Summary

• Tolerability - For patients who have never taken oral RISPERDAL^®, it is recommended to establish tolerability with oral RISPERDAL prior to initiating treatment with RISPERDAL CONSTA^®.¹
• 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 concentration from RISPERDAL CONSTA.¹
• The recommended dose of RISPERDAL CONSTA for the treatment of schizophrenia and monotherapy or adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder is 25 mg intramuscular injection every 2 weeks. Patients not responding to 25 mg may benefit from a higher dose of 37.5 mg or 50 mg.¹
• A lower initial dose of RISPERDAL CONSTA 12.5 mg may be appropriate when clinical factors warrant dose adjustment, such as in patients with hepatic or renal impairment, for certain drug interactions that increase risperidone plasma concentrations, or in patients who have a history of poor tolerability to psychotropic medications. The efficacy of the 12.5 mg dose has not been investigated in clinical trials.¹
• Needle Size - RISPERDAL CONSTA should be administered every 2 weeks by deep intramuscular deltoid or gluteal injection. Each injection should be administered by a health care professional using the appropriate enclosed safety needle. For deltoid administration, use the 1-inch (21 gauge UTW) needle alternating injections between the two arms. For gluteal administration, use the 2-inch (20 gauge TW) needle alternating injections between the two buttocks. Do not administer intravenously.¹
• Deltoid and gluteal intramuscular injections of RISPERDAL CONSTA at the same doses are bioequivalent and, therefore, interchangeable.¹
• The maximum dose of RISPERDAL CONSTA should not exceed 50 mg every 2 weeks.¹
• Upward dosage adjustment should not be made more frequently than every 4 weeks.¹
• Do not combine two different dosage strengths of RISPERDAL CONSTA in a single administration.¹
• Switching Antipsychotics - There are no systematically collected data to specifically address switching patients from other antipsychotics to RISPERDAL CONSTA or concerning concomitant administration with other antipsychotics. 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.¹
• There are no data to specifically address the reinitiation of treatment. When restarting patients who have had an interval off treatment with RISPERDAL CONSTA, supplementation with oral RISPERDAL (or another antipsychotic medication) should be administered.¹
• RISPERDAL CONSTA requires close attention to the step-by-step “Instructions for Use” to help ensure successful administration. Use the components provided. See section 2.8 of the full Prescribing Information for complete details.
• The RISPERDAL CONSTA dose pack should be stored in the refrigerator (36°-46°F; 2°-8°C) and protected from light.  Remove the dose pack from the refrigerator and allow it to sit at a controlled room temperature (59-77 degrees F°) for at least 30 minutes before reconstituting to support patient comfort during the injection. Do not warm any other way.

PRODUCT LABELING

Please refer to the following section of the enclosed Full Prescribing Information that is relevant to your inquiry: DOSAGE AND ADMINISTRATION.

DOSING GUIDELINES

Marder et al (2003)² published guidelines for dosing and initiating treatment of RISPERDAL CONSTA in patients with or without current antipsychotic treatment.

Initiating risperidone long-acting injection for adult schizophrenia patients

In general, the initial dose of RISPERDAL CONSTA should be 25 mg every 2 weeks. Patients who were previously on an oral antipsychotic or who had been taking no antipsychotic should receive oral antipsychotic coverage during the first 3 weeks of RISPERDAL CONSTA treatment. This 3-week oral antipsychotic coverage is needed because the main release of risperidone after a single injection starts from 3 weeks onward, is maintained from 4-6 weeks, and subsides by 7 weeks. Steady-state concentrations are achieved after 4 consecutive RISPERDAL CONSTAs given every 2 weeks. First-episode patients should begin with 25 mg and should be monitored closely for side effects.²

A higher dose of RISPERDAL CONSTA (37.5 mg or 50 mg) may be considered as the starting dose if a patient has a history of refractory schizophrenia requiring high antipsychotic doses (e.g., high doses of conventional depot). If a higher dose is needed, clinicians may consider 37.5 mg every 2 weeks. If symptoms persist after steady-state plasma concentrations are reached (after at least 4 injections), the dose may be increased to 50 mg every 2 weeks. Some clinicians in other countries have started a few severely ill patients at 50 mg every 2 weeks.²

Hypersensitivity challenge

If a patient is oral risperidone naïve, a hypersensitivity challenge with a test dose of 1-2 mg/day of oral risperidone for 2 consecutive days is recommended before the first injection of risperidone long-acting. Patients who take a test dose should continue taking their current antipsychotic treatment. If a patient has taken oral risperidone in the past, a test dose is not necessary. The short duration of the hypersensitivity challenge may only indicate an immediate hypersensitivity to risperidone and is unlikely to reveal a delayed allergic reaction (e.g., allergic skin reactions).²

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 risperidone long-acting 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 most patients, a short taper (e.g., 3-4 days) will be adequate, but more symptomatic patients may benefit from a more gradual taper.²

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 risperidone long-acting. No coverage with oral risperidone or another oral antipsychotic is needed.²

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.²

Managing missed doses

The appropriate strategy for patients who have missed a dose or doses of RISPERDAL CONSTA will depend on whether a steady-state plasma concentration of RISPERDAL CONSTA has been reached. Generally, steady-state plasma concentrations are achieved after 4 injections.²

Steady-state plasma concentration achieved

The next dose of RISPERDAL CONSTA should be given as soon as possible if steady-state concentrations of RISPERDAL CONSTA have been achieved and only 3-6 weeks have passed since the last injection. Clinicians should monitor for symptom recurrence. If more than 6 weeks have elapsed since the last injection, risperidone long-acting should be initiated as soon as possible and 3 weeks of coverage with an oral antipsychotic should be given.²

Steady-state plasma concentration not achieved (<4 consecutive injections)

RISPERDAL CONSTA should be reinitiated as soon as possible and oral antipsychotic coverage for 3 weeks should be given.²

Managing breakthrough symptoms

Clinicians should determine what type of breakthrough symptoms the patient is experiencing (e.g., psychotic, depressive, or anxiety symptoms) and devise a strategy accordingly.

For breakthrough psychotic symptoms, an oral antipsychotic should be added to quickly control symptoms. The oral antipsychotic can be discontinued if the breakthrough episode is successfully treated. Consider increasing the dose of RISPERDAL CONSTA if the symptoms are severe and persist with an adequate dose of oral antipsychotic supplementation or return when the oral antipsychotic is discontinued. A dose increase of RISPERDAL CONSTA will not have an immediate effect on breakthrough psychotic symptoms since the effect from the dose increase will take 3 weeks to begin to elevate the patient’s plasma drug level.²

Changing the dose of risperidone long-acting injection

Clinicians should wait until the drug has achieved steady-state plasma concentration at the present dose before deciding whether the dose should be increased or decreased. If warranted, the dose can be increased or decreased in 12.5 mg increments within the dose range of 25 to 50 mg.²

DOSING IN PIVOTAL TRIALS

Schizophrenia Trial

Kane et al (2003)³ published the results from a 12-week, double-blind, placebo-controlled multicenter, randomized trial to evaluate the efficacy and tolerability of RISPERDAL CONSTA in 400 patients with schizophrenia (n=370 ITT population). Prior to the 12-week double-blind period, patients were screened for one week followed by a run-in phase of one week when previous treatments were discontinued and oral risperidone was initiated at 2 mg/day and then titrated up to 4 mg/day for at least three days. Patients then entered the double-blind period and were randomized to receive six injections of placebo, RISPERDAL CONSTA 25 mg, 50 mg, or 75 mg every two weeks. Oral risperidone supplementation was given to patients randomized to RISPERDAL CONSTA during the first 3 weeks of the double-blind phase. Patients randomized to receive RISPERDAL CONSTA 25 mg, 50 mg, and 75 mg were given oral risperidone 2 mg, 4 mg, and 6 mg, respectively. Patients randomized to receive placebo injections were given oral placebo supplementation. No oral supplementation was permitted during weeks 4-12 of the double-blind phase. There were significant improvements from baseline on the PANSS total score as well as the positive and negative subscale scores in the three RISPERDAL CONSTA groups compared to placebo (P<0.05).

RISPERDAL CONSTA (25 mg, 50 mg, and 75 mg) was more effective than placebo in treating patients with schizophrenia for up to 12 weeks as assessed by the total PANSS score and the positive and negative subscales, with no apparent added benefit of a dose above 50 mg. RISPERDAL CONSTA was generally well tolerated with a similar incidence of EPS in the placebo and 25-mg groups. In addition, little pain or discomfort was experienced at the injection site.

Adjunctive Trial in the Maintenance Treatment of Bipolar I Disorder

Macfadden et al (2009)⁴ presented the results from a double-blind, prospective, randomized, placebo-controlled study in adult patients (18-70 years of age) with Bipolar I Disorder who relapse frequently. The two-phase study included an open-label stabilization phase (16 weeks; n=240) and a double-blind relapse-prevention phase (up to 52 weeks; n=124). Patients maintaining a stable dose and treatment response during the last 4 weeks of the open-label stabilization entered the double-blind phase. During the open-label phase, patients received RISPERDAL CONSTA 25 to 50 mg in addition to TAU (treatment as usual). TAU was defined as any medication used to treat bipolar disorder including mood stabilizers, antidepressants, and anxiolytics. All oral antipsychotics were tapered off after the first three weeks. During the double-blind phase, patients were randomized to receive either RISPERDAL CONSTA plus TAU or placebo plus TAU. Patients received the same dose of RISPERDAL CONSTA as they were receiving at the end of the open-label phase. Doses of TAU medications and RISPERDAL CONSTA could not change during the double-blind treatment. Modal RISPERDAL CONSTA doses in patients during the double-blind phase were 25 mg in 67.7%, 37.5 mg in 27.7%, and 50 mg in 4.6%. A Kaplan-Meier survival analysis indicated that the time to relapse was significantly longer in patients assigned to RISPERDAL CONSTA plus TAU than in those assigned to placebo plus TAU (P=0.010). The most common adverse events (≥10%) were tremor, insomnia, muscle rigidity, and mania.

Monotherapy Trial in the Maintenance Treatment of Bipolar I Disorder

Quiroz et al (2010)⁵ conducted a randomized, double-blind, placebo-controlled, multicenter study evaluating the use of RISPERDAL CONSTA for the prevention of mood episodes in adult patients (18-65 years of age) with Bipolar I Disorder. Patients were separated into 3 groups based on mood and medication status: acute episode, stable on risperidone for at least 4 weeks, or stable on another antipsychotic or mood stabilizer for at least 4 weeks. Five hundred fifty-nine patients were initially enrolled. Patients with an acute episode or patients taking another antipsychotic or mood stabilizer before the study received 3-weeks of oral risperidone. Patients taking risperidone before the study or those who achieved an initial response during the 3-week oral risperidone phase were enrolled in a 26-week open-label RISPERDAL CONSTA stabilization phase (n=501). Patients were either initiated on 25 mg RISPERDAL CONSTA every 2 weeks or continued their dose of RISPERDAL CONSTA from screening if they were stable. The 12.5 mg dose was available for those who were unable to tolerate 25 mg of RISPERDAL CONSTA. The maximum dose was 50 mg of RISPERDAL CONSTA every 2 weeks. Doses could be titrated at 4-week intervals based on patient response during the first 18 weeks of the stabilization period. Patients maintaining a stable dose and treatment response during the last 8-weeks of the open-label stabilization phase entered a double-blind treatment phase and were randomized to either their current dose of RISPERDAL CONSTA (n=154) or placebo (n=149). Patients continued in the double-blind phase until they either completed 24 months, met relapse criteria, withdrew from the study, or the study was terminated. During the double-blind phase, 77% of patients received 25 mg of RISPERDAL CONSTA (modal dose). There was a significant delay in time to relapse of a mood episode for patients treated with RISPERDAL CONSTA compared to placebo (P<0.001). The most common adverse events (≥5%) were insomnia, depression, mania, bipolar I disorder, agitation, and headache.

CASE REPORT ON ADMINISTRATION

Tang et al (2007)⁶ reported a case of a 39-year-old male patient with retinal artery occlusion after receiving RISPERDAL CONSTA.  The dose of the RISPERDAL CONSTA was not reported. Thirty minutes after receiving the injection into his right gluteal muscle, the patient began to experience a change in vision in his right eye. The patient presented to his physician four days after the injection when the blurred vision in his right eye persisted. The patient had 20/20 visual acuity in both eyes. However, there was a superior field deficit in the right eye. Intraocular pressures were 10 and 11 mm Hg. Examination revealed a microsphere in the inferior branch retinal artery of the right eye, which occluded the artery and resulted in poor perfusion to areas distal to the occlusion. The physician hypothesized that the microsphere embolized from the injection site, through the patent foramen ovale, and into the patient’s right fundus. No changes in the left fundus were noted.

SELECTED ADDITIONAL REFERENCES

Additionally, a letter to the editor addressing dosing strategies⁷ and an article describing a clinical audit of adherence to dosing recommendations for RISPERDAL CONSTA⁸ have been included in the References section.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 09 February 2024.