Summary

• Please refer to the following sections of the enclosed Full Prescribing Information that are relevant to your inquiry: DOSAGE AND ADMINISTRATION, DOSAGE FORMS AND STRENGTHS, and HOW SUPPLIED ¹
• RISPERDAL CONSTA must be reconstituted only with the diluent supplied in the dose pack, and must be administered with only the appropriate needle supplied in the dose pack for gluteal (2-inch needle) or deltoid (1-inch needle) administration. All components are required for administration. Do not substitute any components of the dose pack. To assure that the intended dose of risperidone is delivered, the full contents of the vial must be administered. Administration of partial contents may not deliver the intended dose of risperidone. It is recommended to administer immediately after reconstitution.¹
• The published literature provides mixed information on the maximum injection volume that should be used to ensure safe and tolerable delivery of medications by deltoid intramuscular (IM) injection. Some authors consider 1 mL and others consider 2 mL to be the maximum injection volume that is safe for deltoid IM injection.^2-11
• In two deltoid administration studies, RISPERDAL CONSTA (2 mL) was safe and well tolerated when administered as a single injection or as multiple injections.^{12, 13}

BACKGROUND

The published literature provides mixed information on the maximum injection volume that is safe for deltoid muscle administration. Because the deltoid is a small and sometimes poorly developed muscle, injections should be given in the densest part of the muscle.^{7, 14, 15} Furthermore, because the deltoid injection site is relatively small and is proximal to the axillary and radial nerves, the precise location of the injection site is important and the volume that should be used to ensure safe delivery is limited.^{2, 5-7, 16-19}

A review of the published literature regarding appropriate volumes for deltoid muscle administration in adults vary, and several are summarized in Table: Published Information Applicable to Deltoid IM Injection Volume. As the table illustrates, some authors consider 1 mL and others consider 2 mL to be the maximum volume that is safe for deltoid intramuscular injection. The information listed in the table is not specific to studies of RISPERDAL CONSTA; it is general information intended for any medication that is approved for deltoid intramuscular injection in adults.

CLINICAL STUDIES

Open-Label Studies

Thyssen et al (2010)¹² conducted two studies to evaluate the pharmacokinetics, safety, and tolerability of RISPERDAL CONSTA administered into the deltoid muscle of adult patients with chronic schizophrenia. Both studies used a 2-mL volume for both deltoid and gluteal injections of RISPERDAL CONSTA.

Study 1

Study Design/Methods

• Study 1 was a randomized, multicenter, open-label, single-dose, two-way crossover study in adult patients diagnosed with schizophrenia by DSM-IV criteria.
• The pharmacokinetic (PK) study evaluated the bioequivalence of RISPERDAL CONSTA administered into the deltoid muscle versus administration into the gluteal muscle. Dose-proportionality between 37.5 mg and 50 mg injected into the deltoid muscle and between 25 mg and 50 mg injected into the gluteal muscle was also evaluated.
• After a screening period, 170 patients were enrolled in the study and randomized into two groups. Each patient received two injections in a randomized order, each of which was followed by an 85-day observation period.
• Patients in Group 1 received a single IM injection of RISPERDAL CONSTA 25 mg into the gluteal muscle (2-inch, 20-gauge needle, 2-mL volume) and a single IM injection of RISPERDAL CONSTA 37.5 mg into the deltoid muscle (1-inch, 21-gauge needle, 2-mL volume). Each patient in Group 2 received a single IM injection of RISPERDAL CONSTA 50 mg into the gluteal muscle and a single IM injection of RISPERDAL CONSTA 50 mg into the deltoid muscle. Patients were allowed to continue their current oral antipsychotic therapy excluding the following drugs: thioridazine, clozapine, ziprasidone, or risperidone.
• Blood samples were collected predose and throughout the 85-day observation period for both treatment groups. Plasma concentrations of risperidone, 9-hydroxyrisperidone, and the active antipsychotic fraction (risperidone plus 9-hydroxyrisperidone) were measured.
• PK parameters evaluated included area under the plasma concentration-time curve from last quantifiable plasma concentration (AUC_last) and from time zero to infinity (AUC_∞), observed peak plasma concentration (C_max), time to reach the observed maximum peak concentration (t_max), and elimination half-life (t_1/2).
• Deltoid and gluteal injections of RISPERDAL CONSTA were considered bioequivalent administration routes if the 90% confidence intervals for the ratio of mean deltoid muscle values to gluteal muscle values for C_max and AUC for the 50-mg dose fell within 80% to 125% acceptance bounds. Patient Safety was also evaluated.

Results

• Seventy-nine percent (135/170) of patients completed the study. Withdrawal of consent was the most common reason for study discontinuation. No patients withdrew because of poor tolerability at the injection site; however, two patients withdrew prematurely due to adverse events.
• Patients were 21 to 57 years of age (mean age, 41 years) and majority male (66%), with body mass index ranging from 19 to 38 kg/m².

Efficacy

• The shape of the plasma concentration-time profiles of the active antipsychotic fraction, risperidone, and 9-hydroxyrisperidone were comparable for all treatments.
• The peak (C_max) and total (AUC) systemic exposure was higher in patients receiving RISPERDAL CONSTA 37.5 mg or 50 mg into the deltoid muscle than in patients receiving RISPERDAL CONSTA 25 mg into the gluteal muscle; neither the C_max nor the AUC exceeded plasma concentrations obtained in patients receiving RISPERDAL CONSTA 50 mg into the gluteal muscle. Regardless of injection site or dose, median t_max was about 30 days and the t_1/2 was between 2 and 4 days for the active antipsychotic fraction and risperidone.
• RISPERDAL CONSTA 50 mg administered into the deltoid muscle was considered bioequivalent, with respect to peak and total exposure, to RISPERDAL CONSTA 50 mg injected into the gluteal muscle. See Table: Bioequivalence of Deltoid Versus Gluteal Injection. After adjustment for dose differences, RISPERDAL CONSTA 37.5 mg injected into the deltoid muscle was bioequivalent to RISPERDAL CONSTA 25 mg injected into the gluteal muscle.

• A sensitivity analysis showed that bioequivalence was maintained when those subjects whose predose active moiety concentration >5% were excluded.
• Dose-proportionality analysis was assessed with comparison of doses and administration sites across Group 1 and Group 2, showing that all were dose-proportional and had similar PK parameters after dose-normalization of lower doses to 50-mg injections.
• The geometric least-squares mean ratios of 37.5-mg dose administered into the deltoid muscle (dose-normalized to a 50-mg injection) compared to a 50-mg deltoid injection and a 25-mg dose administered into the gluteal muscle (dose-normalized to a 50-mg injection) compared to a 50-mg gluteal injection both approached 1.00.

Safety

• Overall, 64% of patients experienced ≥1 treatment-emergent adverse event (TEAE), (48% with gluteal injection and 49% with deltoid injection), and 1% discontinued due to adverse events.¹³ The most common TEAEs were headache (15%) and nasopharyngitis (12%).¹² Adverse events related to the injection site occurred in ≤2% of all treatment groups.¹³
• Injection-site reactions were reported at a slightly higher frequency with deltoid administration than with gluteal administration; however, these reactions were considered mild in nature and not clinically meaningful.¹²
• Up to day 15, investigators rated no injection-site reactions as showing induration, tenderness, redness, or swelling at either the deltoid or gluteal injection sites.
• For the majority of patients, after administration of RISPERDAL CONSTA at both the gluteal and deltoid muscles, patient-rated injection-site pain on the visual analog scale (VAS) showed no or minimal changes at 2, 12, and 24 hours after injection. The median change on the VAS from baseline was 0 mm at all time points. Two hours after injection, mean change from baseline in injection-site pain was highest; ratings returned to baseline VAS scores 24 hours later for the gluteal administration of RISPERDAL CONSTA 25 mg and 50 mg and deltoid injection of RISPERDAL CONSTA 37.5 mg. Patients receiving deltoid administration of RISPERDAL CONSTA 50 mg returned to baseline scores on the VAS on day 3.¹³
• Serious adverse events occurred in 6% of patients (n=10), most unrelated to study medication, with the exception of one case of psychotic disorder and one case of drug toxicity.¹² Two deaths occurred (cough/drug toxicity and suicide) in subjects receiving RISPERDAL CONSTA 50 mg administered into the gluteal muscle; deaths were thought to be unrelated to study medication. RISPERDAL CONSTA had similar tolerability regardless of the dose or injection site.

Study 2

Study Design/Methods

• Study 2 was an 8-week, randomized, multicenter, open-label, multi-dose study in adult patients with chronic schizophrenia previously receiving gluteal injections of RISPERDAL CONSTA (25 mg or 37.5 mg) for at least one month who required higher doses.¹²
• Fifty-three patients were enrolled into the study. Patients received RISPERDAL CONSTA 37.5 mg or 50 mg every two weeks into the deltoid muscle as 2-mL injections. The four deltoid injections were alternated between the right and the left arm. Doses could be increased or decreased depending on clinical need.
• The primary objective of this study was to assess the proportion of patients who discontinued treatment with RISPERDAL CONSTA after multiple doses administered into the deltoid muscle; however, only PK and Safety Results were presented in this publication (refer to Quiroz et al (2011) for discontinuation rates²¹).
• Blood samples were collected predose (day 1), reflecting the PK of the 25-mg or 37.5-mg gluteal injections, and on days 43 through 57, reflecting the pharmacokinetics after multiple deltoid injections.

Results

• Of the 53 enrolled patients, 51 received at least two deltoid injections. Eighty-three percent (44/53) of patients completed the study.
• Patients were excluded from the PK analysis due to additional dose modifications, sampling outside of the specified time window, and intake of concomitant medications with potential for PK interaction.
• Patients were 19 to 59 years of age (mean age, 42 years) and majority male (72%), with body mass index ranging from 20 to 38 kg/m².
• Steady-state plasma concentrations increased with each deltoid injection. RISPERDAL CONSTA 37.5 mg and 50 mg administered into the deltoid muscle yielded similar steady-state plasma concentrations when dose-normalized.
• No patients withdrew because of tolerability problems at the injection site; however, two patients withdrew prematurely due to adverse events.¹³
• Overall, 40% of patients experienced ≥1 treatment-emergent adverse event, and 4% discontinued due to adverse events. The most common TEAEs were injection-site pain (8%), fatigue (6%), and sedation (6%).¹²
• Serious adverse events occurred in 4% (n=2) of patients and were considered unrelated to study medication. No deaths occurred.
• The incidence of injection-site reactions was 1.9%; scores were increased 2 hours after injection but returned to normal by the next injection. Injection-site pain was reported in 7.5% of patients.
• Investigator-rated mild injection-site reactions were observed in 19% (n=10) of patients 2 hours after injection, resolving to normal before the next injection. Investigators did not observe moderate or severe induration, tenderness, redness, or swelling at the injection site. Patient-reported injection-site pain on the VAS 2 hours after injection was slightly higher (4.2-6.1 mm) than at baseline (2.4 mm), returning to normal before the next injection. Patients receiving RISPERDAL CONSTA 50 mg reported higher pain ratings (approximately 5-10 mm) than those receiving 37.5 mg (approximately 1-3 mm).¹³

Quiroz et al (2011)²¹ described local injection-site tolerability and safety results from two studies evaluating RISPERDAL CONSTA and comparability of systemic exposure of deltoid versus gluteal injections.

Study 1: Single-dose study

Study Design/Methods

• Randomized, multicenter, two-way crossover study (n=170) measuring Safety and pharmacokinetic properties by comparing single-dose DM (deltoid muscle) and GM (gluteal muscle) injections of RISPERDAL CONSTA in patients with chronic stable schizophrenia.
• RISPERDAL CONSTA 25 or 50 mg via GM; RISPERDAL CONSTA 37.5 or 50 mg via DM

Results

Investigator-rated

• Injection-site reactions rating: mild: 51 (30%) moderate 9 (5%). Incidences of injection site reactions were slightly higher following deltoid injection (37.5 mg: 21%; 50 mg; 27%) than gluteal injection (25 mg: 12%; 50 mg: 14%).
• Based on TEAEs reported on injection-site reactions, the tolerability of RISPERDAL CONSTA was similar for all dosage strengths regardless of the injection site.
• Tenderness was the most common injection site reaction: GM: 10% (both 25 and 50 mg); DM 18% (37.5 mg) 19% (50 mg)
• Redness: GM 3% (25 mg); 6% (50 mg); DM 5% (37.5 mg) 8% (50 mg)
• Post-injection reactions occurred most frequently at 2 and 12 hours and resolved with no reports beyond day 3 except for one occurrence of redness (50 mg; DM).

Patient-rated

• Mean change from baseline VAS scores (mm) 2 hours post injection: 25 mg GM: 1.1; 50 mg GM: 0.5; 37.5 mg DM: 3.4; 50 mg DM: 1.1
• Mean scores were comparable to baseline scores after 24 hours for all doses except 50 mg DM, for which scores normalized by 3 days after injection.

Study 2: Multi-dose study

Study Design/Methods

• Multi-dose, multicenter, safety study (n=53) evaluating DM injection of RISPERDAL CONSTA in patients with schizophrenia
• RISPERDAL CONSTA 37.5 mg or 50 mg DM every 2 weeks for 4 doses (flexible dosing)

Results

Investigator-rated

• Mild injection site reactions were seen in 10 (19%) patients. Post injection reactions were rated as “absent” 2 weeks after administration.
• No moderate or severe reactions or dose-related differences were observed. No patients discontinued treatment due to site related TEAEs. Injection-site pain and injection-site reactions were reported as AEs by 7.5% and 1.9% of patients, respectively.

Patient-rated

• Mean increase in VAS scores from pre-dose to post dose: 50 mg DM: 5-10 mm; 37.5 mg DM: 1-3 mm
• Mean scores returned to baseline by 2 weeks.

SURVEY STUDY

Heres et al (2012)²² conducted a survey of sixty German patients stabilized on gluteal RISPERDAL CONSTA therapy in an outpatient clinic and offered a switch to deltoid administration including a 3-month follow up period.

Methods

• Sixty patients who routinely report to a LAI outpatient clinic were offered a switch to the deltoid administration of RISPERDAL CONSTA. The four psychiatrists offering the switch were trained through role-plays not to bias the patient towards either staying with or switching their injection method.
• Prior to being offered the switch, all patients were asked to report their preference for receiving injections from a female or male nurse in addition to the levels of pain (1= no pain; 7= extreme pain) and shame (1= no shame; 7= extreme shame) experienced with gluteal injections.
• Descriptive, free-text explanatory reasons were collected regarding their decision to switch or not switch their administration route.
• A follow-up assessment was conducted after 3 months.

Results

• Deltoid administration was chosen by 34/60 (57%) patients.
• There was no significant difference in the perceived level of shame (P=0.436) or pain experienced (P=0.074) between those who switched and those who did not.
• There were no significant differences in age, duration of schizophrenia, BMI, CGI, gender, religious beliefs or preference for receiving the injection from a male or female nurse.
• Main reasons for switching to deltoid administration included “less burden from undressing” and “injection possible in standing position.” Reasons for not switching included a “fear of increased pain with a deltoid injection” and the possibility of “scar tissue or a local dermal reaction in visible body spots.”
• Three-month follow-up assessment:
  • 25/34 patients in the “switcher” group participated in the follow-up assessment (two patients relapsed, one moved, and six did not follow through with the switch)
  • 15/25 patients who switched continued to receive the deltoid injection with “more convenient” and “more practical” than the gluteal injection being the main reasons
  • Ten patients returned to the gluteal injection primarily due to ”increased pain with the deltoid injection.”

CASE REPORTS

Elliott et al (2010)²³ described a case of a 32-year old African American male with chronic paranoid schizophrenia and a history of nonadherence. Upon admission to an inpatient psychiatric hospital, RISPERDAL CONSTA 25 mg every 2 weeks was initiated along with 2 mg oral risperidone daily. Oral risperidone was given for 20 weeks due to a lack of response. The patient initially received injections in the DM and refused GM administration. After 3 doses, RISPERDAL CONSTA was titrated to 37.5 mg, which was then increased to 50 mg every 2 weeks on the fifth DM injection. One week following the 16th DM dose, the total risperidone steady-state plasma concentration level was 15 ng/mL. At week 18, the administration route was changed from DM to GM in an attempt to maximize response. The patient was thought to be a CYP-450 2D6 rapid metabolizer. Four days after the third 50-mg GM dose, the total risperidone level was 16 ng/mL. When the fourth GM dose was given, the total risperidone level was 5 ng/mL, which then increased to 12 ng/mL two weeks later. RISPERDAL CONSTA was discontinued after the patient received 25 doses (including DM and GM) of 50 mg due to a lack of efficacy. Oral haloperidol 5 mg daily was initiated and titrated to a total daily dose of 25 mg. Three weeks after initiating haloperiol, bupropion XL 150 mg daily was given as well. The patient responded to the new medication regimen. The authors concluded that differences in absorption rates between injection sites may result in inconsistent steady-state blood levels when switching from DM and GM administration.

Saxena et al (2008)²⁴ reported a case of a 58-year old man diagnosed with schizophrenia who had received several prior antipsychotic treatments, including fluphenazine decanoate from 1974-1980 and 1985-1987, and haloperidol decanoate from 1993-2007. For at least seven years, the patient would accept his biweekly injections only in his left arm, in the deltoid muscle, which resulted in the development in 2007 of three egg-shaped, hard, painful, noninfected lumpy nodules, which occupied approximately 75% of this area. In August 2007, the patient began treatment with RISPERDAL CONSTA administered in the deltoid muscle. The nodules decreased considerably in size, pain, and density, and by June 2008 they occupied approximately 12% of the area.

SELECTED ADDITIONAL REFERENCE(S)

An additional study mentioning RISPERDAL CONSTA deltoid administration has been identified and the citation has been included for your reference.²⁵

LITERATURE SEARCH

A literature search of MEDLINE^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted through October 4, 2023. The following relevant citations were identified for your reference.