Long-Term Efficacy and Safety of Paliperidone 6-Month Formulation: An Open-Label 2-Year Extension of a 1-Year Double-Blind Study in Adult Participants With Schizophrenia.

BACKGROUND: Paliperidone palmitate 6-month (PP6M) demonstrated noninferiority to paliperidone palmitate 3-month in preventing relapse in patients with schizophrenia in a phase 3 double-blind (DB) study (NCT03345342). Here, we report long-term efficacy and safety results from a 2-year single-arm, open-label extension (OLE; NCT04072575) of this DB study. METHODS: Participants who completed the DB study without relapse were enrolled and followed-up every 3 months up to 2 years. Participants received 4 PP6M gluteal injections (700/1000 mg eq.) at baseline, 6-month, 12-month, and 18-month visits. Efficacy endpoints included assessment of relapse, Positive and Negative Syndrome Scale total score, Personal and Social Performance score, and Clinical Global Impression-Severity scale change from baseline. Safety was assessed by treatment-emergent adverse events (TEAEs), physical examinations, and laboratory tests. RESULTS: Of 178 participants enrolled, 154 (86.5%) completed the OLE (mean age: 40.4 years, men: 70.8%; mean duration of PP6M exposure during OLE: 682.1 days). Overall, 7/178 (3.9%) participants relapsed between 20 and 703 days after enrolment. Mean (SD) changes from baseline to endpoint were as follows: Positive and Negative Syndrome Scale total score, 0.7 (8.22); Clinical Global Impression-Severity, 0.0 (0.51); and Personal and Social Performance Scale, 0.5 (7.47). Overall, 111/178 participants (62.4%) reported ≥1 TEAE; most common (>5%) TEAEs were headache (13.5%) and increased blood prolactin/hyperprolactinemia (18.0%); 8/178 (4.5%) participants experienced serious TEAEs, and 6/178 (3.4%) participants withdrew due to TEAEs. No deaths were reported. CONCLUSIONS: The relapse rate observed with PP6M during the 2-year OLE was low (3.9%). Clinical and functional improvements demonstrated in the DB study were maintained during OLE, and no new safety concerns were identified. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04072575; EudraCT number: 2018-004532-30.

A Randomized, Double-Blind, Multicenter, Noninferiority Study Comparing Paliperidone Palmitate 6-Month Versus the 3-Month Long-Acting Injectable in Patients With Schizophrenia.

BACKGROUND: This double-blind (DB), randomized, parallel-group study was designed to evaluate efficacy and safety of paliperidone palmitate 6-month (PP6M) formulation relative to paliperidone palmitate 3-month (PP3M) formulation in patients with schizophrenia. METHODS: Following screening, patients entered an open-label (OL) maintenance phase and received 1 injection cycle of paliperidone palmitate 1-month (PP1M; 100 or 150 mg eq.) or PP3M (350 or 525 mg eq.). Clinically stable patients were randomized (2:1) to receive PP6M (700 or 1000 mg eq., gluteal injections) or PP3M (350 or 525 mg eq.) in a 12-month DB phase; 2 doses of PP6M (corresponding to doses of PP1M and PP3M) were chosen. RESULTS: Overall, 1036 patients were screened, 838 entered the OL phase, and 702 (mean age: 40.8 years) were randomized (PP6M: 478; PP3M: 224); 618 (88.0%) patients completed the DB phase (PP6M: 416 [87.0%]; PP3M: 202 [90.2%]). Relapse rates were PP6M, 7.5% (n = 36) and PP3M, 4.9% (n = 11). The Kaplan-Meier estimate of the difference (95% CI) between treatment groups (PP6M - PP3M) in the percentages of patients who remained relapse free was -2.9% (-6.8%, 1.1%), thus meeting noninferiority criteria (95% CI lower bound is larger than the pre-specified noninferiority margin of -10%). Secondary efficacy endpoints corroborated the primary analysis. Incidences of treatment-emergent adverse events were similar between PP6M (62.1%) and PP3M (58.5%). No new safety concerns emerged. CONCLUSIONS: The efficacy of a twice-yearly dosing regimen of PP6M was noninferior to that of PP3M in preventing relapse in patients with schizophrenia adequately treated with PP1M or PP3M. TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT03345342.

Practical considerations for managing breakthrough psychosis and symptomatic worsening in patients with schizophrenia on long-acting injectable antipsychotics.

With more long-acting injectable (LAI) antipsychotics available for treating schizophrenia, each with variable durations of action (2 weeks to 3 months), it is important to have clear management strategies for patients developing breakthrough psychotic symptoms or experiencing symptomatic worsening on LAIs. However, no treatment guidelines or clinical practice pathways exist; health-care providers must rely on their own clinical judgment to manage these patients. This article provides practical recommendations-based on a framework of clinical, pharmacokinetic, and dosing considerations-to guide clinicians' decisions regarding management of breakthrough psychotic symptoms. Management options include ruling out/addressing medical illness or substance abuse/misuse as a contributing factor, addressing stressors, optimizing nonpharmacologic treatments, treating medical/psychiatric comorbidities, ensuring proper LAI administration technique, addressing missed LAI doses or lack of steady-state attainment, and increasing LAI dose directly or indirectly by shortening the injection interval (off-label). If these strategies do not work sufficiently with frequent monitoring, the LAI could be supplemented with a low dose of the corresponding oral formulation for fast symptom control (off-label). However, caution should be exercised with this strategy, because data on the safety of concomitant use of LAI and oral antipsychotics (OAPs) are limited, especially over extended periods. If symptoms abate, therapy optimization could be continued and slow discontinuation of the OAP could be considered. For persistent/worsening symptoms, the OAP should be increased to optimum effective dose while intensifying the initial steps used before it was added. If this fails, switching the OAP or LAI could be considered. We believe that these strategies will help clinicians manage breakthrough psychotic symptoms during LAI treatment and improve overall outcomes among those who can benefit from LAIs.

The Effect of Longer Dosing Intervals for Long-Acting Injectable Antipsychotics on Outcomes in Schizophrenia.

Medication nonadherence in schizophrenia can have serious implications including relapses and hospitalization. Long-acting injectable (LAI) antipsychotics require fewer administrations, while ensuring sustained medication coverage. In this review, we summarize the expected real-world benefits of longer dosing intervals in the management of schizophrenia. LAIs are associated with improved clinical outcomes of less frequent relapses and reduced functional impairment, encouraging patients to regain control of their lives. Aripiprazole lauroxil and paliperidone palmitate three-monthly (PP3M) LAIs have longer dosing intervals of 2-3 months and provide improved outcomes in patients with schizophrenia. Paliperidone palmitate six-monthly (PP6M) LAI provides the longest dosing interval, twice-yearly dosing, among existing LAIs. Decreasing the frequency of LAI administrations has the potential to reduce occurrence of serious outcomes associated with poor medication adherence. By eliminating the need for daily oral antipsychotic dosing, LAIs could increase the likelihood of patient acceptance, decrease stigma, and promote self-esteem. Longer intervals of medication coverage may be desirable for patients with higher risk of relapse including adults with recent-onset schizophrenia, those living in circumstances that may deprive them of regular access (eg, homeless), those that are in transitions between care settings or to reduce interpersonal contact during public health emergencies (eg, COVID-19 pandemic).

Earlier Use of Long-Acting Injectable Paliperidone Palmitate Versus Oral Antipsychotics in Patients With Schizophrenia: An Integrated Patient-Level Post Hoc Analysis.

Objective: To assess the efficacy and safety of paliperidone palmitate (PP) long-acting injectable antipsychotic (LAI) versus oral antipsychotic (OAP) treatment in adult patients diagnosed with schizophrenia (per DSM-IV or DSM-5 criteria) and varying duration of illness (0-3 years and > 3 years).Methods: Patient-level data from the PRIDE, PROSIPAL, and DREaM studies were included in a post hoc analysis. Efficacy and safety outcomes, including relapse assessments, Personal and Social Performance scale scores, Medication Satisfaction Questionnaire total scores, and treatment-emergent adverse events (TEAEs), were measured systematically. Treatment failure (TF) included relapses due to psychiatric hospitalizations, arrest or incarceration, suicidal or homicidal ideation or behavior, discontinuation due to inadequate efficacy and/or safety or tolerability, treatment supplementation due to inadequate efficacy, and significant worsening of symptoms.Results: Fewer TFs were observed with PP versus OAP in both the 0-3 years group (17.7% and 25.3%, respectively) and the > 3 years group (32.3% and 42.4%, respectively). Time to first TF was significantly longer with PP versus OAP treatment in both duration of illness groups. TEAE rates were similar between the PP and OAP groups, with no new safety signals identified.Conclusions: This post hoc analysis suggests that PP provides significant benefit in reducing TF or relapse compared with OAPs regardless of duration of illness and highlights the potential benefit of implementing PP earlier in the course of schizophrenia.Trial Registration: ClinicalTrials.gov identifiers NCT01157351 (PRIDE), NCT01081769 (PROSIPAL), and NCT02431702 (DREaM).

Baseline risk characterization of early versus later adopters of long-acting paliperidone palmitate formulations.

Early Post-Marketing Phase Vigilance (EPPV) is a unique system that encourages reporting of serious adverse reactions for medications newly introduced to Japan. When a once-monthly paliperidone palmitate formulation (PP1M) was introduced in Japan in 2013, EPPV detected a signal of increased mortality, but this signal was not subsequently confirmed. To clarify whether that signal reflected increased adverse event reporting or an atypically high baseline mortality risk among early adopters of PP1M, we evaluated the baseline risk characteristics of early, mid, and later adopters of PP1M in a Japanese database and did a similar evaluation of PP1M and the three-monthly formulation (PP3M) in two US databases. In Japan, early adopters compared with later adopters were older (mean 39.16 vs 33.70 years) but had a lower proportion of male patients (32.0% vs 44.44%), and a lower mean number of antipsychotic medications (distinct active medical substances) other than paliperidone (2.62 vs 2.85). In the United States, the baseline characteristics of early adopters of PP1M and PP3M did not suggest higher mortality risk than later adopters. These results offer no convincing evidence that the unconfirmed early signal of increased mortality with PP1M was due to increased baseline mortality risk among early adopters.

Comparing Relapse Rates in Real-World Patients with Schizophrenia Who Were Adequately versus Not Adequately Treated with Paliperidone Palmitate Once-Monthly Injections Before Transitioning to Once-Every-3-Months Injections.

Purpose: This retrospective cohort study evaluated real-world data on relapses in adult patients with schizophrenia who transitioned to long-acting injectable paliperidone palmitate once-every-3-months (PP3M) following treatment with once-monthly paliperidone palmitate (PP1M). Patients and Methods: Data derived from the IBM® MarketScan® Multi-State Medicaid Database were analyzed. Adults aged ≥18 years with ≥1 schizophrenia diagnosis claim and ≥12 months of continuous medical and prescription enrollment before and/or at index date of PP3M were eligible for inclusion. Patients were matched on propensity score to 2 PP3M cohorts: (1) adequately treated (AT), defined as patients treated with PP1M for ≥4 months, with the last 2 doses the same and a PP3M initiation dose meeting the corresponding PP1M-to-PP3M dose conversion, or (2) not adequately treated (NAT), defined as patients who received ≤2 or no PP1M doses. Relapse rates and time to relapse distributions based on the first occurrence of a qualifying event during the 2-year follow-up period were compared between PP3M cohorts using Kaplan-Meier survival curves and log rank test statistics. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Two sensitivity analyses using different matched populations were performed to assess the robustness of the primary findings. Results: Propensity score matching yielded a sample of 1314 patients (657 per group). Most patients were male (68.9%) and aged 25-64 years (90.1%). The relapse rate was significantly lower in the AT (18.4%) versus NAT cohort (26.8%), P = 0.0002. Risk of relapse decreased by 35% for AT versus NAT (HR: 0.65 [95% CI: 0.51-0.81]). Relapse reductions favored the AT cohort in both sensitivity analyses (HR: 0.67 [95% CI: 0.54-0.83] and HR: 0.74 [95% CI: 0.56-0.97]). Conclusion: In this analysis of Medicaid claims data, patients adequately treated with PP1M before transitioning to PP3M demonstrated significantly lower relapse rates and delayed time to relapse.

Time to onset and time to resolution of extrapyramidal symptoms in patients with exacerbated schizophrenia treated with 3-monthly vs once-monthly paliperidone palmitate.

OBJECTIVE: The aim of this study was to evaluate the safety of 3-monthly paliperidone palmitate (PP3M) vs once-monthly paliperidone palmitate (PP1M) treatment with regard to extrapyramidal symptom (EPS)-related treatment-emergent adverse events (TEAEs) in patients with schizophrenia, previously stabilized on PP1M treatment. PATIENTS AND METHODS: Data on overall incidence, time to onset (TTO), and time to resolution (TTR) of EPS-related TEAEs (overall, subclasses such as dyskinesia, dystonia, hyperkinesia, parkinsonism, and tremor) from a randomized double-blind (DB) non-inferiority study were compared between PP3M and PP1M. Subgroup analysis was performed by age (18-25, 26-50, and 50+ years) and final open-label (OL) dose (50/75, 100, and 150 mg eq.). RESULTS: Overall incidence of spontaneously reported EPS-related TEAEs decreased from 12.6% (PP1M) in OL phase to 8.3% (PP3M) and 7.4% (PP1M) in the DB phase; overall median TTO and TTR values were comparable between both groups. Among patients with reported EPS-related TEAEs, the median TTO for all EPS-related TEAEs was 17 days (PP1M) in OL phase and 115 days (PP3M) and 98.5 days (PP1M) in DB phase; median TTR was 36.5 days (PP1M) in OL phase and 91 days (PP3M) and 85.5 days (PP1M) in DB phase. No clear dose- or age-related differences in TTO and TTR of EPS-related TEAEs were noted. CONCLUSION: Despite differences in apparent half-life and pharmacokinetic profiles (peak plasma exposure of PP3M formulation is 70% higher than that of PP1M formulation), both PP3M and PP1M formulations exhibited comparable incidence of EPS-related TEAEs, TTO, and TTR in patients with schizophrenia.

An assessment of injection site reaction and injection site pain of 1-month and 3-month long-acting injectable formulations of paliperidone palmitate.

PURPOSE: To evaluate injection site reactions and pain following paliperidone palmitate 1-month (PP1M) and 3-month (PP3M) administration using safety data of double-blind (DB), noninferiority study. METHODS: Patients (n = 1,429) with schizophrenia, treated with PP1M (50-150 mg-eq, 17-week open-label [OL] phase) were randomized to PP1M or PP3M in 48-week DB phase. FINDINGS: PP1M and PP3M injections were well tolerated. Incidence of induration, redness, and swelling were low in both phases (OL: 9-12%; DB: 7-13%), and were mostly mild in both groups. Mean (SD) visual analog scale scores decreased from OL-baseline (22.0 [21.6]) to DB-baseline (19.5 [20.6] vs. 18.4 [20.4]) and DB-endpoint (15.6 [17.9] vs. 15.5 [18.3]). PRACTICE IMPLICATIONS: Injection site reactions and pain were low and similar between both treatments, regardless of administration site and dose.

Community pharmacists and mental illness: a survey of service provision, stigma, attitudes and beliefs.

Background Half of Americans experience mental illness during their lifetime. Significant opportunity exists for community pharmacists to deliver services to these patients; however, personal and practice-related barriers may prevent full engagement. Objective To assess the demographics, practice characteristics, service provision, stigma, attitudes and beliefs of a national sample of community pharmacists towards individuals with mental illness. Setting National random sample of 3008 community pharmacists in the USA. Method 101-item cross-sectional mailed survey questionnaire on: (1) demographics, (2) knowledge and practice characteristics, (3) provision of clinical pharmacy services, and (4) comparative opinions. Main outcome measure Scaled measures of service provision (comfort, confidence, willingness and interest) and comparative opinions (stigma, attitudes and beliefs) of mental illness, four linear regression models to predict service provision. Results A total of 239 responses were received (response rate 7.95%). Across pharmacy services, ratings for willingness/interest were higher than those for comfort/confidence. Pharmacists who reported providing medication therapy management (MTM) services for patients reported higher comfort (18.36 vs. 17.46, p < 0.05), confidence (17.73 vs. 16.01, p < 0.05), willingness (20.0 vs. 18.62, p < 0.05) and interest (19.13 vs. 17.66, p < 0.05). Pharmacists with personal experience with mental illness also resulted in higher scores across all four domains of service provision, lower levels of stigma (18.28 vs. 20.76, p < 0.05) and more positive attitudes (52.24 vs. 50.53, p < 0.01). Regression analyses demonstrated increased frequency of MTM service delivery and more positive attitudes as significantly predictive across all four models for comfort, confidence, willingness and interest. Increased delivery of pharmacy services was significantly associated with both willingness and interest to provide mental illness-specific services. Conclusion Despite willingness/interest to provide services to patients with mental illness, decreased levels of comfort/confidence remain service-related barriers for community pharmacists.