Summary

• There currently are no systematically collected data to support the use of INVEGA SUSTENNA concomitantly with another antipsychotic.
• Since paliperidone is the major active metabolite of risperidone, caution should be exercised when INVEGA SUSTENNA is coadministered with risperidone or with oral paliperidone for extended periods of time. Safety data involving concomitant use of INVEGA SUSTENNA with other antipsychotics is limited.¹
• Pharmacokinetic (PK) modeling simulations have been conducted to predict plasma paliperidone concentrations when paliperidone palmitate 1-month (PP1M) is added to existing treatment with oral paliperidone extended-release (ER), as well as when oral paliperidone ER 3 mg/day is used to supplement PP1M 156 mg.^2,3
• Retrospective studies by Kenar et al (2023)⁴ and Calvin et al (2023)⁵ described the use of INVEGA SUSTENNA as part of dual-long-term injectable (LAI) antipsychotic regimens.
• Several case reports and case series describe the use of INVEGA SUSTENNA with other antipsychotics.^6-11

DOSAGE STRENGTH INFORMATION

Doses of INVEGA SUSTENNA ER injectable suspension may be expressed in milligram equivalents (mg eq) of paliperidone (active moiety) or milligrams of paliperidone palmitate. Dosage information in this response has been converted to mg of paliperidone palmitate to reflect the commercially available dosage strengths in the United States. The conversion factor from mg eq to mg is 1.56.

• INVEGA SUSTENNA doses expressed as 39, 78, 117, 156, and 234 mg of paliperidone palmitate are equal to 25, 50, 75, 100, and 150 mg eq of paliperidone, respectively.

PK simulations

Paliperidone palmitate added to existing treatment with oral paliperidone ER

PK modeling simulations² were conducted to determine the change in paliperidone plasma concentration when paliperidone palmitate is added to existing treatment with oral paliperidone ER. The first simulation evaluated the effects of adding PP1M to existing treatment with oral paliperidone ER 6 mg/day. PP1M was administered following the recommended dosing regimen of 234 mg given on day 1 and 156 mg 1 week later, both via intramuscular (IM) deltoid injections, followed by once monthly injections of 117 mg. This simulation is depicted in Figure: Paliperidone Palmitate Added to Paliperidone ER 6 mg: 90% Prediction Intervals with Medians. In this figure, the big arrows represent PP1M injections, and the small arrows represent paliperidone ER oral doses. The simulation model illustrated that the median maximum plasma concentration (C_max) for PP1M added to oral paliperidone ER was 55 ng/mL, compared to a median C_max of 19 ng/mL for oral paliperidone ER 6 mg/day.

Similarly, a second simulation evaluated the effect on paliperidone plasma concentration of adding PP1M, administered as 234 mg on day 1, 1 week later, and once monthly thereafter, to existing treatment with oral paliperidone ER 12 mg/day. The simulation model illustrated that the median C_max for PP1M added to oral paliperidone ER was 80 ng/mL, compared to a median C_max of 38 ng/mL for oral paliperidone 12 mg/day.

Based on this PK modeling simulation, the use of PP1M concomitantly with oral paliperidone ER is not recommended.

Oral paliperidone ER 3 mg/day used to supplement paliperidone palmitate 156 mg

The PK simulation³ below depicts the expected paliperidone plasma concentration for simulated patients receiving PP1M 234 mg every 4 weeks at steady-state, including after conversion to PP1M 156 mg every 4 weeks plus oral paliperidone ER 3 mg every day. In the figure below, Medians on a Linear Scale, all simulated patients received PP1M 234 mg at 12, 8, and 4 weeks before time zero. The orange line depicts the median expected paliperidone plasma concentration in patients who continued to receive the 234 mg dose every 4 weeks. The black line depicts the median expected paliperidone plasma concentration in patients who received PP1M 156 mg at week 0, week 4, and week 8 and oral paliperidone ER 3 mg/day from weeks 0-12.

The table below, Expected Changes in Paliperidone Plasma Concentrations, depicts the expected change in median peak and trough plasma concentrations for this simulation for the first 3 cycles after conversion from PP1M 234 mg every 4 weeks to PP1M 156 mg every 4 weeks plus paliperidone ER 3 mg daily.

Retrospective studies

Kenar et al (2023)⁴ conducted a real-world, retrospective, mirror-image study evaluating the number of hospitalizations in patients who switched from oral antipsychotics to dual-LAI antipsychotics.

Results

• Eighty-three patients were included in the study (mean age, 34.7 years), of which 96.4% were receiving oral antipsychotics before switching to dual-LAI antipsychotics.
• Patients were diagnosed with schizophrenia (44.6%), schizoaffective disorder (41.0%), bipolar disorder (7.2%), mental impairment (4.8%), and organic mental disorder (2.4%).
• Additional LAI antipsychotics administered with INVEGA SUSTENNA as part of the dual-LAI antipsychotic regimens were aripiprazole 1-monthly (31.3%), flupentixol LAI (24.1%), zuclopenthixol LAI (18.1%), and haloperidol LAI (6.0%).
• A statistically significant improvement in the number of hospitalizations was reported after switching to all regimens of dual-LAI antipsychotics vs oral antipsychotics (pre-dual-LAI treatment hospitalizations, 5.95; post-dual-LAI treatment hospitalizations, 0.99; P<0.001).
• No significant adverse effects were reported in any patients on the dual-LAI antipsychotic regimens.

Calvin et al (2023)⁵ conducted a real-world retrospective, 12-month mirror-image study between September 2014 and January 2022 in France, evaluating the before and after outcomes of treatment with dual-LAI antipsychotics in patients with schizophrenia or schizoaffective disorder.

Results

• Thirteen patients were included in the study (mean age at the initiation of dual-LAI treatment, 45.2 years; male, 77%); 9 patients were diagnosed with schizophrenia and 4 with schizoaffective disorder.
• The mean age at disorder onset was 24.5 years, and the mean antipsychotic treatment duration before switching to dual-LAIs was 18.5 years, with patients having received a mean of 5.5 different antipsychotics before the study. Drug resistance was the reason for initiating dual-LAIs in all patients.
• Six combinations of dual-LAIs were used, with INVEGA SUSTENNA included in 2 regimens:
  • Zuclopenthixol, 3 patients (mean chlorpromazine equivalent [CPZ eq.] 367 mg and INVEGA SUSTENNA 117 mg/28 days)
  • Aripiprazole, 1 patient (mean CPZ eq. 300 mg and INVEGA SUSTENNA 150 mg/28 days [non-standard dosing])
• The reasons for hospitalizations were similar before and after treatment with dual-LAIs. In the 12 months before vs after dual-LAIs, a significant reduction was reported in the average number of hospitalizations (2.6 vs 1.3; P=0.017) and the total duration of hospitalizations (142 days vs 95 days; P=0.046).
• No significant differences in tolerance outcomes were reported before and after treatment with any of the dual-LAI regimens.

CASE series/case rEPORTS

McElyea et al (2023)⁶ described a 41-year-old male with schizoaffective disorder who presented to the emergency department with a small bowel obstruction. Due to agitation, he was treated with intravenous (IV) chlorpromazine and IM olanzapine. Within 12 hours, he developed altered mental status, tachycardia, and hyperthermia. Repeat computed tomography scans revealed several pill-shaped radiopaque objects in his colon. His home medications included chlorpromazine, lithium, INVEGA SUSTENNA, and clonazepam, and that his last INVEGA SUSTENNA injection was administered 1 week ago. Over the next 24 hours, he developed symptoms of Neuroleptic Malignant Syndrome (NMS) and was treated with benzodiazepines, IV hydration, external cooling, cessation of antipsychotics, and an enema to remove the suspected chlorpromazine in his colon. Bromocriptine was started to prevent NMS recurrence in the background of a long-acting injectable (LAI) antipsychotic, which led to a marked improvement in symptoms.

Teodoro et al (2022)⁷ described a 25-year-old female diagnosed with schizophrenia. After initial treatment with olanzapine and risperidone, she was transitioned to clozapine 300 mg/day and INVEGA SUSTENNA due to symptom persistence. She developed clozapineinduced isolated bilateral asymmetric periorbital edema without any systemic or inflammatory symptoms or remarkable bloodwork. She had no known history of relevant allergic reactions. Clozapine was reduced to 150 mg/day and INVEGA SUSTENNA was continued, leading to marked clinical improvement, good tolerability, and resolution of the edema over the next 3 days. She was discharged with clozapine 150 mg/day and INVEGA SUSTENNA 234 mg/month.

Mutlu et al (2022)⁸ described 6 patients with schizophrenia using clozapine and INVEGA SUSTENNA. In 2 patients, clozapine was added to INVEGA SUSTENNA 234 mg due to treatment resistance and noncompliance. In 4 patients, INVEGA SUSTENNA 156 mg was added to clozapine due to insufficient response of clozapine and noncompliance (in 2 patients). After combination use of clozapine and INVEGA SUSTENNA, there were fewer hospitalizations, and Clinical Global Impressions (CGI) and Global Assessment of Functioning (GAF) scores improved.

Hyperprolactinemia (n=1) and hyperprolactinemia with amenorrhea (n=1) were reported in association with INVEGA SUSTENNA treatment.

Evernden et al (2021)⁹ described a 39-year-old Canadian female diagnosed with psychosis and schizophrenia. She had a 4-year history of multiple medication nonadherence leading to an initiation of concomitant INVEGA SUSTENNA and once-monthly LAI aripiprazole every 28 days in opposite deltoid muscles. One year post discharge, the patient remains on dual LAI therapy and has not had any psychiatric presentations since initiating dual LAI therapy.

Legrand et al (2014)¹⁰ described a 51-year-old male with schizoaffective disorder (bipolar subtype) who was successfully treated with INVEGA SUSTENNA 234 mg plus olanzapine pamoate 300 mg. Injections of each drug were administered monthly, 14 days apart and were well tolerated.

Raj et al (2013)¹¹ described a case report of a 45-year-old male who experienced neutropenia and lymphopenia during concomitant treatment with INVEGA SUSTENNA and oral risperidone.

Other ReLEVANT LITERATURE

Citations of a cross-sectional study,¹² reviews,^13-15 and case series^16,17 and reports^18,19 discussing the concomitant use of INVEGA SUSTENNA and other antipsychotics are included here for your reference.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 29 August 2024.