Long-Acting Injectable Aripiprazole Lauroxil for Schizophrenia

Out of the Pipeline

Long-acting injectable aripiprazole lauroxil for schizophrenia

Ahsan Y. Khan, MD, DFAPA, DABAM, and Muhammad Ovais, MD

Administered IM Approximately 80% of patients with schizo- Table 1 every 4 to 6 weeks, phrenia relapse within 5 years1 despite the Fast facts about aripiprazole aripiprazole lauroxil availability and increased use of second- lauroxil generation antipsychotics. Long-acting is an option for Brand name: Aristada depot formulations are a proven, effective patients who need Indication: Schizophrenia treatment option for patients with schizo- Approval date: October 5, 2015 a longer-acting phrenia. In October 2015, another long- antipsychotic acting injectable antipsychotic, aripiprazole Manufacturer: Alkermes lauroxil, was FDA-approved for schizo- Dosing forms: 441 mg, 662 mg, 882 mg phrenia.2 Aripiprazole lauroxil is adminis- Recommended dosage: 441 mg, 662 mg, or 882 mg monthly, or 882 mg every 6 weeks tered IM every 4 to 6 weeks in the deltoid or gluteal region and is available in multiple dosages (Table 1). beginning treatment with aripiprazole lau- Mechanism of action roxil; establishing tolerability might take as Aripiprazole lauroxil is a prodrug of aripip- long as 2 weeks because of the half-life of razole. Prodrugs are chemical compounds aripiprazole. that exert their pharmacological effects after Aripiprazole lauroxil can be started at they undergo a biologic transformation and 441 mg, 662 mg, or 882 mg administered transform into a more active metabolite.3 monthly; these dosages correspond to 300 The development of prodrugs is an estab- mg, 450 mg, and 600 mg of aripiprazole, or lished method used to improve physio- 10 mg/d, 15 mg/d, ≥20 mg/d of oral aripip- chemical or pharmacokinetic properties of razole, respectively (Table 2).2 Aripiprazole the pharmacologically active compound. lauroxil can be administered either in the del- After IM injection, aripiprazole lauroxil toid muscle (441 mg only) or gluteal muscle is most likely converted by an enzyme- (441 mg, 662 mg, or 882 mg).2,4,5 Treatment mediated hydrolysis to N-hydroxymethyl with the 441-mg, 662-mg, or 882-mg dosages aripiprazole, which is then hydrolyzed to can be given every 4 weeks but the 882-mg aripiprazole. Aripiprazole’s mechanism dosage can be given every 6 weeks and only of action is mediated through a combina- in the gluteal muscle, which provides greater Discuss this article at tion of partial agonist activity at D2 and dosing flexibility compared with extended- www.facebook.com/ 5-HT1A receptors and antagonistic activity release injectable aripiprazole.2,4,5 CurrentPsychiatry 2,4 at 5-HT2A receptors. Dr. Khan is Professor, Department of Psychiatry, and Dr. Ovais is an ob- server physician, Saint Louis University School of Medicine, St. Louis, Dosing and administration Missouri. Disclosures If your patient has never taken aripiprazole, Dr. Khan is a speaker for Janssen, Alkermes, and Lundbeck/Otsuka. ensure that she (he) will tolerate the drug by Dr. Ovais reports no financial relationship with any company whose Current Psychiatry products are mentioned in this article or with manufacturers of 50 July 2016 initiating a trial of oral aripiprazole before competing products. Out of the Pipeline

Table 2 Aripiprazole lauroxil: Dosage and administration

Previously Aripiprazole lauroxil established oral aripiprazole dosage Dosage Injection site Needle gauge 10 mg/d 441 mg/month Deltoid/Gluteal 21/20 15 mg/d 662 mg/month Gluteal 20 ≥20 mg/d 882 mg/month Gluteal 20 Source: Reference 2

Table 3 Recommendations for missed doses of aripiprazole lauroxil Clinical Point Dosage of last Oral supplementation based on time since last injection aripiprazole lauroxil Supplementation injection None required Required for 7 days Required for 21 days 441 mg/month ≤6 weeks >6 but ≤7 weeks >7 weeks with oral aripiprazole 662 mg/month ≤8 weeks >8 but ≤12 weeks >12 weeks is required for 21 882 mg/month ≤8 weeks >8 but ≤12 weeks >12 weeks days before the first 882 mg/6 weeks ≤8 weeks >8 but ≤12 weeks >12 weeks aripiprazole lauroxil Source: Reference 2 injection

Supplementation with oral aripipra- for 30 seconds if the syringe is not used zole is required for 21 days before the first within 15 minutes.2 aripiprazole lauroxil injection.2,4 The next injection should not be given earlier than 14 Efficacy days after the previous dose. When a dose The efficacy of aripiprazole lauroxil for treat- is missed, follow the guidelines outlined in ing patients with schizophrenia has been Table 3.2 established, in part, on the basis of efficacy After a single injection, aripiprazole data from clinical trials of oral aripiprazole. starts to appear in the systemic circulation at In addition, efficacy has been established in a Day 5 or Day 6 and continues to be released 12-week, multicenter, randomized, placebo- for another 36 days.2 Steady-state con- controlled, double-blind, fixed-dose study of centration will be reached after the fourth 622 individuals age 18 to 70 with schizophre- monthly injection. The termination half-life nia.4,5 All eligible patients were diagnosed of aripiprazole lauroxil ranged from 29 to with schizophrenia as defined by DSM-IV-TR 35 days after each monthly injection.2 criteria and confirmed by the Structured Clinical Interview for DSM-IV Disorders, Packaging. Aripiprazole lauroxil is avail- Clinical Trial Version and were experienc- able as single-dose, pre-filled, color-coded ing an acute exacerbation of their illness at syringes for IM injection at 441 mg (light the time of the study. To be eligible for the blue), 662 mg (green), and 882 mg (bur- study, participants had to have a Positive gundy); syringes do not require refrig- and Negative Syndrome Scale (PANSS) eration (Table 2).2 The syringe needs to be total score of 70 to 120 and score of ≥4 for tapped at least 10 times to dislodge any ≥2 of the selected positive items (delusions, material that might have settled. Shake the conceptual disorganization, hallucinatory syringe vigorously for at least 30 seconds to behavior, and suspiciousness/persecution). Current Psychiatry ensure a uniform suspension. Shake it again Individuals also were required to have a Vol. 15, No. 7 51 Out of the Pipeline

Table 4 Adverse reactions in aripiprazole lauroxil-treated patients Aripiprazole Aripiprazole Placebo lauroxil, 441 mg lauroxil, 882 mg Adverse reaction (n = 207) (n = 207) (n = 208) Akathisia 4% 11% 11% Headache 3% 3% 5% Injection site pain 2% 3% 4% Insomnia 2% 3% 4% Increased weight 1% 2% 2% Restlessness 1% 3% 1% Increased blood creatine phosphokinase 0% 2% 1% Clinical Point Source: Reference 2 Reduce aripiprazole lauroxil dosage Clinical Global Impression-Severity scale should not receive aripiprazole lauroxil. to the next lower score of ≥4. Efficacy was assessed using the Hypersensitivity reactions have ranged dosage when used PANSS and Clinical Global Impression– from pruritus and urticaria to anaphylaxis.2 in combination Improvement scale (CGI-I). Patients were randomized in a 1:1:1 ratio Drug−drug interactions. Reduce aripipra- with a strong to receive IM aripiprazole lauroxil, 441 mg, zole lauroxil dosage to the next lower dos- CYP3A4 inhibitor aripiprazole lauroxil, 882 mg, or placebo age when used in combination with strong once monthly in the gluteal region for 12 cytochrome P450 (CYP) 3A4 inhibitors weeks. The gluteal muscle was selected as (eg, itraconazole, clarithromycin) or strong the injection site to maintain blinding to CYP2D6 inhibitors (eg, quinidine, fluox- the study drug.4,5 After establishing toler- etine, paroxetine) for more than 2 weeks or ability to oral aripiprazole, participants if the patient is known to be a poor metabo- received oral aripiprazole or placebo daily lizer of CYP2D6, because concentration of for the first 3 weeks. The IM injections were aripiprazole lauroxil could increase. No administered on Days 1, 29, and 57. dose adjustment is required if the patient Efficacy was measured primarily as is already taking 441 mg/month or if change in total PANSS score from the base- CYP450 modulators are added for less than line to day 854,5; secondary efficacy variable 2 weeks.2 Similarly, a dosage increase is rec- was the CGI-I score at day 85. Statistically ommended when aripiprazole lauroxil is significant separation in PANSS score was used in combination with strong CYP3A4 observed in each aripiprazole lauroxil dos- inducers (eg, carbamazepine, rifampin).2 age group (441 mg and 882 mg) compared with placebo. Significant improvement in Overdose both active treatment groups was observed No data are available on aripiprazole lau- as early as Day 8 and continued throughout roxil overdose. However, there is one the study (P ≤ .004). The number of patients known case of oral aripiprazole overdose who improved much or very much on the in a patient who ingested 1,260 mg of oral CGI-I was significantly greater in either aripiprazole (42 times the maximum rec- aripiprazole lauroxil group, compared with ommended daily dosage) but recovered placebo (P < .001). completely.2 Common side effects reported in at least 5% of all overdose cases include Contraindications vomiting, somnolence, and tremor. If an Allergic reactions. Patients who are overdose occurs, call a poison control cen- Current Psychiatry 52 July 2016 hypersensitive to oral aripiprazole ter immediately. continued on page 58 Out of the Pipeline

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Most commonly observed adverse reaction Related Resources during clinical trials of aripiprazole lauroxil • Kennedy WK. When and how to use long-acting injectable was akathisia (incidence ≥5% and at least antipsychotics. Current Psychiatry. 2012;11(8):40-43. twice rate seen with placebo).2 Other com- • Citrome L, Du Y, Risinger R, et al. Effect of aripiprazole lau- roxil on agitation and hostility in patients with schizophre- mon adverse reactions are shown in Table 4 nia. Int Clin Psychopharmacol. 2016;31(2):69-75. (page 52).2 Recently, the FDA issued a warn- Drug Brand Names ing that compulsive or uncontrollable urges Aripiprazole • Abilify Itraconazole • Sporanox to gamble, binge eat, shop, and have sex Aripiprazole extended-release Olanzapine • Zyprexa • Abilify Maintena Paroxetine • Paxil have been reported with all formulations Aripiprazole lauroxil • Aristada Quetiapine • Seroquel of aripiprazole.7 According to reports, these Carbamazepine • Tegretol Quinidine • Quinidex urges stopped when the drug was discontin- Clarithromycin • Biaxin Rifampin • Rifadin Fluoxetine • Prozac Risperidone • Risperdal ued or the dosage reduced. Although rare, Clinical Point Acknowledgement these impulse-control problems could result The overall Maaz A. Khan, a student at the University of Oklahoma, Norman, in harm if they are not recognized. See the Oklahoma, contributed to this article. full prescribing information for a complete safety profile of set of adverse reactions. aripiprazole lauroxil References is similar to that of 1. Robinson D, Woerner MG, Alvir JM, et al. Predictors of relapse oral aripiprazole ‘Black-box’ warning for patients following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 1999;56(3): with dementia 241-247. Aripiprazole lauroxil, similar to all other 2. Aristada [package insert]. Waltham, MA; Alkermes; 2015. atypical antipsychotics, has a “black-box” 3. Turncliff R, Hard M, Du Y, et al. Relative bioavailability and safety of aripiprazole lauroxil, a novel once-monthly, long- warning stating that (1) it is not approved acting injectable atypical antipsychotic following deltoid and for treating dementia-related psychosis, gluteal administration in adult subjects with schizophrenia. Schizophr Res. 2014;159(2-3):404-410. and (2) it is associated with an increased 4. Meltzer HY, Risinger R, Nasrallah HA, et al. A randomized, risk of death with off-label use to treat double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia. J Clin Psychiatry. behavioral problems in older adults 2015;76(8):1085-1090. 2 with dementia-related psychosis. Meta- 5. Citrome L. Aripiprazole long-acting injectable formulations analysis of 17 placebo-controlled trials in for schizophrenia: aripiprazole monohydrate and aripiprazole lauroxil. Expert Rev Clin Pharmacol. 2016; patients taking an atypical antipsychotic 9(2):169-186. (olanzapine, aripiprazole, risperidone, 6. U.S. Food and Drug Administration. Public health advisory: deaths with antipsychotics in elderly patients or quetiapine) revealed a risk of death in with behavioral disturbances. http://www.fda.gov/drugs/ drug-treated patients 1.6 to 1.7 times that drugsafety/postmarketdrugsafetyinformationforpatients andproviders/ucm053171. Published April 11, 2005. 6 of placebo-treated patients. Accessed April 29, 2016. 7. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA warns about new impulse-control Adverse reactions problems associated with mental health drug aripiprazole The overall safety profile of aripiprazole lau- (Abilify, Abilify Maintena, Aristada). http://www.fda.gov/ Drugs/DrugSafety/ucm498662.htm. Published May 3, 2016. roxil is similar to that of oral aripiprazole. Accessed June 20, 2016. Bottom Line Aripiprazole lauroxil is a novel, long-acting second-generation antipsychotic that offers flexibility in terms of safe and effective dosing and can be administered in the deltoid (441 mg) or gluteal muscle (626 mg and 882 mg) and at dosing intervals of 4 to 6 weeks. Safety and tolerability profile of aripiprazole lauroxil are similar to that of oral aripiprazole. Aripiprazole lauroxil represents a new treatment option Current Psychiatry 58 July 2016 for patients with schizophrenia.