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Safety Experience in Elderly Patients with Psychosis Associated with Alzheimer's Disease: In three, 10-week, placebo-controlled studies of ABILIFY in elderly patients with psychosis associated with Alzheimer's disease (n = 938; mean age: 82.4 years; range: 56 to 99 years), the adverse reactions that were reported at an incidence of ≥ 3% and ABILIFY incidence at least twice that for placebo were lethargy [placebo 2%, ABILIFY 5%], somnolence (including sedation) [placebo 3%, ABILIFY 8%], and incontinence (primarily, urinary incontinence) [placebo 1%, ABILIFY 5%], excessive salivation [placebo 0%, ABILIFY 4%], and light-headedness [placebo 1%, ABILIFY 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 WARNINGS].
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 (e.g., stroke, transient ischemic attack), including fatalities, in ABILIFY-treated patients (mean age: 84 years; range: 78 to 88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse events in patients treated with ABILIFY. ABILIFY is not approved for the treatment of patients with dementia-related psychosis. [See also WARNINGS and Increased Mortality in Elderly Patients with Dementia-Related Psychosis as previously mentioned.]
Suicidal Thoughts and Behaviours in Children, Adolescents, and Young Adults: Patients with major depressive disorder (MDD), both adult and paediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behaviour (suicidality) or unusual changes in behaviour, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behaviour (suicidality) in children, adolescents, and young adults (ages 18 - 24 years) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24 years; there was a reduction with antidepressants compared to placebo in adults aged 65 years and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 7. (See Table 7.)
Click on icon to see table/diagram/imageNo suicides occurred in any of the paediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behaviour, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and paediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and non-psychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and non-psychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behaviour, and the other symptoms described previously, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for ABILIFY should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described previously represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
It should be noted that ABILIFY is not approved for use in treating depression in the paediatric population.
Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including ABILIFY. Rare cases of NMS occurred during ABILIFY 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 (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: 1) immediate discontinuation of 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.
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.
Tardive dyskinesia 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 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.
Extrapyramidal symptoms (EPS): In paediatric clinical trials of aripiprazole, akathisia and Parkinsonism were observed. If signs and symptoms of other EPS appear in a patient taking aripiprazole, dose reduction and close clinical monitoring should be considered.
Venous Thromboembolism: Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with ABILIFY and preventive measures undertaken.
Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycaemia/diabetes mellitus, dyslipidaemia, and body weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
Hyperglycaemia/Diabetes Mellitus: Hyperglycaemia, 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 reports of hyperglycaemia in patients treated with ABILIFY. 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 hyperglycaemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycaemia-related adverse reactions in patients treated with the atypical antipsychotics. 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 hyperglycaemia-related adverse reactions 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 (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Adults: In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with schizophrenia or bipolar disorder, the mean change in fasting glucose in ABILIFY-treated patients (+ 4.4 mg/dL; median exposure 25 days; N = 1057) was not significantly different than in placebo-treated patients (+ 2.5 mg/dL; median exposure 22 days; N = 799). Table 8 shows the proportion of ABILIFY-treated patients with normal and borderline fasting glucose at baseline (median exposure 25 days) that had treatment-emergent high fasting glucose measurements compared to placebo-treated patients (median exposure 22 days). (See Table 8.)
Click on icon to see table/diagram/imageAt 24 weeks, the mean change in fasting glucose in ABILIFY-treated patients was not significantly different than in placebo-treated patients [+ 2.2 mg/dL (n=42) and + 9.6 mg/dL (n=28), respectively].
The mean change in fasting glucose in adjunctive ABILIFY-treated patients with major depressive disorder was slightly lower than in placebo-treated patients. Table 9 shows the proportion of adult patients with changes in fasting glucose levels from three placebo-controlled, adjunctive trials in patients with major depressive disorder. (See Table 9.)
Click on icon to see table/diagram/imagePaediatric Patients & Adolescents: In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and paediatric patients with bipolar disorder (10 to 17 years), the mean change in fasting glucose in ABILIFY-treated patients (+ 4.8 mg/dL; with a median exposure of 43 days; N = 259) was not significantly different than in placebo-treated patients (+1.7 mg/dL; with a median exposure of 42 days; N = 123).
In an analysis of two placebo-controlled trials in paediatric and adolescent patients with irritability associated with autistic disorder (6 to 17 years) with median exposure of 56 days, the mean change in fasting glucose in ABILIFY-treated patients (-0.2 mg/dL; N = 83) was not significantly different than in placebo-treated patients (-0.6 mg/dL; N = 33).
In an analysis of two placebo-controlled trials in paediatric and adolescent patients with Tourette's disorder (6 to 18 years) with median exposure of 57 days, the mean change in fasting glucose in ABILIFY-treated patients (0.79 mg/dL; N = 90) was not significantly different than in placebo-treated patients (-1.66 mg/dL; N = 58).
Table 10 shows the proportion of patients with changes in fasting glucose levels from the pooled adolescent schizophrenia and paediatric bipolar patients (median exposure of 42 to 43 days), from two placebo-controlled trials in paediatric patients (6 to 17 years) with irritability associated with autistic disorder (median exposure of 56 days), and from the two placebo-controlled trials in paediatric patients (6 to 18 years) with Tourette's Disorder (median exposure 57 days). (See Table 10.)
Click on icon to see table/diagram/imageAt 12 weeks in the pooled adolescent schizophrenia and paediatric bipolar disorder trials, the mean change in fasting glucose in ABILIFY-treated patients was not significantly different than in placebo-treated patients [+2.4 mg/dL (n = 81) and +0.1 mg/dL (n = 15), respectively].
Dyslipidaemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
There were no significant differences between ABILIFY- and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/non-fasting total cholesterol, fasting triglycerides, fasting LDLs, and fasting/non-fasting HDLs. Analyses of patients with at least 12 or 24 weeks of exposure were limited by small numbers of patients.
Adults: Table 11 shows the proportion of adult patients, primarily from pooled schizophrenia and bipolar disorder monotherapy placebo-controlled trials, with changes in total cholesterol (pooled from 17 trials; median exposure 21 to 25 days), fasting triglycerides (pooled from eight trials; median exposure 42 days), fasting LDL cholesterol (pooled from eight trials; median exposure 39 to 45 days, except for placebo-treated patients with baseline normal fasting LDL measurements, who had median treatment exposure of 24 days) and HDL cholesterol (pooled from nine trials; median exposure 40 to 42 days). (See Table 11.)
Click on icon to see table/diagram/imageIn monotherapy trials, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/non-fasting), fasting triglycerides, and fasting LDL cholesterol were similar between ABILIFY- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/non-fasting), 1/71 (1.4%) vs. 3/74 (4.1%); Fasting Triglycerides, 8/62 (12.9%) vs. 5/37 (13.5%); Fasting LDL Cholesterol, 0/34 (0%) vs. 1/25 (4.0%), respectively; and at 24 weeks, Total Cholesterol (fasting/non-fasting), 1/42 (2.4%) vs. 3/37 (8.1%); Fasting Triglycerides, 5/34 (14.7%) vs. 5/20 (25%); Fasting LDL Cholesterol, 0/22 (0%) vs. 1/18 (5.6%), respectively.
Table 12 shows the incidence of patients with changes in total cholesterol (fasting/non-fasting), fasting triglycerides, fasting LDL cholesterol, and HDL cholesterol from three placebo-controlled adjunctive trials in adult patients with major depressive disorder. (See Table 12.)
Click on icon to see table/diagram/imagePaediatric Patients & Adolescents: Table 13 shows the proportion of adolescents with schizophrenia (13 to 17 years) and paediatric patients with bipolar disorder (10 to 17 years) with changes in total cholesterol and HDL cholesterol (pooled from two placebo-controlled trials; median exposure 42 to 43 days) and fasting triglycerides (pooled from two placebo-controlled trials; median exposure 42 to 44 days). (See Table 13.)
Click on icon to see table/diagram/imageIn monotherapy trials of adolescents with schizophrenia and paediatric patients with bipolar disorder, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/non-fasting), fasting triglycerides, and fasting LDL cholesterol were similar between ABILIFY- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/non-fasting), 0/57 (0%) vs. 0/15 (0%); Fasting Triglycerides, 2/72 (2.8%) vs. 1/14 (7.1%), respectively; and at 24 weeks, Total Cholesterol (fasting/non-fasting), 0/36 (0%) vs. 0/12 (0%); Fasting Triglycerides, 1/47 (2.1%) vs. 1/10 (10.0%), respectively.
Table 14 shows the proportion of patients with changes in total cholesterol (fasting/non-fasting) and fasting triglycerides (median exposure 56 days) and HDL cholesterol (median exposure 55 to 56 days) from two placebo-controlled trials in paediatric patients (6 to 17 years) with irritability associated with autistic disorder. (See Table 14.)
Click on icon to see table/diagram/imageTable 15 shows the proportion of patients with changes in total cholesterol (fasting/non-fasting) and fasting triglycerides (median exposure 57 days) and HDL cholesterol (median exposure 57 days) from two placebo-controlled trials in paediatric patients (6 to 18 years) with Tourette's Disorder. (See Table 15.)
Click on icon to see table/diagram/imageWeight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
Adults: In an analysis of 13 placebo-controlled monotherapy trials, primarily from pooled schizophrenia and bipolar disorder, with a median exposure of 21 to 25 days, the mean change in body weight in ABILIFY-treated patients was +0.3 kg (N = 1673) compared to -0.1 kg (N = 1100) in placebo-controlled patients. At 24 weeks, the mean change from baseline in body weight in ABILIFY-treated patients was -1.5 kg (n = 73) compared to -0.2 kg (n = 46) in placebo-treated patients.
In the trials adding ABILIFY to antidepressants, patients first received 8 weeks of antidepressant treatment followed by 6 weeks of adjunctive ABILIFY or placebo in addition to their ongoing antidepressant treatment. The mean change in body weight in patients receiving adjunctive ABILIFY was +1.6 kg (N = 456) compared to +0.6kg (N = 451) in patients receiving adjunctive placebo.
Table 16 shows the percentage of patients with weight gain ≥7% of body weight by indication. (See Table 16.)
Click on icon to see table/diagram/imagePaediatric Patients & Adolescents: In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and paediatric patients with bipolar disorder (10 to 17 years) with median exposure of 42 to 43 days, the mean change in body weight in ABILIFY-treated patients was + 1.6 kg (N = 381) compared to + 0.3 kg (N = 187) in placebo-treated patients. At 24 weeks, the mean change from baseline in body weight in ABILIFY-treated patients was + 5.8 kg (n = 62) compared to + 1.4 kg (n = 13) in placebo-treated patients.
In two short-term, placebo-controlled trials in patients (6 to 17 years) with irritability associated with autistic disorder with median exposure of 56 days, the mean change in body weight in ABILIFY-treated patients was + 1.6 kg (n = 209) compared to + 0.4 kg (n = 98) in placebo-treated patients.
In two short-term, placebo-controlled trials in patients (6 to 18 years) with Tourette's Disorder with median exposure of 57 days, the mean change in body weight in ABILIFY-treated patients was + 1.5 kg (n = 105) compared to + 0.4 kg (n = 66) in placebo-treated patients.
Table 17 shows the percentage of paediatric and adolescent patients with weight gain ≥ 7% of body weight by indication. (See Table 17.)
Click on icon to see table/diagram/imageIn an open-label trial that enrolled patients from the two placebo-controlled trials of adolescents with schizophrenia (13 to 17 years) and paediatric patients with bipolar disorder (10 to 17 years), 73.2% of patients (238/325) completed 26 weeks of therapy with ABILIFY. After 26 weeks, 32.8% of patients gained ≥ 7% of their body weight, not adjusted for normal growth. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of paediatric patients and adolescents by comparisons to age-and gender-matched population standards. A z-score change < 0.5 SD is considered not clinically significant. After 26 weeks, the mean change in z-score was 0.09 SD.
In an open-label trial that enrolled patients from two short-term, placebo-controlled trials, patients (6 to 17 years) with irritability associated with autistic disorder, as well as de novo patients, 60.3% (199/330) completed one year of therapy with ABILIFY. The mean change in weight z-score was 0.26 SDs for patients receiving > 9 months of treatment.
In a 52-week open-label, multicentre study evaluating the safety and tolerability of once-daily oral ABILIFY in children and adolescents with Tourette's Disorder (7 to 17 years), 70% of patients were exposed to aripiprazole for 337 to 364 days and 21.7% (15/69) of patients treated with aripiprazole reported weight increased as a treatment-emergent adverse event.
When treating paediatric patients for any indication, weight gain should be monitored and assessed against that expected for normal growth.
Orthostatic Hypotension: ABILIFY 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 adult patients on oral ABILIFY (n = 2467) included (ABILIFY incidence, placebo incidence) orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%); and of paediatric patients 6 to 18 years of age (n = 732) on oral ABILIFY included orthostatic hypotension (0.5%, 0%), postural dizziness (0.4%, 0%), and syncope (0.2%, 0%) [see Clinical Trials Experience under ADVERSE REACTIONS].
The incidence of a significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure ≥ 20 mmHg accompanied by an increase in heart rate ≥ 25 bpm when comparing standing to supine values) for ABILIFY was not meaningfully different from placebo (ABILIFY incidence, placebo incidence): in adult oral ABILIFY-treated patients (4%, 2%) and in paediatric oral ABILIFY-treated patients aged 6 to 18 years (0.4%, 1%).
ABILIFY 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) [see Drugs Having Clinically Important Interactions with ABILIFY under INTERACTIONS].
Leukopenia, Neutropenia, and Agranulocytosis: In clinical trial and/or post-marketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including ABILIFY. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of ABILIFY at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue ABILIFY in patients with severe neutropenia (absolute neutrophil count < 1000/mm3) and follow their WBC counts until recovery.
Seizures/Convulsions: In short-term, placebo-controlled trials, patients with a history of seizures excluded seizures/convulsions occurred in 0.1% (3/2467) of undiagnosed adult patients treated with oral ABILIFY and in 0.1% (1/732) of paediatric patients (6 to 18 years).
As with other antipsychotic drugs, ABILIFY should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
Potential for Cognitive and Motor Impairment: ABILIFY, like other antipsychotics, may have the potential to impair judgment, thinking, or motor skills. For example, in short-term, placebo-controlled trials, somnolence (including sedation) was reported as follows (ABILIFY incidence, placebo incidence): in adult patients (n = 2467) treated with oral ABILIFY (11%, 6%) and in paediatric patients age 6 to 17 years (n = 611) (24%, 6%). Somnolence (including sedation) led to discontinuation in 0.3% (8/2467) of adult patients and 3% (20/732) of paediatric patients (6 to 18 years) on oral ABILIFY in short-term, placebo-controlled trials.
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.
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 ABILIFY for patients who will be experiencing conditions which may contribute to an elevation in core body temperature (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration).
Suicide: The possibility of a suicide attempt is inherent in psychotic illnesses, bipolar disorder, and major depressive disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for ABILIFY should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.
Dysphagia: Oesophageal 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. ABILIFY and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Increased Mortality in Elderly Patients with Dementia-Related Psychosis as previously mentioned].
Pathological Gambling and Other Compulsive Behaviours: Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviours. Because patients may not recognize these behaviours as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Compulsive behaviours may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.
Sleep apnoea and related disorders: Sleep apnoea and related disorders have been reported in patients treated with atypical antipsychotic drugs, including aripiprazole, with or without concomitant weight gain or prior history of sleep apnoea.
Aripiprazole should be used with caution in patients who have sleep apnoea or risk factors for developing sleep apnoea, which include: overweight/obesity, males, and concomitant use of central nervous system depressants.
Falls: Antipsychotics, including ABILIFY, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
CYP2D6 Poor Metabolizers: Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3 to 8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM). The rest are extensive metabolizers (EM). PMs have about an 80% increase in aripiprazole exposure and about a 30% decrease in exposure to the active metabolite compared to EMs, resulting in about a 60% higher exposure to the total active moieties from a given dose of aripiprazole compared to EMs. Co-administration of ABILIFY with known inhibitors of CYP2D6, such as quinidine or fluoxetine in EMs, approximately doubles aripiprazole plasma exposure, and dose adjustment is needed [see Drugs Having Clinically Important Interactions with ABILIFY under INTERACTIONS]. Similarly, PMs have higher exposure to aripiprazole compared to EMs; hence, PMs should have their initial dose reduced by one-half. Laboratory tests are available to identify CYP2D6 PMs. Aripiprazole does not inhibit or induce the CYP2D6 pathway [see Dosage Adjustments for Cytochrome P450 Considerations under DOSAGE & ADMINISTRATION and PHARMACOLOGY: Pharmacokinetics under Actions].
Hepatic and Renal Impairment: No dosage adjustment for ABILIFY is required on the basis of a patient's hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute) [see PHARMACOLOGY: Pharmacokinetics under Actions].
Other Specific Populations: No dosage adjustment for ABILIFY is required on the basis of a patient's sex, race, or smoking status [see PHARMACOLOGY: Pharmacokinetics under Actions].
Drug Abuse and Dependence: Controlled Substance: ABILIFY is not a controlled substance.
Abuse and Dependence: ABILIFY 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 behaviour, 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 behaviour).
Use in Children: Safety and effectiveness in paediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established.
The pharmacokinetics of aripiprazole and dehydro-aripiprazole in paediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight [see PHARMACOLOGY: Pharmacokinetics under Actions].
Schizophrenia: Safety and effectiveness in paediatric patients with schizophrenia were established in a 6-week, placebo-controlled clinical trial in 202 paediatric patients aged 13 to 17 years [see Schizophrenia under DOSAGE & ADMINISTRATION, Clinical Trials Experience under ADVERSE REACTIONS, and Pharmacology: Pharmacodynamics: CLINICAL STUDIES: Schizophrenia under Actions]. Although maintenance efficacy in paediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and paediatric patients.
Bipolar I Disorder: Safety and effectiveness in paediatric patients with bipolar mania were evaluated in a 4-week, placebo-controlled clinical trial in 197 paediatric patients aged 10 to 17 years. Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, ABILIFY is not recommended for use in patients below 13 years of age [see Bipolar Disorder under DOSAGE & ADMINISTRATION, Clinical Trials Experience under ADVERSE REACTIONS, and Pharmacology: Pharmacodynamics: CLINICAL STUDIES: Bipolar Disorder under Actions]. Although maintenance efficacy in paediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and paediatric patients.
The efficacy of adjunctive ABILIFY with concomitant lithium or valproate in the treatment of manic or mixed episodes in paediatric patients has not been systematically evaluated.
Irritability Associated with Autistic Disorder: Safety and effectiveness in paediatric patients demonstrating irritability associated with autistic disorder were established in two 8-week, placebo-controlled clinical trials in 212 paediatric patients aged 6 to 17 years [see INDICATIONS/USES, Irritability Associated with Autistic Disorder under DOSAGE & ADMINISTRATION, Clinical Trials Experience under ADVERSE REACTIONS, and Pharmacology: Pharmacodynamics: CLINICAL STUDIES: Irritability Associated with Autistic Disorder under Actions]. A maintenance trial was conducted in paediatric patients (6 to 17 years of age) with irritability associated with autistic disorder. The first phase of this trial was an open-label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were stabilized (defined as > 25% improvement on the ABC-I subscale, and a CGI-I rating of "much improved" or "very much improved") on ABILIFY for 12 consecutive weeks. Overall, 85 patients were stabilized and entered the second, 16-week, double-blind phase where they were randomized to either continue ABILIFY treatment or switch to placebo. In this trial, the efficacy of ABILIFY for the maintenance treatment of irritability associated with autistic disorder was not established.
Tourette's Disorder: Safety and effectiveness of aripiprazole in paediatric patients with Tourette's Disorder were established in one 8-week (aged 7 to 17) and one 10-week trial (aged 6 to 18) in 194 paediatric patients [see Tourette's Disorder under DOSAGE & ADMINISTRATION, Clinical Trials Experience under ADVERSE REACTIONS, and Pharmacology: Pharmacodynamics: CLINICAL STUDIES: Tourette's Disorder under Actions]. Maintenance efficacy in paediatric patients has not been systematically evaluated.
Juvenile Animal Studies: Aripiprazole in juvenile rats caused mortality, CNS clinical signs, impaired memory and learning, and delayed sexual maturation when administered at oral doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). At 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other CNS signs were observed in both genders. In addition, delayed sexual maturation was observed in males. At all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. The changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. A No Observed Adverse Effect Level (NOAEL) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0-24) for aripiprazole or its major active metabolite in adolescents at the maximum recommended paediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies.
Aripiprazole in juvenile dogs (2 months old) caused CNS clinical signs of tremors, hypo activity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day. Mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values. A NOAEL could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0-24) for aripiprazole or its major active metabolite in adolescents at the maximum recommended paediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period.
Use in the Elderly: No dosage adjustment is recommended for elderly patients [see also WARNINGS, Increased Mortality in Elderly Patients with Dementia-Related Psychosis as previously mentioned and PHARMACOLOGY: Pharmacokinetics under Actions].
Of the 13,543 patients treated with oral ABILIFY in clinical trials, 1,073 (8%) were ≥ 65 years old and 799 (6%) were ≥ 75 years old. Placebo-controlled studies of oral ABILIFY in schizophrenia, bipolar mania, or major depressive disorder did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.
ABILIFY is not approved for treatment of patients with psychosis associated with Alzheimer's disease [see also WARNINGS and Increased Mortality in Elderly Patients with Dementia-Related Psychosis as previously mentioned].
