SummarY

• RISPERDAL CONSTA is not approved for use in patients less than 18 years of age.¹
• Risperidone long-acting injection (RLAI) improved symptoms in 81% of children and adolescents (N=42) with conduct disorder (CD), bipolar disorder, or schizophrenia enrolled in an interventional study. The most common adverse events were weight gain, daytime somnolence, and muscle stiffness.²
• RISPERDAL CONSTA was found to be an alternative treatment in a naturalistic treatment study of 19 Brazilian patients (mean age: 12.1 years) with early onset bipolar disorder who failed to respond to prior medication regimens or encountered treatment adherence issues.³
• Significant clinical improvements were observed when switching from oral antipsychotic treatment with risperidone or olanzapine to RISPERDAL CONSTA in 31 adolescent Chinese patients with early onset/stable schizophrenia in an open-label trial.⁴
  • Mean Positive and Negative Syndrome Scale (PANSS) total scores, while generally low at baseline, significantly improved at week 6 and at the end of treatment.
  • Adverse events observed in ≥5% of patients (generally considered mild to moderate in severity) included: depression, anxiety, headache, insomnia.
• Several retrospective studies^5-7 and case studies^8-12 describe RISPERDAL CONSTA used successfully in children and adolescents with various psychiatric diagnoses.

PRODUCT LABELING

Please refer to the following section of the enclosed Full Prescribing Information which is relevant to your inquiry: USE IN SPECIFIC POPULATIONS.

CLINICAL STUDIES

Open-Label Studies

Ceylan et al (2017)² conducted an interventional study to examine the effectiveness and adverse effects of RISPERDAL CONSTA in children and adolescents (n=42) with CD (n=32), bipolar disorder (n=14), and schizophrenia (n=2). Six patients had comorbid CD and bipolar disorder.

Study Design/Methods

• Patients aged 12-17 years who were noncompliant on oral antipsychotics were recruited for this study to receive the intervention, a minimum of 4 injections of RLAI in an inpatient setting.
• The use of other antipsychotics was not permitted.
• Clinical Global Impressions (CGI) scores are measured at baseline and 2 months after treatment completion to observe efficacy.
• The Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS) instrument was implemented to assess adverse events. Participants were monitored at monthly follow-ups after discharge.
• RLAI 25 mg IM was administered every 2 weeks.

Results

Efficacy

• According to physician-assessed CGI scores taken 2 months after treatment commencement, 34 patients were classified as improved (9 very much improved, 25 much improved), 7 as minimally improved, 1 as no improvement. Four of the patients with minimal or no improvement also had comorbid mental retardation
• Improvement was seen in patients with the following diagnoses: 13/14 with bipolar affective disorder; 25/32 conduct disorder; 1/2 with schizophrenia.

Safety

• There was no significant correlation between number of RLAI doses and the LUNSERS score (P=0.284; r = -0.169).
• Most common adverse events among males and females: weight gain (52.4%), daytime somnolence (23.8%), muscle stiffness (21.4%)
• Other adverse events included: menstrual irregularities (39.2%) and swollen/tender breasts (28.6%)
• 18 patients (42.8%) discontinued: nonadherence (n=7), weight gain (n=4), dystonia (n=3), galactorrhea (n=2), galactorrhea and weight gain (n=2)

Boarati et al (2013)³ conducted a 6-month, open-label naturalistic trial in Brazil assessing the Efficacy and Safety of RISPERDAL CONSTA in the treatment of early onset bipolar disorder in 19 children and adolescents (mean age:12.1 years).

Study Design/Methods

• Inclusion criteria:
  • Bipolar diagnoses confirmed by 2 child and adolescent psychiatrists in face-to-face clinical interviews and two structured interviews (the Child Behavior Check List and the Diagnostic Interview for Children and Adolescents)
  • Severe pediatric bipolar symptomatology: CGI-Severity of Illness (CGI-S)>5
  • Severe functional impairment: Children’s Global Assessment Scale (CGAS)<31
  • Previous use of oral risperidone with good tolerability but poor adherence to oral medications
• Exclusion criteria included but were not limited to the following:
  • Comorbidity with pervasive developmental disorders, schizophrenia or mental retardation (IQ<70)
  • History of severe extrapyramidal symptoms or neuroleptic malignant syndrome
  • Current use of depot antipsychotics
• Dosing/Treatment Plan
  • Time 0 (T0)- RLAI was initiated at 25 mg IM every 15 days - Oral risperidone/other medications were continued during the first 3 weeks.
  • Time 1 (T1) - Short-term treatment endpoint (2 months) - Patients with CGAS >31 or CGI-S <3 could choose to return to oral medication and leave the study. Patients who did not improve could have their therapeutic regimen changed.
  • Time 2 (T2) - Long-term treatment endpoint (6 months) - Evaluation of the maintenance of improvement and tolerability of RLAI.
• The CGAS, CGI-S and CGI- Improvement (CGI-I) were used as guidance to assess treatment response and if a change in the dose or additional medication or the discontinuation of RLAI was warranted.

Results

Patient Characteristics

• The final study sample consisted of 16 males and 3 females; bipolar I disorder (89.5%); bipolar disorder not otherwise specified (10.5%). Eighteen patients reported a familial history of psychiatric disorders.
• The mean onset of the first affective episode was 6.9 years and the first manic episode, 8.0 years.
• Patients were severely impaired: Baseline mean CGAS (20.6); CGI-S (5.9). Six patients had been hospitalized previously and nine patients presented with ≥1 psychiatric comorbidities (ADHD [4], Tourette syndrome [2], conduct disorder [2] and enuresis [1].
• The mean dose administered at T1 was 37.5 mg and 46.3 mg at T₂.
• Three patients concomitantly used other medications:
  • carbamazepine/chlorpromazine (mood stabilizer/adjunctive anxiety control)
  • chlorpromazine (adjunctive sleep aid)
  • divalproex/methyphenidate (mood stabilizer/ ADHD)

Efficacy

• Significant improvement in global functioning and symptom severity was observed during this period:Short-Term Treatment (T₀ to T₁)
  • CGAS (20.6 vs 42.9, P<0.001)
  • CGI-S (5.9 vs 3.9, P<0.0001)
  • Mean CGI-I score at T1 endpoint: 2.2
• A trend of sustained improvement was observed during this period:Long-Term Treatment (T₁ to T₂)
  • CGAS (42.9 vs 49.2, P<0.0001)
  • CGI-S (3.9 vs 3.4, P=0.21)
  • CGI-I (2.2 vs 2.4, P=0.834)

Safety

• During the T0 to T2 period side effects reported include: elevated prolactin levels (57.9%), weight gain (36.8%), increased appetite (31.6%), and (T₁ to T ₂) mild transient tremors (10.5%). One episode of mild transient oculogyric crisis during the T₀ to T₁ period was reported.
• The mean weight gain at T1 was +1.1 kg and +5.7 kg at T₂.
• The mean prolactin level was high at T0 (17.7 ng/dL) however there were no significant changes during the treatment periods (T₁:26.8 ng/dL; T₂: 24.2 ng/dL)
• Some children and adolescents who initially resisted an injectable product reconsidered following psychoeducation and guidelines.

Ruan et al (2011)⁴ conducted a 6-month, open-label study assessing the efficacy and safety of RISPERDAL CONSTA in the treatment of early onset/stable schizophrenia in 31 adolescent Chinese patients (mean age: 15.9 years; 41.9% male).

Study Design/Methods

• Inclusion criteria: treatment with stable doses of oral olanzapine or risperidone for ≥4 weeks prior to screening; baseline PANSS total score ≤80 and a score ≤4 on each of the following PANSS items: conceptual disorganization, hallucinatory behavior, suspiciousness and unusual thought content.
• Exclusion criteria included but were not limited to the following: severe tardive dyskinesia; history of NMS; documented organic CNS disease; current seizure requiring medication; clinically severe ECG abnormalities; acute, unstable, or severe untreated medical illness; serious suicidal ideation/behavior within the past 6 months; high risk for violent behavior.
• Dosing:
  • 4-week run-in period; current oral antipsychotic treatment and other concomitant psychotropics continued.
  • RLAI initiated at 25 or 37.5 mg IM (gluteal) every two weeks based upon pre-study oral antipsychotic medication.
  • Based upon disease conditions/symptoms, 12.5 mg increment titrations (max: 50 mg) occurred at scheduled visits following at least four weeks of treatment with each dose.
  • Concomitant medications: oral supplementation (first two weeks of RLAI therapy, titrated down and discontinued during week 3; as needed for breakthrough psychosis); benzodiazepines (insomnia); trihexyphenidyl (EPS); pre-trial psychotropics.
• The change in PANSS total score from baseline to endpoint served as the primary Efficacy parameter.
• Secondary parameters included changes in CGI and ESRS (Extrapyramidal Symptom Rating Scale) scores.

Results

Patient Characteristics

• Pre-study oral risperidone and olanzapine were received by 13 and 18 patients, respectively.
• The 24-week trial was completed by 25 patients (80.6%) who received all 12 scheduled injections.
  • Final RLAI dose (last-observation-carried-forward): 25 mg (n=17, 54.8%); 37.5 mg (n=9; 29%); 50 mg (n=5; 16.1%)
  • 3 patients received oral risperidone supplementation (21 days, 28 days and 7 weeks at a dose of 1, 1.5 and 1 mg/day, respectively).
• Antidepressants, anti-parkinsonian agents and sedative/hypnotics were concomitantly used in 12.9%, 6.5% and 3.2% of patients, respectively.

Efficacy

• Mean PANSS total scores, while generally low at baseline, significantly improved at weeks 6 (-1.3; P<0.05), 12 (-2.8; P<0.05), 18 (-2.4; P<0.01), 24 (-4.2; P<0.01) and at the end of treatment (-3.3; P<0.01).
  • A significant reduction in mean PANSS scores was observed across all five symptom domains from baseline to endpoint.
    • Positive symptoms (-1; P<0.01)
    • Negative symptoms (-0.9; P<0.05)
    • Disorganized thoughts (-1.1; P<0.01)
    • Uncontrolled hostility/excitement (-0.4; P<0.05)
    • Anxiety/depression (-1; P<0.01)
• At the end of treatment CGI-severity significantly improved (mean reduction, baseline to endpoint: 0.3; P<0.001).
  • From baseline to end of treatment the proportion of patients with very mild to mild CGI increased from 45.6% to 58.8%, respectively.

Safety

• Adverse events observed in ≥5% of patients (generally considered mild to moderate in severity) included: depression (12.9%); anxiety (9.7%); headache (9.7%); insomnia (6.4%).
• ESRS scores while low at baseline were significantly reduced following RLAI therapy in patients previously receiving oral risperidone (0.48 to 0.4, P<0.05 versus baseline) and slightly increased in patients previously receiving oral olanzapine (0.39 to 0.41).
  • EPS related events during RLAI treatment included akathisia (n=1) and non-acute dystonia (n=2).
• During the 24-week study, mean serum prolactin concentrations significantly decreased from 87.4 ng/mL (baseline) to 40.2 ng/mL (end of treatment; P<0.01) in patients previously receiving oral risperidone and significantly increased from 31.3 ng/mL (baseline) to 42.9 ng/mL (end of treatment, P<0.05) in patients previously receiving oral olanzapine.
  • Adverse events potentially related to elevated prolactin levels included non-puerperal lactation (n=2) and dysmenorrhea (n=3).
• While patients previously treated with oral risperidone and olanzapine experienced mean body weight and BMI decreases from baseline to endpoint, these reductions were significant in the olanzapine group only (weight: 54.3 kg to 49.2 kg, P<0.01; BMI 27.1 kg/m² to 25.7 kg/m², P<0.05).
• No clinically significant changes in ECG findings (including QT_c) were observed.
• Self-ratings of local injection site pain (gluteal) were low for both treatment groups and decreased over the 24-week study.

Retrospective Studies

Fortea et al (2018)⁵ conducted a retrospective study assessing the use of second generation long-acting injectable antipsychotics in children and adolescents (mean age 16.3 years) hospitalized in an acute psychiatric ward in Spain. Thirty patients started treatment with RISPERDAL CONSTA (n=11, dose range 25-50 mg), paliperidone palmitate (n=7, dose range 50-150 mg), and aripiprazole long-acting injection (n=12, dose range 300-400 mg) during the study. Patients were switched from oral antipsychotics or intramuscular fluphenazine, mainly due to low treatment compliance (90%) and poor insight (73.3%). Patients had a variety of diagnoses, with psychotic disorder (73% in RLAI group), disruptive behavior disorder (45% in RLAI group), and ADHD (45% in RLAI group) being most common. Comorbidities were present in 93.3% of patients overall, with half of the patient’s using cannabis.

CGAS improved significantly from admission to discharge in all treatment groups; 32-point improvement (P<0.001), with no significant between group differences. The RLAI group had a 33-point improvement over an average length of hospitalization of 20 days. There were no discontinuations due to adverse events. Adverse events reported in patients treated with RLAI included hyperprolactinemia (n=3), sedation (n=1), and dystonia (n=1). Hyperprolactinemia was experienced significantly more often in the RLAI group (n=3) vs the aripiprazole long-acting injection group (n=0), P=0.014.

Ardic et al (2018)⁶ conducted a 24-week retrospective study in Turkey evaluating the outcomes of RISPERDAL CONSTA in 11 adolescents with conduct disorder exhibiting severe aggressive behaviors. Patients were prescribed oral risperidone and switched to RLAI 25 mg administered every 15 days due to poor compliance with their oral regimens. Nine patients were female (mean age 15.1±0.9 years) and 2 were male (mean age 14.5±2.1 years).

Disease severity, measured by CGI-S scores, significantly improved during treatment (6.6±0.5 at baseline to 2.2±1.1 at the last visit, P<0.001). Improvements in clinical symptoms, measured by CGI-I scores, also occurred (2.4 at week 8 to 1.9 at week 24, P=0.001). Patients were evaluated for weight gain and the occurrence of EPS. No significant change in mean body weight was found and EPS improved during treatment. At week 8, 2 patients (18.2%) reported no EPS but at week 24, 6 patients reported no EPS (54.5%).

Demirkaya et al (2017)⁷ conducted a retrospective study in Turkey assessing the effectiveness and tolerability of RISPERDAL CONSTA in 14 children and adolescents with CD characterized as moderately ill or more severe (CGI-S≥4). The mean patient age was 13.9±2.9 years (range, 6-17 years) with all but one patient being an adolescent. All patients had at least one comorbidity, substance use disorders being most common (n=8), followed by ADHD (n=6). Patients were originally prescribed oral medications but were noncompliant and became dangerous to themselves and their surroundings. Oral medications were discontinued and RLAI 25 mg was administered every two weeks in the gluteal muscle. Patients continued treatment until they showed symptom improvement and agreed to take oral medication (mean duration of RLAI treatment, 3.1 months [range, 1.5-8 months]).

The study evaluator was blinded to previous CGI scores and follow-up. A 14-year-old girl with CD and disruptive mood dysregulation was lost to follow-up after 2 months and minimal improvements. For the remaining 13 patients CGI-S scores significantly improved from a range of 4-7 at baseline to a range of 1-4 at endpoint (Z=-3.198; P<0.001). CGI-I scale scores showed “very much improvement” in 3 patients (23.1%), “much improvement” in 7 patients (53.8%), “mild improvement” in 2 patients (15.4%), and “no change” in 1 patient (7.7%). The patient with “no change” was a 6-year-old boy with CD, ADHD, and enuresis nocturna who had only 50% compliance with receiving RLAI injections. All other patients received 100% of their scheduled injections. Adverse events reported included weight gain (n=2), sedation (n=1), stomach pain (n=1), increase in appetite (n=1), muscle cramp (n=1), and dry mouth (n=1).

Case Series

Fu-I et al (2009)⁸ reported on three adolescent boys with bipolar disorder who were prescribed RISPERDAL CONSTA after nonadherence to oral medications.

Patient 1 was an 11-year-old boy who dropped out of school due to his psychiatric condition. He was diagnosed with school phobia at age 6 and major depressive disorder at age 10. The patient was initially prescribed sertraline; however, after four weeks he experienced a manic episode, and the medication was discontinued. Three months after the manic episode, he was initiated on oral risperidone ranging between 0.5 to 1.5 mg/day. Although there was improvement in the patient’s symptoms, he soon became noncompliant due to social stigma and returned to an impaired state. With the family’s consent, RLAI was initiated at a dose of 25 mg every 2 weeks. The patient had significant improvement after the third injection and his aggressive and manic symptoms were controlled after the fifth injection. After receiving five doses of RLAI, his CGI and CGAS scores improved from 6 to 3 and from 21 to 61, respectively. The patient’s prolactin level was 42 ng/mL at the 2nd injection and decreased to 5.5 ng/mL by the 5th injection. The patient’s cholesterol was 98 mg/dL prior to receiving RLAI and was 134 mg/dL by the 5th injection. Upon control of the patient’s symptoms, oral risperidone 3 mg/day was substituted for RLAI.

Patient 2 was a 14-year-old boy diagnosed with ADHD at age 5 and treated with methylphenidate. At age 6 the patient experienced a depressive episode and was initiated on sertraline 25 mg/day. Treatment with sertraline was discontinued because the patient became agitated, euphoric, hyperenergized and required less sleep. When the patient was presented with a second episode of depression, fluoxetine 20 mg/day was prescribed, but it had the same effects as sertraline and was also discontinued. His behavior grew worse, and he was eventually expelled from school. At age 7, he was prescribed valproic acid 500 mg/day combined with risperidone 1 mg/day and attained significant control of his symptoms; however, these medications were later discontinued due to side effects. Over the next several years, the patient was treated unsuccessfully with oxcarbazepine 900 mg/day, ziprasidone 120 mg/day, lithium 1500 mg/day, haloperidol 2 mg/day, quetiapine 300 mg/day, topiramate 500 mg/day, and divalproate 2000 mg/day given either alone or in combination. At age 13, the patient finally attained control of his symptoms on risperidone 3 mg/day. Due to partial compliance, he was presented in a critical medical situation with severe impairment (CGI score = 7 and CGAS score = 25). With the parent’s consent, RLAI was initiated at a dose of 25 mg every 2 weeks. After the fifth injection the patient’s externalizing symptoms were controlled and he was readmitted to school. After receiving 18 doses of RLAI, his CGI and CGAS scores improved from 7 to 2 and 21 to 71, respectively. Prior to treatment with RLAI, the patient's prolactin and cholesterol levels were 18.4 ng/mL and 230 mg/dL, respectively. At the 18th injection, prolactin (6.4 ng/mL) and cholesterol levels (105 mg/dL) were noted to have decreased. The patient continued treatment with RLAI for 9 months.

Patient 3 was a 14-year-old boy with a history of anxiety and phobias starting at age 7 after his father’s death. At age 9, after witnessing violence in the home, the patient presented with hallucinations, sadness, irritability, agitation, insomnia, crying easily, and had a low tolerance with frustration. At age 11 he was diagnosed with major depressive disorder and prescribed fluoxetine 20 mg/day. However, three months later the patient experienced a manic episode and was prescribed risperidone 2 mg/day with carbamazepine 800 mg/day. The patient attained control of his symptoms but used the medications irregularly. At age 14, RLAI was initiated at a dose of 25 mg every 2 weeks. After receiving 12 doses of RLAI, his CGI and CGAS scores improved from 6 to 2 and 31 to 71, respectively. The patient’s prolactin level was 10.3 ng/mL at the 3rd injection and decreased to 2.5 ng/mL by the 12th injection. His cholesterol was 102 mg/dL prior to taking RLAI and increased to 110 mg/dL by the 12th injection. He has been stable for the last 6 months, but due to the risk of nonadherence, he has continued monotherapy with RLAI at a dose of 25 mg every 2 weeks.

Nakadoi et al (2013)⁹ reported on two adolescent females with anorexia nervosa who received RISPERDAL CONSTA after refusing to eat.

Patient 1 was a 13-year-old girl with broader autism phenotype (BAP). She started to refuse to eat and showed aggressive outbursts and ritualistic behavior three months after starting to diet. She began oral risperidone (1-2 mg/day) after hospital admission. Refusal to eat and take medications continued and she was started on RLAI 25 mg every 2 weeks. A significant improvement was noted in about 6 weeks. Eating was more regular and there was an improvement in aggressive outbursts.

Patient 2 was a 14-year-old girl with autistic spectrum disorder (ASD). She started to refuse to eat four months after starting to diet and was seen by a psychiatrist. She was prescribed olanzapine 5 mg/day after hospital admission with no improvement in symptoms. She refused to drink or take medications. RLAI 25 mg every 2 weeks was started. A significant improvement was noted about 8 weeks later. She was able to eat and drink. Aggressive outbursts changed the ability to talk about her feelings on eating and drinking.

Case Report

Pope et al (2016)¹⁰ described the case of a 17-year-old male with mood disorder-not otherwise specified and comorbid cannabis abuse who was admitted to an inpatient psychiatric hospital due to increased irritability and aggression. The patient had a history of noncompliance and was restarted on oral risperidone upon admission. He experienced neck stiffness, believed to be EPS, which resolved upon initiation of benztropine. The dose of oral risperidone was increased and 25 mg RLAI was added to the regimen. He was discharged with a plan to continue RLAI 25 mg every 2 weeks through a community agency with injectable services. During his 14-day hospitalization, CGI-S scores decreased from 4 at admission to 3 at discharge and his overall CGI-I score was 3.

Umehara et al (2014)¹¹ reported a 10-year-old male with anorexia nervosa who was successfully treated with RISPERDAL CONSTA. The child, who had no previous psychiatric disorders, was presented with a 1-year history of restrictive eating, agitation during meals, and distortion of body image. Because he was severely underweight (71% of ideal body weight), the child was hospitalized, began enteral feedings, and was treated with olanzapine. Olanzapine was discontinued due to excessive sedation, and, approximately 7 months after initial presentation, the child began treatment with risperidone 1 mg/day. His symptoms (body image distortion and agitation during enteral feedings) abated, and he resumed eating meals. Risperidone was discontinued 2 months later at the request of his mother, but the child relapsed. Oral risperidone was re-initiated, symptoms improved, but eventually the child refused to take the drug. Treatment with RLAI 12.5 mg every 2 weeks began and over the next 7 months the child gained weight, achieving 96% of his ideal body weight. He was discharged from the hospital, then RLAI was tapered and discontinued approximately 4 months later. The child was noted to have been continuing to eat meals at this last follow-up, 1.5 years later.

Tutkunkardas et al (2011)¹² reported on a 16-year-old male prescribed RISPERDAL CONSTA following non-adherence to oral medication. At an early age the patient was diagnosed with ADHD and responded well to methylphenidate 25 mg TID. The patient was stable for approximately 4 years although medication compliance was an issue. He was switched to long-acting methylphenidate 36 mg/day and titrated to 54 mg/day. The patient exhibited problems related to defiance and conduct including fire-setting and stealing. A diagnosis of CD was added. Risperidone 0.5 mg/day was prescribed and was titrated to 2mg/day with bimonthly dose increments. There were no signs of improvement, and the patient eventually refused to take any oral medications. When the patient's symptoms became unbearable and posed a threat to others, he was prescribed RLAI 25 mg every 15 days. After 30 to 45 days from the time of his first injection, he began to show signs of improvement. After 6 months of treatment with RLAI, he no longer met the criteria for CD and received a diagnosis of oppositional defiant disorder (ODD) and ADHD. He displayed substantial improvement and was switched to oral risperidone. He slowly tapered from risperidone and at 2 years from the time of his first injection of RLAI, he was reported to be stable and remained on methylphenidate. The only side effect he experienced with RLAI treatment was a nearly 20% weight gain, which he lost after discontinuing RLAI.

OTHER RELEVANT LITERATURE

Retrospective studies describing the use of RLAI in adolescent or pediatric patients have been included in the References section below.^13-15

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 03 December 2024. The following relevant citations were identified for your reference.