Summary

• Tolerability Testing: For patients who have never taken oral paliperidone or oral or injectable risperidone, it is recommended to establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with INVEGA SUSTENNA.¹
• Initiation Regimen Development: The dosing recommendations for INVEGA SUSTENNA are the result of a clinical development program that evaluated refinements aimed at optimizing the dosing strategy for the treatment of schizophrenia. Earlier phase 2/3 trials did not utilize the recommended initiation dosing regimen (234 mg injection followed by 156 mg injection one week later, both administered in the deltoid muscle). However, following the results of population pharmacokinetic (PK) modeling², the initiation regimen in subsequent trials was optimized.
• Initiation Dosing: The recommended initiation of INVEGA SUSTENNA is with a dose of 234 mg on treatment day 1 and 156 mg one week later, both administered in the deltoid muscle. To avoid a missed dose, patients may be given the second initiation dose 4 days before or after the one-week time point. The initiation regimen for INVEGA SUSTENNA was designed to rapidly attain steady-state paliperidone concentrations when initiating therapy without the use of oral supplementation. Following the second initiation dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle.³
• Population PK Modeling: Simulation results from a population PK model suggested that a paliperidone palmitate 1-month (PP1M) initiation dosing regimen of 234 mg on day 1 and 156 mg on day 8, both administered in the deltoid muscle using a weight-adjusted needle length, rapidly achieved plasma paliperidone levels that are similar to those observed at steady state with the suggested monthly dose of PP1M 117 mg for the treatment of schizophrenia (as well as the daily dose of paliperidone extended-release [ER] 6 mg/day at steady state).²

DOSAGE STRENGTH INFORMATION

Doses of INVEGA SUSTENNA 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.

TOLERABILITY TESTING

Some publications specified that oral tolerability testing was conducted in schizophrenia patients without documented earlier exposure to at least four doses of risperidone or paliperidone or one dose of risperidone long-acting injection (RLAI)^4,5 or to at least four doses of risperidone or paliperidone or one dose of RLAI or INVEGA SUSTENNA.⁶

The publications for several schizophrenia clinical studies described the methods used for establishing tolerability:

• Paliperidone ER 3 mg/day for at least 2 consecutive days^7,8
• Paliperidone ER 3 mg/day or risperidone 1 mg/day for at least 2⁹ or 3 days^10,11
• Paliperidone ER for 4 days^4-6,12 at a dose of 3 mg/day^4,5,12
• Paliperidone ER 6 mg/day for 4-6 days^13-16
• Paliperidone ER 3 to 9 mg/day for 2 weeks¹⁷

A commentary reviewing the recommended dosing of INVEGA SUSTENNA for schizophrenia recommends that patients previously unexposed to risperidone or paliperidone receive two daily oral doses of either paliperidone ER 3 mg/day or risperidone 1 mg/day prior to initiating treatment with INVEGA SUSTENNA.¹⁸

A case was reported of a 19-year-old man who had tolerated five days of treatment with oral risperidone (gradually increased to 2 mg twice daily) and subsequently experienced an anaphylactoid reaction following administration of INVEGA SUSTENNA 234 mg.¹⁹

POPULATION PHARMACOKINETIC MODELING

Samtani et al (2009)^2,20 evaluated the optimal initiation dosing strategy for PP1M by intramuscular (IM) deltoid injection using a population PK simulation model and data from schizophrenia clinical trials.

Study Design/Methods

• Analysis was conducted to identify an optimal dosing strategy for the initiation of treatment with INVEGA SUSTENNA in adult patients with schizophrenia with a population PK simulation model using data from clinical trials.
• The initiation strategy was chosen to meet the following parameters:
  • By the end of 1 week after the first dose, paliperidone plasma concentrations must exceed the target threshold of 7.5 ng/mL. This concentration corresponds to a central D₂-receptor occupancy of approximately 60% (receptor occupancy of 60%-80% is generally required for antipsychotic efficacy).
  • On days 8 and 36, paliperidone plasma concentrations must remain within the concentration window (3.5-50.0 ng/mL). The concentration window was based on findings from the paliperidone ER phase 3 clinical trial program, in which 90% of patient plasma concentrations were within this window at the recommended dose of paliperidone ER 6 mg, a dose shown to be efficacious and well tolerated.
• Model-based projections for the suggested initiation regimen were compared with available observed data from the PP1M schizophrenia clinical trial program where the corresponding deltoid injection dosing strategy had been utilized.^6,16,21,22
• Impacts of body mass index (BMI) and needle length on PP1M dosing were also described.

Results

• The population PK model showed that injection of PP1M into the deltoid muscle provided a 37% higher fraction of paliperidone in the systemic circulation than injection in the gluteal muscle.
• Simulation data 1 week after the initial dose of PP1M showed that a greater percentage of patients achieved a target paliperidone concentration of >7.5 ng/mL after receiving a 234-mg deltoid injection than after a 156-mg deltoid injection.

• Simulation data suggest that after the initial dose of PP1M 234 mg on day 1 by deltoid administration, patients should receive a dose of PP1M 156 mg on day 8 administered by deltoid injection.
• This regimen (234 mg/156 mg) rapidly achieves plasma paliperidone levels that are similar to those observed at steady state with the suggested monthly dose of PP1M 117 mg as well as the daily dose of paliperidone ER 6 mg at steady state (3.5-50 ng/mL).
• 90% prediction interval of pre-dose exposure on days 8 and 36 was 4.5-51.0 ng/mL with the 234 mg/156 mg regimen, which is similar to the potentially therapeutic concentration window of 3.5-50 ng/mL previously described.

• Overlay plots comparing the results from the population PK simulations and the actual observed plasma concentration from the schizophrenia clinical trial program^6,16,21,22 indicated considerable similarity between PP1M 234 mg on day 1 and 156 mg on day 8, and maintenance with 117 mg monthly, and once daily paliperidone ER 6 mg.
• The population PK model and previous schizophrenia clinical trials showed that patients with higher BMI (≥25 kg/m²) had a lower median paliperidone plasma concentration than patients with normal BMI (<25 kg/m²) after the initiation of PP1M 234 mg on day 1 and 156 mg on day 8 (prior to day 36).
• Schizophrenia clinical trial data have indicated that a greater difference in paliperidone plasma C_max was observed when a 1½-inch versus a 1-inch needle was used to administer the IM injection in the deltoid vs gluteal muscle, and this was thought to be related to BMI.
• Schizophrenia clinical trial data and population PK simulations suggest that the impact of BMI on paliperidone plasma concentrations can be mitigated by administering the day 1 (234 mg) and day 8 (156 mg) IM injections in the deltoid muscle with a 1½-inch needle in patients ≥90 kg and a 1-inch needle in patients with <90 kg.
• A lower percentage of patients who were morbidly obese (≥40 kg/m²) than of those in any other BMI category (normal, overweight, or obese) achieved paliperidone concentrations >7.5 ng/mL one week after initiating treatment with PP1M 234 mg (See Table: Percentage of Patients Achieving Paliperidone Concentration >7.5 ng/mL One Week After Initiating Treatment with 234 mg Paliperidone Palmitate [by BMI category]).

Authors' Conclusions

The authors concluded that population PK simulation and schizophrenia clinical trial data showed that treatment with INVEGA SUSTENNA should be initiated with deltoid injections and a weight-adjusted needle length with a dose of 234 mg paliperidone palmitate on day 1 and 156 mg paliperidone palmitate on day 8.

Dosing Window Flexibility During Treatment Initiation

Samtani et al (2013)³ presented the results of additional PK simulations evaluating expanding the day 8 initiation window to ± 4 days. When comparing regimens in which administration of the second initiation dose (PP1M 156 mg) occurred on either day 4, day 8, or day 12, there was a ± 3 ng/mL variation in median maximum plasma concentrations, with considerable overlap. The day 1/day 4 regimen resulted in minor concentration excursions that exceeded the exposure window for the day 1/day 8 regimen by approximately 1 day around the C_max. The authors state that no new safety concerns exist for the 234 mg day 1/156 mg day 4 regimen, as peak concentrations fell below those for 234 mg day 1/234 mg day 8, the highest initiation regimen studied in clinical trials. However, an analysis of data from schizophrenia clinical trials suggest that an increase in the incidence of AEs may occur when administering the second initiation dose on day 4 instead of day 8 as recommended. The simulations also suggest that when administering the second injection on day 4, day 8, or day 12, plasma concentrations remain close to the desired paliperidone exposure during the following month.

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 13 May 2024.