Summary

• The safety and effectiveness of INVEGA SUSTENNA in patients <18 years of age have not been established.¹
• The use of INVEGA SUSTENNA in patients <18 years of age has been reported in 4 retrospective studies^2-5 and several case reports.^6-11

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate extended-release injectable suspension may be expressed in milligram equivalents 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.

PUBLISHED LITERATURE

Retrospective Studies

Sun et al (2024)⁴ conducted a single-center retrospective chart review from October 2015 to October 2022 at an acute care psychiatric hospital in the United States (US). The dosing strategies, safety and effectiveness of 5 long-acting injectable (LAI) antipsychotics, including INVEGA SUSTENNA, in adolescent and pediatric patients with psychiatric disorders were evaluated.

Results

Patient demographics

• Forty-five patients were newly initiated on LAIs (mean age [±standard deviation (SD)], 15.6 [±1.67] years; male, 57.8%; Black or African-American, 60%; White, 37.8%), with a primary diagnosis of schizophrenia spectrum and other psychotic disorders (42.2%); bipolar disorders (31.1%); disruptive, impulse control, and conduct disorders (13.3%); autistic disorder (11.1%); and attention-deficit or hyperactivity disorder (ADHD; 2.2%).
• INVEGA SUSTENNA was the most commonly prescribed LAI antipsychotic (n=21; 46.7%).

Dosing regimens

• Of the patients receiving INVEGA SUSTENNA, 14 each received a loading dose and a maintenance dose per the adult dosing recommendation, and 7 each received a loading dose and a maintenance dose different from the adult dosing recommendation.
• The non-standardized dosing regimens for INVEGA SUSTENNA are summarized in Table: Non-Standard INVEGA SUSTENNA Dosing Regimens.

Length of stay and readmission rates

• For patients treated with INVEGA SUSTENNA, the mean (SD) length of hospital stay was 20.9 (13.0) days, with 5 patients (23.8%) being readmitted within 6 months, with a mean of 70.6 (32.6) days to readmission.

Adverse effects

• Five patients receiving INVEGA SUSTENNA reported adverse effects, including weight gain, metabolic effect, constipation, difficulty thinking or concentrating, and extrapyramidal symptoms (n=1, each).

Treatment retention

• Among the 26 of 45 patients who received psychiatric care post-hospitalization at an outpatient clinic, 10 (38.5%) adhered to LAI antipsychotics 6 months post-discharge.

Simpson et al (2024)⁵ conducted a retrospective study between January 2016 and November 2019 in a community mental health clinic in the US to evaluate the safety and tolerability of the off-label use of INVEGA SUSTENNA in young and adolescent patients with autism spectrum disorder (ASD) and or intellectual disability (ID).

Results

• Twenty-six patients were included (age range, 3 to 20 years; male, 76.9%; White, 53.8%; African American, 38.5%; Asian, 3.8%; and biracial, 3.8%).
• All patients had an ID diagnosis, and 92.3% had ASD. The most common psychiatric diagnoses were Intermittent Explosive disorder (88.5%), ADHD (38.5%), and anxiety (23.1%).
• At the time of INVEGA SUSTENNA initiation, all patients were on an antipsychotic and concomitant psychotropic medications, including alpha-2 agonists (44%), stimulants (36%), antidepressants (28%), and mood stabilizers (12%). Overall, at the time of INVEGA SUSTENNA initiation, the study population was using an average of 2.8 psychotropic medications.
• In 25 of 26 patients, noncompliance with oral antipsychotic medication was the leading reason to switch to INVEGA SUSTENNA.
• The most common starting maintenance dose (after standard initiation) of INVEGA SUSTENNA was 156 mg every month (n=11), ranging from 39 mg every month (n=1; male patient aged 3 years at initiation) to 156 mg every 3 weeks (n=4; male patients aged 10-15 years at initiation).
• Dosing tended to increase during the study period; the most common dosing of INVEGA SUSTENNA during the study period or at discontinuation was 234 mg every 3 weeks (n=10; aged 9-19 years during initiation).
• Patients were on INVEGA SUSTENNA for a mean (SD) period of 21.1 (14.0) months (n=25; range, 1-45 months); 17 patients continued with INVEGA SUSTENNA at the study endpoint.
  • Eight (32%) patients discontinued INVEGA SUSTENNA during the study period; the mean (SD) time before discontinuation was 17.5 (12.4) months.
  • The reasons for discontinuation were lack of efficacy, difficulty in attending visits to get injections, injections not well tolerated, oculogyric crisis, hyperprolactinemia, periods of shaking/sweating/ill symptoms for 36 to 48 hours after injections, planned taper off the medication, and ability to retake oral medication (n=1, each).
• There was a significant reduction in emergency department and hospital visits in the 12 months after INVEGA SUSTENNA initiation (P=0.02).
• No significant change in body mass index (BMI) was observed at initiation and the end of the study or discontinuation (BMI before initiation, 24.4; BMI after initiation, 25.5; P=0.15).

Petrić et al (2019)³ conducted a retrospective, noninterventional study to evaluate the effectiveness and tolerability of INVEGA SUSTENNA compared to oral risperidone in adolescent drug-naïve patients with first-episode schizophrenia during the first 12 months of treatment. The study included patients between 15-18 years of age (N=36) from a medical center in Croatia.

Results

Efficacy

• The median doses of INVEGA SUSTENNA (n=18) and risperidone (n=18) were 117 mg monthly and 3 mg daily, respectively.
• Mean change from baseline to endpoint in Positive and Negative Syndrome Scale (PANSS) total scores was -43.89 for INVEGA SUSTENNA and -35.89 for risperidone (P<0.004). Compared to risperidone, INVEGA SUSTENNA patients showed significantly greater improvement in PANSS positive symptoms (P=0.023) and general psychopathology (P=0.025).
• Mean change from baseline to endpoint in Personal and Social Performance Scale total scores were 36.83 (6.09) for INVEGA SUSTENNA and 29.0 (4.31) for risperidone (P<0.001).
• Mean change from baseline to endpoint showed significantly lower median Clinical Global Impressions - Severity (CGI-S) score for INVEGA SUSTENNA compared with patients taking risperidone (P<0.018).
• Patients receiving risperidone had a significantly higher number of hospitalizations. During the 12-month study period, 2 (11.1%) patients receiving INVEGA SUSTENNA and 9 (50.0%) patients receiving risperidone were hospitalized (P=0.027).

Safety

• Overall, 2 (12.5%) patients taking INVEGA SUSTENNA and 4 (22.2%) patients taking risperidone reported at least 1 adverse event possibly related to treatment. Reported side effects were hyperprolactinemia (1 patient in each group) and weight gain in a patient on INVEGA SUSTENNA and 3 patients on risperidone.

Limitations

• The study limitations included a small sample size, retrospective design, patients were not blinded, and adherence was not measured in the risperidone group.

Fortea et al (2018)² conducted a retrospective, observational study to assess the off-label use of long-acting injectable (LAI) antipsychotics initiated in patients under the age of 18 years during hospitalization in Barcelona between January 2013 and June 2016 (N=30).

• Twenty-nine patients were switched from an oral antipsychotic and 1 patient was switched from intramuscular fluphenazine to risperidone.
  • Twelve patients initiated aripiprazole LAI (dose range: 300-400 mg), 11 risperidone LAI (dose range: 25-50 mg), and 7 INVEGA SUSTENNA (dose range: 78-234 mg), primarily due to low treatment compliance (90%) and poor insight (73.3%).
  • Patients initiated on INVEGA SUSTENNA (mean age: 16.5 years) had diagnoses including: psychotic disorder (86%), disruptive behavior disorder (43%), attention deficit/hyperactivity disorder (ADHD) (29%), and intellectual disability (14%). In addition, 86% had comorbid cannabis misuse.
• Global functioning was assessed at baseline and discharge using the Children's Global Assessment Scale (CGAS).
  • One risperidone and 1 paliperidone patient did not complete transition between oral and LAI at discharge. Oral prescription at discharge was not considered in the statistical analysis.
  • CGAS improved significantly (32 points; P<0.001) between admission and discharge, with no differences between LAIs (P=0.94). An exploratory analysis found no significant differences between patients with and without cannabis use.
• Two patients receiving INVEGA SUSTENNA reported adverse events (hyperprolactinemia [n=1] and akathisia [n=1]), which did not lead to treatment discontinuation.

Case Reports

Naguy et al (2024)¹¹ described a case of a 16-year-old male patient with schizoaffective disorder who was maintained on INVEGA SUSTENNA 156 mg every 4 weeks with partial response and presented to the hospital with recurrent constipation and fecal impaction. From the patient's medical history, a temporal association was noted between constipation and an increase in the paliperidone dose of 6 mg to 9 mg/day, resulting in a diagnosis of anismus due to paliperidone-induced dystonia. The patient was administered procyclidine (2 doses of 2.5 mg/day), and over 3 days, bowel movements and rigidity improved. Three months after the initial presentation, the patient has remained well-maintained on this treatment regimen with stable mental health and no incidents of constipation, tenesmus, fecal impaction, or encopresis.

Wang et al (2023)⁹ reported the use of INVEGA SUSTENNA in a 16-year-old female with schizophrenia. The patient was diagnosed with schizophrenia in 2018 and was initiated on aripiprazole (15 mg twice daily) and olanzapine (10 mg twice daily). Her medication was modified to paliperidone extended-release tablets (3 mg in the morning and 9 mg in the evening) and olanzapine (5 mg in the morning and 10 mg in the evening) at discharge. However, the patient reported fluctuations in psychotic symptoms over the course of her menstrual cycle. It was reported that the plasma concentration of paliperidone dropped to 12-18 ng/mL at the start of the menstrual cycle from 30-55 ng/mL before the menstrual cycle. In August 2020, the patient was switched to INVEGA SUSTENNA (monthly maintenance dose of 156 mg or 100 mg/eq). In the follow-ups for >2 years, the patient did not experience any further psychotic symptoms during and outside the menstrual cycle, and the plasma concentration of paliperidone was in the therapeutic range (25-53 ng/mL).

Naguy et al (2021)¹⁰ reported the use of INVEGA SUSTENNA in a 15-year-old male with obsessive-compulsive disorder (OCD). The patient presented to hospital with hypersexual behaviors and was initially diagnosed with comorbid bipolar spectrum disorder and ADHD symptoms. He was treated with oral paliperidone and clonazepam, for which he developed side effects, including asymptomatic hyperprolactinemia and weight gain. The patient was discharged from the hospital, but his hypersexual behaviors and treatment noncompliance persisted. Due to this, the patient was switched to a once-every-4-week dose of 156 mg INVEGA SUSTENNA with concomitant behavioral therapy. The patient was also initiated on fluoxetine for OCD symptoms and valproate for impulse dyscontrol. He developed extrapyramidal rigidity with no clinical resolution. Finally, the patient was treated with naltrexone and INVEGA SUSTENNA. Four weeks into the treatment, his mother noted improvement in his oversexualized behavioral symptoms, and he showed improvement on the Hypersexual Behavior Inventory scale. After 3 months, the patient showed good tolerability of the treatment.

Pope et al (2016)⁶ conducted a retrospective chart review assessing the use of LAI antipsychotics in adolescents (age: 14-17 years) diagnosed with a serious mental illness upon acute inpatient psychiatric hospitalization. INVEGA SUSTENNA was prescribed in 5 patients due to a history of noncompliance and in 1 patient for undocumented reasons. Unless otherwise noted, INVEGA SUSTENNA was well tolerated with monthly doses planned post discharge through a community agency with pediatric injectable services. Additional details of the cases are provided in the Table: Use of Paliperidone Palmitate in Adolescents With Serious Mental Illnesses.

Fàbrega et al (2015)⁷ reported the use of INVEGA SUSTENNA in 2 inpatients diagnosed with psychotic spectrum disorders (Diagnostic and Statistical Manual of Mental Disorders, fourth edition [DSM-IV] criteria). The first patient was a 14-year-old, Caucasian male with a diagnosis of undifferentiated schizophrenia and mild intellectual disability. Due to poor compliance, the patient was switched from aripiprazole 5 mg daily to a LAI. Oral paliperidone 6 mg daily was initiated with tolerability and improved clinical symptoms followed by a switch to INVEGA SUSTENNA (78 mg administered on day 1 and day 8 followed by a maintenance dose of 78 mg every 28 days; site of administration not reported). From baseline to discharge on day 17, improvement was noted on the PANSS total scale (94 versus 66, respectively) and General Assessment of Functioning (GAF: 15 versus 45, respectively). There were no adverse events as reported on the Udvalg for Kliniske Undersogelser (UKU) rating scale. After 1 year of treatment on INVEGA SUSTENNA 78 mg every 28 days, no adverse events were observed and the patient was noted as having an improvement in social skills and affective reactivity.

The second case report describes a 17-year-old African male diagnosed with psychotic disorder not otherwise specified and conduct disorder. The patient was previously treated with oxcarbazepine, methylphenidate, atomoxetine, aripiprazole and quetiapine. INVEGA SUSTENNA was considered due to clinical symptoms and poor social support. The patient tolerated oral paliperidone 3 mg daily and received a single initiation dose of INVEGA SUSTENNA 78 mg. Three days after receiving the first dose of INVEGA SUSTENNA, the patient experienced oculogyric crisis which resolved after treatment with biperiden 4 mg. The patient received a second dose of INVEGA SUSTENNA 78 mg 1 week later with good tolerability and continued on a monthly maintenance dose of INVEGA SUSTENNA 78 mg with biperiden 4 mg daily. From baseline to discharge on day 14, clinical improvement was noted on the PANSS total (75 versus 68, respectively) and GAF (20 versus 45, respectively). Drowsiness, asthenia and oculogyric dystonia were reported on the UKU rating scale. During the next 2 months, the patient refused treatment as a result of somnolence and concentration difficulties. Due to behavioral disruption he was readmitted to the hospital and switched to zuclopentixol decanoate 100 mg every 14 days plus biperiden 4 mg daily which led to clinical improvement with tolerability. However, 1 month as an outpatient he began to experience concentration difficulties and diurnal somnolence. Zuclopentixol was switched to oral aripiprazole 15 mg/day but noncompliance led to behavioral difficulties and paranoid interpretations. The patient was restarted on INVEGA SUSTENNA and biperiden upon readmission. No further details were provided.

Kowalski et al (2011)⁸ reported the use of INVEGA SUSTENNA in a 5-year-old boy with autistic disorder. He was initially treated with risperidone (maximum daily dose of 1 mg) and aripiprazole (maximum daily dose of 2 mg) administered in both tablet and liquid formulations, which provided noticeable improvements in aggression and tantrums. However, he began to refuse taking oral medications, leading to discontinuation of psychotropic medications and disruptive behavior.

After considering the injectable formulation of risperidone, INVEGA SUSTENNA was initiated due to its less frequent dosing. The patient was administered 3 test doses of oral paliperidone 1.5 mg, which was well-tolerated. He was then given INVEGA SUSTENNA 39 mg intramuscularly. After 3 monthly INVEGA SUSTENNA doses, the patient showed improvement, with tantrums and aggression diminishing in severity and frequency. Improvement was noted on 4 of the 5 subscales of the Aberrant Behavior Checklist. His CGI-S scores improved from a 6, or "severely ill" at baseline to a 2, or "minimally ill" after 3 months of treatment.

The authors noted that INVEGA SUSTENNA was well tolerated; however, the patient was noted to have an increase in appetite and an increase in body mass index from 16.4 to 19.2.

LITERATURE SEARCH

A literature search of Ovid MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 03 September 2024.