRATION (2.1 and 2.2)].
`
`3 DOSAGE FORMS AND STRENGTHS
`
`ABILIFY® (aripiprazole) Tablets are available as described in Table 2.
`
`
`
`
`
`Table 2: ABILIFY Tablet Presentations
`Tablet
`Tablet
`Strength
`Color/Shape
`green
`modified rectangle
`blue
`modified rectangle
`pink
`modified rectangle
`yellow
`round
`white
`round
`pink
`round
`
`15 mg
`
`20 mg
`
`30 mg
`
`2 mg
`
`5 mg
`
`10 mg
`
`Tablet
`Markings
`"A-006"
`and "2"
`"A-007"
`and "5"
`"A-008"
`and "10"
`"A-009"
`and "15"
`"A-010"
`and "20"
`"A-011"
`and "30"
`
`8
`
`

`

`
`
`ABILIFY® DISCMELT™ (aripiprazole) Orally Disintegrating Tablets are available as
`described in Table 3.
`
`10 mg
`
`Table 3: ABILIFY DISCMELT Orally Disintegrating Tablet Presentations
`Tablet
`Tablet Color
`Tablet
`Strength
`/ Shape
`Markings
`pink (with scattered specks)
`"A" and "640"
`round
`"10"
`yellow (with scattered specks)
`"A" and "641"
`round
`"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.
`
`15 mg
`
`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.
`
`4 CONTRAINDICATIONS
`
` Reactions have ranged from
`to ABILIFY.
`Known hypersensitivity reaction
`pruritus/urticaria to anaphylaxis [see ADVERSE REACTIONS (6.3)].
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Use in Elderly Patients with Dementia-Related Psychosis
`
`Increased Mortality
`
`Elderly patients with dementia-related psychosis treated with atypical antipsychotic
`drugs are at an increased risk of death compared to placebo. ABILIFY
`(aripiprazole) is not approved for the treatment of patients with dementia-related
`psychosis [see BOXED WARNING].
`
`Cerebrovascular Adverse Events, Including Stroke
`
`In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of
`dementia-related psychosis, there was an increased incidence of cerebrovascular adverse
`events (eg, stroke, transient ischemic attack), including fatalities, in aripiprazole-treated
`patients (mean age: 84 years; range: 78-88 years). In the fixed-dose study, there was a
`statistically significant dose response relationship for cerebrovascular adverse events in
`
`9
`
`

`

`
`
`patients treated with aripiprazole. Aripiprazole is not approved for the treatment of
`patients with dementia-related psychosis [see also BOXED WARNING].
`
`Safety Experience in Elderly Patients with Psychosis Associated with
`Alzheimer’s Disease
`
`In three, 10-week, placebo-controlled studies of aripiprazole in elderly patients with
`psychosis associated with Alzheimer’s disease (n=938; mean age: 82.4 years; range: 56-
`99 years), the treatment-emergent adverse events that were reported at an incidence of
`≥3% and aripiprazole incidence at least twice that for placebo were lethargy [placebo 2%,
`aripiprazole 5%], somnolence (including sedation) [placebo 3%, aripiprazole 8%], and
`incontinence (primarily, urinary incontinence) [placebo 1%, aripiprazole 5%], excessive
`salivation (placebo 0%, aripiprazole 4%), and lightheadedness (placebo 1%, aripiprazole
`4%).
`
`The safety and efficacy of ABILIFY in the treatment of patients with psychosis
`associated with dementia have not been established. If the prescriber elects to treat such
`patients with ABILIFY, vigilance should be exercised, particularly for the emergence of
`difficulty swallowing or excessive somnolence, which could predispose to accidental
`injury or aspiration [see also BOXED WARNING].
`
`5.2 Neuroleptic Malignant Syndrome (NMS)
`
`A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant
`Syndrome (NMS) may occur with administration of antipsychotic drugs, including
`aripiprazole. Rare cases of NMS occurred during aripiprazole treatment in the worldwide
`clinical database. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity,
`altered mental status, and evidence of autonomic instability (irregular pulse or blood
`pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may
`include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute
`renal failure.
`
`The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
`diagnosis, it is important to exclude cases where the clinical presentation includes both
`serious medical illness (eg, pneumonia, systemic infection) and untreated or inadequately
`treated extrapyramidal signs and symptoms (EPS). Other important considerations in the
`differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and
`primary central nervous system pathology.
`
`10
`
`

`

`
`
`The management of NMS should include: 1) immediate discontinuation of antipsychotic
`drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic
`treatment and medical monitoring; and 3) treatment of any concomitant serious medical
`problems for which specific treatments are available. There is no general agreement
`about specific pharmacological treatment regimens for uncomplicated NMS.
`
`If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
`reintroduction of drug therapy should be carefully considered. The patient should be
`carefully monitored, since recurrences of NMS have been reported.
`
`5.3 Tardive Dyskinesia
`
`A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop
`in patients treated with antipsychotic drugs. Although the prevalence of the syndrome
`appears to be highest among the elderly, especially elderly women, it is impossible to rely
`upon prevalence estimates to predict, at the inception of antipsychotic treatment, which
`patients are likely to develop the syndrome. Whether antipsychotic drug products differ
`in their potential to cause tardive dyskinesia is unknown.
`
`The risk of developing tardive dyskinesia and the likelihood that it will become
`irreversible are believed to increase as the duration of treatment and the total cumulative
`dose of antipsychotic drugs administered to the patient increase. However, the syndrome
`can develop, although much less commonly, after relatively brief treatment periods at low
`doses.
`
`There is no known treatment for established cases of tardive dyskinesia, although the
`syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
`Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs
`and symptoms of the syndrome and, thereby, may possibly mask the underlying process.
`The effect that symptomatic suppression has upon the long-term course of the syndrome
`is unknown.
`
`Given these considerations, ABILIFY should be prescribed in a manner that is most
`likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment
`should generally be reserved for patients who suffer from a chronic illness that (1) is
`known to respond to antipsychotic drugs and (2) for whom alternative, equally effective,
`but potentially less harmful treatments are not available or appropriate. In patients who
`do require chronic treatment, the smallest dose and the shortest duration of treatment
`
`11
`
`

`

`
`
`producing a satisfactory clinical response should be sought. The need for continued
`treatment should be reassessed periodically.
`
`If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, drug
`discontinuation should be considered. However, some patients may require treatment
`with ABILIFY despite the presence of the syndrome.
`
`5.4 Hyperglycemia and Diabetes Mellitus
`
`Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar
`coma or death, has been reported in patients treated with atypical antipsychotics. There
`have been few reports of hyperglycemia in patients treated with ABILIFY [see
`ADVERSE REACTIONS (6.2, 6.3)]. Although fewer patients have been treated with
`ABILIFY, it is not known if this more limited experience is the sole reason for the
`paucity of such reports. Assessment of the relationship between atypical antipsychotic
`use and glucose abnormalities is complicated by the possibility of an increased
`background risk of diabetes mellitus in patients with Schizophrenia and the increasing
`incidence of diabetes mellitus in the general population. Given these confounders, the
`relationship between atypical antipsychotic use and hyperglycemia-related adverse events
`is not completely understood. However, epidemiological studies which did not include
`ABILIFY suggest an increased risk of treatment-emergent hyperglycemia-related adverse
`events in patients treated with the atypical antipsychotics included in these studies.
`Because ABILIFY was not marketed at the time these studies were performed, it is not
`known if ABILIFY is associated with this increased risk. Precise risk estimates for
`hyperglycemia-related adverse events in patients treated with atypical antipsychotics are
`not available.
`
`Patients with an established diagnosis of diabetes mellitus who are started on atypical
`antipsychotics should be monitored regularly for worsening of glucose control. Patients
`with risk factors for diabetes mellitus (eg, obesity, family history of diabetes) who are
`starting treatment with atypical antipsychotics should undergo fasting blood glucose
`testing at the beginning of treatment and periodically during treatment. Any patient
`treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia
`including polydipsia, polyuria, polyphagia, and weakness. Patients who develop
`symptoms of hyperglycemia during treatment with atypical antipsychotics should
`undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when
`the atypical antipsychotic was discontinued; however, some patients required
`continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
`
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`5.5 Orthostatic Hypotension
`
`Aripiprazole may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor
`antagonism. The incidence of orthostatic hypotension-associated events from short-term,
`placebo-controlled trials of patients on oral ABILIFY included (aripiprazole incidence,
`placebo incidence): in adults with Schizophrenia (n=926): orthostatic hypotension (1.9%,
`1%), postural dizziness (0.8%, 0.7%), and syncope (0.6%, 1%); in pediatric patients 13 to
`17 yrs of age with Schizophrenia (n=202): orthostatic hypotension (1.5%, 0%), postural
`dizziness (1.0%, 0%), and syncope (0.5%, 0%); in adults with Bipolar Mania (n=597):
`orthostatic hypotension (0.7%, 0%), postural dizziness (0.5%, 0.2%), and syncope (0.3%,
`0.7%): and in adult patients with agitation associated with Schizophrenia or Bipolar
`Mania (n=501) on ABILIFY Injection included: orthostatic hypotension (0.6%, 0%),
`postural dizziness (0.2%, 0.5%), and syncope (0.4%, 0%).
`
`The incidence of a significant orthostatic change in blood pressure (defined as a decrease
`of at least 30 mmHg in systolic blood pressure when changing from a supine to standing
`position) for aripiprazole was not meaningfully different from placebo (aripiprazole
`incidence, placebo incidence): in adult patients with Schizophrenia (14%, 12%), in
`pediatric patients with Schizophrenia (1%, 0%), in adults with Bipolar Mania (3%, 2%),
`or in adults with agitation associated with Schizophrenia or Bipolar Mania (4%, 4%).
`
`Aripiprazole should be used with caution in patients with known cardiovascular disease
`(history of myocardial infarction or ischemic heart disease, heart failure or conduction
`abnormalities), cerebrovascular disease, or conditions which would predispose patients to
`hypotension
`(dehydration, hypovolemia, and
`treatment with antihypertensive
`medications).
`
`If parenteral benzodiazepine therapy is deemed necessary in addition to aripiprazole
`injection treatment, patients should be monitored for excessive sedation and for
`orthostatic hypotension [see DRUG INTERACTIONS (7.3)].
`
`5.6 Seizures/Convulsions
`
`trials of oral aripiprazole-treated patients,
`short-term placebo-controlled
`In
`seizures/convulsions occurred in 0.1% (1/926) of adult patients with Schizophrenia, in
`0% (0/202) of pediatric patients (13 to 17 yrs) with Schizophrenia, in 0.3% (2/597) of
`adult patients with Bipolar Mania, and in 0.2% (1/501) of aripiprazole injection-treated
`adult patients with agitation associated with Schizophrenia or Bipolar Mania.
`
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`
`
`As with other antipsychotic drugs, aripiprazole should be used cautiously in patients with
`a history of seizures or with conditions that lower the seizure threshold, eg, Alzheimer’s
`dementia. Conditions that lower the seizure threshold may be more prevalent in a
`population of 65 years or older.
`
`5.7 Potential for Cognitive and Motor Impairment
`
`ABILIFY, like other antipsychotics, may have the potential to impair judgment, thinking,
`or motor skills. For example, in short-term, placebo-controlled trials of patients on oral
`ABILIFY, somnolence (including sedation) was reported as follows (aripiprazole
`incidence, placebo incidence): in adult patients with Schizophrenia (10%, 8%), in
`pediatric patients with Schizophrenia (17%, 6%), in adult patients with Bipolar Mania,
`(14%, 7%), in adult patients on ABILIFY Injection with agitation associated with
`Schizophrenia or Bipolar Mania (9%, 6%). Somnolence (including sedation) led to
`discontinuation in 0.1% (1/926) of adult patients with Schizophrenia, 0.5% (1/202)
`pediatric patients (13 to 17 yrs) with Schizophrenia, on oral ABILIFY in short-term,
`placebo-controlled trials, but did not lead to discontinuation of any adult patients with
`Bipolar Mania or with agitation associated with Schizophrenia or Bipolar Mania.
`
`Despite the relatively modest increased incidence of these events compared to placebo,
`patients should be cautioned about operating hazardous machinery,
`including
`automobiles, until they are reasonably certain that therapy with ABILIFY does not affect
`them adversely.
`
`5.8 Body Temperature Regulation
`
`Disruption of the body’s ability to reduce core body temperature has been attributed to
`antipsychotic agents. Appropriate care is advised when prescribing aripiprazole for
`patients who will be experiencing conditions which may contribute to an elevation in
`core body temperature, (eg, exercising strenuously, exposure to extreme heat, receiving
`concomitant medication with anticholinergic activity, or being subject to dehydration)
`[see ADVERSE REACTIONS (6.3)].
`
`5.9 Dysphagia
`
`Esophageal dysmotility and aspiration have been associated with antipsychotic drug use,
`including ABILIFY. Aspiration pneumonia is a common cause of morbidity and
`mortality in elderly patients, in particular those with advanced Alzheimer’s dementia.
`Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk
`
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`
`
`for aspiration pneumonia [see WARNINGS AND PRECAUTIONS (5.1) and ADVERSE
`REACTIONS (6.3)].
`
`5.10 Suicide
`
`The possibility of a suicide attempt is inherent in psychotic illnesses and bipolar disorder,
`and close supervision of high-risk patients should accompany drug therapy. Prescriptions
`for ABILIFY should be written for the smallest quantity consistent with good patient
`management in order to reduce the risk of overdose [see ADVERSE REACTIONS (6.2,
`6.3)].
`
`5.11 Use in Patients with Concomitant Illness
`
`Cl