Risperidone for Children With Autistic Spectrum Disorder
Risperidone for Children With Autistic Spectrum Disorder
With the increase in AAP prescriptions and the prevalence of off-label prescribing, children are at risk for drug-induced adverse effects and long-term dangers. According to a recent report from the FDA, from 1993 through the first three months of 2008, 1207 children for whom risperidone was prescribed experienced adverse effects serious enough to warrant medical attention. Further, 31 out of 1,215,000 prescriptions for patients aged birth through 12 years of age resulted in death (Collins, 2008). Of these deaths, 10 were related to nervous system disorders, nine were cardiac related, eight were the result of miscellaneous causes, and four had an indeterminate cause of death. Other warnings and precautions include hyperglycemia, insomnia, anxiety, diabetes, extrapyramidal effects, and development of breast tissue in boys and girls.
A placebo-controlled study of the adverse effects for risperidone for children used the Side Effects Review (Aman et al., 2005). The following adverse effects were the most common (placebo and risperidone, respectively): somnolence (12% and 37%), enuresis (29% and 33%), excessive appetite (10% and 33%), rhinitis (8% and 16%), difficulty waking (8% and 12%), and constipation (12% and 10%). Difficulty falling asleep and anxiety improved in children taking risperidone compared with children taking a placebo at statistically significant levels. The same adverse effects tended to recur through 6 months of treatment, although often at reduced levels. Somnolence and increased appetite are the most common adverse effects (Aman et al., 2005).
In another study of 10 adolescents with schizophrenia or bipolar disorder, eight of 10 participants demonstrated severe adverse effects (Mandoki, 1995). Extrapyramidal symptoms developed in six of the 10 youths, and four of those required the addition of anticholinergic medication. In addition, dysphoric mood developed in four patients, and two of these patients met the criteria for major depression and required the addition of an antidepressant. Three patients had a significant weight increase. Galactorrhea developed in one of the three adolescent girls (this patient was 17 years old). However, all 10 patients showed overall clinical improvement in their target symptoms during treatment with risperidone. These preliminary and uncontrolled findings indicate an extremely high incidence of severe adverse effects. A host of adverse effects occurred across clinical trials but were not necessarily compared with placebo control subjects. The most common adverse reactions in clinical trials (≥ 10%) were somnolence, an increased appetite, fatigue, rhinitis, upper respiratory tract infection, vomiting, coughing, urinary incontinence, increase in saliva, constipation, fever, Parkinsonism, dystonia, abdominal pain, anxiety, nausea, dizziness, dry mouth, tremor, rash, akathisia, and dyspepsia. The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in > 1% of adults and/or > 2% of pediatric subjects) were somnolence, nausea, abdominal pain, dizziness, vomiting, agitation, and akathisia (Jerrell & McIntyre, 2008).
The most commonly reported adverse effect is weight gain (Calarge et al., 2009, Wetterling and Mubigbrodt, 1999). In a study of adolescents, the average weight gain while taking risperidone was 3.9 kg or 6.6% of body mass (Ratzoni et al., 2002). Cases of a weight gain of more than 25% of original body mass have been reported (Varley & McClellan, 2009). Moreover, the risk of extreme weight gain is higher in adolescents than in adults (Ratzoni et al., 2002). Response to medication monitoring requires check of weight in addition to behavior and neurological status (Fleischhaker et al., 2008). Although this report identified no new safety concerns, the FDA panel expressed concern with the rise in the use of AAP medications, especially for children with attention deficit hyperactivity disorder, ASD, and other developmental disabilities (Collins, 2008).
Incidence of dyskinesia upon withdrawal can be reduced with appropriate dosing (Harrison-Woolruch, Garcia-Quiroga, Ashton, & Herbison, 2007). The manufacturer's guidelines report that dosing should be initiated at 0.25 mg per day for patients weighing less than 20 kg and 0.5 mg per day for patients weighing more than 20 kg. After a minimum of 4 days from treatment initiation, the dose may be increased to the recommended dose of 0.5 mg per day for patients weighing more than 20 kg and 1 mg per day for patients weighing more than 20 kg. This dose should be maintained for a minimum of 14 days. Risperidone requires weaning from the medication, with the decrease in dosage occurring at the same pace as the increase. Parents require education about dyskinesia upon withdrawal. Many parents administer medications inconsistently or cease administration of all medications at the first sign of any adverse effects. Parents need to be warned of the effects of inconsistent or rapid withdrawal of risperidone.
Analysis of adverse effects in children based on the extant literature does not lend itself to a meta-analysis because most study participants withdraw from the study or the study does not last long enough for adverse effects to present themselves (Malone, 2006). Moreover, the heterogeneity of adverse effects makes a quantitative analysis difficult.
Risks and Adverse Effects
With the increase in AAP prescriptions and the prevalence of off-label prescribing, children are at risk for drug-induced adverse effects and long-term dangers. According to a recent report from the FDA, from 1993 through the first three months of 2008, 1207 children for whom risperidone was prescribed experienced adverse effects serious enough to warrant medical attention. Further, 31 out of 1,215,000 prescriptions for patients aged birth through 12 years of age resulted in death (Collins, 2008). Of these deaths, 10 were related to nervous system disorders, nine were cardiac related, eight were the result of miscellaneous causes, and four had an indeterminate cause of death. Other warnings and precautions include hyperglycemia, insomnia, anxiety, diabetes, extrapyramidal effects, and development of breast tissue in boys and girls.
A placebo-controlled study of the adverse effects for risperidone for children used the Side Effects Review (Aman et al., 2005). The following adverse effects were the most common (placebo and risperidone, respectively): somnolence (12% and 37%), enuresis (29% and 33%), excessive appetite (10% and 33%), rhinitis (8% and 16%), difficulty waking (8% and 12%), and constipation (12% and 10%). Difficulty falling asleep and anxiety improved in children taking risperidone compared with children taking a placebo at statistically significant levels. The same adverse effects tended to recur through 6 months of treatment, although often at reduced levels. Somnolence and increased appetite are the most common adverse effects (Aman et al., 2005).
In another study of 10 adolescents with schizophrenia or bipolar disorder, eight of 10 participants demonstrated severe adverse effects (Mandoki, 1995). Extrapyramidal symptoms developed in six of the 10 youths, and four of those required the addition of anticholinergic medication. In addition, dysphoric mood developed in four patients, and two of these patients met the criteria for major depression and required the addition of an antidepressant. Three patients had a significant weight increase. Galactorrhea developed in one of the three adolescent girls (this patient was 17 years old). However, all 10 patients showed overall clinical improvement in their target symptoms during treatment with risperidone. These preliminary and uncontrolled findings indicate an extremely high incidence of severe adverse effects. A host of adverse effects occurred across clinical trials but were not necessarily compared with placebo control subjects. The most common adverse reactions in clinical trials (≥ 10%) were somnolence, an increased appetite, fatigue, rhinitis, upper respiratory tract infection, vomiting, coughing, urinary incontinence, increase in saliva, constipation, fever, Parkinsonism, dystonia, abdominal pain, anxiety, nausea, dizziness, dry mouth, tremor, rash, akathisia, and dyspepsia. The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in > 1% of adults and/or > 2% of pediatric subjects) were somnolence, nausea, abdominal pain, dizziness, vomiting, agitation, and akathisia (Jerrell & McIntyre, 2008).
The most commonly reported adverse effect is weight gain (Calarge et al., 2009, Wetterling and Mubigbrodt, 1999). In a study of adolescents, the average weight gain while taking risperidone was 3.9 kg or 6.6% of body mass (Ratzoni et al., 2002). Cases of a weight gain of more than 25% of original body mass have been reported (Varley & McClellan, 2009). Moreover, the risk of extreme weight gain is higher in adolescents than in adults (Ratzoni et al., 2002). Response to medication monitoring requires check of weight in addition to behavior and neurological status (Fleischhaker et al., 2008). Although this report identified no new safety concerns, the FDA panel expressed concern with the rise in the use of AAP medications, especially for children with attention deficit hyperactivity disorder, ASD, and other developmental disabilities (Collins, 2008).
Incidence of dyskinesia upon withdrawal can be reduced with appropriate dosing (Harrison-Woolruch, Garcia-Quiroga, Ashton, & Herbison, 2007). The manufacturer's guidelines report that dosing should be initiated at 0.25 mg per day for patients weighing less than 20 kg and 0.5 mg per day for patients weighing more than 20 kg. After a minimum of 4 days from treatment initiation, the dose may be increased to the recommended dose of 0.5 mg per day for patients weighing more than 20 kg and 1 mg per day for patients weighing more than 20 kg. This dose should be maintained for a minimum of 14 days. Risperidone requires weaning from the medication, with the decrease in dosage occurring at the same pace as the increase. Parents require education about dyskinesia upon withdrawal. Many parents administer medications inconsistently or cease administration of all medications at the first sign of any adverse effects. Parents need to be warned of the effects of inconsistent or rapid withdrawal of risperidone.
Analysis of adverse effects in children based on the extant literature does not lend itself to a meta-analysis because most study participants withdraw from the study or the study does not last long enough for adverse effects to present themselves (Malone, 2006). Moreover, the heterogeneity of adverse effects makes a quantitative analysis difficult.
