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RISPERDAL CONSTA® (risperidone long acting injection)

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Adverse Event of RISPERDAL CONSTA - Prolactin Effects

Last Updated: 11/12/2024

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
Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.¹
Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.¹
Potential prolactin-related adverse events include amenorrhea, galactorrhea, gynecomastia, and decreased libido in female patients, and erectile and/or ejaculatory dysfunction, gynecomastia, and decreased libido in male patients.²
In a meta-analysis of 10 paliperidone palmitate clinical trials, prolactin levels were elevated in 38.8% of patients who received paliperidone palmitate, and potentially prolactin-related events occurred in 3.4% of patients. Three of the trials in the meta-analysis also included a RISPERDAL CONSTA treatment arm. Prolactin levels were elevated in 35.4% of patients who received RISPERDAL CONSTA, and potentially prolactin-related events occurred in 4.1% of patients. The rate of potentially prolactin-related events did not differ significantly between paliperidone palmitate and RISPERDAL CONSTA.³

BACKGROUND

All antipsychotics, which block the inhibitory actions of dopamine on lactotrophic cells in the anterior pituitary, can increase prolactin secretion.⁴ The increase in prolactin level may vary depending on the extent of dopamine blockade. Hyperprolactinemia is included as class labeling for all available antipsychotics, except clozapine and aripiprazole.

Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents. Hyperprolactinemia may suppress hypothalamic gonadotropin releasing hormones, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male subjects.¹ In the absence of hypogonadism, there is a lack of consistent evidence to establish whether antipsychotic-induced hyperprolactinemia is an independent risk factor for bone loss and osteoporosis.⁵ While individuals with schizophrenia are known to have an increased risk for low bone mineral density and osteoporosis, prospective clinical trials to differentiate between etiological mechanisms and effects of disease and treatment have not been conducted.

Management of Hyperprolactinemia

The Endocrine Society Clinical Practice Guideline for the Diagnosis and Treatment of Hyperprolactinemia (2011)⁶ includes several recommendations for treatment of hyperprolactinemia, which differ depending on whether the patient is symptomatic or asymptomatic. In symptomatic patients with suspected medication-induced hyperprolactinemia, the guideline recommends discontinuing the medication for 3 days or using an alternative medication, and then reassessing prolactin levels. Alternative antipsychotics may include those with lower dopamine antagonist activity or aripiprazole (partial dopamine antagonist). Use of dopamine agonists to treat hyperprolactinemia should only be considered if substitution with an alternative medication is not possible due to the potential to exacerbate psychosis. In asymptomatic patients, the guideline recommends no treatment. However, if the patient also has hypogonadal symptoms or low bone mass, therapy with estrogen or testosterone should be considered.

The American Psychiatric Association (APA) Practice Guidelines for the Treatment of Patients with Schizophrenia (2020)⁴ provided several recommendations for management of clinical symptoms due to neuroleptic-induced hyperprolactinemia. Reducing the dose of the antipsychotic medication or switching to a prolactin-sparing antipsychotic may decrease the severity or alleviate the symptoms associated with hyperprolactinemia. In patients who must remain on antipsychotic medication, administration of a dopamine agonist such as bromocriptine should also be considered. An additional study looked at low-dose cabergoline in the treatment of risperidone-induced hyperprolactinemia.⁷ Trives et al (2013)⁸ conducted an open-label, pilot study in 13 patients who experienced hyperprolactinemia while treated with RISPERDAL CONSTA monotherapy (median dose 37.5 mg) or RISPERDAL CONSTA in combination with oral risperidone or paliperidone palmitate. All patients in the study had serum prolactin levels at least twice the upper limit of normal or had clinical symptoms of hyperprolactinemia. Aripiprazole 2.5 mg daily was added to their regimen for 2 days, then the dose was increased to 5 mg daily over a 1-month period. The median prolactin level at baseline was 84 mcg/L which decreased to 39 mcg/L at 1 month (n=13) and 31 mcg/L at 3 months (n=8). Some clinical symptoms of hyperprolactinemia improved slightly, but there was no significant change from baseline. The Clinical Global Impression Schizophrenia Scale did not decrease after the addition of aripiprazole.

CLINICAL STUDIES

Schizophrenia or Schizoaffective Disorder

Trial Design	Prolactin Results
Double-Blind Trials
Meltzer et al (2013)⁹ compared 2 dosage regimens of RLAI (50 mg every 2 weeks [n=82] or 100 mg every 2 weeks [n=78]) in a multicenter, randomized, DB, 24-week study that enrolled 160 patients with treatment resistant schizophrenia. Patients enrolled in the trial had received 2 or more antipsychotic regimens in the past but continued to have symptoms.	LS mean PRL levels increased significantly (P<0.001) in both groups by 6 weeks with no further increase at 24 weeks. Increases in PRL occurred in patients who had not received RIS or PAL prior to the study entry. PRL Levels RLAI 50 mg: 30.2, 44.7, 45.7 ng/mL at baseline, week 6, and week 24, respectively. RLAI 100 mg: 32.2, 46.7, 48.2 ng/mL at baseline, week 6, and week 24, respectively. Sexual dysfunction was reported, but not the number of patients affected.
Pandina et al (2011)¹⁰ conducted a 13-week, randomized, DB, double-dummy, active-controlled, parallel-group, multicenter study assessing noninferiority of PALM to RLAI in adult patients with schizophrenia (N=1214, safety analysis set). PALM (n=606): Deltoid injection of PALM 234 mg on day 1 followed by a 156-mg deltoid injection on day 8; thereafter, patients received flexibly dosed PALM injections on days 36 (78 or 156 mg) and 64 (78, 156, or 234 mg) in either the deltoid or gluteal muscle. RLAI (n=608): RLAI 25 mg on days 8 and 22, followed by 25 or 37.5 mg on days 36 and 50; thereafter, patients received flexible doses of 25, 37.5, or 50 mg on days 64 and 78, all in the gluteal muscle.	From baseline to endpoint mean increases in PRL were noted in both treatment groups with larger increases observed in women (PALM: +21.8 ng/mL; RLAI: +15.6 ng/mL) vs men (PALM: +9.38 ng/mL; RLAI: 6 ng/mL). The most common potentially PRL-related treatment-emergent AEs were erectile dysfunction (men: PALM, n=4; RLAI, n=3) and amenorrhea (women: PALM, n=4; RLAI, n=4).
Simpson et al (2006)¹¹ conducted a 1-year, randomized, DB trial in patients with schizophrenia or schizoaffective disorder receiving RLAI 25 mg or 50 mg every 2 weeks (N=324). *Post Hoc Analysis:* A post hoc analysis of the Simpson (2006) trial assessed the following outcome: recent diagnosis¹²	Mean PRL levels (ng/mL): RLAI 25 mg group (SD): Baseline: 24.0 (27.5); Endpoint 33.7 (27.4), P<0.05 RLAI 50 mg group (SD): Baseline: 25.6 (50.9); Endpoint 49.6 (44.2), P<0.001 (P value between groups P<0.001)
Chue et al (2005)¹³ conducted a 12-week, DB, double-dummy, randomized, noninferiority study in patients with schizophrenia receiving RLAI (25, 50, or 75 mg every 2 weeks [n=319]) or RIS oral (2, 4, or 6 mg/day [n=321]).	Mean PRL level (ng/mL): RIS Oral (SD): Baseline: 38.9 (1.6); Endpoint: 38.0 (1.8), P=0.012 RLAI (SD): Baseline: 37.4 (1.7); Endpoint: 32.6 (1.6), P<0.001 (P value between groups P=0.025) (ULN are 13 ng/mL for males and 23 ng/mL for females) Reports of clinical symptoms potentially related to PRL during DB treatment: 2.5% in the oral RIS group (nonpuerperal lactation in 2 patients, dysmenorrhea in 1, abnormal sexual function in 2, ejaculation failure in 1 and hyperprolactinemia in 2) 1.3% in the RLAI group (nonpuerperal lactation in 2 patients, dysmenorrhea in 1 and abnormal sexual function in 1) PRL levels were elevated in many patients at baseline (245 patients in the oral RIS group and 217 in the RLAI group) and decreased to within normal range in 29 patients in the oral RIS group and 28 patients in the RLAI group at endpoint.
Meta-Analysis
Sampson et al (2016)¹⁴ conducted a meta-analysis of 12 studies that enrolled 5,723 patients with schizophrenia or related psychoses and compared RLAI to PBO, other antipsychotics, or no treatment.	Two studies (n=467) comparing RLAI and general oral antipsychotics found no difference between groups for prolactin-related adverse events. One randomized study (n=666) found a higher rate of PRL-related AEs in patients treated with RLAI compared to QUE (RiR 3.07; CI 1.13-8.36). Two randomized studies (n=729) found a higher rate of PRL-related AEs in patients treated with RLAI compared to ARI (RiR 9.91; CI 2.78-35.29). One study (n=640) comparing RLAI and oral RIS found no difference in the rate of PRL-related AEs, impotence/ejaculation failure, dysmenorrhea, galactorrhea, or sexual dysfunction between the 2 groups. Three studies (n=2,421) comparing RLAI to PALM found no difference between the 2 groups in the rates of amenorrhea, galactorrhea, hyperprolactinemia, erectile dysfunction, or any PRL-related AE.
Open-Label Studies (N≥50)
Micluţia et al (2015)¹⁵ conducted a 12-month prospective safety study in 1,354 adults with schizophrenia, schizophreniform disorder, or schizoaffective disorder. Patients were either newly diagnosed and initiated treatment with RLAI or had established disease and were switched from another antipsychotic to RLAI. RLAI dose: 25, 37.5, or 50 mg	87.6% of patients (n=1,186) completed 6 months and 71.3% (n=966) completed 12 months of treatment with RLAI. AEs, % (n) and SAEs, % (n) Amenorrhea 1.2% (16) and 0.1% (2) Galactorrhea 1.0% (15) and 0.3% (4) Hyperprolactinemia 0.4% (5) and 0.2% (3)
Covell et al (2012)¹⁶ conducted a 12-month, randomized, OL study assessing the safety and efficacy of staying on long-acting FLU or HAL decanoate vs switching to RLAI in patients diagnosed with schizophrenia or schizoaffective disorder (N=62). *Stay* (n=30): HAL decanoate (n=19): mean dose: 114.7 mg FLU decanoate (n=11): mean dose: 37.5 mg *Switch* (n=32) RLAI: 25, 37.5, or 50 mg every 2 weeks (flexible dosing)	PRL levels significantly increased in Switch vs Stay patients, with mean levels exceeding 20 ng/mL after 1 month of treatment. *Baseline, 6-month, and 12-month PRL Levels (ng/mL)* Stay: 18.5 (n=23); 16 (n=21); 15.2 (n=18) Switch: 16.7 (n=26); 23.4 (n=18); 19 (n=14) Additionally, women had significantly higher PRL levels than men.
Mosolov et al (2012)¹⁷ conducted a cross-sectional study of remission rates in schizophrenia patients utilizing a 6-month follow-up period to assess symptomatic stability. Patients who were stable but did not meet the symptomatic criteria for remission were included in a 1-year observational study. RLAI (n=42) (25, 37.5 or 50 mg) administered every 2 weeks. Routine antipsychotic treatment (n=35): atypical monotherapy, n=5; typical monotherapy, n=24; combined therapy, n=6	Potentially PRL-Related Adverse Events: RLAI: secondary amenorrhea, n=9; galactorrhea, n=1; menorrhagia leading to study discontinuation and hospitalization, n=1 Routine treatment: secondary amenorrhea, n=2 (oral RIS, n=1 and HAL decanoate/chlorpromazine, n=1)
Doknic et al (2011)¹⁸ conducted a prospective, cross-sectional study to determine bone remodeling/bone mass, weight gain, metabolic profile and neuroendocrine status in outpatients with controlled schizophrenia receiving RLAI (N=26). Results were compared against 35 healthy controls matched for gender, age, BMI and education. Mean RLAI dose: 38 mg every 2 weeks for a mean duration of 18 months. Laboratory values were obtained at 08:00 hours following an overnight fast. BMD determined by dual-x-ray absorptiometry.	Results: Compared to controls, CTx (bone resorption) increased to the upper limit of normal during RLAI therapy, particularly in patients treated for 12-24 months (P=0.016). Osteocalcin levels (bone formation) did not differ between treatment vs control groups (P=0.3). RLAI patients had significantly higher PRL levels compared to controls (1,715 mU/L vs 350 mU/L, respectively; P=0.001). Overall prevalence of hyperprolactinemia in schizophrenia patients was 84.6%. The prevalence and severity of hyperprolactinemia was greater in females vs males. Mild (PRL 550 males/600 females-1000 mU/L): 42.3% (8 females; 5 males) Moderate (PRL 1000-2000 mU/L): 30.8% (5 females; 3 males) Severe (PRL >2000 mU/L): 11.5% (3 females) Female schizophrenic patients had significantly lower serum estradiol levels vs controls (148.9 pg/mL vs 347.5 pg/mL; P=0.001). Serum testosterone in males did not differ per treatment group vs controls.
Dubois et al (2011)¹⁹ conducted a 12-month, multicenter, OL, noninterventional, observational study assessing the efficacy and safety of RLAI in Belgian patients with early-episode schizophrenia (N=105). Following the initial stabilization period (within 4 weeks after acute event) RLAI 25, 37.5, or 50 mg was administered every 2 weeks according to official labeling. RIS melting tablet was administer as treatment during acute psychosis and within the first 3 weeks of RLAI treatment.	During RLAI treatment, hyperprolactinemia was reported in 3.8% (n=4) of patients. Percentages of reproductive system/breast disorders reported during the study along with those considered probably related to RLAI by investigator, unless otherwise noted: Galactorrhea: 1.9% (n=2) and 1.9% (n=2), respectively Sexual Dysfunction: 1.9% (n=2) and 1% (n=1), respectively Amenorrhea: 1% (n=1) and 1% (n=1), respectively Lactation Disorder: 1% (n=1) and 1% (n=1, very likely related) Menstruation Irregular: 1% (n=1) and 0, respectively
Li et al (2011)²⁰ conducted a 13-week, active-controlled, parallel-group, multicenter, OL, rater-blinded, comparative study to assess the noninferiority of PALM to RLAI in Chinese patients with acute schizophrenia (N=452). PALM (n=229): Deltoid IM injection on day 1 (234 mg) and day 8 (156 mg) with the optional injection site of the gluteal muscle for days 36 (78 or 156 mg) and 64 (78 to 234 mg). RLAI (n=223): Gluteal IM injection on days 8 and 22 (25 mg); flexible doses of 25 or 37.5 mg on days 36 and 50; and flexible doses of 25 to 50 mg every 2 weeks thereafter beginning on day 64. Oral RIS supplementation at initiation and with dose increases.	Similar incidences of potentially PRL-related AEs were observed for both treatment groups (PALM: 8.3% vs RLAI: 9%): Increased Serum PRL: PALM: 7.4% vs RLAI: 5.4% Galactorrhea: PALM only: 0.4% Hyperprolactinemia: PALM: 0.4% vs RLAI: 2.2% Amenorrhea: RLAI only: 2.3% Amenorrhea-Galactorrhea Syndrome: RLAI only: 0.8% Mean baseline PRL levels in both treatment groups were above the ULN for both men and women. (Different local laboratories used different reference ranges for PRL levels. The highest upper limit of normal range used for this study was 25 ng/mL for men and 35 ng/mL for women.) Overall, while not statistically significant, fewer PALM vs RLAI patients had PRL levels above the ULN compared at endpoint. Women had significantly larger mean PRL changes (baseline to endpoint) compared to men for both PALM (women: 37.7 ng/mL; men: 9.8 ng/mL) and RLAI (women: 31.1 ng/mL; men: 8.2 ng/mL).
Louzã et al (2011)²¹ conducted a 50-week, multicenter, OL, noncomparative study assessing the efficacy and safety of switching clinically stable Brazilian patients with schizophrenia and a history of oral antipsychotic nonadherence to RLAI (N=59). Outgoing antipsychotics were continued for the first 3 weeks and then discontinued. RLAI was administered 25-50 mg every 2 weeks. Concomitant medications included oral RIS (n=17, 32.1%) and HAL (n=14; 26.4%).	The safety population consisted of 53 patients who received at least 1 RLAI injection. Of those patients, 9 (17%) experienced increased PRL levels. PRL levels significantly increased from baseline to endpoint (36.2 ng/mL to 49.9 ng/mL; P=0.006). (Endpoint = week 50 or last evaluation due to early withdrawal) Three (5.7%) early discontinuations were due to AEs (sexual dysfunction, decreased libido, psychomotor agitation, and worsening of pre-existing symptoms).
Arunpongpaisal et al (2010)²² conducted a 12-week, OL study in Thai patients with chronic schizophrenia receiving flexibly dose RLAI 25, 37.5, or 50 mg every 2 weeks (N=184).	Potentially PRL-related AEs included galactorrhea (0.5%) and sexual dysfunction (0.5%).
Gaebel et al (2010)²³ conducted a 2-year, OL, international, randomized study comparing flexibly doses RLAI (25, 37.5, or 50 mg every 2 weeks; n=329) and QUE ( 300-400 mg/day [target dose; n=337] or up to 750 mg as needed) in patients with schizophrenia or schizoaffective disorder who were switched from oral RIS, olanzapine, or conventional neuroleptics (N=710)	Potentially PRL-related treatment emergent AEs:RLAI: 4.6%; QUE: 1.5% Hyperprolactinemia in women: RLAI: 27/134; QUE: 4/146 Hyperprolactinemia in men: RLAI: 16/195; QUE: 1/191 PRL levels (mIU/L) at endpoint in women: RLAI: 1590.5; QUE: 855.1 PRL levels (mIU/L) at endpoint in men: RLAI: 767.4; QUE: 367.0
Girardi et al (2010)²⁴ conducted a 6-month, observational, OL, mirror image study with an 18-month follow-up extension period in patients with schizophrenia or schizoaffective disorder who switched from oral antipsychotics (OLA, CLOZ, QUE, HAL, ARI, or RIS) to RLAI (25, 50, or 75 mg every 2 weeks) because of inadequate response (N=88).	Treatment-emergent hyperprolactinemia: Previous oral antipsychotics: 97% RLAI: 29% (P<0.001)
Macfadden et al (2010)²⁵ conducted a 2-year, prospective, rater-blinded, OL, active-controlled, multicenter, randomized study comparing the safety and efficacy of RLAI (mean modal dose: 41.8 mg) vs oral ARI (mean modal dose: 19.9 mg/day) for long-term maintenance of patients with schizophrenia (ITT population N=355).	The mean change in PRL levels, from baseline to endpoint, was 200 mIU/mL for RLAI (n=110) and 491 mIU/mL for ARI (n=100). Adverse events potentially related to PRL were reported in a higher percentage of patients receiving RLAI (14%) vs ARI (1.1%).
Napryeyenko et al (2010)²⁶ conducted a 6-month, OL, international study in patients recently diagnosed with schizophrenia or schizoaffective disorder (≤2 years ago; N=302) receiving flexibly dosed RLAI (25, 37.5, or 50 mg every 2 weeks).	Potentially PRL-related AEs were amenorrhea (n=1), dysmenorrhea (n=1), galactorrhea (n=4), loss of libido (n=1), hyperprolactinemia (n=3), menses delayed (n=2), and menorrhagia (n=1)
Parellada et al (2010)²⁷ conducted a 6-month, prospective, naturalistic study conducted in 12 countries in Europe in patients with schizophrenia and other psychiatric disorders receiving flexibly dosed RLAI 25, 37.5, 50, or 75 mg every 2 weeks (N=5,134).	PRL-related, treatment emergent AEs (baseline vs during RLAI treatment, respectively): amenorrhea: (13 vs 23); erectile dysfunction: (6 vs 20); galactorrhea: (1 vs 12)
Rossi et al (2009)²⁸ conducted a 52-week, prospective, OL study in patients with symptomatically stable schizophrenia or schizoaffective disorder switching from a previous antipsychotic to flexibly dosed RLAI 25, 37.5, or 50 mg every 2 weeks (N=347).	PRL levels were not reported Endocrine-related AEs were reported in 18 patients (7.7%) consisting mainly of amenorrhea, galactorrhea, and impotence
Bushe et al (2008)²⁹ conducted a naturalistic study in the UK assessing the prevalence and severity of hyperprolactinemia in patients (primarily diagnosed with schizophrenia and bipolar disorder) receiving antipsychotics (N=178; dose information on RLAI not provided).	Highest prevalence rates of hyperprolactinemia per antipsychotic group were: amisulpride 89%, RLAI 67% and RIS 55% when used as antipsychotic monotherapy.
Docherty et al (2007)³⁰ conducted a 3-month, prospective, OL, flexible-dose, multicenter study evaluating the use of a treatment manual in a community mental health center to facilitate the administration of RLAI in patients diagnosed with schizophrenia/schizoaffective disorder currently treated with oral RIS for ≥4 weeks (N=60).	The mean total duration of therapy was 71.8±22 days. Week 12 mean modal dose was 39.4 mg. A nonsignificant decrease in PRL levels occurred from baseline to week 12, last observation carried forward (51.55±51.68 ng/mL vs 43.85±31.41 ng/mL, respectively).
Gharabawi et al (2007)³¹ conducted a 1-year, prospective, OL, single-arm, multicenter, pilot study (N=87). RLAI: 50 mg every 2 weeks for 4 weeks; then 50 mg once monthly for 48 weeks	The mean PRL level (SD) was 43.1 (41.0) ng/mL at baseline and decreased by 1.1 ng/mL at week 52.
Keks et al (2007)³² conducted a 53-week, OL, randomized, controlled, noninferiority study comparing RLAI (25 or 50 mg every 2 weeks; n=247) and OLA (5-20 mg/day; n=300) in patients with schizophrenia or schizoaffective disorder (N=547).	PRL levels were not reported Three percent of patients in the RLAI and OLA groups reported treatment emergent sexual AEs Five patients in the RLAI group and 2 patients in the OLA group reported nonpuerperal lactation Two patients in each group reported impotence and One patient in each group discontinued due to sexual AEs
Lindenmayer et al (2007)³³ described results from 2 extension trials:Trial A: 1-year OL extension of a 12-week, DB, randomized, PBO-controlled trial (Kane 2003)³⁴ (RLAI 25, 50, or 75 mg every 2 weeks; N=271)Trial B: 1-year OL extension of a 12-week, OL trial (Lindenmayer 2004)³⁵ (RLAI 25, 37.5, or 50 mg every 2 weeks; N=100)	Trial A: 10% of patients reported AEs potentially related to PRL [nonpuerperal lactation (3%), abnormal sexual function (3%), amenorrhea (1%)]. Trial B: 6% of patients reported AEs potentially related to PRL [nonpuerperal lactation (2%), abnormal sexual function (2%), amenorrhea (2%)].
Moller et al (2005)³⁶ conducted a 6-month, OL trial in patients with schizophrenia or other psychotic disorders receiving flexibly dosed RLAI 25, 37.5, or 50 mg every 2 weeks (N=1,876).	Twenty-six patients reported treatment-emergent endocrine-related AEs (1%), 8 of which received concomitant therapy with an SSRI The most often reported endocrine-related AEs were abnormal sexual function or impotence
Lindenmayer et al (2004)³⁵ conducted a 12-week, OL trial in patients with schizophrenia switched to flexibly doses RLAI (25, 37.5, or 50 mg every 2 weeks) from oral treatment with HAL, QUE, or OLA N=141).	Ten patients (7%) reported hyperprolactinemia; 4% in the prior HAL group, 11% in the prior QUE group, and 6% in the prior OLA group Mean serum PRL levels (ng/mL): Baseline: 23.5±2.4 vs Endpoint: 52.2±3.7 One patient reported dysmenorrhea, though it was judged as not being related to RLAI
Turner et al (2004)³⁷ conducted a 12-week, OL trial in patients with schizophrenia switched from treatment with a conventional depot antipsychotic to flexibly dosed RLAI 25, 37.5, or 50 mg every 2 weeks (N=166).	Hyperprolactinemia was reported by 11% of patients Four patients (2%) reported AEs possibly related to PRL (other than hyperprolactinemia) Two patients who reported decreased libido had PRL levels within normal limits One patient with temporary hyperprolactinemia at week 2 experienced ejaculatory failure One patient, with a history of impotence due to neuroleptic medication, had hyperprolactinemia at run-in and throughout the study. The patient’s report of mild impotence resolved 31 days after beginning RLAI treatment.
Abbreviations: AEs, adverse events; ARI, aripiprazole; BMD, bone mineral density; CI, confidence interval; CLOZ, clozapine; DB, double-blind; FLU, fluphenazine; HAL, haloperidol; ITT, intent-to-treat; LOCF, last observation carried forward; LS, least squared; MAOIs, monoamine oxidase inhibitors; OL, open-label; OLA, olanzapine; PALM, paliperidone palmitate; PBO, placebo; PRL, prolactin; QUE, quetiapine; RIS, risperidone; RLAI, risperidone long-acting injection; RiR, risk ratio; SAEs, serious adverse events; SSRI, selective serotonin reuptake inhibitor; ULN, upper limit of normal; vs, versus.

Bipolar Trials

Bipolar Disorder

Trial Design	Prolactin Results
Double-Blind Trials
Vieta et al (2012)³⁸ conducted an international, randomized, DB, double-dummy, multicenter trial with 3 periods assessing the efficacy of RLAI in preventing the recurrences of mood episodes in patients with Bipolar I Disorder (N=415). RLAI: 25, 37.5, or 50 mg every 2 weeks (fixed dosing after week 8) and oral PBO or PBO or OLA: 10 mg and PBO injection	Amenorrhea was reported in 8% and galactorrhea in 5% of patients receiving RLAI Adverse events that were potentially PRL-related were reported in 14% of patients.
Quiroz et al (2010)³⁹ presented results from an international, randomized, DB, PBO-controlled, multicenter study evaluating the use of RLAI for the prevention of mood episodes in adult patients with Bipolar I Disorder (N=559). Period 1: Screening Period 2 (3 weeks): OL Oral RIS Treatment Period 3 (26 weeks): OL RLAI Stabilization at doses of 12.5-50 mg every 2 weeks. Period 4 (up to 24 months): DB, PBO-Controlled Withdrawal Phase -Stabilized patients were randomized to either RLAI (at the dose received during the last 8 weeks of the stabilization phase; no titration allowed) or PBO. Period 5 (8 weeks): OL Extension	Baseline to Period 3 PRL levels increased by a mean of 17.1 ng/mL. However, from DB baseline to endpoint, mean PRL levels decreased by 8.8 ng/mL for the RLAI group and 27.3 ng/mL for the PBO group. In both treatment groups mean PRL levels were higher in women vs men. Potentially PRL-related AEs (nonserious according to investigators) occurred in 13 patients (3%) during Period 2, 37 patients (7%) in Period 3 and 6 RLAI patients (4%) and 1 PBO patient (1%) during Period 4.
Macfadden et al (2009)⁴⁰ conducted a 16-week, OL, stabilization phase (n=275), followed by a 52-week randomized, DB, PBO-controlled relapse-prevention phase (n=139) in patients with bipolar disorder who frequently relapse OL phase: RLAI: 25, 37.5, or 50 mg every 2 weeks (flexible dose; augmentation of treatment as usual) DB treatment: RLAI: 25, 37.5, or 50 mg every 2 weeks (n=72) or PBO (n=67) (augmentation of treatment as usual for both groups)	At DB baseline: RLAI plus TAU: 24.4±29.1 ng/m and PBO plus TAU 36.4±052.2 Mean change from base to DB endpoint: RLAI plus TAU: 14.3±36.1 and PBO plus TAU: 20.9±52.5; (P<0.001)
Meta-Analysis
Kishi et al (2016)⁴¹ conducted 2 meta-analyses of 7 randomized, controlled trials comparing RLAI to PBO or LAI antipsychotics to oral medications. Mean and median duration of the trials was 15 months. RLAI arm: 6 trials (n=424) PBO arm: 2 trials (n=284) Oral medication arm: (antipsychotics, mood stabilizers, antidepressants, or combinations): 6 trials (n=283)	RLAI associated with higher risk of PRL-related AEs (galactorrhea, decreased libido) than PBO (RR=4.82; 95% CI 1.88-12.4; P=0.001). RLAI associated with higher risk of PRL-related AEs (galactorrhea, decreased libido, menstrual changes) than oral medications (RR=2.66; 95% CI 1.12-6.33; P=0.03).
Abbreviations: AEs, adverse events; DB, double-blind; CI, confidence interval; LAI, long-acting injection; OL, open-label; OLA, olanzapine; PBO, placebo; PRL, prolactin; RIS, risperidone; RLAI, risperidone long-acting injection; RR, relative risk; TAU, treatment as usual.

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 24 October 2024.

Case reports, retrospective studies, and open-label studies (N≤50) are not included in this reply. For more information about oral RISPERDAL^® (risperidone)⁴² and its effect on prolactin, please contact Medical Information at 1-800-526-7736 9AM to 5PM, EST.

References

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1	RISPERDAL CONSTA (risperidone long-acting injection) [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; https://imedicalknowledge.veevavault.com/ui/approved_viewer?token=7994-63671f9d-1035-4290-a18b-1c9102cceb15.
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42	RISPERDAL (risperidone) [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/RISPERDAL-pi.pdf.