Initiation of aripiprazole once-monthly in patients with schizophrenia

Abstract

Objective:

This article provides rationale for recommendations on how to initiate aripiprazole once-monthly 400 mg (AOM 400), an injectable suspension, in patients with schizophrenia, supported by pharmacokinetic (PK) data and based on clinical studies.

Methods:

An overview of data from a PK study, PK simulations, controlled clinical trials, and a naturalistic study is presented.

Results:

Pharmacokinetic data support 400 mg as the starting and maintenance dose of AOM; the plasma concentration profile of aripiprazole after initiating AOM 400 was consistent with therapeutic concentrations observed with oral aripiprazole 10 to 30 mg/d. PK simulations and observed data from a single-dose clinical trial indicate that median aripiprazole plasma concentrations reach therapeutic levels within 7 days of initiating AOM 400. Because of interpatient variability, a 14-day overlap with oral aripiprazole or another antipsychotic medication is considered sufficient to ensure therapeutic concentrations. In clinical studies, when patients initiated AOM 400 with concomitant oral aripiprazole (10–15 mg/d based on stabilized dose) or continued their previous antipsychotic for ≤14 days, mean aripiprazole plasma concentration after 4 weeks (93 to 112 ng/mL) was in range of the therapeutic window established for aripiprazole (94.0–534.0 ng/mL). In clinical studies, the 400-mg starting dose of AOM was efficacious and well tolerated. Across studies of variable duration and design, 1296/1439 (90.1%) patients initiated AOM 400 and required no dose change. Overall rates of discontinuation due to lack of efficacy across clinical studies were low in patients treated with AOM 400 (range, 2.3%–10.0%). In a post hoc analysis from a naturalistic study, cross-titration from other oral antipsychotic therapies to oral aripiprazole before initiating AOM 400 was better tolerated with a >1- to 4-week cross-titration period versus a ≤1-week period, as evidenced by lower rates of discontinuation due to adverse events during cross-titration (2.7% [7/239] vs 10.4% [5/48]). The efficacy and safety of AOM 400 in the month after initiation in the pivotal maintenance studies were comparable between subpopulations of patients previously stabilized on 10- or 30-mg doses of oral aripiprazole.

Conclusions:

Findings from PK data, PK simulations, and clinical studies all support that 400 mg is the appropriate initiation dose of AOM for patients with schizophrenia. When switching to oral aripiprazole before initiating AOM 400, tapering the prior oral antipsychotic while titrating up the oral aripiprazole dose (target dose 10–30 mg/d) over >1 to 4 weeks may be an effective strategy. The efficacy, safety, and tolerability of AOM 400 were comparable regardless of whether patients were previously stabilized on oral aripiprazole 10 or 30 mg/d or other antipsychotic therapy and continued to receive the same oral antipsychotic for the first 14 days after initiating AOM 400.

Key words: :

• Antipsychotic
• Aripiprazole once-monthly
• Dosing information
• Long-acting injectable
• Schizophrenia
• Switching
• Treatment initiation

Introduction

Schizophrenia is a chronic, disabling, and progressive disease, with heterogeneous symptoms and disease course among patients1–3. Patients with schizophrenia may be exposed to substantial psychosocial risks and biological harm secondary to relapse4. A recent systematic review and meta-analysis found that patients with a first episode of schizophrenia who discontinue antipsychotic therapy have a weighted mean 1-year relapse rate of 77% (range, 57%–91%), which increases to more than 90% at 2 years5. This is in contrast to a 1-year weighted mean relapse risk of 3% (range, 0%–4%) in patients who were continuously treated with antipsychotic therapy5. Similar results were reported in a nationwide cross-sectional survey of patients who were treated with a prescription medication for schizophrenia – patients who were completely adherent to their medication were significantly less likely to report a mental-health–related or non-mental-health–related hospitalization6. Long-acting injectable (LAI) antipsychotics provide an effective and important treatment option that alleviates the burden of daily dosing, which may improve adherence7; recent estimates of oral antipsychotic nonadherence in patients with schizophrenia were as high as 60% early in the course of treatment (i.e., within 90 days of filling their earliest prescription)8.

Aripiprazole once-monthly 400 mg is an extended-release injectable suspension of aripiprazole that is approved for the treatment of schizophrenia in the United States9 and the maintenance treatment of schizophrenia in Canada and Europe10^,11. It is a powder of aripiprazole reconstituted in sterile water for intramuscular injection in the gluteal muscle9^,10. Although the mechanism of action of aripiprazole remains unknown9, it is believed to exert its effects through partial agonist activity at dopamine D₂ and serotonin 5-HT_1A receptors and antagonistic activity at serotonin 5-HT_2A receptors9^,12. Absorption of aripiprazole once-monthly 400 mg into the systemic circulation is slow and prolonged following administration (time to maximum concentration = 5–7 days; absorption half-life = 28 days) because of the low solubility of aripiprazole particles9–11.

Aripiprazole once-monthly 400 mg is the only antipsychotic that is a dopamine D₂ partial agonist and available as an LAI. In two randomized, double-blind, multicenter, placebo- or active-controlled studies (referred to hereafter as the pivotal studies), aripiprazole once-monthly 400 mg reduced the rates of and delayed the time to impending relapse relative to placebo or a subtherapeutic dose of aripiprazole once-monthly in patients with schizophrenia13^,14. Here we examine the evidence from pharmacokinetic (PK) investigations and clinical studies that can provide information on how to initiate treatment with aripiprazole once-monthly 400 mg in clinical practice. Additional considerations for treatment in patients taking concomitant medications that inhibit or induce cytochrome P450 (CYP) 3A4 or who are known CYP2D6 poor metabolizers are addressed in the prescribing information9–11.

Initiating treatment with aripiprazole once-monthly

Supportive PK data

Clinical PK data

The approved starting and maintenance dose of aripiprazole once-monthly is 400 mg, with the option to reduce to 300 mg for tolerability reasons9–11. Clinical PK data support 400 mg as the starting and maintenance dose of aripiprazole once-monthly. Results from a 24-week, open-label, parallel-arm PK study in patients with schizophrenia demonstrated that the plasma concentration profile of aripiprazole once-monthly 400 mg falls within the concentrations observed with daily dosing of oral aripiprazole 10 to 30 mg/d at steady state15. Mean ± SD steady-state maximum concentration (C_max) of aripiprazole once-monthly 400 mg (316 ± 160 ng/mL)15 was similar to that achieved with oral aripiprazole 20 to 30 mg/d (range, 393–452 ng/mL)16, and the minimum steady-state concentration (C_min, 212 ± 113 ng/mL)15 was similar to steady-state C_min achieved with 15 to 20 mg/d of oral aripiprazole (mean C_min, 214 ng/mL, interquartile range 124–286 ng/mL [n = 283; mean dose 19.8 ± 8.2 mg/d, range 5–60 mg/d])17. Patients entering the PK study had been stabilized on oral aripiprazole 10 mg/d for ≥14 days before their first injection and received 14 days of concomitant oral aripiprazole 10 mg/d after their first injection of aripiprazole once-monthly 400 mg15.

Mean trough plasma concentration 28 days after initiation (i.e., the first dose) of aripiprazole once-monthly 400 mg (C₂₈) was 102 ± 58.1 ng/mL in the PK study. In the pivotal studies, mean aripiprazole C₂₈ was 112 ± 78.9 ng/mL in the 52-week study and 98.2 ± 79.9 ng/mL in the 38-week study. In a separate clinical study in which patients continued their concomitant atypical oral antipsychotic (other than oral aripiprazole) for up to 2 weeks after initiating aripiprazole once-monthly 400 mg (n = 60), mean aripiprazole C₂₈ was 93 ± 42 ng/mL18.

To establish a therapeutic window for aripiprazole, population PK simulations of oral aripiprazole once-daily at steady state were performed and results were compared with evidence from the 52-week pivotal trial. The median simulated steady-state C_min for oral aripiprazole 10 mg/d (94.0 ng/mL) and the 75th percentile of the simulated steady-state C_max for oral aripiprazole 30 mg/d (534.0 ng/mL) were selected as conservative estimates of the lower and upper bounds for the therapeutic window. Examination of the safety, tolerability, and PK data from the 52-week pivotal study demonstrated that these values corresponded to the clinically defined therapeutic window. Moreover, as reported above, mean trough plasma concentrations after the first injection (C₂₈) were within or near this therapeutic window (94.0–534.0 ng/mL) across all aripiprazole once-monthly clinical studies with available data.

PK model and simulations

To further describe the PK profile of aripiprazole upon initiation of aripiprazole once-monthly and to address whether 400 mg is an optimal initiation dose for most patients with schizophrenia, population PK modeling was applied. The model was then used to simulate the PK of aripiprazole after administration of aripiprazole once-monthly 400 mg in various clinical scenarios.

A total of 6153 aripiprazole concentration records from 663 patients enrolled in five clinical trials were used to develop and refine the model, including one phase 3 trial (the pivotal 52-week trial) in patients with schizophrenia and four phase 1 trials. Based on the patients in the phase 3 trial, a population of 10,000 patients was simulated with similar characteristics for the population PK model. The model was then used to simulate C_min and C_max, average predicted drug concentration (C_avg), and dose interval area under the concentration versus time curve (AUC_0–τ) for each patient under a variety of scenarios, including initiation of aripiprazole once-monthly 400 mg with or without oral aripiprazole therapy. Additionally, to establish a therapeutic window for modeling and simulation of aripiprazole once-monthly 400 mg, simulations of once-daily oral aripiprazole 10 and 30 mg were performed using the final population PK model.

The estimated model parameters showed that the elimination of aripiprazole once-monthly 400 mg was absorption-rate limited. Although covariate analysis found that the absorption rate was body mass index (BMI) and sex dependent, steady-state C_min, C_max, and AUC_0–τ did not exhibit any trends for BMI or sex; thus these factors were not considered clinically relevant. Evaluations of the final model indicated there were no significant biases and that the model represented an adequate fit to the data and was appropriate for use in simulations.

To evaluate different initiation dosing scenarios for aripiprazole once-monthly 400 mg, four simulations of aripiprazole plasma concentration versus time profiles were performed: (1) patients stabilized on oral aripiprazole 20 mg/d followed by 15 days of oral aripiprazole 10 mg/d beginning with the first injection of aripiprazole once-monthly, (2) patients stabilized on oral aripiprazole 10 mg/d followed by 14 days of oral aripiprazole 10 mg/d beginning with the first injection of aripiprazole once-monthly, (3) patients who were not treated with oral aripiprazole or other antipsychotic therapy before the first injection of aripiprazole once-monthly 400 mg and then received oral aripiprazole 10 mg/d for 14 days beginning with the first injection of aripiprazole once-monthly, and (4) patients who were not treated with oral aripiprazole or other antipsychotic therapy before or concomitantly with aripiprazole once-monthly 400 mg. The median plasma concentration versus time profile of aripiprazole once-monthly 400 mg was within the therapeutic window (94.0–534.0 ng/mL) for all dose initiation scenarios – with or without a lead-in oral aripiprazole stabilization period – within 7 days of initiating aripiprazole once-monthly 400 mg (range at day 7: 118.0–282.8 ng/mL; Figure 1A). In patients who did not receive oral aripiprazole therapy before or concomitantly with initiation of aripiprazole once-monthly 400 mg (scenario 4), the median concentration was close to the lower threshold throughout the first dosing interval (i.e., between the first and second injections), suggesting that a proportion of patients would have plasma concentrations below the estimated therapeutic window without concomitant or prior stabilization on oral aripiprazole therapy (Figure 1A). When patients initiated aripiprazole once-monthly 400 mg with concomitant oral aripiprazole for 14 days, median aripiprazole concentrations were similar by day 7 and almost identical from day 14 onward between patients who were (scenario 2) or were not (scenario 3) stabilized on oral aripiprazole before initiating aripiprazole once-monthly 400 mg (Figure 1A). Because some patients may initially have plasma concentrations below the estimated therapeutic window without concomitant oral aripiprazole therapy, concomitant oral therapy is recommended to keep aripiprazole levels within the estimated therapeutic window. Per the US, EU, and Canadian prescribing information9–11, patients should take oral aripiprazole (10–20 mg) concomitantly with the first dose of aripiprazole once-monthly 400 mg for the first 14 days. The US and Canadian prescribing information9^,11 also indicate that, in lieu of oral aripiprazole, patients may continue taking their current oral antipsychotic for the first 14 days of treatment with aripiprazole once-monthly.

Figure 1. PK simulation of (A) median concentration vs day for the first two doses of AOM 400, stratified by dose initiation scheme and (B) steady-state median concentrations over time for AOM 400 and median oral aripiprazole 10 and 30 mg concentrations. AOM 400 = aripiprazole once-monthly 400 mg; PK = pharmacokinetic.

Based on PK simulations and observed data, the median steady-state plasma concentration versus time profile for aripiprazole once-monthly 400 mg falls within median values for oral aripiprazole 10 and 30 mg/d. Figure 1B illustrates simulations of aripiprazole once-monthly 400 mg with 5th and 95th percentiles and predicted median concentrations for 10 and 30 mg/d oral aripiprazole, which all fall within the 94.0- to 534.0-ng/mL therapeutic window.

Evidence from clinical trials

Dose of aripiprazole once-monthly

As observed in clinical studies, the starting dose of 400 mg is efficacious and well tolerated; 90.1% of patients across clinical studies initiated and remained on the 400-mg dose (range, 89.9%–96.4%; Figure 2), and ∼10% of patients had their aripiprazole once-monthly dose reduced to 300 mg based on tolerability and/or investigator judgment13^,14^,19. Furthermore, across clinical studies, overall rates of discontinuation due to lack of efficacy were low in patients treated with aripiprazole once-monthly 400 mg (range, 2.3%–10.0%), providing further support for the 400-mg dose as efficacious for the majority of patients.

Figure 2. Aripiprazole once-monthly dose: percentage of patients in clinical studies who initiated AOM 400 and required no dose change. AOM 400 = aripiprazole once-monthly 400 mg. *Data are from the enrolled sample in the single-blind, AOM 400 stabilization phase. †Data are from randomized patients in the double-blind AOM 400 treatment group. ‡Data are from the phase B safety sample (i.e., all patients who received ≥1 dose of AOM 400 during phase B). §Data represent patients in the safety sample who were randomized to AOM 400.

Oral aripiprazole prior to initiating aripiprazole once-monthly 400 mg

Before initiating aripiprazole once-monthly, tolerability to oral aripiprazole should be established in patients with no history of oral aripiprazole tolerability9–11. No studies with aripiprazole once-monthly 400 mg have examined the optimal duration for assessing oral aripiprazole tolerability as a predefined endpoint. However, relevant information may be found in the design and results of a 12-week, multicenter, randomized, double-blind, placebo-controlled study that examined the efficacy, safety, and tolerability of aripiprazole once-monthly 400 mg for the treatment of acute exacerbations of psychotic symptoms in adult patients with schizophrenia19. Patients with no history of oral aripiprazole treatment were administered open-label oral aripiprazole 10 mg/d for 3 days to establish tolerability (n = 195/340 [57.4%]). Findings from the full sample suggest that 3 days were adequate to establish tolerability, because the rate of discontinuations by week 10 due to adverse events (AEs) was low (n = 20/340 [5.9%])19 and similar to rates observed with oral aripiprazole treatment in patients with acute exacerbations of schizophrenia20.

Cross-titration and oral overlap

Information about how to initiate aripiprazole once-monthly 400 mg in patients not currently treated with oral aripiprazole may be found in protocols and results of clinical studies13^,14^,21. Because the two pivotal studies were registrational trials, a conservative approach was used, in which patients first converted from their prior antipsychotic to oral aripiprazole monotherapy over 4 to 6 weeks (the oral conversion phase; Figure 3A) and were then stabilized on oral aripiprazole (the oral stabilization phase). This was followed by a switch from oral aripiprazole to aripiprazole once-monthly 400 mg with 2 weeks of concomitant oral aripiprazole (Figure 3B). During the first week of the oral conversion phase in both studies, patients initiated oral aripiprazole 5 mg/d (then increased to 10 mg/d) and maintained doses of their prior antipsychotic. During the second week, the oral aripiprazole dose was maintained at 10 mg/d or increased to 15 mg/d. During the third and fourth weeks, patients began tapering their prior antipsychotics so that they were discontinued by the end of weeks 4 to 6. The dose of oral aripiprazole during weeks 4 to 6 was either maintained at 10 mg or increased to 15 to 30 mg/d based on the physician’s judgment, although the target dose range was 10 to 15 mg/d. In a multicenter, open-label, mirror-image, naturalistic study of hospitalization rates in patients with schizophrenia21, the recommended initial dose of oral aripiprazole in patients who converted from other antipsychotics to oral aripiprazole was 10 or 15 mg/d; the dose could be titrated up to 30 mg/d, depending on the patients’ symptoms and the investigators’ judgment.

Figure 3. (A) Cross-titration: converting patients from other oral antipsychotics to oral aripiprazole before initiating aripiprazole once-monthly 400 mg. Schematic based on protocols for the 52- and 38-week pivotal trials13^,14. Dotted line represents optional alternative dosing. (B) Oral overlap: initiating AOM 400 with concomitant oral aripiprazole. AOM 400 = aripiprazole once-monthly 400 mg. *Add short-term concomitant medications as needed to control symptoms (e.g., agitation, insomnia, nausea). †Gradually withdraw concomitant medications. ‡The target monotherapy starting dose may be >15 mg/d, depending on investigator judgment and the patient’s clinical need. §If there are adverse events with AOM 400, consider reducing the AOM dose to 300 mg. ∥Consider reducing the oral aripiprazole dose to 10 mg in patients stabilized on oral aripiprazole 20 mg, depending on patients' symptoms and physicians' judgment.

The median average daily doses of oral aripiprazole during the oral conversion phase were 11.9 and 12.5 mg/d in the 52- and 38-week pivotal studies, respectively. During the oral stabilization phases, when patients were stabilized on oral aripiprazole 10 to 30 mg/d, the median average daily dose of oral aripiprazole was 17.7 mg/d in the 52-week study and 18.8 mg/d in the 38-week study13^,14. In the naturalistic, observational study, the median average daily dose of oral aripiprazole during the oral conversion phase was 15.0 mg/d. The overall efficacy, safety, and tolerability findings from the pivotal and naturalistic studies suggest that oral aripiprazole 10 to 30 mg/d is an effective dose range in clinical practice for patients to receive before initiating aripiprazole once-monthly 400 mg.

In the pivotal studies, patients cross-titrated from other oral antipsychotics to oral aripiprazole for up to 6 weeks13^,14; however, the optimal duration of cross-titration was not examined. To address this, a post hoc analysis was conducted using data from the multicenter, open-label, mirror-image, naturalistic study of hospitalization rates in patients with schizophrenia in which the more flexible study design was better aligned with clinical practice relative to the pivotal studies21. Detailed study design and patient inclusion and exclusion criteria have been described previously21. Briefly, adult patients with schizophrenia who were treated with oral antipsychotic therapy in the 7 months before screening and were currently receiving an atypical oral antipsychotic were included in the study21. For the first 2 weeks after the first injection of aripiprazole once-monthly 400 mg, patients who were previously stabilized on oral aripiprazole 10 to 20 mg/d were treated with oral aripiprazole 10 mg/d, and patients who were previously stabilized on oral aripiprazole >20 to 30 mg/d were treated with oral aripiprazole 15 mg/d. Patients who were treated with antipsychotics other than oral aripiprazole and had previously been exposed to oral aripiprazole were treated with oral aripiprazole 10 mg/d.

To assess the optimal length of cross-titration from another oral antipsychotic to oral aripiprazole, the rate of discontinuations due to AEs during oral conversion, stratified by duration of the oral aripiprazole cross-titration period (≤1 vs >1–4 weeks) was calculated; no inferential statistics were performed. Rates of discontinuations due to AEs were numerically higher in patients cross-titrated from other oral antipsychotic therapies to oral aripiprazole for ≤1 week before initiating aripiprazole once-monthly 400 mg compared with patients who cross-titrated for >1 to 4 weeks (10.4% [5/48] vs 2.7% [7/239], respectively). The higher rate of discontinuations due to AEs in patients who cross-titrated from other oral antipsychotics to oral aripiprazole for ≤1 week suggests that cross-titrating for >1 week from other antipsychotics to oral aripiprazole is better tolerated, although clinicians should make treatment decisions based on individual patient profiles. Most patients (n = 325) were treated with oral aripiprazole for >1 to 4 weeks, and the majority of them (n = 81.5% [265/325]) continued on to treatment with aripiprazole once-monthly 400 mg21. These findings suggest that ‘starting low and going slow’ when cross-titrating from other oral antipsychotics to oral aripiprazole before initiating aripiprazole once-monthly 400 mg may translate to an effective switching strategy in clinical practice (Figure 3A). In addition to supporting a >1- to 4-week cross-titration period, these findings also suggest that this time period may be sufficient to assess therapeutic response to oral aripiprazole before initiation of aripiprazole once-monthly, although a prospective study is warranted. In the pivotal studies, the lengthier cross-titration period (up to 6 weeks) was established because they were more conservative registrational trials.

Other switching strategies

Strategies for switching directly from other oral antipsychotics to aripiprazole once-monthly 400 mg have not been evaluated in large clinical trials. Nonetheless, in general, rebound and withdrawal effects are more likely when switching between antipsychotics that differ substantially in their receptor binding affinity and half-lives22. For example, in patients with no history of oral aripiprazole tolerability treated with antipsychotics having anticholinergic properties (e.g., olanzapine, quetiapine), switching abruptly to oral aripiprazole may result in rebound psychosis or agitation, akathisia, insomnia, or anxiety22, all of which have also been reported as AEs in clinical trials with aripiprazole9. Moreover, the longer time to steady state of oral aripiprazole can increase the risk for rebound symptoms when switching from an antipsychotic with a shorter half-life, such as ziprasidone or immediate release quetiapine22. A meta-analysis of randomized controlled trials in patients with schizophrenia who switched oral antipsychotic therapy found that gradual and overlapping switch strategies, in which the new and old antipsychotics are slowly tapered until the new antipsychotic reaches a therapeutic dose and the old antipsychotic is discontinued, result in fewer all-cause discontinuations compared with abrupt initiation and discontinuation of the new and old antipsychotics, respectively23. For example, plateau switch strategies, in which oral aripiprazole is initiated gradually with delayed abrupt or gradual discontinuation of antipsychotics with anticholinergic properties and/or a shorter half-life, may be recommended24^,25. Anxiolytics and sedatives may also be used prophylactically in particularly sensitive patients who experience rebound or withdrawal effects, such as agitation, anxiety, or insomnia22^,25.

To date, there are no large randomized clinical trials that evaluated switching from other LAIs to aripiprazole once-monthly 400 mg, and clinical trial data are lacking. Physicians should rely on their clinical judgment and the prescribing information (i.e., package inserts) for other LAIs to determine whether a complete washout or overlap is needed when discontinuing other LAIs.

Effect of prior dose of oral aripiprazole

To evaluate the effect of previous low (10 mg/d) or high (30 mg/d) doses of oral aripiprazole on outcomes in the month after switching to aripiprazole once-monthly 400 mg, a post hoc analysis of the efficacy and tolerability of aripiprazole once-monthly 400 mg in patients who switched from oral aripiprazole 10 or 30 mg/d in the pivotal studies was performed13^,14^,26. The post hoc analysis was conducted using data from patients who initiated aripiprazole once-monthly 400 mg in the aripiprazole once-monthly stabilization phase in the 52-week study, and from patients randomized to aripiprazole once-monthly 400 mg during the stabilization phase in the 38-week study. Data from the pivotal studies were analyzed by study, stratified by oral aripiprazole dose (10 vs 30 mg/d) before the first injection of aripiprazole once-monthly 400 mg. Because this was a post hoc analysis, neither trial was powered to detect statistically significant differences between treatment groups based on prior oral aripiprazole dose (10 vs 30 mg/d). Thus, only descriptive statistics were calculated (means and SDs for Positive and Negative Syndrome Scale [PANSS] change scores and percentages for treatment-emergent AEs [TEAEs]). Efficacy was assessed using the change from baseline in the PANSS total score27 at 4 weeks after initiation of aripiprazole once-monthly 400 mg. Tolerability was inferred from TEAEs that occurred in ≥5% of patients during the first 4 weeks following initiation of aripiprazole once-monthly 400 mg26.

A total of 317 patients were included in this post hoc analysis (52-week study, n = 222; 38-week study, n = 95)26. There were 105 patients stabilized on oral aripiprazole 10 mg/d (n = 75 and 30, respectively) and 212 patients stabilized on oral aripiprazole 30 mg/d (n = 147 and 65, respectively). Patient disposition and baseline demographics are listed in Table 1. Across treatment groups, mean age at baseline ranged from 39.2 to 42.2 years, and more than half of patients in each treatment group were white. Mean BMI at baseline ranged from 28.1 to 30.0 kg/m². Mean (SD) PANSS total scores at baseline ranged from 52.1 (12.5) to 62.3 (11.5)26. In the 52-week study, two patients stabilized on oral aripiprazole 10 mg/d experienced an AE (1 each, somnolence and allergic dermatitis) in the 4 weeks after initiating aripiprazole once-monthly 400 mg that led to discontinuation and one patient in the 30 mg/d oral stabilization group discontinued because of an AE (akathisia) within the 4 weeks after aripiprazole once-monthly 400 mg initiation. In the 38-week study, no patients stabilized on oral aripiprazole 10 or 30 mg/d experienced an AE that led to discontinuation within the first 4 weeks after initiating aripiprazole once-monthly 400 mg.

Table 1. Baseline demographics and disposition in the 4 weeks after initiating aripiprazole once-monthly 400 mg in the pivotal studies by prior oral aripiprazole dose*.

	52-week study		38-week study
	10 mg (n = 75)	30 mg (n = 147)	10 mg (n = 30)	30 mg (n = 65)
Mean (SD) age, y	39.2 (10.9)	40.2 (10.6)	42.2 (10.8)	42.1 (9.6)
Male sex, n (%)	43 (57.3)	92 (62.6)	14 (46.7)	47 (72.3)
Race, n (%)
White	38 (50.7)	79 (53.7)	17 (56.7)	38 (58.5)
Black or African American	12 (16.0)	43 (29.3)	5 (16.7)	15 (23.1)
Asian	20 (26.7)	15 (10.2)	7 (23.3)	8 (12.3)
Other	5 (6.7)	10 (6.8)	1 (3.3)	4 (6.2)
Mean (SD) BMI, kg/m^2	28.1 (6.6)	29.3 (8.5)	29.0 (6.1)	30.0 (7.4)
Completed 4 wks, n (%)	71 (94.7)	139 (94.6)	30 (100)	60 (92.3)
Discontinued, n (%)	4 (5.3)	8 (5.4)	0	5 (7.7)
AEs	2 (2.7)	1 (0.7)	0	0
Impending relapse with AE	1 (1.3)	1 (0.7)	0	2 (3.1)
Impending relapse without AE	0	0	0	2 (3.1)
Other†	1 (1.3)	6 (4.1)	0	1 (1.5)

AE = adverse event; BMI = body mass index.

*Data represent baseline of the aripiprazole once-monthly 400 mg stabilization phase in the 52-week study and baseline of the double-blind maintenance phase in the 38-week study.

†52-week study: patient withdrew consent, withdrawn by investigator, or lost to follow-up; 38-week study: lost to follow-up.

Aripiprazole once-monthly 400 mg demonstrated efficacy in both subgroups of patients in both studies, indicating that a prior dose of oral aripiprazole did not affect the initial efficacy of aripiprazole once-monthly 400 mg after switching. After initiating aripiprazole once-monthly 400 mg, stabilized patients remained stable; mean ± SD change from baseline in PANSS total scores at 4 weeks was consistent across groups and ranged from 0 ± 7.2 to −1.83 ± 6.0 (Figure 4). Tolerability of aripiprazole once-monthly 400 mg in the 4weeks after switching from oral aripiprazole did not differ between subgroups. The most common TEAEs (≥5% incidence, Figure 5) were injection site pain (n = 7 [9.3%] in the oral aripiprazole 10-mg treatment group in the 52-week study) and insomnia (n = 6 [9.2%] in the oral aripiprazole 30-mg treatment group in the 38-week study). In the first month after initiation of aripiprazole once-monthly 400 mg, rates of AEs remained <10% in both oral aripiprazole dosing groups, and there was no apparent pattern of individual AEs associated with prior dose of oral aripiprazole. Across both pivotal studies, the prior stable dose of aripiprazole (10 or 30 mg/d) did not appear to affect response to aripiprazole once-monthly 400 mg.

Figure 4. Effect of prior stabilization dose of oral aripiprazole: change in PANSS total score from baseline to 4 weeks after initiating aripiprazole once-monthly 400 mg, stratified by prior stabilization dose of oral aripiprazole (10 or 30 mg/d). PANSS = Positive and Negative Syndrome Scale. *Data are from the aripiprazole once-monthly stabilization phase. †Data are from the double-blind treatment phase.

Figure 5. Effect of prior stabilization dose of oral aripiprazole: incidence of TEAEs ≥5% in the 4 weeks after initiating aripiprazole once-monthly 400 mg, stratified by prior stabilization dose of oral aripiprazole (10 or 30 mg/d). AE = adverse event; TEAE = treatment-emergent adverse event. *Data are from the aripiprazole once-monthly stabilization phase. †Data are from the double-blind treatment phase.

These findings are consistent with the overall efficacy results from the pivotal studies13^,14 and complement the findings from the PK study in patients with schizophrenia15 (i.e., treatment with oral aripiprazole 10 or 30 mg/d before initiation of aripiprazole once-monthly achieves therapeutic drug concentrations during the first dosing interval). Furthermore, rates of discontinuation due to lack of efficacy, with or without AEs, were low in both full pivotal studies (52-week study, 2.1% and 0.2%, respectively; 38-week study, 4.9% and 3.4%, respectively)13^,14, suggesting that the recommended dosing schedule and dose ranges are effective. In the clinical studies, patients continued to receive oral aripiprazole for 2 weeks after their first aripiprazole once-monthly 400-mg injection (10 or 15 mg/d oral aripiprazole based on prior stable dose, with an option to increase or decrease for efficacy or tolerability reasons). Overall, findings suggest that for the first 2 weeks after initiating aripiprazole once-monthly 400 mg, maintaining oral aripiprazole at 10 mg/d, reducing the dose from 20 to 10 mg/d, or reducing the dose from >20 to 30 mg/d to 15 mg/d may all be effective treatment strategies (Figure 3B).

Conclusions

Data from clinical trials demonstrate that the 400-mg dose of aripiprazole once-monthly is an efficacious, safe, and tolerable initiation dose in patients with schizophrenia. PK simulations and a clinical PK study further support initiation of aripiprazole once-monthly with a 400-mg dose. When switching patients to oral aripiprazole before initiating aripiprazole once-monthly 400 mg, slowly tapering the prior oral antipsychotic while titrating up the oral aripiprazole dose over >1 to 4 weeks may be an effective strategy, with a target oral aripiprazole dose between 10 and 30 mg/d. Regardless of prior stabilization on oral aripiprazole, concomitant treatment with oral aripiprazole for 14 days after the first injection of aripiprazole once-monthly 400 mg is recommended to ensure plasma levels within the therapeutic range. In patients who maintain oral antipsychotic therapy for 2 weeks after aripiprazole once-monthly 400 mg initiation, the efficacy, safety, and tolerability of aripiprazole once-monthly 400 mg are consistent among patients who were previously stabilized on oral aripiprazole 10 to 30 mg/d and in patients who were previously stabilized on other oral antipsychotic therapy.

Transparency

Declaration of funding

This research was supported by Otsuka Pharmaceutical Development & Commercialization, Inc. and H. Lundbeck A/S.

Declaration of financial/other relationships

R.A.B., D.K., and A.R. have disclosed that they are employees of Otsuka Pharmaceutical Development & Commercialization, Inc. A.E. has disclosed that she is an employee of Lundbeck LLC. A.-G.N. and F.L. have disclosed that they are employees of H. Lundbeck A/S. W.L. has disclosed that he is an employee of Otsuka Pharmaceutical Europe, Ltd.

CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no relevant financial or other relationships to disclose.

Note of Correction:

Please note this is an updated version of this article originally posted online ahead of print on the 5th February 2015. This version is now correct.

Acknowledgments

Editorial support for the preparation of this manuscript was provided by Amy Roth Shaberman PhD of C4 MedSolutions, LLC (Yardley, PA, USA), a CHC Group company, with funding from Otsuka Pharmaceutical Commercialization & Development, Inc., and H. Lundbeck A/S.