Summary

• There are no systematically collected data to specifically address switching patients from other antipsychotics to risperidone long-acting injection (RLAI).¹
• Several clinical trial publications discuss dosing strategies utilized during conversion to RISPERDAL CONSTA.^2–4
• No definitive dose equivalency studies have been conducted between RISPERDAL CONSTA and other antipsychotics based on therapeutic response.
• Based on a consensus building series of surveys sent to research and clinical experts (N=43) to determine dosing estimates that result in similar efficacy, Gardner et al (2010)⁵proposed that oral olanzapine 20 mg/day is equivalent to: aripiprazole 30 mg/day, clozapine 400 mg/day, paliperidone ER 9 mg/day, quetiapine 750 mg/day, oral risperidone 6.0 mg/day, ziprasidone 160 mg/day, RISPERDAL CONSTA 50 mg/14 days, fluphenazine decanoate 25 mg/14 days, and haloperidol decanoate 150 mg/28 days.
• A study was conducted comparing the pharmacokinetics and effectiveness of RISPERDAL CONSTA and oral risperidone to determine equivalent switching doses for patients with schizophrenia. The authors suggested that patients originally receiving daily doses of oral risperidone 3 mg or less receive 25 mg of RISPERDAL CONSTA every 2 weeks, while those on >3 mg but <5 mg receive 37.5 mg. The higher dose of 50 mg every 2 weeks was recommended for patients previously receiving >5 mg/day of oral risperidone.⁶
• Doses of 25, 50, or 75 mg of RISPERDAL CONSTA every 2 weeks were bioequivalent to daily oral doses of 2, 4, or 6 mg of oral risperidone, respectively, in a study designed to compare the steady-state bioavailability of risperidone and the active moiety (risperidone and 9-hydroxyrisperidone) after oral risperidone and RISPERDAL CONSTA administration. Mean steady-state peak moiety levels and plasma fluctuations were lower with the RISPERDAL CONSTA compared with oral risperidone.⁷

BACKGROUND

There are no systematically collected data to specifically address switching patients from other antipsychotics to RISPERDAL CONSTA, or concerning concomitant administration with other antipsychotics.¹ New and previous antipsychotics should be continued for 3 weeks after the first injection of RISPERDAL CONSTA to ensure that therapeutic concentrations are maintained until the main release phase of risperidone from the injection site has begun. After a single intramuscular (gluteal) injection of RISPERDAL CONSTA, there is a small initial release of the drug (<1% of the dose), followed by a lag time of 3 weeks. The main release of the drug starts from 3 weeks onward, is maintained from 4 to 6 weeks, and subsides by 7 weeks following the intramuscular (IM) injection. For patients who have never taken oral risperidone, it is recommended to establish tolerability with oral risperidone prior to initiating treatment with RISPERDAL CONSTA.

Conversion to risperidone long-acting injection

From an oral conventional or atypical antipsychotic

Patients converting from an oral antipsychotic should continue to take the current dose of the oral antipsychotic for 3 weeks following the first injection of RISPERDAL CONSTA 25 mg, until the first dose of RISPERDAL CONSTA reaches therapeutic levels. After 3 weeks, clinicians may begin to decrease the dose of the oral antipsychotic. The length of the taper will depend on the stability of the patient. For many patients, a short taper (e.g., 3-4 days) will be adequate, but patients who are severely ill may benefit from a more gradual taper.⁹

From a conventional depot antipsychotic

Generally, physicians should initiate RISPERDAL CONSTA instead of the conventional depot antipsychotic at the next scheduled injection date. Patients who have been regularly receiving effective doses of a conventional depot antipsychotic (e.g., fluphenazine and haloperidol decanoate) for about 6 months or longer will generally maintain an adequate plasma drug concentration for at least 1 or 2 months after their last injection. Therefore, patients should not require a dose of the conventional depot antipsychotic when they receive their first injection of RISPERDAL CONSTA. No coverage with oral risperidone or another oral antipsychotic is needed.⁹

From multiple antipsychotics

If a switch from multiple antipsychotics to RISPERDAL CONSTA is appropriate, the transition should be made slowly. When possible, each of the current antipsychotics should be gradually discontinued until the patient is only taking RISPERDAL CONSTA. Clinician judgment should dictate the starting dose of RISPERDAL CONSTA.⁹

Dose Equivalency to Other Antipsychotics

Gardner et al (2010)⁵ conducted a broad, two-stage, survey of research and clinical experts (N=43) to determine a representative set of clinically equivalent dosing estimates for most typical and atypical antipsychotics. The survey presented oral olanzapine 20 mg/day as the reference treatment for all equivalency estimates, and participants received instructions to prioritize efficacy over tolerability in estimates of dose equivalency. In comparison with olanzapine 20 mg/day, the median reported dose equivalency of RISPERDAL CONSTA was 50 mg/14 days. Please see Table: Dose Equivalency of Atypical Antipsychotics to Oral Olanzapine for additional dose equivalencies of oral and long-acting atypical antipsychotics.

Dose Equivalence to Oral Risperidone

Bai et al (2007)

In a 48-week, single-blind, randomized clinical trial conducted in a single center in Taiwan, Bai et al (2007)⁶ investigated the comparative efficacy and pharmacokinetics of RISPERDAL CONSTA and of oral risperidone to determine equivalent switching doses in adult patients hospitalized with schizophrenia.

Study Design/Methods

Patients had a DSM-IV diagnosis of schizophrenia disorder, and their PANSS total scores and CGI scores were stable from the screening visit to baseline. They were required to have received oral risperidone for ≥3 months before screening and to be in good general health. Patients (n=50) were randomized to continue the same oral risperidone regimen (n=25) or to receive RISPERDAL CONSTA (n=25). Patients in the RISPERDAL CONSTA group continued oral risperidone for the first 3 weeks of therapy, after which oral doses were tapered within 3 days (in all groups, supplemental oral risperidone was allowed if symptoms worsened). Initial dosing in the RISPERDAL CONSTA group was established according to each patient’s prior stable oral dosage; patients receiving

• ≤4 mg/day of oral risperidone received RISPERDAL CONSTA 25 mg every 2 weeks
• >4 to ≤6 mg/day of oral risperidone received RISPERDAL CONSTA 37.5 mg every 2 weeks
• >6 mg/day of oral risperidone received RISPERDAL CONSTA 50 mg every 2 weeks.

Increases in the RISPERDAL CONSTA dose were allowed in increments of 12.5 mg to a maximum of 50 mg every 2 weeks. Serum concentrations of risperidone and 9-hydroxyrisperidone were determined at baseline and at weeks 4, 8, 12, 16, 20, and 24. Efficacy assessments compared directly with the pharmacokinetics included PANSS total score, performed at baseline and at week 48.

Results

Of the 50 patients enrolled, 5 patients withdrew from the RISPERDAL CONSTA group. Five patients in the RISPERDAL CONSTA group and 10 in the oral risperidone group required dose adjustment. Mean serum prolactin was decreased by 17.3±36.3 ng/mL in the RISPERDAL CONSTA group and was increased by 8.8±21.2 ng/mL in the oral group (P=0.046). Table: Changes in Serum Metabolites, Prolactin Levels, and PANSS Total Scores shows results of stratification of the RISPERDAL CONSTA groups by initial oral risperidone dosage. Treatment-group stratification revealed greater decreases from baseline to week 24 in total metabolite concentration (P=0.028) and in 9-hydroxyrisperidone metabolites concentration (P=0.023) in patients treated with RISPERDAL CONSTA 37.5 mg than were seen in those initiated with 25-mg or 50-mg injections. Patients who received RISPERDAL CONSTA 25 mg or 37.5 mg every 2 weeks showed an increase in PANSS score (P=0.058), decreased serum metabolic concentrations (P=0.028), and an increased tendency for relapse.

The standard of dose-equivalence used in switching may require some adjustment. Patients originally receiving daily doses of oral risperidone 3 mg or less receive 25 mg of RISPERDAL CONSTA every 2 weeks, while those on >3 mg but <5 mg receive 37.5 mg. The higher dose of 50 mg every 2 weeks was recommended for patients previously receiving >5 mg/day of oral risperidone.

Bai et al (2006)

Bai et al (2006)¹⁰ also assessed the efficacy and safety of RISPERDAL CONSTA versus oral risperidone in a 12-week, randomized, single-blind study similar in design to the 24-week trial (Bai et al [2007]⁶).

Eerdekens et al (2004)

Eerdekens et al (2004)⁷ describe the results from an open-label, 15-week, multicenter trial designed to compare the steady-state bioavailability of risperidone tablets given orally once per day and RISPERDAL CONSTA given every 2 weeks in patients with DSM-IV schizophrenia (18-65 years of age).

Study Design/Methods

Patients stabilized on oral risperidone (2, 4, or 6 mg/day) for at least 1 month before the trial started were assigned to receive 25 mg, 50 mg, or 75 mg of RISPERDAL CONSTA (IM) every 2 weeks, respectively (see Table: Dosing Schedule for All Patients).

Assessments included plasma concentrations of unchanged risperidone and the active moiety (risperidone and 9-hydroxyrisperidone), the PANSS, the CGI (Clinical Global Impressions) scale, the ESRS (Extrapyramidal Symptom Rating Scale), adverse events, vitals signs, and injection site evaluation.

Results

Pharmacokinetics

Dose-proportional increases in the steady state C_min, C_max, and AUC (area under the curve) were observed for both the risperidone oral and IM dosing (Table: Pharmacokinetic Parameters after Oral Risperidone and RLAI). Total body exposure (AUC₁₄ days) to the active moiety during one dosing interval was equivalent after oral and IM dosing within the bioequivalence range of 80% to 125%. The mean C_max (peak) values of the active moiety seen with RISPERDAL CONSTA dosing were significantly lower (25-32%) compared to risperidone oral dosing (P<0.05). Mean steady-state C_min (trough) did not differ between oral and IM dosing. RISPERDAL CONSTA resulted in less fluctuation in plasma levels compared to oral dosing.

Efficacy

Clinical symptoms, as measured by the PANSS and CGI, remained stable or improved throughout the trial in all three groups. At the last RISPERDAL CONSTA on day 64 (at steady-state plasma levels), clinical improvement (20% or greater reduction in PANSS total scores) was noted in 44-57% of patients in the three groups.

Safety

Adverse events were reported by 76%, 81%, and 76% of patients in Group I, II, and III, respectively. The most common adverse events were influenza-like symptoms or of a psychiatric nature including insomnia, condition aggravated, anxiety and depression. Serious adverse events were reported in 4 patients; none were considered to be related to the trial treatment by the investigators. Scores on the ESRS were low at baseline and declined during the trial in all three groups. In most patients, no induration, pain, redness, or swelling were evident to the investigators. Overall, no pain at the injection site was reported by more than 60% of the patients throughout the trial and less than 5% reported that an injection was “rather painful”. No clinically relevant changes in laboratory results or vital signs were noted.

Conversion to RISPERDAL CONSTA

Several articles, discussing strategies utilized during conversion to RISPERDAL CONSTA, are summarized in the Table: Risperidone Long-Acting Injection Conversion Strategies.

SELECTED ADDITIONAL REFERENCES

Additional citations discussing dose response, dose conversion and/or dose equivalence of antipsychotics, including RISPERDAL CONSTA, have been included in the References section for your review.¹²

LITERATURE SEARCH

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 18 September 2023.