Summary

• As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.¹
• Hyperprolactinemia may suppress hypothalamic gonadotropin-releasing hormone (GnRH), resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients.¹
• Prolactin-related adverse events may include amenorrhea, galactorrhea, gynecomastia, erectile dysfunction, sexual dysfunction, ejaculation disorder, and decreased libido.
• For information regarding other adverse events related to elevated prolactin levels or the management of risperidone-induced hyperprolactinemia, please contact Medical Information at 1-800-JANSSEN (1-800-526-7736).

PRODUCT LABELING

Please refer to the following sections of the enclosed Full Prescribing Information that are relevant to your inquiry: WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

CLINICAL Data

Double-Blind Pivotal and Clinical Trials - Adults and Adolescents

Open-label/Case-Control (N≥50)/Post hoc Studies - Adult and Adolescents

Open-label/Case-Control/Post hoc/Case Noncase Studies in Adults and Adolescents

Study Design	Summary
Open-label Studies
Gómez-Revuelta et al (2021)4 conducted a 6 week prospective, randomized, flexible-dose, open-label study in 266 patients comparing the effectiveness of ARI (n=136) or RIS (n=130) for the treatment of a first episode of psychosis. UKU adverse event rating scale was used to evaluate adverse events. The mean age of patients was 32.0±10.7 years in the ARI group and 32.6±10.1 years in the RIS group (P=0.609). Male comprised 54.4% of the ARI group and 54.6% the RIS group (P=0.973).	Outcomes UKU rating (higher score means more symptoms) Amenorrhea: ARI, 0; RIS, 9 Galactorrhea: ARI, 0; RIS, 3 Diminished sexual desire: ARI, 3; RIS, 13 Erectile dysfunction: ARI, 3; RIS, 12 Ejaculatory dysfunction: ARI, 1; RIS, 13
de Araujo et al (2016)5 conducted a cross-sectional study to evaluate anthropometric, biochemical, hormonal, and quality of life changes in 108 adults with schizophrenia who were treated with RIS (n=43) or OLA (n=65) for ≥1 year. UKU side effect rating scale used to score severity of antipsychotic-related adverse events. The mean age of patients was 45.3±12.1 years in the RIS group and 34.4±12.5 years in the OLA group (P=0.09). Males comprised 32.3% of the RIS group and 67.7% of the OLA group (P=0.008).	Outcomes Prolactin values: RIS, 15.3 ng/mL and OLA, 7.3 ng/mL (P=0.04). UKU rating (higher score means more symptoms) Galactorrhea: RIS, 9.0; OLA, 9.0 Gynecomastia: RIS, 5.25; OLA, 2.0 (P=0.01)
Eberhard et al (2007)6 conducted a 5-year, open-label, longitudinal, multicenter trial assessing the effects of RIS on prolactin levels and associated side effects in 218 patients. Prolactin ULN reference values were 300 nmol/L for men and 500 nmol/L for women. The UKU scale was utilized for evaluation of side effects. Diagnoses: Mean Age Schizophrenia (n=151): 38.1 years Bipolar/schizoaffective (n=30): 43.5 years Delusional (n=9): 39.2 years Psychosis NOS (n=15): 31.7 years Other (n=13): 38.3 years Treatment: RIS monotherapy (n=181) RIS plus atypical (n=7) RIS plus ≥1 conventional (n=30)	Outcomes Significantly higher mean prolactin levels were initially observed in women vs men (2387 nmol/L vs 967 nmol/L, respectively; P<0.001). Of the 59 patients with complete data over the 5-year period, mean prolactin levels decreased significantly from baseline to year 5 (1192 nmol/L vs 412 nmol/L, respectively). A significant linear and quadratic trend was observed (P<0.001). For patients receiving continuous RIS monotherapy (n=20) over the 5-year period, a highly significant linear reduction of prolactin was observed (P<0.001). Concomitantly used drugs, other than RIS, were not associated with prolactin increases. No correlation between prolactin levels and sexual side effects was observed. According to the UKU scale, the following effects were observed during RIS use (males + females combined): Galactorrhea, 14%; gynecomastia, 5%.
Melkersson et al (2005)7 evaluated the degree and frequency of prolactin elevation and associated symptoms in patients receiving RIS (n=18; mean age: 41 years), CLO (n=28; mean age, 40 years), or OLA (n=29; mean age, 39 years) for DSM-IV schizophrenia, schizophreniform disorder, or schizoaffective disorder. In addition, the effects on LH, FSH, EST, testosterone, GH, and IGF-1 were also analyzed. Fasting blood samples were drawn prior to the morning dose of antipsychotic. Hyperprolactinemic symptoms were assessed through patient interview. Median daily doses received for ≥2.5 months: RIS: 3 mg (range, 1-8 mg) CLO: 400 mg (range, 25-600 mg) OLA: 10 mg (range, 5-20 mg)	Outcomes Eighty-nine percent of RIS patients, 24% of OLA patients, and 0% of patients receiving CLO, were found to have elevated prolactin levels (≥10 μg/L in men & menopausal women; ≥20 μg/L in premenopausal women). Median prolactin levels were significantly higher in the RIS (27.5 μg/L; P=0.00001) and OLA (7.1 μg/L; P=0.001) groups compared to patients receiving CLO (4.5 μg/L). When evaluating gender groups, significantly (P=0.04) more women (n=14/33; 42%) then men (n=9/42; 21%) experienced hyperprolactinemia. Symptoms related to hyperprolactinemia (amenorrhea, oligomenorrhea, galactorrhea, impotence, oligospermia, and /or decreased libido) were reported in 5 out of 9 women (56%) and 3 out of 9 men (33%) receiving RIS along with 1 out of 12 women receiving OLA (8%). No significant difference in hyperprolactinemic symptom frequency was observed between gender groups.
Case-Control Studies
Etminan et al (2015)8 conducted a case-control study, identifying the risk of gynecomastia with RIS treatment in 15- to 25-year-old males. The IMS LifeLink database was used as the data source for the study. Diagnosis of gynecomastia was made based on ICD-9 criteria. For each case, 10 controls were chosen and matched to the cases by age, follow-up, and calendar times (cases and controls had the same follow-up time and cohort entry date).	Characteristics of cases and controls are listed in Characteristics of Cases and Controls. Users of RIS within 1 year had 3 times the risk of developing gynecomastia than nonusers (RR, 3.25, 95% CI, 1.98-5.33). Current users of RIS had approximately 4 times the risk of developing gynecomastia than nonusers (RR, 3.91, 95% CI, 2.01-7.62). When the analysis was stratified to children (≤18 years of age) taking RIS, the risk of gynecomastia was 5 times higher than for nonusers (RR, 5.44, 95% CI, 1.50-19.74). Characteristics of Cases and Controls
Etminan et al (2014)9 conducted a case-control study to examine the risk of gynecomastia with RIS use in men. A nested case-control study was conducted which included men aged 40-85 years in the United States using the IMS Lifelink health plan claims database. Cases were defined as those newly diagnosed with gynecomastia according to ICD-9. For each case, a risk set of controls was created with the same follow-up, cohort entry time, and age of the case. From the risk set, 10 controls were selected and matched to the index date of the case. Individuals with previous conditions that may attribute to gynecomastia (eg, Klinefelter syndrome, testicular cancer, breast cancer) were excluded. The risk of gynecomastia with RIS was compared with that of OLA and QUE.	Characteristics of cases and controls are listed in Characteristics of Cases and Controls. The adjusted RR for gynecomastia for users of RIS within 60 days compared with nonusers of atypical antipsychotics was 1.69 (95% CI, 1.05-2.72). The adjusted RR for gynecomastia for users of RIS within 30 days compared with nonusers of atypical antipsychotics was 1.69 (95% CI, 1.10-2.59). The adjusted RR for users of RIS compared with users of OLA and QUE within 30 days was 1.40 (95% Cl, 0.79-2.48) and 1.41 (95% Cl, 0.85-2.34), respectively. Characteristics of Cases and Controls
Post hoc Analyses
Takeuchi et al (2015)10 conducted a post hoc analysis of data from the CATIE trial [Lieberman et al (2005)11], a double-blind, randomized trial comparing RIS to other antipsychotics in patients with schizophrenia. This post hoc analysis evaluated the efficacy and safety of RIS versus OLA administered QD or BID for up to 18 months. There were 341 patients randomized to RIS (QD, n=173) and 336 patients randomized to OLA (QD, n=169). Mean age of the 4 treatment groups ranged from 39.8-41.9 years and 70.4%-76.2% were males. Mean RIS dose: 3.75 mg/day for QD; 4.04 mg/day for BID (P=0.046) Mean OLA dose: 18.8 mg/day for QD; 21.0 mg/day for BID (P=0.003) Study discontinuation rate in the 4 groups ranged from 62.4% to 74.4%. The mean time to discontinuation was 236 days (QD) versus 258 days (BID) in the RIS group and 306 days (QD) versus 331 days (BID) in the OLA group.	Gynecomastia/galactorrhea: RIS, 11.0% for QD and 8.9% for BID OLA, 7.1% for QD and 7.8% for BID There was no significant difference in the incidence of these adverse events between the QD and BID dosing groups.
Case Noncase Study
Batteux et al (2020)12 conducted a case - noncase study of drug induced gynecomastia on the basis of spontaneously reported adverse drug reactions in male patients The study utilized data from the French national pharmacovigilance database between January 2008 to December 2015 (n=107,127). Data was expressed as the ROR and its 95% confidence interval. Cases were identified by screening for the following MedDRA preferred terms: ‘‘gynecomastia’’, ‘‘breast enlargement’’, and ‘‘breast disorder male’’. The mean age of men was 58.1±19 years.	Neuroleptics and related drugs accounted for 28 cases, 6.5% of the suspect drugs with a statistically significant ROR. Drug induced gynecomastia RIS: 9 cases and 3.6 ROR [1.85-7.01]
Abbreviations: ARI, aripiprazole; BID, twice daily; CI, confidence interval; CLO, clozapine; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition; EST, estradiol; FSH, follicle stimulating hormone; GH, growth hormone; ICD-9, International Classification of Diseases, 9th revision; IGF-1, insulin-like growth factor; LH, luteinizing hormone; MedDRA, Medical Dictionary for Regulatory Activities; NOS, not otherwise specified; OLA, olanzapine; QD, once daily; QUE, quetiapine; RIS, risperidone; ROR, reporting odds ratio; RR, rate ratio; SD, standard deviation; UKU, Udvalg for Kliniske Undersogelser; ULN, upper limit of normal.

Open-label Studies/Post hoc Analyses – Pediatric/Adolescents

Open-label/Post hoc Studies in Pediatric and Adolescent Patients

Study Design	Summary
Open-label Studies
Koch et al (2023)13 reported results from a 3-month, nonrandomized, interception cohort study (SATIETY) between December 2001 and December 2014 that evaluated the use of SDAs in routine clinical practice in the treatment of pediatric patients (N=396; mean age (±SD), 14 (±3.1) years; male, 55.1%) with mood or schizophrenia spectrum disorders, as well as aggressive behavior disorders. RIS was used for 157 patients (mean age [±SD], 13.5 [±3.7] years; male, 62.4%) Inclusion Criteria: SDA-naïve (≤1 week lifetime SDA exposure) or SDA-free (≥4 weeks off SDA) patients aged between 4 to 17 years with a clinical indication to start SDA and with a postbaseline prolactin level or SeAE assessment Exclusion Criteria: SDA switches and SDA polypharmacy Endpoints Primary: Serum prolactin levels and new-onset SeAEs Secondary: Hyperprolactinemia by severity level; low prolactin values; prolactin change within 12 weeks of treatment; relationship of prolactin levels with pubertal status, sex, and SDA dose; and relationship of SeAE with prolactin levels, pubertal status or sex, and treatment discontinuation	Prolactin Levels Median prolactin levels at 12 weeks for RIS: 47.0 ng/mL (IQR, 31.5, 71.7 ng/mL) Mean and peak prolactin levels for RIS were significantly higher than other SDAs (P<0.0001) Median treatment duration on RIS until peak prolactin levels reached: 4.7 weeks (IQR: 4.0, 9.1) Hyperprolactinemia Based on age and sex-specific thresholds, 87.6% of patients had hyperprolactinemia after 12 weeks LOCF on RIS. Low Prolactin Levels At 12 weeks LOCF, low prolactin levels were absent in the RIS group. SeAEs in patients treated with RIS Any SeAEs: 29.4% of patients Menstrual disturbance: 35.4% of postpubertal female patients Decreased erection: 16.1% of postpubertal male patients Decreased libido: 12.5% of postpubertal male and female patients Gynecomastia: 9.2% of pre- and postpubertal male patients Mastalgia: 6.4% of patients Galactorrhea: 18.8% of postpubertal female patients and 1 postpubertal male patient Discontinuation due to RIS-Related SeAEs Individual SeAEs leading to discontinuation: galactorrhea (n=4), delayed menses (n=2), and extremely high prolactin value (n=2).
Hopkins et al (2022)14 evaluated patient-level AE data from multiple clinical trials of RIS and used EBGM (3-fold threshold) to determine the relative risk of drug-related AEs. PTs related to RIS were obtained from 17 controlled clinical trials (via the YODA project) conducted in patients with schizophrenia, bipolar disorder, autism, or Alzheimer’s disease (N=4400). A total of 2117 adult patients with schizophrenia (RIS=1892; PBO=225) were included from 7 clinical trials.	AE fold-risk was plotted against the cumulative percentage of occurrence in pooled patients in 7 RIS clinical trials (n=1892) vs PBO (n=225): Galactorrhea: 16- to 17-fold increased risk in <5% of RIS-treated patients. Gynecomastia: ~20-fold increased risk in <5% of RIS-treated patients.
Eugene et al (2018)15 conducted a retrospective data analysis in adolescent patients aged 12 to 17 (n=6141) to identify the most frequently reported medications and corresponding side effects. The study utilized data from the US FAERS from 2014-2017.	RIS accounted for the largest amount of ADRs cases (n=788). 90.1% of cases occurred in men. The most frequently occurring ADRs in RIS included were: gynecomastia (21.3%), abnormal weight gain (10.7%), and obesity (7.3%). RIS was most frequently prescribed in adolescents for bipolar disorder (14.4%), attention deficit/hyperactivity disorder (12.5%), and depression (7.8%).
Pozzi et al (2016)16 conducted a 2-year observational study in 184 pediatric outpatients (<18 years old) who were treated with RIS (n=142), ARI (n=33), or other antipsychotics (n=9). Patients in the RIS and ARI groups were treated for DBD with ASD (n=53), DBD with intellectual disabilities (n=43), psychosis spectrum disorders (n=14), tic/Tourette disorders (n=26), or other conditions (n=39). Mean age was 11.9 ±3.0 years in the RIS group and 14.1±3.0 years in the ARI group. Most patients were male (RIS, 85.2%; ARI, 60.6%). At 2-years, 41.5% in the RIS group and 39.4% in the ARI group had discontinued the study.	Outcomes ADRs resulted in 22 discontinuations. Excessive appetite/weight gain (>7% of baseline) occurred in 12 patients. Drug-related adverse events associated with hyperprolactinemia included: Hyperprolactinemia with complications: n=6 Gynecomastia in males: n=2 Amenorrhea in females: n=4
Roke et al (2012)17 conducted an observational study assessing the risk of hyperprolactinemia and sexual side effects in males, 10-20 years old, diagnosed with ASD (n=89) and/or DBD (n=9), chronically treated (mean, 53 months) with RIS (group 1; n=51; mean dose, 1.5 mg/day) or never have been treated with an antipsychotic (group 2; antipsychotic naïve, n=47). Exclusion Criteria: History of thyroid disease; syndromes/chronic diseases affecting puberty; endocrine disorders; use of oral corticosteroids or anticonvulsants; known cause of hyperprolactinemia Concomitant Medications: psychostimulants; melatonin; atomoxetine Endpoints: ASFQ; pubertal (Tanner) stage; exam for prolactin-related side effects; height/weight/BMI z-scores; nonfasting serum prolactin; TSH; RIS/9-OH-RIS levels (compliance)	Outcomes Mean height/BMI z-scores, pubertal stage, ethnicity and use of concomitant medications were similar between groups. At the time of measurement, undetectable RIS and 9-OH-RIS levels were observed in 27% (n=4) and 8% (n=4) of group 1 patients, respectively. Hyperprolactinemia was significantly more common in RIS-treated patients versus those not treated with an antipsychotic (47%, n=24 vs 2%, n=1, respectively; P<0.0001) and was asymptomatic in 46% (n=11/24) and 100% (n=1/2) of those patients, respectively. During RIS treatment, the OR of experiencing hyperprolactinemia was 71.9 (95% CI, 7.7-676.3). Results were not influenced by adjustment for age and BMI z-score. Gynecomastia, as measured by physical exam, was detected in 43% (n=22/51) and 21%(n=10/47) of patients in groups 1 and 2, respectively (P=0.05; P=0.02 after adjustment for age and BMI z-score), and was present in 8 patients with hyperprolactinemia (OR, 2.86, 95% CI, 1.16-7.06; P=0.26). Diminished sexual functioning was reported in 14% (n=7/51) and 0% of patients in groups 1 and 2, respectively (P=0.013), and tended to occur more often in patients with hyperprolactinemia. Hyperprolactinemia did not appear to be predicted by mean RIS dose, RIS plasma levels, or duration of treatment in male patients, but did appear to be predicted by current RIS dose (OR, 2.4, 95% CI, 1.1-5.5; P=0.035) and 9-OH-RIS levels (OR, 1.15, 95% CI, 1.02-1.09; P=0.03).
Calarge et al (2009)18 conducted a cross-sectional study investigating the association between hyperprolactinemia and variants of the dopamine D2 receptor gene in children and adolescents (n=107; age, 7-17 years) chronically treated with RIS (≥ 6 months). Dose: Minimum RIS serum concentration was 0.5 ng/mL to be entered into study	Outcomes Hyperprolactinemia was defined as a prolactin level of >18.4 ng/mL in males and >24.1 ng/mL in females. The median prolactin level was 18.7 ng/mL (range, 13.4-28.5 ng/mL). Fifty percent of the participants exhibited hyperprolactinemia. Of the 99 patients queried, 14% reported adverse events potentially related to hyperprolactinemia: breast tenderness (n=5), gynecomastia (n=7), galactorrhea (n=1), irregular menses (n=3), menarche (n=4), and oligomenorrhea (n=2).
Migliardi et al (2009)19 conducted a 12-month, open-label, longitudinal, naturalistic study examining prolactin levels in children/adolescents receiving RIS or OLA for various psychiatric illnesses. Mean Age and 12-month Dose RIS (n=28) Males (prepubertal, n=18; peri/postpubertal, n=4): 10.1 years; 1.7 mg/day Females (prepubertal, n=3; peri/postpubertal, n=3): 12.8 years; 2 mg/dayOLA (n=13) Males (prepubertal, n=2; peri/postpubertal, n=5): 14 years; 8.9 mg/day Females (prepubertal, n=1; peri/postpubertal, n=5): 14.3 years; 7.1 mg/day Endpoints Prolactin levels (prolactin normal ranges for chemoluminescent assay: male [3-15 ng/mL]; female [4-23 ng/mL]) were measured via chemoluminescent assay at baseline and again at 1, 3, 6, and 12 months following treatment initiation. The treating physician recorded clinical symptoms of hyperprolactinemia. Blood samples were obtained at 1 and 3 months following treatment initiation for determination of RIS, 9-OH-RIS, and OLA plasma concentrations via HPLC (quantification limit 2 ng/mL for all analytes). Samples were drawn at 8 AM, approximately 12-13 hours after the last dose.	Prolactin Elevations Compared to OLA, mean prolactin levels were 4.9 ng/mL higher in patients receiving RIS. When considering an interaction between treatment and treatment duration, mean prolactin levels after 1, 3, 6, and 12 months of RIS treatment were higher compared to OLA, however, between group differences were only significant after 1 and 3 months. Mean prolactin levels appear to be 10.3 times higher during treatment with RIS vs OLA. Plasma Drug Concentrations and Prolactin Levels Plasma concentrations were obtained after 1 and 3 months of treatment only. In RIS patients, controlling for gender and individual differences, 9-OH-RIS and the active moiety (RIS + 9-OH-RIS) were significantly associated with prolactin changes at month 3 (1 ng/mL increase in 9-OH-RIS concentrations increased prolactin levels by 0.39 ng/mL; P=0.05). In females, plasma OLA concentrations had a significant effect on prolactin levels (1 ng/mL increase in OLA concentrations increased prolactin levels by 2.1 ng/mL; P=0.001). Hyperprolactinemia Symptoms One 14-year-old RIS patient developed mild transient galactorrhea following 3-4 weeks of treatment. Prolactin levels at baseline and 1 month were 7.2 ng/mL and 22.5 ng/mL, respectively. RIS dosage (1 mg/day) was not modified and symptoms disappeared after 2 weeks of observation.
Post hoc Analysis
Findling et al (2003)20 pooled data from 5 clinical trials in disruptive behavioral disorders up to 55 weeks in duration to assess prolactin levels and related adverse events in a post hoc analysis. There were 592 children and adolescents with a mean age of 9.9 years included in the primary analysis. The mean RIS dose was 1.26 mg/day. SHAP were assessed in 2 ways (SHAP Analysis). The SHAP(A) group included the following events: gynecomastia irrespective of age, amenorrhea, menorrhagia, breast enlargement, lactation nonpuerperal, menstrual disorder, and vaginal hemorrhage. Dysmenorrhea during puberty was excluded. The SHAP(B) group excluded males 10 years or older with gynecomastia, females with less than 31 days of breast enlargement (gynecomastia), and females with amenorrhea <1 week.	Outcomes The mean baseline prolactin level was 7.8 ng/mL. Prolactin levels tended to rise during the first 4-7 weeks of RIS treatment (mean prolactin level 29.4 ng/mL), and then steadily decreased to 23.4 ng/mL at 8-12 weeks, then 19.6 ng/mL at 16-24 weeks, then 18.5 ng/mL at 28-36 weeks, and 16.1 ng/mL at 40-48 weeks. SHAP A total of 15 SHAP were reported in 13 patients, using the SHAP(B) definition. All SHAP had resolved in 9 patients by study endpoint. Nine events resolved without any intervention, 1 event resolved with dose reduction, and 1 event resolved after temporary discontinuation of RIS. SHAP Analysis
Abbreviations: ADR, adverse drug reaction; AM, morning; ARI, aripiprazole; ASD, autism spectrum disorders; ASFQ, Antipsychotics and Sexual Functioning Questionnaire; BMI, body mass index; CI, confidence interval; DBD, disruptive behavior disorders; EBGM, Empirical Bayes Geometric Mean; FAERS, Food and Drug Administration Adverse Events Reporting System; HPLC, high-performance liquid chromatography; IQR, interquartile range; LOCF, last observation carried forward; OLA, olanzapine; OR, odds ratio; PBO, placebo; RIS, risperidone; SD, standard deviation; ADSDA, serotonin-dopamine antagonists/partial agonist; SeAE, sexual adverse effect; SATIETY, Second-Generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth; SHAP, Side-effects Hypothetically Attributable to elevated Prolactin levels; TSH, thyroid-stimulating hormone; YODA, Yale University Open Data Access.

Other relevant literature

Additional case reports^21-38 and small studies^39-41 where patients treated with risperidone developed galactorrhea are referenced for your review.

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 12 February 2024.