Aripiprazole long-acting injectable formulations for schizophrenia: aripiprazole monohydrate and aripiprazole lauroxil

ABSTRACT

Aripiprazole monohydrate (AM) and aripiprazole lauroxil (AL) are two different long-acting injectable formulations of aripiprazole. AM 400 mg administered once monthly demonstrated efficacy in an acute, double-blind, placebo-controlled, randomized clinical trial, as well as in a double-blind, placebo-controlled, randomized-withdrawal maintenance study, and in two non-inferiority maintenance studies. AL is a prodrug of aripiprazole and available in 441 mg, 662 mg or 882 mg strengths. AL 441 mg and 882 mg administered once monthly demonstrated efficacy in an acute, double-blind, placebo-controlled, randomized clinical trial. The pharmacokinetic profile of AL also led to approval of dosing intervals of every 6 weeks for the 882 mg dose. The overall tolerability profiles of both products are consistent with what is known about oral aripiprazole.

KEYWORDS:

• Antipsychotic
• aripiprazole lauroxil
• aripiprazole monohydrate
• aripiprazole once-monthly
• clinical trials
• depot
• intramuscular
• long-acting injectable
• schizophrenia

Financial & competing interests disclosure

No funding or writing assistance was utilized in the production of this article. In the past 36 months L Citrome has engaged in collaborative research with, or received consulting or speaking fees, from: Alexza, Alkermes, Allergan, AstraZeneca, Avanir, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Forum, Genentech, Janssen, Jazz, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva, Valeant, Vanda. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Aripiprazole is a dopamine D2 receptor partial agonist that has been available as an oral formulation since 2002 with approved indications that include schizophrenia, acute treatment of manic and mixed episodes associated with bipolar I disorder, adjunctive treatment of major depressive disorder, irritability associated with autistic disorder and the treatment of Tourette’s disorder.

• Two long-acting injectable formulations of aripiprazole are now available in the United States, aripiprazole monohydrate (AM) and aripiprazole lauroxil (AL), and are approved for the treatment of schizophrenia; both can be administered in the deltoid or gluteal muscle.

• AM is a powder that is mixed with water to form an aqueous suspension and is available in 400 or 300 mg strengths, with 400 mg being the usual recommended dose unless tolerability problems require a reduction in dose.

• AM administered once monthly demonstrated superiority to placebo in reduction of symptoms in an acute, double-blind, randomized clinical trial, demonstrated superiority to placebo in delaying the time to relapse in a double-blind, randomized, maintenance study and demonstrated noninferiority to oral aripiprazole in relapse rates in two double-blind, randomized, maintenance studies.

• A head-to-head comparison with paliperidone palmitate (PP) showed superiority for AM on a quality of life scale, and pharmacoeconomic models further establish AM as a dominant choice versus PP when higher doses of the latter are utilized.

• AL is a prodrug of aripiprazole and is supplied as an aqueous suspension; it is available in 441, 662 or 882 mg strengths, which corresponds to 300, 450 and 600 mg of aripiprazole, respectively.

• AL 441 and 882 mg administered once monthly demonstrated superiority to placebo in reduction of symptoms in an acute, double-blind, randomized clinical trial; the 662 mg dose was approved based on efficacy at the 441 and 882 mg doses.

• The pharmacokinetic profile of AL also led to the approval of doing intervals of every 6 weeks for the 882 mg dose.

• The tolerability profiles of both AM and AL are consistent with what is known about oral aripiprazole; in the acute, placebo-controlled clinical trials, incidence of injection site pain appeared similar and within the range of 3.9–5.8%.

• The ‘amenities’ of care may differ between the two injections. For example, the multiple dose strengths and flexibility in dosing intervals for AL may be considered advantageous for some patients, whereas for AM, the smaller needle gauge (23G vs. 21G for the smallest option) and the requirement for fewer days of overlapping oral antipsychotic (14 vs. 21 days) may be important for other patients.