Risperdal (risperidone) - 3 indications

Scroll down for more information on each indication:

• for the treatment of schizophrenia; approved July 1996
• as monotherapy or adjunctive therapy with lithium or valproate, for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder; approved December of 2003 
• for the treatment of the irritability associated with autistic disorder; approved October 2006

General Information

Risperdal (risperidone) is an atypical antipsychotic.

Risperdal is specifically indicated:

• for the treatment of schizophrenia
• as monotherapy or adjunctive therapy with lithium or valproate, for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder
• for the treatment of the irritability associated with autistic disorder

Risperdal Consta is not indicated for the treatment of irritability associated with autistic disorder.

Risperdal is supplied as oral tablets and an oral solution. Risperdal Consta is supplied as a long acting injection.

Dosage and Administration is as follows:

Risperdol:

• Schizophrenia
  • Adults
    • Usual Initial Dose Risperdal can be administered once or twice daily. Initial dosing is 2 mg per day. May increase the dose at intervals of 24 hours or greater, in increments of 1 to 2 mg per day, as tolerated, to a recommended dose of 4 to 8 mg per day. In some patients, slower titration may be appropriate.
  • Adolescents
    • The initial dose is 0.5 mg once daily, administered as a single-daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to a recommended dose of 3 mg per day
    • Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily
• Bipolar Mania
  • Adults
    • The usual initial dose range is 2 mg to 3 mg per day. The dose may be adjusted at intervals of 24 hours or greater, in increments of 1 mg per day. The effective dose range is 1 mg to 6 mg per day.
  • Pediatrics
    • The usual initial dose is 0.5 mg once daily, administered as a single-daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to the recommended target dose of 1 mg to 2.5 mg per day.
• Irritability Associated with Autistic Disorder – Pediatrics (Children and Adolescents)
  • The dosage of Risperdal should be individualized according to the response and tolerability of the patient.
  • The total daily dose of Risperdal can be administered once daily, or half the total daily dose can be administered twice daily.
  • For patients with body weight less than 20 kg, initiate dosing at 0.25 mg per day. For patients with body weight greater than or equal to 20 kg, initiate dosing at 0.5 mg per day. After a minimum of four days, the dose may be increased to the recommended dose of 0.5 mg per day for patients less than 20 kg and 1.0 mg per day for patients greater than or equal to 20 kg. Maintain this dose for a minimum of 14 days. In patients not achieving sufficient clinical response, the dose may be increased at intervals of 2 weeks or greater, in increments of 0.25 mg per day for patients less than 20 kg, or increments of 0.5 mg per day for patients greater than or equal to 20 kg. The effective dose range is 0.5 mg to 3 mg per day. No dosing data are available for children who weigh less than 15 kg.

Risperdal Consta

• For patients who have never taken oral Risperdal, tolerability should be established with oral Risperdal prior to initiating treatment with Risperdal CONSTA.
• Administer by deep intramuscular (IM) deltoid or gluteal injection. Each injection should be administered by a health care professional using the appropriate enclosed safety needle (1-inch for deltoid administration alternating injections between the two arms and 2-inch for gluteal administration alternating injections between the two buttocks). Do not administer intravenously.
• 25 mg intramuscular (IM) every 2 weeks. Patients not responding to 25  mg may benefit from a higher dose of 37.5 mg or 50 mg. The maximum dose should not exceed 50 mg every 2 weeks.
• Oral Risperdal (or another antipsychotic medication) should be given with the first injection of Risperdal CONSTA, and continued for 3 weeks (and then discontinued) to ensure adequate therapeutic plasma concentrations from Risperdal CONSTA.
• Upward dose adjustment of Risperdal CONSTA® should not be made more frequently than every 4 weeks. Clinical effects of each upward dose adjustment should not be anticipated earlier than 3 weeks after injection.
•  Avoid inadvertent administration into a blood vessel. 

Mechanism of Action

The mechanism of action of risperidone in schizophrenia is unclear. The drug’s therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone (paliperidone). Antagonism at receptors other than D2 and 5HT2 may explain some of the other effects of risperidone.

Side Effects

Adverse effects associated with the use of Risperdal may include, but are not limited to, the following:

• parkinsonism
• akathisia
• dystonia
• tremor
• sedation
• dizziness
• anxiety
• blurred vision
• nausea
• vomiting
• upper abdominal pain
• stomach discomfort
• dyspepsia
• diarrhea
• salivary hypersecretion
• constipation
• dry mouth
• increased appetite
• increased weight
• fatigue
• rash
• nasal congestion
• upper respiratory tract infection
• nasopharyngitis
• pharyngolaryngeal pain

The Risperdal drug label comes with the following Black Box Warning: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Risperdal is not approved for use in patients with dementia-related psychosis

Indication 1 -for the treatment of schizophrenia

approved July 1996

Clinical Trial Results

Adults Short-Term Efficacy The efficacy of Risperdal in the treatment of schizophrenia was established in four short-term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for schizophrenia.

The results of the trials follow:

(1) In a 6-week, placebo-controlled trial (n=160) involving titration of Risperdal in doses up to 10 mg/day (twice-daily schedule), Risperdal was generally superior to placebo on the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on the SANS.

(2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of Risperdal (2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice daily schedule), all 4 Risperdal groups were generally superior to placebo on the BPRS total score, BPRS psychosis cluster, and CGI severity score; the 3 highest Risperdal dose groups were generally superior to placebo on the PANSS negative subscale. The most consistently positive responses on all measures were seen for the 6  mg dose group, and there was no suggestion of increased benefit from larger doses.

(3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of Risperdal (1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the four highest Risperdal dose groups were generally superior to the 1 mg Risperdal dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None of  the dose groups were superior to the 1 mg group on the PANSS negative subscale. The most consistently positive responses were seen for the 4 mg dose group.

(4) In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2  fixed doses of Risperdal (4 and 8 mg/day on a once-daily schedule), both Risperdal dose groups were generally superior to placebo on several PANSS measures, including a response measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg than for the 4 mg dose group.

In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic medication were randomized to Risperdal (2-8 mg/day) or to an active comparator, for 1  to  2 years of observation for relapse. Patients receiving Risperdal experienced a significantly longer time to relapse over this time period compared to those receiving the active comparator.

Indication 2 - as monotherapy or adjunctive therapy with lithium or valproate, for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder

approved December of 2003 

Clinical Trial Results

Monotherapy

The efficacy of Risperdal in the treatment of acute manic or mixed episodes was established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with or without psychotic features. The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS). 

The results of the trials follow: (1) In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes, which involved a dose range of Risperdal 1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 4.1 mg/day), Risperdal was superior to placebo in the reduction of YMRS total score. (2) In another 3-week placebo-controlled trial (n=286), which involved a dose range of 1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day), Risperdal was superior to placebo in the reduction of YMRS total score.

Adjunctive Therapy with Lithium or Valproate

The efficacy of Risperdal with concomitant lithium or valproate in the treatment of  acute manic or mixed episodes was established in one controlled trial in adult patients who met the DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic features and with or without a rapid cycling course. (1) In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms were randomized to receive Risperdal, placebo, or an active comparator, in combination with their original therapy. Risperdal, in a  dose range of 1-6 mg/day, once daily, starting at 2  mg/day (mean modal dose of 3.8  mg/day), combined with lithium or valproate (in a therapeutic range of 0.6  mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of YMRS total score. (2) In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium, valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms were randomized to receive Risperdal or placebo, in combination with their original therapy. Risperdal, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine (in  therapeutic ranges of 0.6  mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for valproate, or 4-12 mcg/mL for carbamazepine, respectively) was not superior to lithium, valproate, or carbamazepine alone in the reduction of YMRS total score. A possible explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxyrisperidone.

Indication 3 - for the treatment of the irritability associated with autistic disorder

approved October 2006

Clinical Trial Results

Short-Term Efficacy

The efficacy of Risperdal in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in children and adolescents (aged 5  to  16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects were under 12 years of age and most weighed over 20 kg (16-104.3 kg). Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured the emotional and behavioral symptoms of autism, including aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.

The results of these trials are as follows: (1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or Risperdal 0.5-3.5 mg/day on a weight-adjusted basis. Risperdal, starting at 0.25 mg/day or 0.5  mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day), significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with placebo. (2) In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged 5 to 12 years, Risperdal 0.02 to 0.06 mg/kg/day given once or twice daily, starting at 0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day, equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared with placebo.

Long-Term Efficacy

Following completion of the first 8-week double-blind study, 63 patients entered an open-label study extension where they were treated with Risperdal for 4 or 6 months (depending on whether they received Risperdal or placebo in the double-blind study). During this open-label treatment period, patients were maintained on a mean modal dose of Risperdalof 1.8-2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day). Patients who maintained their positive response to Risperdal (response was defined as ≥ 25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very much improved’) during the 4-6 month open-label treatment phase for about 140 days, on average, were randomized to receive Risperdal or placebo during an 8-week, double-blind withdrawal study (n=39 of the 63  patients). A pre-planned interim analysis of data from patients who completed the withdrawal study (n=32), undertaken by an independent Data Safety Monitoring Board, demonstrated a significantly lower relapse rate in the Risperdal group compared with the placebo group. Based on the interim analysis results, the study was terminated due to demonstration of a statistically significant effect on relapse prevention. Relapse was defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to baseline of the randomized withdrawal phase).