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Last Updated: 12/26/2022
Click on the following links to related sections within the document: Second Initiation Dose and Maintenance Dose.
Abbreviations: D, deltoid muscle; G, gluteal muscle; PP1M, paliperidone palmitate 1-month
aINVEGA SUSTENNA [Prescribing Information].1 bSamtani (2009).2
Educational Dose Illustrator
INVEGA SUSTENNA Educational Dose Illustrator (EdDI) is an educational website http://www.educationaldoseillustrator.com that allows users to visualize how various INVEGA SUSTENNA dosing scenarios from the Prescribing Information affect the paliperidone plasma concentrations over time. No user registration is required. Please note: simulations may not be representative of individual patient response because the dosing scenarios are based upon aggregated pharmacokinetic (PK) information. Scenarios illustrating the management of missed initiation and maintenance doses based on recommendations from the INVEGA SUSTENNA Prescribing Information can be found on this website.
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.
PRODUCT LABELING PUBLISHED AND UNPUBLISHED LITERATURE Dosing Window Flexibility During Treatment Initiation
Samtani et al (2009)2, 3 presented results from a population PK simulation model on the flexibility of dosing windows and the management of missed doses of paliperidone palmitate 1-month (PP1M) during initiation or maintenance treatment of schizophrenia.
Comparison of simulations for patients who received their second initiation dose (PP1M 156 mg) ±2 days on either side of the recommended day 8 injection showed that the median Cmax varies by ±2 ng/mL. The PK model suggests an acceptable dosing flexibility window of ±2 days for the second initiation dose on day 8.
Samtani et al (2013)4 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 Cmax. 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 schizophrenia clinical trials. However, an analysis of data from schizophrenia clinical trials suggest that an increase in the incidence of adverse events 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.
Dosing Window Flexibility During Maintenance Treatment
Samtani et al (2009)2, 3 presented results from a population PK simulation model on the flexibility of dosing windows and the management of missed doses of PP1M during initiation or maintenance treatment of schizophrenia.
Simulations of PP1M 234 mg ±7 days on either side of the recommended monthly injection showed a median Cmax 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 paliperidone palmitate 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.
Management of Missed Doses During Treatment Initiation
The recommended initiation regimen (234 mg on day 1 and 156 mg one week later, both administered in the deltoid muscle) rapidly achieves potentially therapeutic concentrations of paliperidone. Deviations from this regimen may lead to sub-therapeutic concentrations, therefore the doses should be administered as close to the recommended schedule as possible. Three scenarios of a missed second initiation dose were evaluated in a population PK model, and considerations for the management of a missed second initiation dose were developed (see Table: Management of a Missed Second Initiation Dose of Paliperidone Palmitate).1, 5
Management of a Missed Second Initiation Dose of Paliperidone Palmitate1, 5
|<4 weeks since first injection||Administer the second initiation dose of 156 mg in the deltoid muscle as soon as possible|
|4 to 7 weeks since first injection||Resume dosing with two injections of 156 mg in the following manner:|
|>7 weeks since first injection||Restart dosing with recommended initiation:|
Simulations found that if the target date for the second PP1M injection is missed by less than 4 weeks, then the patient should be administered the second injection of 156 mg in the deltoid muscle as soon as possible with a third PP1M injection of 117 mg in either the deltoid or gluteal muscles 5 weeks after the first injection (regardless of the timing of the second injection). This strategy helps reattain drug levels that would normally be observed with a day 1 and day 8 initiation (See Figure: Simulation of Reinitiation of Paliperidone Palmitate 4 Weeks After the First Dose).
For a missed dose between 4 and 7 weeks since the first injection, simulations showed that two deltoid injections of 156 mg one week apart, followed by the normal monthly cycle of 117 mg in the deltoid or gluteal muscles helped reattain potentially therapeutic concentrations rapidly.
The third scenario sought to identify a cut-off time that would lead to a decline of median concentrations below 7.5 ng/mL after administration of a single dose of 234 mg in the deltoid muscle on day 1. A paliperidone concentration of 7.5 ng/mL is associated with a D2 receptor occupancy of 60% and is thought to be required for antipsychotic efficacy. The simulation showed that it would take 7 weeks for concentrations to decline below the critical threshold of 7.5 ng/mL. Therefore, 7 weeks would be a suitable time point to reinitiate PP1Mfollowing the recommended initiation regimen (234 mg injection followed by a 156 mg injection one week later, each given in the deltoid muscle) (See Figure: Simulation of Reinitiation of Paliperidone Palmitate 7 Weeks After the First Dose).
Management of Missed Doses During Maintenance Treatment
The PK simulation model was applied to scenarios where maintenance doses (given at once-monthly intervals) were missed, and reinitiation was attempted with one or two doses of PP1M.Recommendations were developed empirically to maintain steady-state concentrations of paliperidone.3
Table: Management of Missed Maintenance Doses of Paliperidone Palmitate provides the suggested dosing regimen for three scenarios.
Management of Missed Maintenance Doses of Paliperidone Palmitate1, 2
|Timing of Missed Maintenance Dose ||Dosing|
|4 to 6 weeks since last injection||Resume regular monthly dosing as soon as possible at the patient’s previously stabilized dose, followed by injections at monthly intervals.|
|>6 weeks to 6 months since last injection||Resume the same dose the patient was previously stabilized on (unless the patient was stabilized on a dose of 234 mg, then the first 2 injections should each be 156 mg) in the following manner:|
|>6 months since last injection||Restart dosing with recommended initiation:|
Simulations suggest that, for missed maintenance doses 1 month to 6 weeks after the last injection of PP1M, reinitiation of treatment should begin with one injection of PP1M at the previously stable dose in the deltoid or gluteal muscle followed by monthly injections.
For doses missed >6 weeks to <6 months after the previous dose of PP1M, reinitiation of treatment should begin with two deltoid IM injections of the dose the patient was previously stabilized on, given 1 week apart (unless the patient was stabilized on a dose of 234 mg, then the two injections should each be 156 mg), followed by monthly injections in either the gluteal or deltoid muscle.
Simulations showed that, even at the highest dose of PP1M (234 mg), 6 months after the cessation of therapy, the median paliperidone plasma concentration fell below 7 ng/mL. The simulation model suggests that patients who received the last dose of PP1M 6 months before should be reinitiated on treatment with the initiation regimen of IM deltoid injections of PP1M 234 mg on day 1 and 156 mg on day 8. Thereafter, monthly deltoid or gluteal injections should be administered.
OTHER RELEVANT LITERATURE
A review article described the rationale for the dosing window flexibility and management of missed doses, based on the results of population PK modeling.5
A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, and DERWENT® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 18 July 2022.
|1||INVEGA SUSTENNA [(paliperidone palmitate) Extended-Release Injectable Suspension] [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; https://imedicalknowledge.veevavault.com/ui/approved_viewer?token=7994-54c7ff1c-5e50-4845-a605-24e8c5104cd7.|
|2||Samtani MN,Gopal S, Sliwa JK. Management of missed paliperidone palmitate doses based on pharmacokinetic modeling and simulation. Poster presented at: The New Clinical Drug Evaluation Unit; June 29 - July 2, 2009; Hollywood, FL.|
|3||Samtani MN,Haskins JT, Gopal S. Dosing information for paliperidone palmitate - a once-monthly injectable atypical antipsychotic - based on population pharmacokinetic analysis. Poster presented at: US Psychiatric and Mental Health Congress; November 2-5, 2009; Las Vegas, NV.|
|4||Samtani MN,Nuamah I, Gopal S. Expansion of guidance for the day 8 initiation dose of paliperidone palmitate to avoid a missed dose. Neuropsychiatr Dis Treat. 2013;9:721-730.|
|5||Samtani MN,Gopal S, Gassmann-Mayer C. Dosing and switching strategies for paliperidone palmitate: based on population pharmacokinetic modelling and clinical trial data. CNS Drugs. 2011;25(10):829-845.|