A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Abilify Side Effects, and Drug Interactions - Aripiprazole
Abilify Side Effects, and Drug Interactions - Aripiprazole
SIDE EFFECTS
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 =2 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 Eventa
|
|
Body System
|
Aripiprazole
|
Placebo
|
|
Adverse Event
|
(n=926)
|
(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
|
|
a Events 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.
|
An examination of population subgroups did not reveal any clear evidence of differential adverse event incidence on the basis of age, gender, or race.
Dose-Related Adverse Events
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%).
Extrapyramidal Symptoms
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).
Similarly, in a long-term (26-week), placebo-controlled trial, 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 aripiprazole and placebo.
Laboratory Test Abnormalities
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 a long-term (26-week), placebo-controlled trial there were no medically important differences between the aripiprazole and placebo patients in the mean change from baseline in prolactin, fasting glucose, triglyceride, HDL, LDL, and total cholesterol measurements.
Weight Gain
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 >7% of body weight [aripiprazole (8%) compared to placebo (3%)].
Table 2 provides the weight change results from a long-term (26-week), placebo-controlled study of aripiprazole, both mean change from baseline and proportions of patients meeting a weight gain criterion of >7% of body weight relative to baseline, categorized by BMI at baseline:
|
Table 2: Weight Change Results Categorized by BMI at Baseline: Placebo-Controlled Study in Schizophrenia, Safety Sample |
| |
BMI <23 |
BMI 23-27 |
BMI >27 |
| |
Placebo |
Aripiprazole |
Placebo |
Aripiprazole |
Placebo |
Aripiprazole |
|
Mean change from baseline (kg)
|
-0.5 |
-0.5 |
-0.6 |
-1.3 |
-1.5 |
-2.1 |
|
% with > 7% increase BW |
3.7% |
6.8% |
4.2% |
5.1% |
4.1% |
5.7% |
Table 3 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 >7% of body weight relative to baseline, categorized by BMI at baseline:
|
Table 3: 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 >7% increase BW |
30% |
19% |
8% |
ECG Changes
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 QTc 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.
Additional Findings Observed in Clinical Trials
Adverse Events in a Long-Term, Double-Blind, Placebo-Controlled Trial
The adverse events reported in a 26-week, double-blind trial comparing ABILIFY and placebo were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [9% (13/153) for ABILIFY vs. 1% (2/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity (9/13 mild and 4/13 moderate), occurred early in therapy (9/13 <49 days), and were of limited duration (9/13 <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 for ABILIFY was 4% (34/859).
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 >2 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 ADVERSE REACTIONS
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 rigidity; 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.
Cardiovascular System: 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.
Digestive System: Frequent - anorexia, nausea and vomiting; Infrequent - increased appetite, 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.
Endocrine System: Infrequent - hypothyroidism; Rare - goiter, hyperthyroidism.
Hemic/Lymphatic System: Frequent - ecchymosis, anemia; Infrequent - hypochromic anemia, leukopenia, leukocytosis, lymphadenopathy, thrombocytopenia; Rare - eosinophilia, thrombocythemia, macrocytic anemia.
Metabolic and Nutritional Disorders: Frequent - weight loss, creatine phosphokinase increased; Infrequent - dehydration, edema, hypercholesteremia, hyperglycemia, hypokalemia, diabetes mellitus, SGPT increased, hyperlipemia, hypoglycemia, 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.
Musculoskeletal System: 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, dysarthria, 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 hemorrhage.
Respiratory System: 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.
Skin and Appendages: Frequent - dry skin, pruritus, sweating, skin ulcer; Infrequent - acne, vesiculobullous rash, eczema, alopecia, psoriasis, seborrhea; Rare - maculopapular rash, exfoliative dermatitis, urticaria.
Special Senses: Frequent - conjunctivitis, ear pain; Infrequent - dry eye, eye pain, tinnitus, otitis media, cataract, altered taste, blepharitis; Rare - increased lacrimation, frequent blinking, otitis externa, amblyopia, deafness, diplopia, eye hemorrhage, photophobia.
Urogenital System: 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, urolithiasis, priapism.
DRUG ABUSE AND DEPENDENCE
Controlled Substance
ABILIFY (aripiprazole) is not a controlled substance.
Abuse and Dependence
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 (eg, development of tolerance, increases in dose, drug-seeking behavior).
DRUG INTERACTIONS
Given the primary CNS effects of aripiprazole, caution should
be used when ABILIFY is taken in combination with other centrally acting drugs
and alcohol. Due to its a 1-adrenergic receptor antagonism,
aripiprazole has the potential to enhance the effect of certain antihypertensive
agents.
Potential for Other Drugs to Affect ABILIFY
Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6,
CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not
undergo direct glucuronidation. This suggests that an interaction of aripiprazole
with inhibitors or inducers of these enzymes, or other factors, like smoking,
is unlikely.
Both CYP3A4 and CYP2D6 are responsible for aripiprazole metabolism.
Agents that induce CYP3A4 (eg, carbamazepine) could cause an increase in aripiprazole
clearance and lower blood levels. Inhibitors of CYP3A4 (eg, ketoconazole) or
CYP2D6 (eg, quinidine, fluoxetine, or paroxetine) can inhibit aripiprazole elimination
and cause increased blood levels.
Ketoconazole: Coadministration of ketoconazole (200
mg/day for 14 days) with a 15-mg single dose of aripiprazole increased the AUC
of aripiprazole and its active metabolite by 63% and 77%, respectively. The
effect of a higher ketoconazole dose (400 mg/day) has not been studied. When
concomitant administration of ketoconazole with aripiprazole occurs, aripiprazole
dose should be reduced to one-half of its normal dose. Other strong inhibitors
of CYP3A4 (itraconazole) would be expected to have similar effects and need
similar dose reductions; weaker inhibitors (erythromycin, grapefruit juice)
have not been studied. When the CYP3A4 inhibitor is withdrawn from the combination
therapy, aripiprazole dose should then be increased.
Quinidine: Coadministration of a 10-mg single dose of
aripiprazole with quinidine (166 mg/day for 13 days), a potent inhibitor of
CYP2D6, increased the AUC of aripiprazole by 112% but decreased the AUC of its
active metabolite, dehydro-aripiprazole, by 35%. Aripiprazole dose
should be reduced to one-half of its normal dose when concomitant administration
of quinidine with aripiprazole occurs. Other significant inhibitors of CYP2D6,
such as fluoxetine or paroxetine, would be expected to have similar effects
and, therefore, should be accompanied by similar dose reductions. When the CYP2D6
inhibitor is withdrawn from the combination therapy, aripiprazole dose should
then be increased.
Carbamazepine: Coadministration of carbamazepine (200
mg BID), a potent CYP3A4 inducer, with aripiprazole (30 mg QD) resulted in an
approximate 70% decrease in Cmax and AUC values of both aripiprazole and its
active metabolite, dehydro-aripiprazole. When carbamazepine is added to aripiprazole
therapy, aripiprazole dose should be doubled. Additional dose increases should
be based on clinical evaluation.
When carbamazepine is withdrawn from the combination therapy,
aripiprazole dose should then be reduced.
No clinically significant effect of famotidine, valproate,
or lithium was seen on the pharmacokinetics of aripiprazole (see CLINICAL
PHARMACOLOGY: Drug-Drug Interactions).
Potential for ABILIFY to Affect Other Drugs
Aripiprazole is unlikely to cause clinically important pharmacokinetic
interactions with drugs metabolized by cytochrome P450 enzymes. In in vivo
studies, 10- to 30-mg/day doses of aripiprazole had no significant effect on
metabolism by CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole,
warfarin), and CYP3A4 (dextromethorphan) substrates. Additionally, aripiprazole
and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated
metabolism in vitro (see CLINICAL PHARMACOLOGY:
Drug-Drug Interactions).
Alcohol: There was no significant difference between
aripiprazole coadministered with ethanol and placebo coadministered with ethanol
on performance of gross motor skills or stimulus response in healthy subjects.
As with most psychoactive medications, patients should be advised to avoid alcohol
while taking ABILIFY.
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