Risperidone (Page 3 of 12)

5.3 Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and 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.

If NMS is suspected, immediately discontinue Risperidone Oral Solution and provide symptomatic treatment and monitoring.

5.4 Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting 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 predict which patients will 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 increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia, may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, risperidone 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: (1) who suffer from a chronic illness that 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, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

If signs and symptoms of tardive dyskinesia appear in a patient on risperidone, drug discontinuation should be considered. However, some patients may require treatment with risperidone despite the presence of the syndrome.

5.5 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including risperidone. 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 treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. 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, including risperidone, 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, including risperidone, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including risperidone, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including risperidone, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of risperidone.

Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 2.

Table 2. Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania
Risperidone
Placebo 1 to 8 mg/day >8 to 16 mg/day
Mean change from baseline (mg/dL)
n = 555 n = 748 n = 164
Serum Glucose -1.4 0.8 0.6
Proportion of patients with shifts

Serum Glucose

(<140 mg/dL to ≥ 200 mg/dL)

0.6%

(3/525)

0.4%

(3/702)

0%

(0/158)

In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in glucose of +2.8 mg/dL at Week 24 (n = 151) and +4.1 mg/dL at Week 48 (n = 50).

Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 3.

Table 3. Change in Fasting Glucose from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13 to 17 years of age), Bipolar Mania (10 to 17 years of age), or Autistic Disorder (5 to 17 years of age)

Risperidone
Placebo 0.5 to 6 mg/day
Mean change from baseline (mg/dL)
n = 76 n = 135
Serum Glucose -1.3 2.6
Proportion of patients with shifts

Serum Glucose

(<100 mg/dL to ≥126 mg/dL)

0%

(0/64)

0.8%

(1/120)

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n = 119).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 4.

Table 4. Change in Random Lipids from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania
Risperidone
Placebo 1 to 8 mg/day >8 to16 mg/day
Mean change from baseline (mg/dL)

Cholesterol

Change from baseline

n = 559

0.6

n = 742

6.9

n = 156

1.8

Triglycerides

Change from baseline

n = 183

-17.4

n = 307

-4.9

n = 123

-8.3

Proportion of patients with shifts

Cholesterol

(<200 mg/dL to ≥240 mg/dL)

2.7%

(10/368)

4.3%

(22/516)

6.3%

(6/96)

Triglycerides

(<500 mg/dL to ≥500 mg/dL)

1.1%

(2/180)

2.7%

(8/301)

2.5%

(3/121)

In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n = 231) and +5.5 mg/dL at Week 48 (n = 86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n = 52).

Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 5.

Table 5. Change in Fasting Lipids from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), or Autistic Disorder (5 to 17 Years of Age)
Placebo

Risperidone

0.5 to 6 mg/day

Mean change from baseline (mg/dL)

Cholesterol

Change from baseline

n = 74

0.3

n = 133

-0.3

LDL

Change from baseline

n = 22

3.7

n = 22

0.5

HDL

Change from baseline

n = 22

1.6

n = 22

-1.9

Triglycerides

Change from baseline

n = 77

-9

n = 138

-2.6

Proportion of patients with shifts

Cholesterol

(<170 mg/dL to ≥200 mg/dL)

2.4%

(1/42)

3.8%

(3/80)

LDL

(<110 mg/dL to ≥130 mg/dL)

0%

(0/16)

0%

(0/16)

HDL

(≥40 mg/dL to <40 mg/dL)

0%

(0/19)

10%

(2/20)

Triglycerides

(<150 mg/dL to ≥200 mg/dL)

1.5%

(1/65)

7.1%

(8/113)

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n = 114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n = 103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n = 103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n = 120).

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 6.

Table 6. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania
Risperidone

Placebo

(n = 597)

1 to 8 mg/day

(n = 769)

>8 to16 mg/day

(n = 158)

Weight (kg)

Change from baseline

-0.3 0.7 2.2

Weight Gain

≥7% increase from baseline

2.9% 8.7% 20.9%

In longer-term, controlled and uncontrolled studies, risperidone was associated with a mean change in weight of +4.3 kg at Week 24 (n = 395) and +5.3 kg at Week 48 (n = 203).

Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), autistic disorder (5 to 17 years of age), or other psychiatric disorders (5 to 17 years of age) are presented in Table 7.

Table 7. Mean Change in Body Weight (kg) and the Proportion of Subjects With ≥7% Gain in Body Weight From Nine Placebo-Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5 to 17 Years of Age)

Placebo

(n = 375)

Risperidone 0.5 to 6 mg/day

(n = 448)

Weight (kg)

Change from baseline

0.6% 2%

Weight Gain

≥7% increase from baseline

6.9% 32.6%

In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in weight of +5.5 kg at Week 24 (n = 748) and +8 kg at Week 48 (n=242).

In a long-term, open-label extension study in adolescent patients with schizophrenia, weight increase was reported as a treatment-emergent adverse event in 14% of patients. In 103 adolescent patients with schizophrenia, a mean increase of 9 kg was observed after 8 months of risperidone treatment. The majority of that increase was observed within the first 6 months. The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index.

In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric disorders), a mean increase of 7.5 kg after 12 months of risperidone treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year adjusted for age, based on Centers for Disease Control and Prevention normative data). The majority of that increase occurred within the first 6 months of exposure to risperidone. The average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index.

In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the risperidone groups than the placebo group, but not dose related (1.90 kg in the risperidone 0.5 to 2.5 mg group, 1.44 kg in the risperidone 3 to 6 mg group, and 0.65 kg in the placebo group). A similar trend was observed in the mean change from baseline in body mass index.

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

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