Educational Dose Illustrator Website

The 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 PK information.

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

Please refer to the following section of the Full Prescribing Information¹ which is relevant to your inquiry: DOSAGE AND ADMINISTRATION.

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)^12,13 or to at least four doses of risperidone or paliperidone or one dose of RLAI or paliperidone palmitate.¹⁴

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

• INVEGA 3 mg/day for at least 2 consecutive days^15-17
• INVEGA 3 mg/day or RISPERDAL 1 mg/day for at least 2¹⁸ or 3 days^19-21
• INVEGA for 4 days^12-14,22 at a dose of 3 mg/day^12,13,22
• INVEGA 6 mg/day for 4-6 days^23-26
• INVEGA 3 to 9 mg/day for 2 weeks²⁷

A commentary reviewing the recommended dosing of paliperidone palmitate for schizophrenia recommends that patients previously unexposed to risperidone or paliperidone receive two daily oral doses of either INVEGA 3 mg/day or RISPERDAL 1 mg/day prior to initiating treatment with INVEGA SUSTENNA.²⁸

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.²⁹

A case was reported of a 20-year-old female patient with no significant medical history or allergies who experienced anaphylaxis at ~24 hours after receiving her first monthly injection of INVEGA SUSTENNA 156 mg to treat a first psychotic episode related to cannabis abuse. The patient was admitted with angioedema with stridor and was discharged 6 days later on olanzapine, lorazepam, and sertraline; INVEGA SUSTENNA was discontinued.³⁰

DOSING REGIMEN

Initiation Dosing

INVEGA SUSTENNA is designed to deliver paliperidone over a monthly period while extended-release oral paliperidone is administered on a daily basis. Figure: Median Paliperidone Plasma Concentration-Time Profiles for INVEGA SUSTENNA and Paliperidone ER for 5 Weeks illustrates the recommended initiation dosing regimen for INVEGA SUSTENNA compared to oral paliperidone ER doses of 6 and 12 mg once daily.¹

In a PK simulation modeling study in patients with schizophrenia, data suggest that, after the initial dose of 234-mg paliperidone palmitate given on day 1 by IM deltoid injection, patients should receive 156-mg paliperidone palmitate on day 8 by IM deltoid injection. This regimen (234 mg followed by 156 mg one week later, both administered in the deltoid muscle) rapidly achieves plasma paliperidone levels that are similar to those observed at steady state with the suggested monthly dose of paliperidone palmitate 117 mg as well as the daily oral dose of paliperidone ER 6 mg.³¹

Additionally, schizophrenia clinical trial data and population PK simulations suggest that the effect of body mass index on paliperidone plasma concentrations can be mitigated through administration of the day 1 (234 mg) and day 8 (156 mg) IM injections in the deltoid muscle with a longer 1½-inch needle in patients weighing >90 kg and a shorter 1-inch needle in patients weighing <90 kg.

To avoid a missed dose, patients may be given the second initiation dose 4 days before or after the one-week time point.¹

Maintenance Dosing

The recommended maintenance dosing of INVEGA SUSTENNA for each approved indication is displayed in the Table: Recommended Maintenance Dosing of INVEGA SUSTENNA for Adults with Schizophrenia or Schizoaffective Disorder.¹ To avoid a missed monthly dose, patients may be given the paliperidone palmitate injection up to 7 days before or after the monthly time point. The Prescribing Information does not encourage a reoccurring 3-week or 5-week cycle. There is no data to support the routine administration of INVEGA SUSTENNA maintenance doses at intervals shorter or longer than 4 weeks.

Adjustment of the maintenance dose may be made monthly. When making dose adjustments, the prolonged-release characteristics of INVEGA SUSTENNA should be considered, as the full effect of the dose adjustment may not be evident for several months.

In a schizophrenia PK simulation modeling study, steady-state exposure levels were similar between monthly maintenance doses of INVEGA SUSTENNA (39-234 mg) and approved doses of paliperidone ER (3-12 mg). Population PK simulations suggest that the monthly maintenance dose for paliperidone palmitate in schizophrenia should be 117 mg, since this dose has a steady-state exposure profile that is similar to that of paliperidone ER 6 mg/day.^32,33

MISSED DOSES

Samtani et al (2009)³ presented results from a population PK simulation model on the flexibility of dosing windows and the management of missed doses of paliperidone palmitate during initiation or maintenance treatment. The simulation model assessed PK exposure of paliperidone palmitate in patients with dosing variations during specific time windows.

Management of Missed Doses During Treatment Initiation

Deviations from the recommended initiation 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).^1,4

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 paliperidone palmitate. Recommendations were developed empirically to maintain steadystate concentrations of paliperidone. Table: Management of Missed Maintenance Doses of Paliperidone Palmitate provides the suggested dosing regimen for three scenarios.^1,3

CONVERSION TO INVEGA SUSTENNA

Switching from Long-Acting Injectable Antipsychotics

When switching patients currently at steady-state on a long-acting injectable antipsychotic, initiate INVEGA SUSTENNA therapy in place of the next scheduled injection. INVEGA SUSTENNA should then be continued at monthly intervals. The one-week initiation dosing regimen (234 mg on day 1 and 156 mg one week later) is not required.¹

Results from PK modeling simulations suggest that patients previously stabilized on RISPERDAL CONSTA can attain similar levels of active moiety steady-state exposure during maintenance treatment with specific monthly doses of INVEGA SUSTENNA (see Table: Doses of RISPERDAL CONSTA and INVEGA SUSTENNA Needed to Attain Similar Levels of Active Moiety Exposure at Steady State).⁹

Plasma concentrations of the active moiety are maintained close to steady-state concentrations after the switch from RISPERDAL CONSTA to INVEGA SUSTENNA. No oral supplementation is required during the switch in treatment.

Switching from Oral Antipsychotics

Previous oral antipsychotics can be gradually discontinued at the time of initiation of treatment with INVEGA SUSTENNA. 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. Patients previously stabilized on different doses of INVEGA ExtendedRelease tablets can attain similar paliperidone steady-state exposure during maintenance treatment with INVEGA SUSTENNA monthly doses as depicted in Table: Doses of INVEGA and INVEGA SUSTENNA Needed to Attain Similar Steady-State Paliperidone Exposure during Maintenance Treatment.¹

Population PK simulations^10,11 were conducted to determine which dose levels of oral risperidone (RIS) result in similar pharmacokinetics to the INVEGA SUSTENNA 78-234 mg dose levels at steady-state. For oral RIS, active moiety concentrations (risperidone and 9-OH-risperidone [paliperidone]) were compared to paliperidone concentrations for INVEGA SUSTENNA. The results suggest that patients stabilized with oral RIS can attain similar steady-state exposure to active moiety during maintenance treatment with monthly doses of INVEGA SUSTENNA administered via deltoid or gluteal injection. These results are summarized in the Table: Doses of RIS and INVEGA SUSTENNA Needed to Attain Similar Exposure to Active Moiety at Steady-State. The recommended initiation regimen for INVEGA SUSTENNA (234 mg on day 1 and 156 mg on day 8 via deltoid injection) is required for this transition. However, no oral antipsychotic supplementation is required.

DOSAGE ADJUSTMENTS AND DOSAGE IN SPECIFIC POPULATIONS

Geriatric Use

This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with renal impairment, who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, adjust dose based on renal function.^1,34

Renal Impairment

INVEGA SUSTENNA has not been systematically studied in patients with renal impairment.¹ Results from PK modeling simulations suggest that a dose reduction of 25% is necessary for patients with mild renal impairment to achieve exposure comparable to that in patients with normal kidney function.³⁴ For patients with mild renal impairment (creatinine clearance ≥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. Follow with the recommended monthly maintenance dose of 78 mg, administered in either the deltoid or gluteal muscle. Thereafter, adjust monthly maintenance dose based on tolerability and/or efficacy within the strengths of 39 mg, 78 mg, 117 mg, or 156 mg.¹

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

Coadministration with Strong CYP3A4/P-glycoprotein (P-gp) Inducers

Avoid using a strong inducer of CYP3A4 and/or P-gp (eg, carbamazepine, rifampin, St John’s Wort) during a dosing interval for INVEGA SUSTENNA. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets.¹

OTHER RELEVANT LITERATURE

A brief report by Yin et al (2015)³⁵ discussed the administration of INVEGA SUSTENNA via the deltoid versus the gluteal muscle.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT drug file databases (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 18 February 2025.