Summary

• The Educational Dose Illustrator (EdDI) is a free, publicly-available website (http://www.educationaldoseillustrator.com) intended to help US healthcare professionals visualize how dosing affects paliperidone plasma concentrations following administration of INVEGA SUSTENNA or INVEGA TRINZA. No user registration is required.
• The Educational Dose Illustrator is intended to be used as a resource to foster a better understanding and educate healthcare professionals about the dosing recommendations provided in both the INVEGA SUSTENNA and INVEGA TRINZA Prescribing Information by simulating paliperidone plasma concentrations over time. It is intended for educational purposes only. It is not intended to influence prescribing practices. It is not intended to be used to determine patient prescribing, dosages, treatment, or dosing strategies.
• Please note that simulations may not be representative of individual patient response because the dosing scenarios are based upon aggregated pharmacokinetic  information.^1,2

PRODUCT LABELING

Please refer to the following sections of the INVEGA SUSTENNA³ and INVEGA TRINZA⁴ Full Prescribing Information that are relevant to your inquiry: DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY.

Website Overview

The Educational Dose Illustrator can be accessed at the following website:

http://www.educationaldoseillustrator.com

Wilson et al (2013)⁵ presented information regarding the Educational Dose Illustrator. The Educational Dose Illustrator website is designed as an interactive educational resource to simulate the paliperidone plasma concentrations over time resulting from different dosing scenarios set forth in both the INVEGA SUSTENNA and INVEGA TRINZA Prescribing Information. Each scenario is designed to dynamically update following user adjustment from the default scenario. Because the simulated patient blood plasma levels of paliperidone shown in the dosing scenarios are based upon aggregated pharmacokinetic information from clinical studies, the simulations may not be representative of individual patient response.

There are three main sections to the EdDI website including:

• INVEGA SUSTENNA - Schizophrenia
• INVEGA SUSTENNA - Schizoaffective Disorder
• INVEGA TRINZA - Schizophrenia

Common Questions

1. What are the key assumptions to the mathematical modeling approach used in the INVEGA SUSTENNA section of this resource?

The Educational Dose Illustrator is based upon the following assumptions:

• A cumulative (total) paliperidone plasma concentration during treatment with INVEGA SUSTENNA can be determined by calculating the sum of paliperidone plasma levels attributed to each individual dose.
• The paliperidone plasma level attributed to any one dose can be considered the same as if the injection were given as a single dose.
• These assumptions are plausible because the pharmacokinetics of paliperidone after administering INVEGA SUSTENNA are linear and time-independent (e.g., there is no significant induction or concentration- or time-dependent clearance, nor other complicating pharmacokinetic factors with INVEGA SUSTENNA).

2. How is the cumulative paliperidone plasma concentration determined?

The cumulative paliperidone plasma concentration is determined by first graphing the expected plasma levels attributable to each individual dose (thin orange lines). To present the cumulative paliperidone plasma concentration curve (thick orange line), plasma concentrations from all prior administrations are summed. The color of the thick orange line turns red after conversion to INVEGA TRINZA (switching point depicted by a vertical blue line).^1,2

3. How have the data with INVEGA SUSTENNA from this mathematical model been validated?

The modeling data have been verified through two methods¹:

• Comparison with empirical evidence
• Comparison with predictions generated through population-pharmacokinetic modeling & simulation

Acknowledging that the simplified non-compartmental superposition technique may result in slightly different predictions than the population pharmacokinetic methodology, the outcomes of the mathematical model are similar to these two sources.

4. Describe the pharmacokinetic models used to simulate the INVEGA TRINZA scenarios

The simulations were conducted using a 1-compartment model with parallel zero and first-order absorption to describe the pharmacokinetics of INVEGA SUSTENNA⁶ and a 1-compartment model with two saturable absorption processes to describe the pharmacokinetics of INVEGA TRINZA⁷.

5. How has the pharmacokinetic model for INVEGA TRINZA been validated?

The pharmacokinetic characteristics of paliperidone when administered as a single⁸ and multiple⁹ injections of INVEGA TRINZA were well captured by the population pharmacokinetic model⁷ for INVEGA TRINZA.

INVEGA SUSTENNA Website Orientation & Features

INVEGA SUSTENNA - The following orientation provides a description of features specific to the two INVEGA SUSTENNA sections of the Educational Dose Illustrator Website for both the treatment of schizophrenia and schizoaffective disorder.

As noted in the above Figure: INVEGA SUSTENNA SCENARIO ORIENTATION: Standard Dosing.

• A - Prescribing Information Links
• B - Dosing by Product/Indication View
• C - Home Page
  • What is the Educational Dose Illustrator?
  • The difference between individual injections and cumulative paliperidone concentration lines within the graphs
  • How to edit a dose illustrated within the graphs
  • Additional Features
• D - Dosing Scenarios
  • Starting a Patient on INVEGA SUSTENNA
    • Standard Dosing (see Figure: INVEGA SUSTENNA SCENARIO ORIENTATION: Standard Dosing)
    • Dosing in Mild Renal Impairment
    • Initiation Dosing
    • Dosing Window for 2nd Initiation Dose
    • Maintenance Dosing
    • Maintenance Dose Adjustment
    • Maintenance Dosing Window
  • Switching a Patient to INVEGA SUSTENNA
    • Switching from Oral INVEGA ER
    • Switching from Oral Antipsychotics
    • Switching from Long-Acting Injectable Antipsychotics
  • Managing a Missed Dose
    • Missed 2nd Initiation Dose: <4 Weeks Since 1st injection
    • Missed 2nd Initiation Dose: 4-7 Weeks Since 1st injection
    • Missed 2nd Initiation Dose: >7 Weeks Since 1st injection
    • Missed Maintenance Dose: 4 to 6 Weeks Since Last Injection
    • Missed Maintenance Dose: >6 Weeks to 6 Months Since Last Injection
    • Missed Maintenance Dose: >6 Months Since Last Injection
• E - Single Dose Curve View: Compares the typical paliperidone plasma concentrations for up to two INVEGA SUSTENNA dosage strengths (in either the gluteal or deltoid sites of administration).
• F - Read More About INVEGA SUSTENNA: Read more about INVEGA SUSTENNA Common Dosing & Administration Topics.
• G - Graph Information: Opens additional background information about the dosing scenario.
• H - Print Button
• I - Tutorial: Describes both “The X-Axis”, “The Y-Axis”, “The Curves”, “Additional Graph Features” and “How the Graph is Plotted”.
• J - Legend
• K - Individual Dose Curves: These thin orange lines (see P) illustrate the paliperidone plasma concentration of one single dose. Users uncheck the individual dose curves and adjusting the view to represent only the thick orange cumulative paliperidone plasma concentration curve.
• L - Zoom
• M - Learning Points: Reveals additional educational information.
• N - Cumulative Paliperidone Plasma Concentration Curve: This thick orange line indicates the cumulative paliperidone plasma concentration in the body over time. Each individual dose contributes to this curve. Changing the timing, injection location or dosage strength of any dose will affect the total concentration curve.
• M/N - Oral INVEGA ER 6-12 mg/day Exposure Range: The light green shaded area of the graph illustrates the estimated exposure range from use of oral INVEGA ER 6-12 mg/day. The upper gray line represents the median paliperidone plasma concentration of Oral INVEGA ER 12 mg/day, and the lower green line represents the median paliperidone plasma concentration of Oral INVEGA ER 6 mg/day.
• O - Forward/Back Views
• P - Individual Dose Curves: These thin orange lines illustrate the paliperidone plasma concentration of one single dose. Each dose contributes to the total concentration in the body represented by the thick orange cumulative paliperidone plasma concentration curve lines.
• Q - INVEGA SUSTENNA Initiation Doses: As noted in the Prescribing Information, 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 initiate a patient with Mild Renal Impairment, please select “Starting a Patient on INVEGA SUSTENNA”, then select “Dosing Mild Renal Impairment”.
  • No adjustment is permitted to the first INVEGA SUSTENNA 234 mg initiation dose in the deltoid.
  • It is recommended the second initiation dose of INVEGA SUSTENNA 156 mg in the deltoid muscle be given one week after the first dose. To avoid a missed dose, patients may be given the second dose 4 days before or after the one-week time point. Changing the timing of the second initiation dose will affect the total concentration curve (see N).
• R - INVEGA SUSTENNA Monthly Maintenance Doses: As noted in the Prescribing Information, the first monthly maintenance dose should be administered 5 weeks after the first injection, in either the deltoid or gluteal muscle. For Maintenance Dosing in a patient with Mild Renal Impairment, please select “Starting a Patient on INVEGA SUSTENNA”, then select “Dosing Mild Renal Impairment”.
  • The recommended maintenance dose for treatment of schizophrenia is 117 mg; some patients may benefit from lower or higher maintenance doses within the additional available strengths (39 mg, 78 mg, 156 mg, and 234 mg).
  • The recommended maintenance dose for treatment of schizoaffective disorder is 78-234 mg; adjust dose based on tolerability and/or efficacy using available strengths (the 39 mg strength was not studied in the long-term schizoaffective disorder study).
  • The third and subsequent injections after the initiation regimen 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. Changing the timing, injection location or dosage strength of any dose will affect the total concentration curve (see N).
• S - Important Safety Information: View the Important Safety Information at the bottom of each webpage (including links to the Privacy Policy and Legal Notices).

INVEGA TRINZA Website Orientation & Features

INVEGA TRINZA - The following orientation provides a description of features specific to the INVEGA TRINZA section of the Educational Dose Illustrator Website for the treatment of schizophrenia.

As noted in the above Figure: INVEGA TRINZA ORIENTATION: Transition a Patient to INVEGA TRINZA.

• A - Prescribing Information Links
• B - Dosing by Product View
• C - Home Page
  • What is the Educational Dose Illustrator?
  • Line Colors
  • How to edit a dose illustrated within the graphs
  • How prior to transitioning a patient to INVEGA TRINZA, a consistent INVEGA SUSTENNA maintenance dose should be established
  • How to transition a patient on an adequate INVEGA SUSTENNA dose to INVEGA TRINZA
• D - Dosing Scenarios
  • Transition a Patient to INVEGA TRINZA
    • Transition to INVEGA TRINZA
    • Transition to INVEGA TRINZA from RISPERDAL CONSTA
    • Transition to INVEGA TRINZA from Any Other Long-Acting Injectable (LAI) Antipsychotic
    • Mild Renal Impairment
  • Adjust INVEGA TRINZA Dosing Window
    • Adjust Dosing Window for 2nd Injection of INVEGA TRINZA
    • Adjust Dosing Window for 3rd Injection of INVEGA TRINZA
    • Adjust Dosing Window for 4th Injection of INVEGA TRINZA
    • Adjust Dosing Window for 5th Injection of INVEGA TRINZA
  • Manage a Missed Dose
    • 3½ Months to 4 Months Since Last Injection
    • 4 Months to 9 Months Since Last Injection
    • 9 Months Since Last Injection
  • Switch a Patients from INVEGA SUSTENNA
    • Switch to INVEGA SUSTENNA
    • Switch to INVEGA
• E - Single Dose Curve View: View administration of a single INVEGA TRINZA dosage strength
• F - Read More About INVEGA TRINZA: Read more about INVEGA TRINZA Common Dosing & Administration Topics.
• G - Graph Information: Opens additional background information about the dosing scenario.
• H - Print Button
• I - Tutorial: Describes both “The X-Axis”, “The Y-Axis”, “The Curves”, “Additional Graph Features” and “How the Graph is Plotted”.
• J - Legend
• K - Zoom
• L - Learning Points: Reveals additional educational information.
• M - Cumulative Paliperidone Plasma Concentration Curve: This thick red line indicates the cumulative paliperidone plasma concentration in the body over time.
• N - Switching Point: This vertical blue line indicates a product switch has occurred.
• O - Forward/Back Views
• P - INVEGA SUSTENNA Initiation Doses: As noted in the Prescribing Information, 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 initiate a patient with Mild Renal Impairment, please select “Transition a Patient to INVEGA TRINZA”, then select “Mild Renal Impairment”.
  • No adjustment is permitted to the first INVEGA SUSTENNA 234 mg initiation dose in the deltoid.
  • It is recommended the second initiation dose of INVEGA SUSTENNA 156 mg in the deltoid muscle be given one week after the first dose. To avoid a missed dose, patients may be given the second dose 4 days before or after the one-week time point. For illustrative purposes only, the second INVEGA SUSTENNA initiation dose cannot be altered in the INVEGA TRINZA portion of the website.
• Q - INVEGA SUSTENNA Monthly Maintenance Doses: As noted in the Prescribing Information, the first monthly maintenance dose should be administered 5 weeks after the first injection, in either the deltoid or gluteal muscle.
  • The recommended maintenance dose for treatment of schizophrenia is 117 mg; some patients may benefit from lower or higher maintenance doses within the additional available strengths (39 mg, 78 mg, 156 mg, and 234 mg).
  • The third and subsequent injections after the initiation regimen 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. Changing the timing, injection location or dosage strength of any dose will affect the total concentration curve (see M).
  • INVEGA TRINZA is to be used only after INVEGA SUSTENNA has been established as adequate treatment for at least four months. In order to establish a consistent maintenance dose, it is recommended that the last two doses of INVEGA SUSTENNA be the same dosage strength before starting INVEGA TRINZA.
• Website Limitations (Click on the blue “Read More” text (while Editing a Dose) for additional information):
  • Once the user chooses a site of injection (deltoid or gluteal), it will remain constant for all remaining INVEGA SUSTENNA maintenance doses.
  • The dosing window for maintenance doses (± 7 days) is not modifiable in this section.
  • Users may only increase/decrease the INVEGA SUSTENNA maintenance dosage strength by one increment from the last dose.
  • The last maintenance dose of INVEGA SUSTENNA prior to transitioning to INVEGA TRINZA is locked in order to establish a consistent maintenance dose.
• R - INVEGA TRINZA Every 3 Month Maintenance Doses: As noted in the Prescribing Information, initiate INVEGA TRINZA when the next INVEGA SUSTENNA dose is scheduled with an INVEGA TRINZA dose based on the previous INVEGA SUSTENNA dose, using the equivalent 3.5-fold higher dose.
  • INVEGA TRINZA may be administered up to 7 days before or after the monthly time point of the next scheduled INVEGA SUSTENNA dose.
  • Following the initial INVEGA TRINZA dose, INVEGA TRINZA should be administered every 3 months. If needed, dose adjustment can be made every 3 months in increments within the range of 273 mg to 819 mg based on individual patient tolerability and/or efficacy.
• Website Limitations (Click on the blue “Read More” text (while Editing a Dose) for additional information):
  • Once the user chooses a site of injection (deltoid or gluteal), it will remain constant for all remaining maintenance doses for illustrative purposes
  • After a Transition to INVEGA TRINZA, the INVEGA TRINZA dosage strength remains constant for illustrative purposes
  • INVEGA TRINZA may be started in place of the next scheduled INVEGA SUSTENNA dose (± 7 days). This is only possible in the “Transition a Patient to INVEGA TRINZA” scenario.
  • The dosing window for maintenance doses (±14 days) is only modifiable in the “Adjust INVEGA TRINZA Dosing Window” scenario, and only the dosing window for a single maintenance injection may be modified
• S - Important Safety Information: View the Important Safety Information at the bottom of each webpage (including links to the Privacy Policy and Legal Notices).