SUMMAry

• A significant positive dose-related trend has been noted for the occurrence of erectile dysfunction, ejaculation disorder and abnormal sexual function (Cochran-Armitage test; P<0.05).Priapism has been reported during postmarketing surveillance. Severe priapism may require surgical intervention.¹
• Antipsychotic-induced sexual dysfunction has been reported with conventional and atypical antipsychotics and may result from a variety of potential mechanisms, such as blockade of α1 adrenergic receptors, which is thought to play a role in priapism associated with risperidone use.²
• Elevated prolactin levels may play a role in sexual dysfunction. However, several studies have observed no correlation between prolactin elevations and sexual/
  reproductive-related adverse events (AEs) when risperidone was used at clinically relevant doses.^3-9
• Two literature reviews of priapism cases associated with risperidone noted that risperidone has high affinity for α-adrenergic receptors, and has been associated with priapism when administered as a monotherapy or combination therapy.^{2, 10} It is unclear if sexual dysfunction or priapism is correlated with dosage or duration of risperidone therapy.^10-12
• In a 3-week, randomized, double-blind (DB), placebo (PBO)-controlled study evaluating the efficacy and safety of risperidone monotherapy in 111 children and adolescents with bipolar I disorder, AE of ejaculation disorder was reported in 1 (0.9%) patient treated with risperidone.¹³
• In many of the reported cases, sexual dysfunction resolved upon dosage reduction or discontinuation of risperidone. Surgical intervention was necessary in some cases of priapism, with some patients rendered impotent due to prolonged untreated priapism.^14-18
• Retrograde ejaculation has been reported in adults and adolescents during treatment with risperidone. Majority of the events abated with dose reduction or after discontinuation of medication.^19-24
• In many of the reported cases, priapism was noted in adolescent patients (10-16 years old), and the symptoms resolved upon discontinuation of risperidone.^25-27
• Comparison with other antipsychotics:
  • A systematic review of medical literature noted that risperidone was associated with higher odds of erectile or ejaculatory dysfunction compared with olanzapine and perospirone.²⁸
  • A meta-analysis of 2 studies showed no variation in the risk of erectile dysfunction between firstgeneration antipsychotics and risperidone.²⁹
  • In 2 other meta-analyses risperidone was associated with a higher rate of sexual dysfunction compared with quetiapine, ziprasidone, perphenazine, aripiprazole,³⁰ and olanzapine.³¹
  • In a prospective, randomized, flexible-dose, open-label study comparing the effectiveness of RISPERDAL with that of aripiprazole for the treatment of first-episode psychosis (FEP), ejaculatory dysfunction was reported in 9 (13.6%) and 0 (0.0%) patients who received RISPERDAL and aripiprazole, respectively; and erectile dysfunction was reported in 10 (15.2%) and 1 (1.6%) patients, respectively.³²
  • In an analysis of suspected adverse drug reaction (ADR) using the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database (January 2015-December 2020), risperidone was associated with 130 (10.54%) individual cases of priapism.³³
  • Similarly, in a disproportionality analysis of data collected from the Japanese Adverse Event Report (JADER) database (April 2004-February 2021), risperidone and quetiapine were significantly associated with a higher reporting frequency of priapism than olanzapine, aripiprazole, and clozapine.³⁴
  • In an analysis of United States (US) spontaneous reports of ADRs from the FAERS database, the reporting odds ratio (ROR) of priapism with risperidone was 16.4 (95% confidence interval [CI], 11.522.7) for all cases and 16.3 (95% CI, 9.4-26.6) for serious cases.²

PRODUCT LABELING

Please refer to the following sections of Full Prescribing Information¹ which are relevant to your inquiry: WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

Comparison With Other Antipsychotics

Trinchieri et al (2021)²⁸ conducted a systematic review of medical literature to evaluate the occurrence of sexual dysfunction in male patients treated with psychotropic drugs.

Study Design/Methods

• Open-label or single-blind/DB randomized controlled trials and study reports that provided data on the onset of sexual dysfunction during treatment were included in this review.

Results

• Three studies^35-37 (n=274) comparing the effect of risperidone with that of other atypical antipsychotics (olanzapine and perospirone) on erection or ejaculation were included.
• Risperidone was associated with higher odds of erectile or ejaculatory dysfunction compared with other atypical antipsychotics (olanzapine and perospirone; odds ratio [OR], 3.90; 95% CI, 1.32-11.56; heterogeneity [I²], 0%; standard score [Z], 2.46; P<0.01).

Garrido-Sánchez et al (2022)³² conducted a prospective, randomized, flexible-dose, openlabel study comparing the effectiveness of RISPERDAL with that of aripiprazole in patients with FEP.

Study Design/Methods

• Patients aged 15-60 years with FEP who had no prior treatment with antipsychotic medication and were diagnosed with brief psychotic disorder, schizophreniform disorder, schizophrenia, psychotic disorder (not otherwise specified), or schizoaffective disorder based on the Diagnostic and Statistical Manual-IV (DSM-IV) criteria were included.
• Patients were randomized to receive either RISPERDAL at 3-6 mg/d (300-600 Chlorpromazine equivalents [CPZeq]) or aripiprazole at 5-30 mg/d (100-600 CPZeq).

Results

• A total of 266 patients were randomized to receive either RISPERDAL (n=130) or aripiprazole (n=136), of which 145 (54.5%) were males, and mean (standard deviation [SD]) age was 32.3 (10.4) years.
• In the intent-to-treat population, among patients treated with RISPERDAL (n=124) and aripiprazole (n=125), respectively, ejaculatory dysfunction was reported in 9 (13.6%) and 0 (0.0%) patients (Fisher statistics [F], 9.235; P=0.003) and erectile dysfunction was reported in 10 (15.2%) and 1 (1.6%) patient (Chisquared test [X²], 7.603; P=0.006).

Pharmacovigilance Studies

Andersohn et al (2010)² analyzed spontaneous reports of ADRs using the FAERS database (January 1, 2004, to December 31, 2007) to identify whether the presence of safety signals for antipsychotics and priapism is associated with their α1 adrenoceptor affinity.

Results

• A total of 144 cases of priapism were identified to be associated with conventional and atypical antipsychotics.
• The affinity of risperidone to α1 adrenergic receptor was 37×10⁷M^-1.
• The ROR of priapism with risperidone was 16.4 (95% CI, 11.5-22.7) for all cases and 16.3 (95% CI, 9.4-26.6) for serious cases.
• Strong safety signals for drug-induced priapism were noted for antipsychotic drugs with a high α1 adrenoceptor affinity, including risperidone.

Schifano et al (2022)³³ analyzed voluntary reports of suspected ADRs using the FAERS pharmacovigilance database (January 2015-December 2020) to identify the possible medications associated with priapism and assess their signals associated with priapism based on a disproportionality analysis.

Results

• A total of 1233 reports were identified, of which 933 were associated with the 11 drugs having >30 reports of priapism each.
• Median (interquartile range [IQR]) age of priapism occurrence (in reports where the age of priapism was specified) was 36 (25-50) years. Overall, 6 individual reports of female priapism were identified (medications associated with this event was not reported).
• Trazadone was most commonly associated with an ADR of priapism. See Table: Drugs Most Commonly Associated With Individual Reports of Priapism.

Misawa and Takeuchi (2022)³⁴ conducted a disproportionality analysis comparing the reporting frequency of priapism associated with individual second-generation antipsychotics (SGAs) using data collected from the JADER database.

Study Design/Methods

• Data from spontaneous reports of AEs among men aged 10-69 years who received oral SGAs between April 2004 and February 2021 were included.
• Patients who received concomitant antipsychotics and those who did not receive oral SGAs were excluded.
• Subgroup analyses involving age- or sex-unknown cases, or a restricted number of events (n≥3) were also conducted.

Results

• A total of 3169 patients were included in this study, of whom 41 (1.2%) reported priapism.
• Risperidone and quetiapine were associated with a higher reporting frequency of priapism compared with olanzapine, aripiprazole, and clozapine. See Table: aROR of Priapism for Risperidone vs Other SGAs.
  • A similar trend was observed in the crude and all subgroup analyses.

Literature Reviews - Priapism

Ateb et al (2022)¹² conducted a literature search through 2021 and found 43 cases^{10, 15, 18, 38-74} of priapism associated with risperidone. Of these 43 cases, 30 were also a part of a literature review conducted by Paklet et al, which is summarized below.

Results

• Numerous case reports have shown that risperidone-induced priapism may occur days or years after drug initiation even at low or stable doses.
• Polypharmacy may increase the risk of priapism by either the synergistic effect of combining drugs that can independently induce priapism or combining drugs that are known to affect drug metabolism.
• Priapism does not appear to be correlated with either the dosage or duration of psychotropic drug use.
• In published cases, risperidone therapy was replaced with olanzapine, aripiprazole, or clozapine in most cases.

Paklet et al (2013)¹⁰ conducted a literature search and found 33 cases^{15, 17, 38-51, 53, 54, 57, 58, 60, 66-69, 72, 74-77} of priapism associated with risperidone (oral risperidone, n=27; risperidone long-acting injection, n=2; unknown dose, n=3; switching from oral risperidone to longacting risperidone, n=1).

Results

• The authors also noted that most of the cases were reported in patients in their 30s, 40s, and 50s.
• Among the 33 cases included in the literature review, 7 patients required surgical interventions of which, 5 patients were receiving oral risperidone, 1 patient was receiving oral risperidone plus risperidone depot 25 mg, and 1 patient was switching from oral risperidone to risperidone depot.
• Additionally, in a review of data among patients from South London and Maudsley (SLAM) Case Register Interactive Search (CRIS) database, 13 cases of priapism were reported between 2000 and 2010, of which 4 were associated with oral risperidone.
  • Most cases of priapism resolved after treatment discontinuation; however, 1 patient required penile amputation.

OTHER RELEVANT LITERATURE

Additional citations identified during a literature search are included in the references section for your review.^{21, 78-82}

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 17 April 2023.