Aripiprazole has been evaluated for safety in 5592 patients who participated in multiple-dose, premarketing trials in schizophrenia, bipolar mania, and dementia of the Alzheimer’s type, and who had approximately 3639 patient-years of exposure. A total of 1887 aripiprazole-treated patients were treated for at least 180 days and 1251 aripiprazole-treated patients had at least 1 year of exposure.

The conditions and duration of treatment with aripiprazole 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.

Adverse events during exposure were obtained by collecting volunteered adverse events, as well as results of physical examinations, vital signs, weights, laboratory analyses, and ECG. Adverse experiences were recorded by clinical investigators using terminology of their own choosing. In the tables and tabulations that follow, modified COSTART dictionary terminology has been used initially to classify reported adverse events into a smaller number of standardized event categories, in order to provide a meaningful estimate of the proportion of individuals experiencing adverse events.

The stated frequencies of adverse events represent the proportion of individuals who experienced at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. There was no attempt to use investigator causality assessments; ie, all reported events are included.

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatment, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse event incidence in the population studied.

Adverse Findings Observed in Short-Term, Placebo-Controlled Trials of Patients with Schizophrenia

The following findings are based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which aripiprazole was administered in doses ranging from 2 to 30 mg/day.

Adverse Events Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials

Overall, there was no difference in the incidence of discontinuation due to adverse events between aripiprazole-treated (7%) and placebo-treated (9%) patients. The types of adverse events that led to discontinuation were similar between the aripiprazole and placebo-treated patients.

Adverse Events Occurring at an Incidence of 2% or More Among Aripiprazole-Treated Patients and Greater than Placebo in Short-Term Placebo-Controlled Trials

Table 1 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy (up to 6 weeks), including only those events that occurred in 2% or more of patients treated with aripiprazole (doses ³2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo.

Table 1: Treatment-Emergent Adverse Events in Short-Term, Placebo-Controlled Trials
	Percentage of Patients Reporting Event^a
Body System Adverse Event	Aripiprazole (n=926)	Placebo (n=413)
Body as a Whole
Headache	32	25
Asthenia	7	5
Fever	2	1
Digestive System
Nausea	14	10
Vomiting	12	7
Constipation	10	8
Nervous System
Anxiety	25	24
Insomnia	24	19
Lightheadedness	11	7
Somnolence	11	8
Akathisia	10	7
Tremor	3	2
Respiratory System
Rhinitis	4	3
Coughing	3	2
Skin and Appendages
Rash	6	5
Special Senses
Blurred vision	3	1
^aEvents reported by at least 2% of patients treated with aripiprazole, except the following events, which had an incidence equal to or less than placebo: abdominal pain, accidental injury, back pain, dental pain, dyspepsia, diarrhea, dry mouth, myalgia, agitation, psychosis, extrapyramidal syndrome, hypertonia, pharyngitis, upper respiratory tract infection, dysmenorrhea, vaginitis.

Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials comparing various fixed doses (2, 10, 15, 20, and 30 mg/day) of aripiprazole to placebo. This analysis, stratified by study, indicated that the only adverse event to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence (placebo, 7.7%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 15.3%).

In the short-term, placebo-controlled trials the incidence of reported EPS for aripiprazole-treated patients was 6% vs. 6% for placebo. Objectively collected data from those trials on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias) also did not show a difference between aripiprazole and placebo, with the exception of the Barnes Akathisia Scale (aripiprazole, 0.08; placebo, -0.05).

A between group comparison for 4- to 6-week placebo-controlled trials revealed no medically important differences between the aripiprazole and placebo groups in the proportions of patients experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no aripiprazole/placebo differences in the incidence of discontinuations for changes in serum chemistry, hematology, or urinalysis.

In short-term trials, there was a slight difference in mean weight gain between aripiprazole and placebo patients (+0.7 kg vs. -0.05 kg, respectively), and also a difference in the proportion of patients meeting a weight gain criterion of ³ 7% of body weight [aripiprazole (8%) compared to placebo (3%)]. The following table provides the weight change results from a long-term (52-week) study of aripiprazole, both mean change from baseline and proportions of patients meeting a weight gain criterion of ³ 7% of body weight relative to baseline, categorized by BMI at baseline:

Between group comparisons for pooled, placebo-controlled trials revealed no significant differences between aripiprazole and placebo in the proportion of patients experiencing potentially important changes in ECG parameters; in fact, within the dose range of 10 to

30 mg/day, aripiprazole tended to slightly shorten the QT_c interval. Aripiprazole was associated with a median increase in heart rate of 4 beats per minute compared to a 1 beat per minute increase among placebo patients.

Other Adverse Events Observed During the Premarketing Evaluation of Aripiprazole

Following is a list of modified COSTART terms that reflect treatment-emergent adverse events as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with aripiprazole at multiple doses ³2 mg/day during any phase of a trial within the database of 5592 patients. All reported events are included except those already listed in Table 1, or other parts of the

section, those considered in the WARNINGS or PRECAUTIONS, those event terms which were so general as to be uninformative, events reported with an incidence of <0.05% and which did not have a substantial probability of being acutely life-threatening, events that are otherwise common as background events, and events considered unlikely to be drug related. It is important to emphasize that, although the events reported occurred during treatment with aripiprazole, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a Whole: Frequent – flu syndrome, peripheral edema, chest pain, neck pain, neck rigidy; Infrequent – pelvic pain, suicide attempt, face edema, malaise, photosensitivity, arm rigidity, jaw pain, chills, bloating, jaw tightness, enlarged abdomen, chest tightness; Rare – throat pain, back tightness, head heaviness, moniliasis, throat tightness, leg rigidity, neck tightness, Mendelson’s syndrome, heat stroke.

Frequent – hypertension, tachycardia, hypotension, bradycardia; Infrequent – palpitation, hemorrhage, myocardial infarction, prolonged QT interval, cardiac arrest, atrial fibrillation, heart failure, AV block, myocardial ischemia, phlebitis, deep vein thrombosis, angina pectoris, extrasystoles; Rare – vasovagal reaction, cardiomegaly, atrial flutter, thrombophlebitis.

Frequent – anorexia, nausea and vomiting; Infrequent – increased appetitie, gastroenteritis, dysphagia, flatulence, gastritis, tooth caries, gingivitis, hemorrhoids, gastroesophageal reflux, gastrointestinal hemorrhage, periodontal abscess, tongue edema, fecal incontinence, colitis, rectal hemorrhage, stomatitis, mouth ulcer, cholecystitis, fecal impaction, oral moniliasis, cholelithiasis, eructation, intestinal obstruction, peptic ulcer; Rare – esophagitis, gum hemorrhage, glossitis, hematemesis, melena, duodenal ulcer, cheilitis, hepatitis, hepatomegaly, pancreatitis, intestinal perforation.

Frequent – ecchymosis, amenia; Infrequent – hypochromic anemia, leukopenia, leukocytosis, lymphadenopathy, thrombocytopenia; Rare – eosinophilia, thrombocythemia, macrocytic anemia.

Frequent – weight loss, creatine phosphokinase increased; Infrequent – dehydration, edema, hypercholesteremia, hyperglycemia, hypokalemia, diabetes mellitus, SGPT increased, hyperlipemia, hypogycemia, thirst, BUN increased, hyponatremia, SGOT increased, alkaline phosphatase increased, iron deficiency anemia, creatinine increased, bilirubinemia, lactic dehydrogenase increased, obesity; Rare – hyperkalemia, gout, hypernatremia, cyanosis, hyperuricemia, hypoglycemic reaction.

Frequent – muscle cramp; Infrequent – arthralgia, bone pain, myasthenia, arthritis, arthrosis, muscle weakness, spasm, bursitis; Rare – rhabdomyolysis, tendonitis, tenosynovitis, rheumatoid arthritis, myopathy. Nervous System: Frequent – depression, nervousness, increased salivation, hostility, suicidal thought, manic reaction, abnormal gait, confusion, cogwheel rigidity; Infrequent –dystonia, twitch, impaired concentration, paresthesia, vasodilation, hypesthesia, extremity tremor, impotence, bradykinesia, decreased libido, panic attack, apathy, dyskinesia, hypersomnia, vertigo, dysarthia, tardive dyskinesia, ataxia, impaired memory, stupor, increased libido, amnesia, cerebrovascular accident, hyperactivity, depersonalization, hypokinesia, restless leg, myoclonus, dysphoria, neuropathy, increased reflexes, slowed thinking, hyperkinesia, hyperesthesia, hypotonia, oculogyric crisis; Rare – delirium, euphoria, buccoglossal syndrome, akinesia, blunted affect, decreased consciousness, incoordination, cerebral ischemia, decreased reflexes, obsessive thought, intracranial hemmorage.

Frequent – dyspnea, pneumonia; Infrequent – asthma, epistaxis, hiccup, laryngitis; Rare – hemoptysis, aspiration pneumonia, increased sputum, dry nasal passages, pulmonary edema, pulmonary embolism, hypoxia, respiratory failure, apnea.

Frequent – dry skin, pruritis, sweating, skin ulcer; Infrequent –acne, vesiculobullous rash, eczema, alopecia, psoriasis, seborrhea; Rare – maculopapular rash, exfoliative dermatitis, urticaria.

Frequent – conjunctivitus, ear pain; Infrequent – dry eye, eye pain, tinni-tus, otitis media, cataract, altered taste, blepharitis; Rare – increased lacrimation, frequent blinking, otitis externa, amblyopia, deafness, diplopia, eye hemorrhage, photophobia.

Frequent – urinary incontinence; Infrequent – cystitis, urinary frequency, leukorrhea, urinary retention, hematuria, dysuria, amenorrhea, abnormal ejaculation, vaginal hemorrhage, vaginal moniliasis, kidney failure, uterus hemorrhage, menorrhagia, albuminuria, kidney calculus, nocturia, polyuria, urinary urgency; Rare – breast pain, cervicitis, female lactation, anorgasmy, urinary burning, glycosuria, gynecomastia, urolithia-sis, priapism.

Aripiprazole has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ABILIFY misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

Table 2: Weight Change Results Categorized by BMI at Baseline
	BMI<23	BMI 23-27	BMI>27
Mean change from baseline (kg)	2.6	1.4	-1.2
% with ³ 7% increase BW	30%	19%	8%