RISPERDAL CONSTA®
(risperidone long acting injection)
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RISPERDAL CONSTA® (risperidone long acting injection)
Medical Information
Use of RISPERDAL CONSTA in Renal Dysfunction
Last Updated: 06/22/2023
Summary
- Patients with renal impairment may have less ability to eliminate risperidone than normal adults. In patients with moderate to severe renal disease treated with oral RISPERDAL, clearance of the sum of risperidone and its active metabolite decreased by 60% compared with young healthy subjects.1
- Although patients with renal impairment were not studied with RISPERDAL CONSTA, it is recommended that patients with renal impairment be carefully titrated on oral RISPERDAL before treatment with RISPERDAL CONSTA is initiated at a dose of 25 mg. A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose adjustment, such as in patients with renal impairment.1 The efficacy of the 12.5 mg dose has not been investigated in clinical trials.1
- An open-label pharmacokinetic (PK) study evaluated the use of oral risperidone in patients with moderate to severe renal impairment, and case reports described the use of oral risperidone and risperidone long-acting injectable (RLAI) in patients receiving hemodialysis.2
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Please refer to the following sections of the enclosed Full Prescribing Information which are relevant to your inquiry: DOSAGE AND ADMINISTRATION, Dosage in Special Populations, CLINICAL PHARMACOLOGY, Pharmacokinetics, and WARNINGS AND PRECAUTIONS, Use in Patients with Concomitant Illness.
Snoeck et al (1995)2 evaluated the PK of oral risperidone and its active moiety, risperidone plus 9-OH-RIS, in patients with moderate (CrCl, 30-60 mL/min/1.73 m2) and severe (CrCl, 10-29 mL/min/1.73 m2) renal impairment (N=42).
Study Design/Methods
- The population consisted of young healthy individuals (n=8; mean age, 30 years), elderly patients (n=12; mean age, 69 years), patients with moderate renal disease (n=7; mean age, 56 years), patients with severe renal disease (n=7; mean age, 52 years), and patients with liver disease (n=8; mean age, 51 years).
- The PK of oral risperidone in renally impaired patients were compared to those of the healthy young subjects.
- All patients were required to fast for at least 10 hours before receiving a single 1 mg dose of risperidone, which was given 4 hours prior to consuming a standard meal.
- Venous blood samples were obtained just before risperidone administration, and then at designated time points for 96 hours after ingestion.
- Total urine was collected at determined points throughout the 96 hours.
- Plasma and urine concentrations of risperidone and the active moiety were determined by 2 radioimmunoassay procedures.
Results
- The mean±standard deviation PK parameters of the active moiety (risperidone plus 9OHRIS) in young, elderly, and renally impaired patients are summarized in the Table: PK Parameters of the Active Moiety (Risperidone plus 9OH-RIS).
| Young (n=8) | Elderly (n=12) | MR Disease (n=7) | SR Disease (n=7) | Statistical Significance (Renal Disease vs Young) | |
|---|---|---|---|---|---|
| tmax (h) | 2.1±0.6 | 1.6±0.7 | 2.1±1.6 | 1.9±0.9 | None |
| Cmax (ng/mL) | 8.76±2.28 | 10.5±2.6 | 13.8±4.9 | 13.0±4.9 | MR P<0.05 |
| t1/2 (h) | 18.7±4.3 | 24.3±5.5 | 25.3±4.7 | 29.0±4.5 | MR P<0.05, SR P<0.01 |
| AUC0→∞ (ng.h/mL) | 136±37 | 189±44 | 367±250 | 360±168 | MR P<0.001, SR P<0.05 |
| CLoral (mL/min) | 131±40 | 93.0±23.1 | 55.9±19.1 | 61.4±40.4 | MR P<0.001, SR P<0.05 |
| CLR (mL/min/1.73 m2) | 58.4±29.9 | 39.6±10.4 | 18.2±9.1 | 14.4±14.6 | MR P<0.001, SR P<0.01 |
| Abbreviations: 9-OH-RIS, 9-hydroxyrisperidone; AUC0→∞, area under the concentration-time curve from zero time to infinity; CLoral, total oral clearance; CLR, renal clearance; Cmax, peak plasma concentration; MR, moderate renal; PK, pharmacokinetics; SR, severe renal; t1/2, elimination half-life; tmax, time to reach peak plasma concentration. | |||||
Tourtellotte et al (2019)6
- Patient was switched from oral risperidone 6 mg to RLAI 25 mg 5 years before initiating hemodialysis. After 2 months, the RLAI dose was increased to 37.5 mg.
- At time of RLAI initiation, patient had a diagnosis of chronic kidney disease (CKD) stage 3, with a serum creatinine of 2.0 mg/dL and a CrCl of 45 mL/min.
- Though his renal function was declining, no dosing adjustments were made at this time.
- Five years after RLAI initiation, the patient had a serum creatinine of 10.1 mg/dL and CrCl <10 mL/min and was initiated on conventional hemodialysis with standard membrane.
- RLAI was continued at 37.5 mg every 2 weeks. The dose was decreased 2 years later to 25 mg every 2 weeks due to suspected neuroleptic-induced tremor. The dose was decreased again 2 years later to 12.5 mg every 2 weeks due to somnolence and was later discontinued due to family request for switch back to oral risperidone.
- Risperidone, 9-OH-RIS, and active moiety (RISP+OH) plasma concentrations were obtained prior to initiation of hemodialysis, after initiation of hemodialysis and after a dose decrease. See Table: Peak Plasma Concentrations (ng/mL).
- Plasma concentrations were not obtained while patient was on oral risperidone.
- The authors suggested that risperidone concentrations are unchanged by hemodialysis compared to a patient with severe CKD not dependent on hemodialysis. Concentrations were consistently higher than expected, likely due to the accumulation related to decreased renal clearance.
| Draw 1a | Draw 2a | Draw 3b | Draw 4b | Draw 5b | Draw 6b,c | ||
|---|---|---|---|---|---|---|---|
| Risperidone | 18.9 | 19.2 | 21.7 | 11.1 | 8.6 | 5.2 | |
| 9-OH-RIS | 51.1 | 31.7 | 49.1 | 56.9 | 23.1 | 23.4 | |
| Active Moiety | 70.0 | 50.9 | 70.8 | 68.0 | 31.7 | 28.6 | |
| Abbreviations: 9-OH-RIS, 9-hydroxyrisperidone.aDraw 1 & 2 were plasma levels drawn before starting hemodialysis.bDraw 3-6 were plasma levels drawn at 1, 3, 10, 24 months, respectively after initiation of hemodialysis.c | |||||||
Batalla et al (2010)3
- Three years before initiating hemodialysis the patient was diagnosed with renal failure. She started hemodialysis, thrice-weekly, during which she received RLAI 50 mg every 14 days.
- Due to noncompliance and active negativism observed during hemodialysis treatments, she was re-hospitalized and started on risperidone oral solution, titrated to 6 mg nightly.
- After 7 days of treatment at 6 mg/day serum concentrations of risperidone and 9OH-RIS were measured, via high-performance liquid chromatography, before and after one hemodialysis session.
- Despite high flow dialysis, serum levels of drug and metabolite were not significantly affected (See table: Risperidone and 9-OH-RIS Levels Before and After 1 Hemodialysis Session).
- The patient regained fluidity of speech after 2 weeks of treatment. The RLAI (50 mg every 14 days) was reintroduced during week 3.
- With the exception of flat affect, no signs of psychopathological disorders were detected during the fourth week and the patient was subsequently discharged from the hospital.
| Before Hemodialysis | After Hemodialysis | |
|---|---|---|
| 9-OH-RIS, serum | 45 ng/mL | 46 ng/mL |
| Risperidone, serum | 3 ng/mL | 2.6 ng/mL |
| Abbreviations: 9-OH-RIS, 9-hydroxyrisperidone.aHemodialysis 4-Hour Session (polysulphone filter): blood flow of 300 mL/min and dialysis solution flow of 500 mL/min. | ||
Two case reports describe the use of RLAI in patients receiving hemodialysis. Plasma levels of the drug were not reported in both cases. In the first case, RLAI 50 mg did not produce an adequate response in a patient with schizoaffective disorder, and the patient was switched to oral zuclopenthixol.7 In the second case, RLAI 25 mg was able to stabilize a patient with bipolar 1 disorder with psychotic features.5
Published case reports that describe the use of oral risperidone in patients receiving hemodialysis8
LITERATURE SEARCH
A literature search of MEDLINE®
References
| 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. |
| 2 | Snoeck E, Van Peer, A, Sack M, et al. Influence of age, renal and liver impairment on the pharmacokinetics of risperidone in man. Psychopharmacol. 1995;122:223-229. |
| 3 | Batalla A, Vera M, Torra M, et al. Antipsychotic treatment in a patient with schizophrenia undergoing hemodialysis. J Clin Psychopharmacol. 2010;30(1):92-93. |
| 4 | Plagge JM, Clay JE, Redwine RL, et al. Effects of hemodialysis on profound memory deficits in renal insufficiency due to multiple myeloma: a case study. Appl Neuropsycho. 2009;16(1):76-82. |
| 5 | Xiong Y, Narang P, Lippman S. Injectable risperidone during hemodialysis. Prim Care Companion CNS Disord 2018;20(2):17l02212. |
| 6 | Tourtellotte R , Schmidt R. Use of therapeutic drug monitoring of risperidone microspheres long-acting injection in hemodialysis: A case report. Ment Health Clin. 2019;9(6):404-407. |
| 7 | Gonzalez Martín C, Ruiz Gutierrez J, Diez Alcantara A, et al. 4CPS-175 Optimisation of antipsychotic treatment in a patient undergoing dialysis: a case report. Eur J Hosp Pharm 2019;26(Suppl 1):A151. |
| 8 | Gupta M, Annadatha S. Treating bipolar disorder in patients with renal failure having haemodialysis: two case reports. Clin Prac Epid Mental Health. 2008;4(21):1-4. |
| 9 | Railton CJ, Kapur B, Koren G. Subtherapeutic risperidone serum concentrations in an adolescent during hemodialysis: a pharmacological puzzle. Ther Drug Monit. 2005;27(5):558-561. |
| 10 | Szepietowski J, Reich A, Pacan P. Psychodermatoses in haemodialysis patients. Dermatology. 2004;209:344-345. |
| 11 | Bourgeois J, Mistry H. Migraine-associated psychosis and subsequent renal transplant. Psychosomatics. 2010;51(1):77-79. |