Risperidone, tablet, 500 microgram, 1 mg, 2 mg, oral solution 1 mg per mL, Risperdal, oral disintegrating tablet, 500 microgram, 1 mg, 2 mg, Risperdal Quicklet November 2006
Public summary document for Risperidone, tablet, 500 microgram, 1 mg, 2 mg, oral solution 1 mg per mL, Risperdal, oral disintegrating tablet, 500 microgram, 1 mg, 2 mg, Risperdal Quicklet
Page last updated: 02 March 2007
Public Summary Document
Product: Risperidone, tablet, 500 microgram, 1 mg, 2 mg, oral solution 1 mg per mL,
Risperdal, oral disintegrating tablet, 500 microgram, 1 mg, 2 mg, RisperdalQuicklet
Sponsor: Janssen-Cilag Pty Ltd
Date of PBAC Consideration: November 2006
1. Purpose of Application
The submission sought an Authority Required PBS listing for the treatment of severe behavioural disturbances in children and adolescents with autism.
2. Background
This drug had not previously been considered by the PBAC for the treatment of severe behavioural disturbances in children and adolescents with autism.
3. Registration Status
Risperidone is TGA approved for the following indications:
- for the treatment of schizophrenia and related psychoses.
- for the short term treatment of acute mania associated with bipolar 1 disorder.
- for the treatment of behavioural disturbances in dementia.
- for the treatment of conduct and other disruptive disorders in children (over 5 years), adolescents and adults with subaverage intellectual functioning or mental retardation in whom destructive behaviours (eg aggression, impulsivity and self-injurious behaviours) are prominent.
- for the treatment of behavioural disorders associated with autism in children and adolescents.
4. Listing Requested and PBAC’s View
Authority required
Treatment by or under the supervision of a paediatrician or psychiatrist for severe
behavioural disturbances in children and adolescents with autism. Behaviour disturbances
are characterised by severe aggression and injuries to self or others where non-pharmacological
methods have been unsuccessful.
The diagnosis of autism must be made based on the Diagnostic and Statistical Manual
of Mental Disorder, Fourth Edition (DSM-IV) or ICD-10 international classification
of mental and behavioural disorders.
See Recommendation and Reasons for PBAC’s view.
5. Clinical Place for the Proposed Therapy
Autism is characterised by impairment in social interaction and communication, restricted
repetitive and stereotyped behaviour.
Risperidone is indicated for specific behavioural symptoms when they significantly
impact on the child’s function and the daily life of the child and family, to improve
the child’s symptoms such that the child is able to respond optimally to standard
non-drug interventions.
6. Comparator
The submission nominated placebo (no pharmacological therapy) as the main comparator. The PBAC accepted this as appropriate.
7. Clinical Trials
The submission presented one randomised comparative trial comparing risperidone and
placebo in children or adolescents with severe behavioural disturbances associated
with autism (RUPP Autism Network 2002 and 2005); and one randomised comparative trial
comparing risperidone and placebo in children aged 5-12 years of age with disruptive
behavioural symptoms associated with autism and other pervasive developmental disorders
(Shea et al 2004).
These trials had been published at the time of submission, as follows:
|
Trial/First author |
Publication title |
Publication citation |
|---|---|---|
|
McCracken JT et al (RUPP Autism Network 2002) |
Risperidone in children with autism and serious behavioral problems. |
The New England Journal of Medicine, 2002; 347(5): 314-321 |
|
RUPP Autism Network 2005 |
Risperidone treatment of autistic disorder: longer term benefits and blinded discontinuation after 6 months. |
American Journal of Psychiatry, 2005: 162(7): 1361-1369 |
|
Shea S et al 2004 |
Risperidone in the treatment of disruptive behavioural symptoms in children with autistic and other pervasive developmental disorders. |
Pediatrics, 2004; 114(5): 634-641 |
8. Results of Trials
Efficacy in the trials was assessed using the Aberrant Behaviour Checklist (ABC) and
the Change in Clinical Global Impression measurement tool (CGI-C).
The ABC assessed a change in behaviour related to treatment in subjects with developmental
disabilities. There were five sub-scales in the checklist: irritability; lethargy
and social withdrawal; stereotypic behaviour; hyperactivity/ non compliance; and inappropriate
speech. The ABC was completed by the subject’s parent or primary caregiver under guidance
of the investigator.
The CGI-C assessed the change of the subject’s condition compared with baseline and
was measured on a seven point scale: ranging from very much improved to very much
worse. The CGI-C was completed by an independent clinician.
The results from RUPP Autism Network 2002 (baseline to week 8) showed there was a
statistically significant difference in ABC irritability sub-scale score and CGI-C
favouring risperidone in the trial’s primary analysis of change in irritability scores.
During the 8-week discontinuation phase (RUPP Autism Network 2005), 62.5% of children
who had received a minimum of 24 weeks treatment with risperidone relapsed when risperidone
treatment was withdrawn compared with 12.5% of patients who continued risperidone
treatment.
The results of Shea et al 2004 showed that risperidone produced a statistically greater
reduction in ABC irritability sub-scale score versus placebo and there was a statistically
significant greater proportion of CGI-C responders in the risperidone arm versus placebo.
30% of subjects had a pervasive developmental disorder other than autism.
The most common adverse events reported in the risperidone arm (n = 49) of RUPP Autism
Network 2002 were: increased appetite (73%), fatigue (59%) and drowsiness (49%). Weekly
assessment with the Abnormal Involuntary Movement Scale and the Simpson-Angus scale
showed no extrapyramidal symptoms in either group. Parents or caretakers reported
5 neurologic side effects: tremors, dyskinesia, rigidity, akathisia, and difficulty
swallowing.
9. Clinical Claim
The PBAC accepted the submission’s claim that risperidone has significant advantages in effectiveness over placebo but was associated with more toxicity.
10. Economic Analysis
The submission presented a cost-effectiveness approach based on drug costs and effectiveness
measured by the proportion of responders. This approach was considered valid by the
PBAC.
The submission estimated that the trial-based incremental cost per responder would
be < $15,000.
11. Estimated PBS Usage and Financial Implications
12. Recommendation and Reasons
The PBAC recommended listing for severe behavioural disturbances in a child or adolescent
with autism on a cost-effectiveness basis compared with placebo. The PBAC further
recommended that the listing restriction specify that treatment take place under the
supervision of a paediatrician or psychiatrist; that non-pharmacological measures
are continued during treatment; that the diagnosis of autism is made according to
the DSM-IV or ICD10 criteria; and that the number of repeats is limited to two.
In making this recommendation the Committee accepted that the statically significant
differences in the ABC irritability sub-scale score and the CGC-C favouring risperidone
in the key trial (RUPP Autism Network 2002 and 2005) represent a clinically meaningful
improvement in behaviours in the severely affected children and adolescents with autism
targeted by the restriction. The Committee noted that risperidone treatment is associated
with a high rate of somnolence and weight gain but as the median treatment duration
is likely to be short these side effects were of lesser concern.
The PBAC recommended the 20-day safety net rule should not apply.
Recommendation
RISPERIDONE, tablet, 500 microgram, 1 mg, 2 mg, oral solution 1 mg per mL, Risperdal,
oral disintegrating tablet, 500 microgram, 1 mg, 2 mg
Restriction:
Authority required
Treatment under the supervision of a paediatrician or psychiatrist, in combination
with non-pharmacological measures, of severe behavioural disturbances in a child or
adolescent aged less than 18 years with autism. Behaviour disturbances are defined
as severe aggression and injuries to self or others where non-pharmacological methods
alone have been unsuccessful.
The diagnosis of autism must be made based on the Diagnostic and Statistical Manual
of Mental Disorder, Fourth Edition (DSM-IV) or ICD-10 international classification
of mental and behavioural disorders.
Maximum Quantity: 60 / 56 (tablets/orally disintegrating tablets) / 1 (oral solution)
Repeats: 2
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC decision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor welcomes this decision by the PBAC to provide access to the first pharmacological treatment for children and adolescents with autism experiencing behavioural disturbances. Risperidone treatment can provide a significant positive influence on the child’s function and thus favourably impact the daily life of the child, their family and carers.
