Summary

• After the recommended initiation regimen of INVEGA SUSTENNA, the third and subsequent injections are recommended to be given monthly. To avoid a missed monthly dose, patients may be given the injection up to 7 days before or after the monthly time point.¹ However, this does not imply that the dosing interval can be changed to 3- or 5-week cycles.
• There are no data from clinical trials to support the routine administration of INVEGA SUSTENNA maintenance doses at intervals shorter or longer than 4 weeks.
• Pharmacokinetic simulations with INVEGA SUSTENNA deltoid injections were conducted to evaluate the steady state plasma concentration profiles of the highest recommended maintenance dose (234 mg every 4 weeks) compared to two higher than recommended or more frequently administered regimens (two 156 mg injections every 4 weeks or 234 mg every 3 weeks). The two higher/more frequent dosing regimens produced higher plasma concentrations than the recommended highest maintenance dose regimen of 234 mg every 4 weeks. Simulated plasma concentration profiles of the dosing regimens indicated that steady state peak paliperidone levels with two 156 mg injections every 4 weeks were higher than 234 mg every 3 weeks.²
• Two case reports in 3 patients describe the effect of shortening the INVEGA SUSTENNA interval to every 21 days on efficacy, safety, and drug plasma levels.^3,4 See Case Reports

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 25, 50, 75, 100, and 150 mg eq. are equal to 39, 78, 117, 156, and 234 mg of paliperidone palmitate, respectively.

PUBLISHED AND UNPUBLISHED DATA

Alternative Maintenance Dosing Interval

Pharmacokinetic simulations were conducted to investigate the steady state plasma concentration profiles of the highest recommended INVEGA SUSTENNA maintenance dose (234 mg every 4 weeks) versus two higher than recommended or more frequently administered dosing regimens.² Each of the three dosing regimens were simulated with the recommended initiation dosing of 234 mg on day 1 followed by 156 mg on day 8. From day 36 onward the three dosing regimens were: 1) 234 mg every 4 weeks, 2) two 156 mg injections every 4 weeks, and 3) 234 mg every 3 weeks. All doses were simulated with administration in the deltoid muscle. Simulated plasma concentration profiles of the dosing regimens indicated that steady state peak paliperidone levels with two 156 mg injections every 4 weeks were higher than 234 mg every 3 weeks. The two higher/more frequent dosing regimens produced higher plasma concentrations than the recommended highest maintenance dose regimen of 234 mg every 4 weeks. See Figure: Simulated Plasma Paliperidone Concentrations for more details. The higher/more frequent INVEGA SUSTENNA dosing regimen simulations are not aligned with the currently approved labeling for INVEGA SUSTENNA and have not been validated in clinical trials.

Samtani et al (2011)¹ described results from a population pharmacokinetic simulation model on the flexibility of the dosing window of INVEGA SUSTENNA during maintenance treatment. Simulations of INVEGA SUSTENNA 234 mg ±7 days on either side of the recommended monthly injection showed a median maximum plasma concentration (C_max) decrease of 8% (from 52 to 48 ng/mL) at 7 days after the monthly injection and an increase of 4% (from 52 to 54 ng/mL) at 7 days before the monthly injection. Although a ±7 day dosing window is acceptable during monthly dosing of INVEGA SUSTENNA after day 36, it should be considered the exception and does not imply that the dosing interval can be changed to 3- or 5-week cycles.

There are no data from clinical trials to support the routine administration of INVEGA SUSTENNA maintenance doses at intervals shorter or longer than 4 weeks.

Case Reports

Saklad (2018)³ described a case of a 27-year old male patient with a 10 year history of schizophrenia who switched to INVEGA SUSTENNA after discontinuing oral risperidone 6 mg. The patient was put on a maintenance dose of INVEGA SUSTENNA 117 mg (IM deltoid) every 28 days; however, experienced auditory hallucinations after 3 weeks. The dose was increased to 156 mg and then to 234 mg on consecutive months because the patient experienced breakthrough symptoms. After 6 months of INVEGA SUSTENNA 234 mg, auditory hallucinations continued to bother the patient for a few days prior to next injection. INVEGA SUSTENNA dosing interval was subsequently shortened from 28 days to 21 days. After the second dose at the new interval, the patient continued to tolerate the INVEGA SUSTENNA well and no longer reported any breakthrough symptoms.

Cohen (2019) et al⁴ described 2 cases of off-label use of INVEGA SUSTENNA resulting in serum paliperidone levels exceeding the therapeutic window.

A 20-year old, 59 kg male patient who experienced auditory hallucinations (hearing voices) and insomnia and displayed odd behavior, disorganization, and incoherent speech was admitted to a psychiatric care unit. At discharge, the patient was put on INVEGA SUSTENNA 234 mg every 21 days and quetiapine extended-release (ER) 100 mg daily for sleep. One year after discharge, the patient’s residual blood concentration was above the therapeutic window (240 nmol/L); however, aside from a 36% increase in weight gain to 80 kg, the patient tolerated the drug well. The INVEGA SUSTENNA dosing frequency was reduced to 234 mg every 28 days and the quetiapine ER dose was reduced to 50 mg. Approximately 2 years after discharge, the patient was in full remission with a PANSS of 32 and blood concentration of paliperidone remaining high at 250 nmol/L. At the 3-year mark, the patient was still in remission and had not been rehospitalized.

A 31-year old male patient with a history of multiple hospitalizations was readmitted to the psychiatry ward for schizophrenia. Patient was initiated on INVEGA SUSTENNA 234 mg every 28 days for 3 months, then received INVEGA SUSTENNA 234 mg every 21 days. Two years after switching to every 3-week dosing, the patient was rehospitalized due to a lack of efficacy manifested by insomnia, distrustful and irritable behavior, feelings of being bullied or disrespected, and lack of insight into his own psychotic symptoms. The patient tolerated the drug well despite a paliperidone concentration of 610 nmol/L. The patient discontinued INVEGA SUSTENNA and was initiated on clozapine 300 mg/day resulting in an improvement in some of the symptoms. Approximately 1 year after discharge, the clozapine dose was increased to 400 mg/day due to irritability and paranoid symptoms, however, at 18 months after discharge, the patient was rehospitalized due to poor adherence to clozapine and sent to a long-term psychiatric unit.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 06 January 2025.