Aripiprazole (Page 3 of 11)

5.5 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Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn.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, aripiprazole 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 aripiprazole, drug discontinuation should be considered. However, some patients may require treatment with aripiprazole despite the presence of the syndrome.

5.6 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, 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.

Hyperglycemia/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 reports of hyperglycemia in patients treated with aripiprazole [see Adverse Reactions (6.1, 6.2)]. 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 suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Because aripiprazole was not marketed at the time these studies were performed, it is not known if aripiprazole is associated with this increased risk. Precise risk estimates for hyperglycemia-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 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.

Adults
In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with schizophrenia or another disorder, the mean change in fasting glucose in aripiprazole-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 6 shows the proportion of aripiprazole-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).
Table 6: Changes in Fasting Glucose From Placebo-Controlled Monotherapy Trials in Adult Patients

Fasting Glucose Category Change (at least once) from Baseline Treatment Arm n/N %
Normal to High (<100 mg/dL to ≥126 mg/dL) Aripiprazole 31/822 3.8
Placebo 22/605 3.6
Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) Aripiprazole 31/176 17.6
Placebo 13/142 9.2

At 24 weeks, the mean change in fasting glucose in aripiprazole-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].

Pediatric Patients and Adolescents
In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with another disorder (10 to 17 years), the mean change in fasting glucose in aripiprazole-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).
Table 8 shows the proportion of patients with changes in fasting glucose levels from the pooled adolescent schizophrenia and other pediatric patients (median exposure of 42-43 days). Table 8: Changes in Fasting Glucose From Placebo-Controlled Trials in Pediatric and Adolescent Patients

Category Change (at least once) from Baseline Indication Treatment Arm n/N %
Fasting Glucose Normal to High (<100 mg/dL to ≥126 mg/dL) Pooled Schizophrenia and Another Disorder Aripiprazole 2/236 0.8
Placebo 2/110 1.8
Fasting Glucose Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) Pooled Schizophrenia and Another Disorder Aripiprazole 1/22 4.5
Placebo 0/12 0

At 12 weeks in the pooled adolescent schizophrenia and other pediatric disorder trials, the mean change in fasting glucose in aripiprazole-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].

Dyslipidemia
Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
There were no significant differences between aripiprazole — and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting LDLs, and fasting/nonfasting HDLs. Analyses of patients with at least 12 or 24 weeks of exposure were limited by small numbers of patients.

Adults Table 9 shows the proportion of adult patients, primarily from pooled schizophrenia and other 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).

Table 9: Changes in Blood Lipid Parameters From Placebo-Controlled Monotherapy Trials in Adults

Treatment Arm n/N %
Total Cholesterol Normal to High (<200 mg/dL to ≥240 mg/dL) Aripiprazole 34/1357 2.5
Placebo 27/973 2.8
Fasting Triglycerides Normal to High (<150 mg/dL to ≥200 mg/dL) Aripiprazole 40/539 7.4
Placebo 30/431 7.0
Fasting LDL Cholesterol Normal to High (<100 mg/dL to ≥160 mg/dL) Aripiprazole 2/332 0.6
Placebo 2/268 0.7
HDL Cholesterol Normal to Low (≥40 mg/dL to <40 mg/dL) Aripiprazole 121/1066 11.4
Placebo 99/794 12.5

In monotherapy trials in adults, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 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/nonfasting), 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.

Pediatric Patients and Adolescents Table 11 shows the proportion of adolescents with schizophrenia (13 to 17 years) and pediatric patients with another 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).

Table 11: Changes in Blood Lipid Parameters From Placebo-Controlled Monotherapy Trials in Pediatric and Adolescent Patients in Schizophrenia and Another Disorder

Treatment Arm n/N %
Total Cholesterol Normal to High (<170 mg/dL to ≥200 mg/dL) Aripiprazole 3/220 1.4
Placebo 0/116 0
Fasting Triglycerides Normal to High (<150 mg/dL to ≥200 mg/dL) Aripiprazole 7/187 3.7
Placebo 4/85 4.7
HDL Cholesterol Normal to Low (≥40 mg/dL to <40 mg/dL) Aripiprazole 27/236 11.4
Placebo 22/109 20.2

In monotherapy trials of adolescents with schizophrenia and pediatric patients with another disorder, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 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/nonfasting), 0/36 (0%) vs. 0/12 (0%); Fasting Triglycerides, 1/47 (2.1%) vs. 1/10 (10.0%), respectively.

Weight 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 another disorder, with a median exposure of 21 to 25 days, the mean change in body weight in aripiprazole-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 aripiprazole-treated patients was –1.5 kg (n=73) compared to –0.2 kg (n=46) in placebo-treated patients.

Table 14 shows the percentage of adult patients with weight gain ≥7% of body weight by indication.

Table 14: Percentage of Patients From Placebo-Controlled Trials in Adult Patients with Weight Gain ≥7% of Body Weight

Pediatric Patients and Adolescents

Weight gain ≥7% of body weight Indication Treatment Arm N Patients n (%)
Schizophreniaa Aripiprazole 852 69 (8.1)
Placebo 379 12 (3.2)
Another Indication b Aripiprazole 719 16 (2.2)
Placebo 598 16 (2.7)
Another Indication c Aripiprazole 347 18 (5.2)
Placebo 330 2 (0.6)
a 4-6 weeks duration. b 3 weeks duration. c 6 weeks duration.

In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with another disorder (10 to 17 years) with median exposure of 42 to 43 days, the mean change in body weight in aripiprazole-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 aripiprazole-treated patients was +5.8 kg (n=62) compared to +1.4 kg (n=13) in placebo-treated patients.
Table 15 shows the percentage of pediatric and adolescent patients with weight gain ≥7% of body weight by indication.Table 15: Percentage of Patients From Placebo-Controlled Monotherapy Trials in Pediatric and Adolescent Patients with Weight Gain ≥7% of Body Weight

Weight gain ≥7% of body weight Indication Treatment Arm N Patients n (%)
Pooled Schizophrenia and Another Disorder a Aripiprazole 381 20 (5.2)
Placebo 187 3 (1.6)
a 4-6 weeks duration.

In an open-label trial that enrolled patients from the two placebo-controlled trials of adolescents with schizophrenia (13 to 17 years) and pediatric patients with another disorder (10 to 17 years), 73.2% of patients (238/325) completed 26 weeks of therapy with aripiprazole. 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 pediatric 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.

When treating pediatric patients for any indication, weight gain should be monitored and assessed against that expected for normal growth.

Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

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