Long-acting injectable aripiprazole approved in Canada


Aripiprazole data summary: efficacy and safety results
Underutilization of LAIs
Commentary by Dr. Ofer Agid, Centre for Addiction and Mental Health, Associate Professor of Psychiatry, University of Toronto, Toronto, Canada.

A once-monthly long-acting injectable (LAI) formulation of aripiprazole (Abilify Maintena; Otsuka Pharmaceuticals Canada Inc.) has now been approved by Health Canada for maintenance treatment of adult patients with schizophrenia.

It is the first partial dopamine agonist to become available as an LAI. Aripiprazole once-monthly (OM) was previously approved by the U.S. Food and Drug Administration in February 2013.

The recommended starting and maintenance dose is 400 mg administered as an intramuscular injection once a month. Because of the slow-release characteristics of the LAI formulation, patients should continue their current oral antipsychotic for 14 days following the first injection to maintain therapeutic plasma concentrations. A common strategy is to initiate therapy with oral aripiprazole prior to switching to aripiprazole OM. However, there are data to indicate that patients on other oral second-generation atypicals can be switched to aripiprazole OM without requiring a stabilization phase with oral aripiprazole (Potkin et al. Curr Med Res Opin 2013;29:1241-1251).

No dose adjustment is required for patients with renal or hepatic impairment. If there are adverse reactions with the 400 mg dose, a reduction to 300 mg once-monthly may be considered. The drug is not indicated for use in elderly patients with dementia, or in patients younger than age 18 years. Safety and tolerability have not been established in pediatric patients or those aged 65 or older.

Aripiprazole data summary: efficacy and safety results

Aripiprazole is a unique third-generation antipsychotic that acts as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, and as an antagonist at 5-HT2A receptors (Ozdemir et al. Curr Opin Investig Drugs 2002;3:113-120; Jordan et al. Eur J Pharmacol 2002;441:137-140).

Approval of aripiprazole OM in Canada was based on the results of two phase III studies. In the ASPIRE trial (Aripiprazole intramuscular depot program in schizophrenia), subjects entered an oral stabilization phase and received oral aripiprazole 10-30 mg/day for 4-12 weeks (Kane et al. J Clin Psychiatry 2012; 73:617-624). Following a 12-week depot stabilization phase, 403 patients were randomized to aripiprazole 400 mg OM or a placebo intramuscular injection for up to 52 weeks. The primary endpoint was time to exacerbation of psychotic symptoms/impending relapse, defined as clinical worsening (CGI-Improvement >5 and an increase in any PANSS items), hospitalization for psychotic symptoms, risk of suicide (CGI-SS score 4 or 5 on part 1, or a score of 6 or 7 on part 2), or clinically significant violent behaviour.

The trial was terminated early when a pre-planned interim analysis demonstrated significant efficacy of aripiprazole OM versus placebo. The time to exacerbation of psychotic symptoms/impending relapse was significantly delayed with aripiprazole OM (p<0.0001). Relapse rates were 10.0% versus 39.6% with aripiprazole OM and placebo, respectfully; the hazard ratio at the final analysis was 5.03. Significant improvements in mean PANSS scores were seen as early as week 2 of treatment, and at all subsequent assessments.

The most common adverse effects with aripiprazole 400 mg OM were insomnia (10.0% vs. 9.0% with placebo), headache (5.9% vs. 5.2%) and tremor (5.9% vs. 1.5%). The mean change in body weight during the double-blind phase was -0.2 kg with aripiprazole OM.  Clinically significant weight gain (>7% from baseline) was reported in 6.4% of patients receiving aripiprazole OM versus 5.2% on placebo. Elevated prolactin levels were more common in placebo-treated patients (7.1% vs. 1.9%) (Fleischhacker et al. Int Clin Psychopharmacol 2013;28:171-176). This finding was consistent with the prolactin-sparing profile of oral aripiprazole (Kumar et al. Cochrane Database Syst Rev 2013 Oct 15;10:CD009582). New-onset metabolic abnormalities that occurred more commonly with aripiprazole OM were fasting glucose (4.5% vs. 2.5% with placebo), and HDL cholesterol (12.9% vs. 10.8%).

In the ASPIRE EU trial, subjects were stabilized on oral aripiprazole (10-30 mg/day) over 8-28 weeks (Fleischhacker et al. Br J Psychiatry 2014; epublished June 12, 2014). A total of 662 patients then entered the 38-week double-blind maintenance phase and were randomized to aripiprazole 400 mg OM, oral aripiprazole 10-30 mg/day, or a sub-therapeutic dose of aripiprazole OM (50 mg/month; for assay sensitivity). Patients in the two OM arms received concomitant oral aripiprazole (10-20 mg/day) during the first two weeks of treatment. The impending relapse rate at week 26 was 7.12% for aripiprazole 400 mg OM, 7.76% for oral aripiprazole, and 21.80% for the 50 mg OM dose The results indicated that the LAI formulation of aripiprazole was non-inferior to oral aripiprazole and superior to the sub-therapeutic dose (p<0.001). The proportion of patients remaining in the study at six months was higher with aripiprazole 400 mg OM compared to oral aripiprazole or OM 50 mg (81.1% vs. 75.6% and 55.0%); the all-cause discontinuation rates were 25.3%, 32.7% and 53.4%, respectively.

The most common adverse effects with aripiprazole OM were insomnia (11.7% vs. 13.9% with oral aripiprazole), akathisia (10.6% vs. 6.8%), and headache (9.8% vs. 11.3%). A similar proportion of patients reported weight gain and weight loss (9.1% and 9.8%); the mean change in body weight from baseline to week 38 was 0.1 kg with aripiprazole OM, 1.0 kg with oral aripiprazole and -1.6 kg with sub-therapeutic aripiprazole OM.  The incidence of new-onset metabolic abnormalities was low and comparable across groups. The incidence of prolactin abnormalities was 5.4%, indicating a low risk of hyperprolactinemia.

A post-hoc analysis of the ASPIRE EU dataset compared the efficacy and tolerability of aripiprazole OM in obese (BMI ≥30 kg/m2) and non-obese (BMI < 30 kg/m2) patients (Eramo et al. APA 2014; abstract 129). The overall relapse rate was not significantly different between the two groups (7.4% and 8.8%, respectively). The frequency of adverse effects (insomnia, akathisia) was generally similar. However, the incidence of selected adverse effects was somewhat higher in obese subjects, notably headache (12.6% vs. 8.2%), injection site pain (11.6% vs. 5.3%), and upper respiratory tract infection (10.5% vs. <5%). The frequency of weight gain was comparable in both groups (10.5% vs. 8.2%).

In clinical trials, the incidence of QT prolongation with aripiprazole 400 mg OM was comparable to what was seen with placebo (Abilify Maintena Product Monograph, 2014); however, second-generation antipsychotics as a class should be used with caution in patients with a personal or family history of QT prolongation or heart disease.

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Underutilization of LAIs

Long-acting injectable agents may be employed in the acute or maintenance treatment of schizophrenia, according to the most current clinical practice guidelines (National Institute for Health and Care Excellence, 2014; free full text at www.nice.org.uk/nicemedia/live/14382/66534/66534.pdf).

Achieving and sustaining remission are critical for improving social and occupational functioning, and key factors in obtaining better long-term outcomes. In practice, LAI agents may offer advantages over oral agents in achieving/maintaining remission, as noted in a recent Canadian systematic review (Manchanda et al. Can J Psychiatry 2013;58[suppl 1]:5S-13S; free full text at http://publications.cpa-apc.org/media.php?mid=1506). A meta-analysis of antipsychotic treatment trials found that depot formulations were more effective than oral drugs in relapse reduction (Leucht et al. Lancet 2012;379:2063-2071). Moreover, an open-label mirror study reported a lower rate of psychiatric hospitalizations after switching from an oral antipsychotic agent (standard of care) to aripiprazole OM (Kane et al. J Med Econ 2013;16:917-925; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3709884/pdf/JME-16-917.pdf).

These clinical benefits of relapse reduction and fewer in-patient stays may be attributable in part to the more stable drug levels achievable with LAIs and to improved rates of treatment adherence and persistence. In the long-term open-label extension of aripiprazole OM phase III studies, 79.4% of patients remained on treatment at one year, with few patients stopping therapy because of adverse effects (2.9%) or impending relapse (4.0%) (Peters-Strickland et al. APA 2014; abstract NR144).

However, LAI agents are often reserved for patients with problems of adherence or as a last-resort therapy. The result is that an important treatment option is largely underutilized in practice (Rauch & Fleischhacker. CNS Drugs 2013;27:637-652; Kirk Morton & Zubek. J Psychosoc Nurs Ment Health Serv 2013;51:13-18).

The estimated use of LAIs varies widely, from 80% in the U.K. to 15% in New Zealand (Johnson DAW. Br J Psychiatry 2009;195:S7–S12; Humberstone et al. Aust N Z J Psychiatry 2004;38:240-245). Canada has the lowest published rate of LAI use with 6.3% recorded in the Canadian National Outcomes Measurement Study in Schizophrenia (Williams et al. Acta Psychiatr Scand Suppl 2006;113:12–21). LAI use was highest in British Columbia (12.5%) and lowest in Quebec (2.0%) and Ontario (3.1%). A subsequent analysis of prescription drug utilization estimated that LAI use in Canada was 2.4% (Manchanda 2013).

Patient factors, such as suspicion about injected drugs or concerns about a lack of personal control, may contribute to low LAI use (Wijeratne et al. APA 2014; abstract 157). However, physician attitudes also play a role. For example, a U.S. survey found that while 83% of psychiatrists said that some patients in their practice would benefit from an LAI antipsychotic, 39% did not use LAI drugs because they preferred oral therapies or lacked staff support for administering injections (Getzen et al. Ann Clin Psychiatry 2014;26:33-38). Similarly, a qualitative study of Canadian psychiatrists found that clinicians have limited experience with injectable drugs, believe that patients view LAIs in a negative light, and perceive that there are  barriers (storage, staffing, cost) to using LAIs in practice (Iyer et al. Can J Psychiatry 2013;58(5 Suppl 1):23S–29S; free full text at http://publications.cpa-apc.org/media.php?mid=1508). 

Canadian clinical recommendations on LAI use have recently been published to address the problem of LAI underutilization in the management of patients with schizophrenia (Malla et al. Can J Psychiatry 2013;58(5 Suppl 1):30S–35S; free full text http://publications.cpa-apc.org/media.php?mid=1509). The group recommended that LAIs should be discussed as a treatment option with all patients and families throughout the course of illness, including in the first 2-5 years of treatment. Clinicians should correct any biases they may have about injectable therapies and should not assume that patients will be more likely to reject LAIs as a potential therapy. As with other discussions about treatment, clinicians should provide patients with information about the effectiveness, ease of administration, frequency of injections and cost, and assist patients in making an informed decision about their treatment. Patient assessments at the time of every injection are advised, and a detailed evaluation of treatment effectiveness and side effects is recommended at least every three months.

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Comment by:
Ofer Agid, MD

Centre for Addiction and Mental Health
Associate Professor of Psychiatry, University of Toronto
Toronto, Canada

The long-acting injectable formulation of aripiprazole is the third second-generation antipsychotic (SGA) LAI approved in Canada. The two previously approved SGA-LAI compounds were risperidone and paliperidone.

Two recent studies preceded the approval of LAI aripiprazole in Canada: The ASPIRE study (Kane et al. J Clin Psychiatry 2012) showed significant efficacy of aripiprazole LAI versus placebo. The ASPIRE EU trial (Fleischhacker et al. Br J Psychiatry 2014) indicated that aripiprazole LAI was non-inferior to oral aripiprazole and superior to the sub-therapeutic dose of the same compound (Fleischhacker et al. Br J Psychiatry 2014).

LAIs are considered to be underused in the treatment of schizophrenia, despite the evidence showing advantages over oral compounds in certain clinical domains, for example in relapse prevention, maintaining remission, and in achieving more stable drug levels that might lead to a decreased rate of side effects. Moreover, LAIs are usually reserved for patients with adherence problems who relapsed multiple times and are usually positioned as a last-resort therapy. Underutilization of LAI continues despite the recently published Canadian Clinical Recommendations on LAI use, recommending that LAIs be positioned earlier in the course of treatment (Malla et al. Can J Psychiatry 2013).

There are multiple reasons for the underutilization of LAIs. Some are patient-related, such as suspicion about injected drugs, concerns about a lack of personal control, etc. Some are clinician-related, such as a lack of staff support, the clinician’s limited knowledge of LAIs and a lack of experience with them, an assumption that the patients will view LAIs in a negative light, etc.

Several clinical points should be highlighted. A subset of patients with schizophrenia is more likely to benefit from LAIs than oral antipsychotics. LAIs are underutilized and should be placed earlier in our treatment algorithms for patients with schizophrenia.

The recent approval of aripiprazole LAI will likely benefit patients with schizophrenia as it adds to the current medication options, thus increasing the prescribing possibilities for clinicians. Evidence suggests that discussing LAIs with the patient and their family earlier in the course of illness and treatment is beneficial, as it supports their informed decision-making while balancing risks and benefits.

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