Importance of Long-Acting Injectable Antipsychotic Preparation, Administration, and Injection Site Tolerability: A Focus on Paliperidone Palmitate Once-Every-6-Months Formulation

Purpose . Tis post hoc analysis assessed the importance of proper paliperidone palmitate (PP) dose preparation prior to administration and evaluated injection site reactions after dorsogluteal injection of PP once-every-6-months (PP6M) and once-every-3-months (PP3M) formulations from a double-blind (DB) noninferiority study. Design and Methods . Clinically stable patients receiving moderate/high doses of PP once-monthly (PP1M) (156mg/mL; 234mg/1.5mL) or PP3M (546 mg/1.75mL; 819mg/2.63mL) were randomly assigned 2:1 to corresponding dorsogluteal injections of PP6M (1092mg/3.5mL; 1560mg/5mL) or PP3M (546mg/1.75 mL; 819mg/2.63mL) during a 12-month DB phase. Patients receiving PP6M injections received alternating matching placebo injections every 3months between active doses to maintain blinding. Prior to administration, each PP formulation was prepared per specifc instructions to ensure complete resuspension of the medication. Findings . Of 895 PP6M injections, one of two incomplete injections was possibly related to insufcient shaking before administration; neither resulted in an adverse reaction. After dorsogluteal administration, 59 of 478 patients who received PP6M (12.3%) and 11 of 224 patients who received PP3M (4.9%) reported an injection site–related treatment-emergent adverse event (TEAE), with pain being the most commonly reported (7.7% and 4.0%, respectively). Patient-reported pain decreased from baseline to end point in both groups. During the DB phase, injection site-related TEAEs associated with PP6M injections up to 5mL and PP3M injections up to 2.63mL were mild to moderate in severity; none were reported as serious, resulted in treatment discontinuation, or required dermatological consultation. Practice Implications . Tese results inform provider and patient expectations of PP6M administration and reinforce the importance of proper PP dose preparation and administration; future work could assess safety data from real-world clinical practice. Tis trial is registered with NCT03345342.


Introduction
Long-acting injectable antipsychotics (LAIs) ofer several advantages over oral antipsychotic medications for adults diagnosed with schizophrenia, including a reduced need for daily oral medication, allowing patients to focus on their treatment plan and personal goals rather than their medication [1,2].In comparison with oral antipsychotics, LAIs ofer more consistent plasma levels [1], have shown a delayed time to relapse [1][2][3] with the potential to reduce hospitalizations [4], and provide clearer attribution that the cause of relapse is not due to nonadherence [1][2][3]5].
Recent clinical guidance supports the use of LAIs in adults with schizophrenia [6][7][8].Te National Council for Mental Wellbeing lists several recommended practices for prescribers, including initiating a discussion about LAIs in adult patients earlier after schizophrenia diagnosis [6].In addition, the American Psychiatric Association recommends that LAIs be considered for adult patients with schizophrenia if they prefer such treatment or if they have a history of poor or uncertain adherence [7].Medicaid best practice guidelines for the state of Florida recommend initial treatment for schizophrenia with oral antipsychotics alone or oral antipsychotic followed by the same LAI [8].Despite this clinical guidance and evidence supporting LAI use, these formulations are often underutilized in adult patients with schizophrenia [9,10].Several barriers and misconceptions may contribute to LAI underutilization.Clinicians may be unfamiliar with LAIs, have limited experience in administering LAI injections, or may be reluctant to discuss or recommend transitioning patients to an LAI antipsychotic medication if they are clinically stable on current therapy [11].Patients may lack awareness of LAI treatment options or have logistical challenges in traveling to appointments for injections [7].Misconceptions or concerns about side efects, fear of injections, and the stigma that LAIs are a last resort or punishment [9] may also be a deterrent for some patients and their caregivers.Unlike oral antipsychotic medications, LAIs may be associated with a range of potential injection site reactions such as injection site pain, induration, redness, and tenderness [12]; however, these adverse events (AEs) are typically mild in severity.Te frequency of injection site reactions and pain after administration of LAIs can be infuenced by several factors, including the type of vehicle used (oil vs. aqueous based), injection volume, the site of injection, dose preparation and administration technique, and patient history with LAIs [12].
Paliperidone palmitate (PP) LAIs have been shown to be efective in delaying time to relapse in patients with schizophrenia [13][14][15][16].In addition to PP once-monthly (PP1M) [17] and PP once-every-3-months (PP3M) [18] formulations, a PP once-every-6-months (PP6M) formulation was approved by the US Food and Drug Administration in 2021 for the treatment of adults with schizophrenia who have been adequately treated with PP1M for ≥4 months (with the last two doses being the same) or who have received PP3M for at least one 3-month cycle [19].
Given the diferences in formulation, injection volume (PP6M, 3.5 or 5 mL; PP3M, up to 2.63 mL; PP1M, up to 1.5 mL), and injection site of each PP LAI product, we herein review the importance of proper PP dose preparation and administration and evaluate injection site reaction data from patients who received dorsogluteal injections of PP6M and PP3M during a 12-month, double-blind (DB) noninferiority study [16].

Paliperidone Palmitate Dose Preparation and
Administration.To reduce the likelihood of an incomplete injection, each PP formulation has specifc preparation and administration requirements to ensure complete resuspension of the medication.An overview of the steps to prepare PP1M, PP3M, and PP6M for injection is shown in Figure 1 [17][18][19].With proper dose preparation and administration, PP6M doses of 1092 mg and 1560 mg result in PP total exposure ranges that are within the exposure range for corresponding doses of PP1M injections (156 mg and 234 mg, respectively) and PP3M injections (546 mg and 819 mg, respectively) (Figure 2) [17][18][19].

Injection Site Reaction Evaluation for PP6M and PP3M
2.2.1.Study Design.Tis was a post hoc analysis of data from the 12-month DB phase of a randomized, active-controlled, multicenter, noninferiority study (NCT03345342) (Figure 3) [16].Te study had three phases: a 28-day screening phase, an open-label (OL) maintenance phase (duration of 1 to 3 months depending on treatment received (one injection cycle of PP1M or PP3M)), and a 12-month DB phase.Patients who entered the study on an oral antipsychotic, injectable risperidone microspheres, or PP1M previously initiated but not stabilized at study entry were eligible to participate in an OL transition phase just prior to the OL maintenance phase to initiate and/or continue treatment with PP1M for up to 4 months.Following the maintenance phase, clinically stable patients treated with moderate or high doses of PP1M (156 or 234 mg) or PP3M (546 or 819 mg) were randomly assigned 2:1 to corresponding dorsogluteal injections of PP6M (1092 mg, n = 230; 1560 mg, n = 248) or PP3M (546 mg, n = 106; 819 mg, n = 118) during a 12-month DB phase.Patients randomly assigned to PP6M received matched placebo injections (20% Intralipid ® ) every 3 months between active doses to maintain blinding.
Prior to study initiation, injection personnel were trained in the proper preparation and administration of PP and placebo injections.Because PP6M is a highly concentrated product, it requires additional shaking for resuspension compared to PP1M or PP3M [19].To resuspend PP6M, the syringe should be held with the tip cap up and shaken very fast in an up-and-down motion with a loose wrist for at least 15 seconds, followed by a brief rest, and then shaken for an additional 15 seconds.If 5 minutes pass before injection, the syringe should be shaken very quickly with the tip cap pointing up again for at least 30 seconds.When properly resuspended, the PP6M suspension will appear uniform and milky white, with no solid product on the sides and top of the syringe [19].For administration, only the needle provided in the kit (1.5-inch, 20 gauge) should be used.Te needle should be attached to the PP6M syringe, and a single injection should be administered deep into the upper-outer quadrant of the gluteal muscle [19].Slow, frm, consistent pressure should be used to press the plunger down completely (approximately 30 seconds total).

Assessments.
Treatment-emergent adverse events (TEAEs) were voluntarily reported by patients or obtained via interview in a nondirected manner at study visits.Injection site-related TEAEs for the PP6M group included TEAEs related to both PP6M and matched placebo injections.
Investigators evaluated the injection sites for erythema/redness, induration/swelling, and tenderness within 30 minutes after each injection using a four- category approach (0 � absent, 1 � mild, 2 � moderate, or 3 � severe).Injection site pain was evaluated using a patient-rated 100 mm visual analog scale (VAS).Te VAS was presented as a 100 mm horizontal line on which the patient's pain intensity is represented by a point between "no pain at all" (0) to "unbearably painful" (100).

Statistical Methods.
Te safety analysis set (all randomly assigned patients who received at least one dose of DB study medication) was used to analyze data during the DB phase.TEAEs, VAS scores, and injection site reactions were summarized using descriptive statistics.No comparative statistical analyses were conducted.

Ethics.
Te study protocol and amendments were approved by an independent ethics committee or institutional review board.Te trial was conducted in compliance with the ethical principles of the Declaration of Helsinki, good clinical practices, and applicable regulatory requirements.All patients provided written informed consent before study participation.Both instances were related to increased resistance within the syringe during injection; neither resulted in an adverse event.One instance was possibly related to insufcient shaking before administration, highlighting the need for proper dose preparation.

Injection Site-Related Treatment-Emergent Adverse
Events.In the DB phase of the study, injection site-related TEAEs were reported in 59 of 478 patients (12.3%) in the PP6M group and 11 of 224 patients (4.9%) in the PP3M group.Injection site pain was the most commonly reported TEAE in both treatment groups (PP6M: 37 patients (7.7%); PP3M: 9 patients (4.0%) (Figure 4).All other injection siterelated TEAEs, including induration, redness, and swelling, occurred in <2% of patients in both treatment groups.None of the injection site-related TEAEs were reported as serious, resulted in treatment discontinuation, or required dermatological consultation.

4
Perspectives in Psychiatric Care and high doses (Figure 5).Te mean patient-rated VAS scores for PP6M placebo injections given at months 3 and 9 were similar to those for active PP6M 1092 mg and 1560 mg injections at other timepoints (Figure 5).

Discussion
Administration of frst-generation oil-based formulations of LAI antipsychotics, such as fuphenazine decanoate and haloperidol decanoate, is associated with signifcant injection site reactions and pain [20].Repeated large-volume administrations of these oil-based LAI formulations are shown to cause muscle granuloma, fbrosis, and accumulation of oil in some patients [21], which may contribute to poor treatment adherence and thus, medication discontinuation and symptomatic relapse [22].To prevent leakage from injection sites and reduce the incidence of injection site adverse efects associated with oil-based LAI antipsychotics, the Z-track technique is often recommended [12].Newer generation LAI antipsychotics, including all available PP formulations (PP1M, PP3M, and PP6M), have minimal injection site pain, possibly because they are aqueous-based suspensions [23,24] and do not require a Z-track injection technique.Proper dose preparation is  Perspectives in Psychiatric Care   6 Perspectives in Psychiatric Care required for complete resuspension of the medication and to reduce the risk of an incomplete injection that could lead to patients not experiencing a full therapeutic response.Patient education can improve patient perceptions and assist in diminishing fears around the LAI injection experience.Te consistent release of PP with sustained plasma concentrations over the various treatment frequencies and potential injection TEAEs should be explained to patients prior to PP administration.Regardless of LAI dosing frequency and administration, all patients should maintain regular followup appointments as deemed clinically necessary by the prescriber and the extended treatment team.Unlike PP1M and PP3M, which may be injected into deltoid or gluteal muscles, PP6M can only be injected into gluteal muscle [19].According to the prescribing information [19], PP6M should be injected into the upperouter quadrant of the gluteal muscle, with future injections alternated between the two gluteal muscles [19].In the present study, PP6M and PP3M were both administered in the dorsogluteal region to maintain treatment blinding [16].Te dorsogluteal site may be preferred by patients compared with the ventrogluteal site, given that it is more easily accessed by healthcare providers and less embarrassing for the patient.
Te fndings of this post hoc analysis regarding injection site reactions are consistent with those observed across PPLAI formulations [13][14][15].Results from the present post hoc analysis showed that injection site-related TEAEs associated with PP6M and PP3M administration occurred in 12.3% and 4.9% of patients, respectively, and none were reported as serious, resulted in treatment discontinuation, or required dermatological consultations.Injection site pain was the most commonly reported TEAE in both treatment groups.In the present study, mean VAS scores were comparable between both PP6M and PP3M treatment groups at baseline and decreased over time in both moderate-and high-dose groups.Mean VAS scores for PP6M placebo injections given at months 3 and 9 were similar to VAS scores for active PP6M 1092 mg and 1560 mg injections given at other timepoints.A decrease in VAS scores over the course of multiple injections has been observed in other studies investigating LAI injection site pain [25,26] and has been attributed to patients becoming acclimated to PP injections as they become more experienced with receiving injections.
Several limitations should be considered when interpreting these fndings.First, this post hoc analysis was limited to the DB phase of the noninferiority study and does not capture injection site reactions that occurred in the transition and maintenance phases.Second, patients who were exposed to PP or another LAI for an extended period before study initiation could have described injection site reactions and pain diferently than patients who were naive to treatment with LAIs.Lastly, patients in the PP6M group received placebo injections every 3 months between active doses.Consequently, mean VAS scores are calculated based on data from both PP and placebo injections, which may have impacted injection site-related outcomes.

Conclusion
In conclusion, proper dose preparation and administration can help reduce the risk of an incomplete PP injection.Injection site-related TEAEs were reported in 12.3% of patients who received PP6M during the DB phase of a noninferiority study; none were reported as serious, resulted in treatment discontinuation, or required dermatological consultation.Incidence and type of injection site-related reactions associated with PP6M were similar regardless of dose (1092 mg and 1560 mg) and decreased throughout the duration of the study, demonstrating that larger injection volumes of LAIs (up to 5 mL) can be well tolerated when proper preparation and administration steps are followed.Tese results inform provider and patient expectations of PP6M administration along with the importance of proper PP dose preparation and administration; future work could assess safety data from real-world clinical practice.As new LAI formulations of antipsychotics are approved by the FDA, nursing and pharmacy guidelines, policies, and procedures should be updated to refect how these medications are administered.
3.1.5.Injection Site-Related Pain.Overall, mean (SD) patient-rated VAS scores for injection site pain decreased from DB baseline to end point for patients in the PP6M group(17.22(20.86)) to 5.41 (10.76)) and the PP3M group (14.98 (18.98) to 4.54 (8.93)).Changes from baseline were generally consistent across treatment groups and moderate

Table
[16]line demographics and disease characteristics in the double-blind intention-to-treat analysis set[16].Note.BMI, body mass index; PP3M, paliperidone palmitate once-every-3-months; PP6M, paliperidone palmitate once-every-6-months. a Includes patients who self-identifed as Native Hawaiian or other Pacifc Islander and as multiple races.
bBased on open-label data.

Table 2 :
Investigator evaluation of injection sites during the double-blind phase.