Summary

• INVEGA SUSTENNA has not been systematically studied in patients with renal impairment.¹
• For patients with mild renal impairment (creatinine clearance [CrCl] ≥50 mL/min to <80 mL/min [Cockcroft-Gault Formula]), initiate INVEGA SUSTENNA with a dose of 156 mg on treatment day 1 and 117 mg one week later. Administer both doses in the deltoid muscle. Thereafter, follow with the recommended monthly maintenance dose of 78 mg, administered in either the deltoid or gluteal muscle. Adjust monthly maintenance dose based on tolerability and/or efficacy within the strengths of 39 mg, 78 mg, 117 mg, or 156 mg.²
• INVEGA SUSTENNA is not recommended in patients with moderate or severe renal impairment (CrCl <50 mL/min).¹
• In a case report by Ruppert et al (2023), INVEGA SUSTENNA (156 mg, week 1; 78 mg, week 2 and as monthly maintenance dose) was well-tolerated in a 61-year-old man with schizophrenia and end-stage renal disease (ESRD) requiring hemodialysis.³
• In a case report by Samalin et al (2015), mean plasma concentrations of 9-hydroxy-risperidone did not significantly differ pre- and post-hemodialysis in a patient receiving INVEGA SUSTENNA (117 mg, week 1; 78 mg, week 2; 117 mg monthly thereafter) for paranoid schizophrenia.⁴

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate extended-release injectable suspension may be expressed in milligram equivalents of paliperidone (active moiety) or milligrams of paliperidone palmitate. Dosage information in this response has been converted to mg of paliperidone palmitate to reflect the commercially available dosage strengths in the United States. The conversion factor from mg eq. to mg is 1.56.

• INVEGA SUSTENNA doses expressed as 39, 78, 117, 156, and 234 mg of paliperidone palmitate are equal to 25, 50, 75, 100, and 150 mg eq of paliperidone, respectively.

CLINICAL STUDIES

Renal Impairment

INVEGA SUSTENNA has not been systematically studied in patients with renal impairment.¹

Creatinine clearance (CrCl, mL/min) was calculated by Samtani et al (2009)⁵ using the following Cockcroft-Gault equations, where WT is actual weight in kg and CREA is serum creatinine in µmol/L:^6,7

• CrCl=WT*(140-age)/72/(CREA/88.4), for males
• CrCl=0.85*WT*(140-age)/72/(CREA/88.4), for females

Note:1 mg/dL = 88.4 μmol/L

• In clinical situations where patients may be overweight, obese or ascites may be present, adjusted/ideal versus actual body weight should be considered when calculating CrCl.^6,8

Samtani et al (2009)⁵ conducted a population pharmacokinetic simulation model to determine dosing recommendations based on patient renal function. The simulation model consisted of data pooled from 11 clinical trials consisting of 1795 patients. Investigators studied the impact of renal impairment on the pharmacokinetics and plasma concentration of INVEGA SUSTENNA by conducting comparisons between patients with CrCl >80 mL/min who received multiple deltoid injections of INVEGA SUSTENNA 156 mg and those with a CrCl between 50 to 80 mL/min (classified as mild renal impairment) who received multiple deltoid injections of INVEGA SUSTENNA 117 mg. The simulation model illustrated that the maximum steady state plasma concentration (Css_max) of paliperidone was 33 ng/mL in patients with normal renal function and 30 ng/mL in those with mild renal impairment. These results suggested that a dose reduction of 25% is necessary for patients with mild renal impairment to achieve plasma concentrations of INVEGA SUSTENNA comparable to that in patients with normal renal function. The Table below, Recommended Dosing of Paliperidone Palmitate for Patients with Mild Renal Impairment, provides recommended dosing adjustments for INVEGA SUSTENNA in patients with mild renal impairment.

INVEGA SUSTENNA is not recommended in patients with moderate to severe renal impairment (CrCl<50 mL/min).¹

Dialyzability

The extent to which a drug is affected by dialysis is determined by several physiochemical drug characteristics, which include molecular weight, protein binding, water solubility, and volume of distribution.⁹ It is also important to consider whether the drug has active metabolites that may or may not be removed by dialysis. Please see the Table below, Physiochemical Properties of Paliperidone That Influence Dialysis, for a review of these properties.

Ruppert et al (2023)³ reported the case of a 61-year-old male patient with schizophrenia and ESRD who was admitted to the hospital for hemodialysis and presented with suicidal ideation and paranoid delusions. The patient was initially treated with aripiprazole to avoid worsening the observed tardive dyskinesia, but his paranoia failed to improve. He was switched to oral risperidone, which resolved the paranoia, and he was discharged on 2 mg twice daily. Two weeks later, he was readmitted for hemodialysis (creatinine, 3.64 mg/dL; creatinine clearance, 16.88 mL/min), displayed symptoms of self-harm and paranoia, reported non-adherence to his oral risperidone, and refused hemodialysis. Due to earlier unsuccessful trials with aripiprazole and non-adherence to oral risperidone, 156 mg INVEGA SUSTENNA was initiated, resulting in an improvement in psychotic symptoms without any side effects. A week later, a second dose of 78 mg INVEGA SUSTENNA was well-tolerated. The patient was discharged on a monthly maintenance dose of 78 mg INVEGA SUSTENNA with outpatient psychiatric follow-ups; there were no reports of subsequent hospitalizations.

Samalin et al (2015)⁴ reported the case of a 47-year-old female patient with paranoid schizophrenia who was receiving high-flow hemodialysis for end-stage renal failure. Following unsuccessful trials with olanzapine, risperidone, amisulpride and clozapine, INVEGA SUSTENNA was initiated at half the dose due to a potential decrease in clearance by hemodialysis (117 mg, week 1; 78 mg, week 2; 117 mg monthly thereafter). After 3 weeks, the patient clinically improved and remained stable during follow-up. Overall, the drug was well tolerated. The mean plasma concentration levels of 9-hydroxy-risperidone pre- and post-hemodialysis did not differ significantly during the three months of treatment.

Winters et al (2004)¹⁰ provided a formula to predict the dialyzability of a drug according to the apparent volume of distribution and plasma protein binding (volume of distribution/free fraction of the drug). For paliperidone, this equation yields an unbound volume of distribution of 1873 L or 27 L/kg in an individual who weighs 70 kg. Since the unbound volume of distribution exceeds 3.5 L/kg, it is unlikely that the drug will be dialyzable.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug Files (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 11 July 2024.